具体实施方式

提供了连续多肽，所述连续多肽包含至少一种结合NGF多肽的TrkA ECD多肽。还提供了产生和纯化所述连续多肽的方法。提供了使用结合NGF并抑制NGF介导的信号传导的TrkA ECD多肽的治疗方法。此类方法包括但不限于治疗伴生动物物种的疼痛的方法。还提供了检测来自伴生动物物种的样品中的NGF的方法。

为方便读者，提供了以下本文所使用的术语的定义。

如本文所用，诸如Kd的数字术语是基于科学测量计算的，因此受到适当的测量误差的影响。在一些情况下，数字术语可以包括化整到最接近的有效数字的数值。

如本文所用，“一种/个(a或an)”意指“至少一种/个”或“一种/个或多种/个”，除非另外说明。如本文所用，术语“或”意指“和/或”，除非另外说明。在多个从属权利要求的上下文中，当引用其他权利要求时，“或”的使用仅指替代方案中的那些权利要求。

示例性TrkA多肽

提供了结合NGF的TrkA ECD多肽，例如结合NGF的犬类、猫类和马类TrkA ECD多肽。

“氨基酸序列”意指蛋白质中的氨基酸序列，并且包括其中序列的一个或多个氨基酸的侧基已经被化学修饰的氨基酸序列，以及如下的那些氨基酸序列：其中，相对于已知序列，一个或多个氨基酸已经被替代、插入或缺失，但并未由此消除所需特性，如结合EPO受体的能力。氨基酸序列也可称为肽、寡肽、多肽或蛋白质。

如本文所用，“TrkA”或“TrkA多肽”是包含能够与NGF结合的原肌球蛋白受体激酶A(TrkA)受体的全部或片段的多肽。

例如，除非另外指明，否则“TrkA”是指来自任何脊椎动物来源的TrkA多肽，所述脊椎动物包括哺乳动物如灵长类动物(例如，人和食蟹猴)、啮齿动物(例如，小鼠和大鼠)以及伴生动物(例如，狗、猫和马类)。在一些实施方案中，TrkA是结合NGF的细胞外结构域片段。在一些此类实施方案中，TrkA可称为TrkA细胞外结构域(ECD)。在一些实施方案中，TrkA包含以下的氨基酸序列：SEQ ID NO:1、SEQ ID NO:2、SEQ ID NO:3、SEQ ID NO:4、SEQ ID NO:5、SEQ ID NO:6、SEQ ID NO:7、SEQ ID NO:8、SEQ ID NO:9、SEQ ID NO:10、SEQ ID NO:11、SEQ ID NO:12、SEQ ID NO:13、SEQ ID NO:14、SEQ ID NO:15、SEQ ID NO:25、SEQ ID NO:26、SEQ ID NO:27、SEQ ID NO:28、SEQ ID NO:29、SEQ ID NO:30、SEQ ID NO:31、SEQ IDNO:32或SEQ ID NO:33。

如本文所用，“NGF受体”或“NGFR”是包含结合NGF的低亲和力神经生长因子受体(也称为肿瘤坏死因子受体超家族成员16)的全部或部分的多肽。

例如，除非另外指明，否则“NGFR”是指来自任何脊椎动物来源的NGFR多肽，所述脊椎动物来源包括哺乳动物，如灵长类动物(例如，人和食蟹猴)、啮齿动物(例如，小鼠和大鼠)以及伴生动物(例如，狗、猫和马类)。在一些实施方案中，NGFR是结合NGF的细胞外结构域片段。在一些此类实施方案中，NGFR可称为NGFR细胞外结构域(ECD)。在一些实施方案中，NGFR包含SEQ ID NO:134、SEQ ID NO:135、SEQ ID NO:136、SEQ ID NO:137、SEQ ID NO:138或SEQ ID NO:139的氨基酸序列。

术语“伴生动物物种”是指适合作为人同伴的动物。在一些实施方案中，伴生动物物种是诸如犬类、猫类、狗、猫、马、兔、雪貂、豚鼠、啮齿动物等小型哺乳动物。在一些实施方案中，伴生动物物种是诸如牛、猪等家畜。

“细胞外结构域”(“ECD”)是多肽的延伸超过跨膜结构域到细胞外空间中的一部分。如本文所用，术语“细胞外结构域”可包含完整的细胞外结构域或可包含缺失一个或多个与其配体结合的氨基酸的截短型细胞外结构域。所述细胞外结构域的组成可取决于用于确定哪些氨基酸在膜中的算法。对于给定的蛋白质，不同的算法可预测不同的细胞外结构域，并且不同的系统可表达不同的细胞外结构域。

TrkA多肽的细胞外结构域可以包含结合NGF的TrkA的完整细胞外结构域或截短型细胞外结构域。如本文所用，术语“TrkA多肽的细胞外结构域”或“TrkA ECD”是指不包含跨膜结构域或细胞质结构域的TrkA多肽，即使所述术语遵循开放的过渡词，如“包含(comprising)”、“包含(comprises)”等。在一些实施方案中，TrkA多肽的细胞外结构域是来自伴生物种动物的TrkA的细胞外结构域。例如，在一些实施方案中，TrkA多肽的细胞外结构域源自犬类TrkA、猫类TrkA或马类TrkA。在一些实施方案中，TRKA多肽的细胞外结构域包含以下的氨基酸序列：SEQ ID NO:2、SEQ ID NO:3、SEQ ID NO:4、SEQ ID NO:5、SEQ ID NO:7、SEQ ID NO:8、SEQ ID NO:9、SEQ ID NO:10、SEQ ID NO:12、SEQ ID NO:13、SEQ ID NO:14、SEQ ID NO:15、SEQ ID NO:25、SEQ ID NO:26、SEQ ID NO:27、SEQ ID NO:28、SEQ ID NO:29、SEQ ID NO:30、SEQ ID NO:31、SEQ ID NO:32、SEQ ID NO:33或其任何片段。

NGFR多肽的细胞外结构域可以包含结合NGF的NGFR的完整细胞外结构域或截短型细胞外结构域。如本文所用，术语“NGFR多肽的细胞外结构域”或“NGFR ECD”是指不包含跨膜结构域或细胞质结构域的NGFR多肽，即使所述术语遵循开放的过渡词，如“包含(comprising)”、“包含(comprises)”等。在一些实施方案中，NGFR多肽的细胞外结构域是来自伴生物种动物的NGFR多肽的细胞外结构域。例如，在一些实施方案中，NGFR多肽的细胞外结构域源自犬类NGFR、猫类NGFR或马类NGFR。在一些实施方案中，NGFR多肽的细胞外结构域包含SEQ ID NO:135、SEQ ID NO:137、SEQ ID NO:139的氨基酸序列或其任何片段。

“野生型”是指天然存在的多肽或其片段的未突变形式。可以重组产生野生型多肽。

“变体”或“类似物”在本文中可互换地称为这样的多肽，其与参考多肽的不同之处在于单个或多个氨基酸取代、缺失和/或添加，并且基本上保留了参考多肽的至少一种生物活性。

“生物活性”实体或具有“生物活性”的实体是如下实体：其具有与代谢或生理过程有关或相关的任何功能，和/或具有天然存在的分子的结构功能、调节功能或生化功能。生物活性多肽或其片段包括可以参与生物反应的一种，所述生物反应包括但不限于配体-受体相互作用或抗原-抗体结合。生物活性可以包括改善的期望活性或降低的不期望活性。在实体参与与另一种分子的分子相互作用时，在实体具有减轻疾病病症的治疗价值时，在实体具有诱导免疫应答的预防价值时，在实体具有确定分子的存在的诊断和/或预后价值时，所述实体可以展现生物活性。

如本文所用，关于多肽序列的“氨基酸序列同一性百分比(％)”和“同源性”被定义为，在比对序列并引入空位(如果需要以实现最大序列同一性百分比)后，并且不将任何保守取代视为序列同一性的一部分，候选序列中与特定肽或多肽序列中的氨基酸残基相同的氨基酸残基的百分比。用于确定氨基酸序列同一性百分比的比对可以以本领域熟知的多种方式来实现，例如，使用公众可获得的计算机软件，如BLAST、BLAST-2、ALIGN或MEGALIGN^TM(DNASTAR)软件。本领域技术人员可以确定用于测量比对的适当参数，包括为了在所比较的序列的全长上实现最大比对所需要的任何算法。

在一些实施方案中，在比对序列和引入空位(如果需要)以实现最大序列同一性百分比并且不将任何保守取代视为序列同一性的一部分之后，变体与参考多肽具有至少约50％序列同一性。此类变体包括，例如，其中在多肽的N末端或C末端添加、缺失一个或多个氨基酸残基的多肽。在一些实施方案中，变体与参考多肽的序列具有至少约50％序列同一性、至少约60％序列同一性、至少约65％序列同一性、至少约70％序列同一性、至少约75％序列同一性、至少约80％序列同一性、至少约85％序列同一性、至少约90％序列同一性、至少约91％序列同一性、至少约92％序列同一性、至少约93％序列同一性、至少约94％序列同一性、至少约95％序列同一性、至少约96％序列同一性、至少约97％序列同一性、至少约98％序列同一性或至少99％序列同一性。

如本文所用，“对应于位置n的位置”(其中n是任何数)是指在比对主题多肽和参考多肽的氨基酸序列并引入空位后，与参考多肽的位置n对齐的主题多肽的氨基酸位置。用于确定主题多肽的位置是否对应于参考多肽的位置n的目的的比对可以以本领域技术范围内的各种方式实现，例如使用公众可获得的计算机软件，如BLAST、BLAST-2、CLUSTAL OMEGA、ALIGN或MEGALIGN^TM(DNASTAR)软件。本领域技术人员可以确定用于比对的适当参数，包括为了在所比较的两个序列的全长上实现最大比对所需要的任何参数。在一些实施方案中，主题多肽和参考多肽具有不同的长度。

“点突变”是涉及单个氨基酸残基的突变。突变可能是氨基酸丢失、另一个氨基酸残基对一个氨基酸残基的取代或另外的氨基酸残基的插入。

“氨基酸取代”可以包括但不限于用另一种氨基酸替代多肽中的一个氨基酸。示例性取代在表2中示出。可以将氨基酸取代引入目的分子中，并筛选产物的所需活性，例如，保留/改善的受体结合、降低的免疫原性、减少的ADCC和/或CDC、或增强的药代动力学。

表2.

可根据常见的侧链特性将氨基酸分组：

(1)疏水性：正亮氨酸、Met、Ala、Val、Leu、Ile；

(2)中性亲水性：Cys、Ser、Thr、Asn、Gln；

(3)酸性：Asp、Glu；

(4)碱性：His、Lys、Arg；

(5)影响链取向的残基：Gly、Pro；

(6)芳香族：Trp、Tyr、Phe。

非保守取代将需要将这些类别之一的成员交换为另一类别。

如本文所用，“氨基酸衍生物”是指任何氨基酸、修饰的氨基酸和/或氨基酸类似物，而不是在人中发现的20种常见的天然氨基酸之一。示例性氨基酸衍生物包括在人中未发现的天然氨基酸(例如，可能在一些微生物中发现的硒代半胱氨酸和吡咯赖氨酸)和非天然氨基酸。示例性氨基酸衍生物包括但不限于通过化学产品制造商可商购的氨基酸衍生物(例如，于2017年5月6日访问的sigmaaldrich.com/chemistry/chemistry-products.html？TableP age＝16274965，将其通过引用并入本文)。可以使用利用宿主细胞、来源于真细菌合成酶的正交氨酰基-tRNA合成酶、正交tRNA和氨基酸衍生物的翻译系统在特定位置处将一种或多种氨基酸衍生物掺入多肽中。有关进一步说明，参见例如，美国专利号9,624,485。

在一些实施方案中，变体IgG Fc多肽包含用氨基酸衍生物进行的氨基酸取代。在一些实施方案中，氨基酸衍生物是丙氨酸衍生物、半胱氨酸衍生物、天冬氨酸衍生物、谷氨酸衍生物、苯丙氨酸衍生物、甘氨酸衍生物、组氨酸衍生物、异亮氨酸衍生物、赖氨酸衍生物、亮氨酸衍生物、甲硫氨酸衍生物、天冬酰胺衍生物、脯氨酸衍生物、谷氨酰胺衍生物、精氨酸衍生物、丝氨酸衍生物、苏氨酸衍生物、缬氨酸衍生物、色氨酸衍生物或酪氨酸衍生物。

在一些实施方案中，TrkA ECD多肽包含SEQ ID NO:2、SEQ ID NO:3、SEQ ID NO:4、SEQ ID NO:5、SEQ ID NO:7、SEQ ID NO:8、SEQ ID NO:9、SEQ ID NO:10、SEQ ID NO:12、SEQID NO:13、SEQ ID NO:14或SEQ ID NO:15的氨基酸序列，不同之处在于存在不存在于SEQID NO:2、SEQ ID NO:3、SEQ ID NO:4、SEQ ID NO:5、SEQ ID NO:7、SEQ ID NO:8、SEQ IDNO:9、SEQ ID NO:10、SEQ ID NO:12、SEQ ID NO:13、SEQ ID NO:14或SEQ ID NO:15中的至少一个N连接的糖基化位点。在一些实施方案中，所述至少一个N连接的糖基化位点包含序列天冬酰胺-xaa-丝氨酸，其中xaa是除脯氨酸外的任何氨基酸。在一些实施方案中，所述至少一个N连接的糖基化位点包含序列天冬酰胺-xaa-苏氨酸，其中xaa是除脯氨酸外的任何氨基酸。在一些实施方案中，所述至少一个N连接的糖基化位点不与另一个N连接的糖基化位点重叠。

在一些实施方案中，TrkA ECD多肽包含在SEQ ID NO:3、SEQ ID NO:4、SEQ ID NO:8、SEQ ID NO:9、SEQ ID NO:13或SEQ ID NO:14的氨基酸位置6-8、31-33、84-86、85-87、86-88、88-90、90-92、92-94和/或94-96处的N连接的糖基化位点。在一些实施方案中，TrkA ECD多肽包含在SEQ ID NO:5、SEQ ID NO:10或SEQ ID NO:15的氨基酸位置4-6、29-31、82-84、83-85、84-86、86-88、89-90、90-92和/或92-94处的N连接的糖基化位点。

在一些实施方案中，TrkA ECD多肽包含在对应于SEQ ID NO:3、SEQ ID NO:4、SEQID NO:8、SEQ ID NO:9、SEQ ID NO:13或SEQ ID NO:14的位置30或位置85的氨基酸位置处的除脯氨酸之外的氨基酸。在一些实施方案中，TrkA ECD多肽包含在对应于SEQ ID NO:5、SEQ ID NO:10或SEQ ID NO:15的位置28或位置83的氨基酸位置处的除脯氨酸之外的氨基酸。

在一些实施方案中，TrkA ECD多肽包含在对应于SEQ ID NO:3、SEQ ID NO:4、SEQID NO:8、SEQ ID NO:9、SEQ ID NO:13或SEQ ID NO:14的位置30和/或位置85的氨基酸位置处的缬氨酸、谷氨酸、丙氨酸或异亮氨酸。在一些实施方案中，TrkA ECD多肽包含在对应于SEQ ID NO:5、SEQ ID NO:10或SEQ ID NO:15的位置28和/或位置83的氨基酸位置处的缬氨酸、谷氨酸、丙氨酸或异亮氨酸。

在一些实施方案中，TrkA ECD多肽包含下文表3、表4或表5中列出的一个或多个氨基酸修饰。

表3.

*X指示除脯氨酸外的任何氨基酸(如E、V、A、I等)。

表4.

*X指示除脯氨酸外的任何氨基酸(如E、V、A、I等)。

表5.

*X指示除脯氨酸外的任何氨基酸(如E、V、A、I等)。

在一些实施方案中，TrkA ECD多肽包含一种或多种另外的二硫键。例如，在一些实施方案中，TrkA ECD多肽包含在对应于SEQ ID NO:2、SEQ ID NO:3、SEQ ID NO:4、SEQ IDNO:7、SEQ ID NO:8、SEQ ID NO:9、SEQ ID NO:12、SEQ ID NO:13或SEQ ID NO:14的位置7和位置89的位置处的半胱氨酸。在一些实施方案中，TrkA ECD多肽包含在对应于SEQ ID NO:5、SEQ ID NO:10或SEQ ID NO:15的位置5和位置87的位置处的半胱氨酸。在一些实施方案中，TrkA ECD多肽包含在SEQ ID NO:2、SEQ ID NO:3、SEQ ID NO:4、SEQ ID NO:7、SEQ IDNO:8、SEQ ID NO:9、SEQ ID NO:12、SEQ ID NO:13或SEQ ID NO:14的位置7和位置89处的半胱氨酸。在一些实施方案中，TrkA多肽包含在SEQ ID NO:5、SEQ ID NO:10或SEQ ID NO:15的位置5和位置87处的半胱氨酸。

在一些实施方案中，TrkA ECD多肽包含SEQ ID NO:25、SEQ ID NO:26、SEQ ID NO:27、SEQ ID NO:28、SEQ ID NO:29、SEQ ID NO:30、SEQ ID NO:31、SEQ ID NO:32或SEQ IDNO:33的氨基酸序列。

如本文所用，“糖基化的”是指具有一个或多个共价附接的聚糖部分的多肽。

如本文所用，“聚糖”或“聚糖部分”是指糖苷连接的单糖。

聚糖以几种方式附接至糖肽，其中N连接至天冬酰胺和O连接至丝氨酸和苏氨酸对于重组治疗性糖蛋白是最相关的。N连接的糖基化发生在共有序列Asn-Xaa-Ser/Thr处，其中Xaa可以是除脯氨酸外的任何氨基酸。

如本文所用，“唾液酸化”是指多肽具有一个或多个共价附接的唾液酸部分。

已经开发了多种用于生产糖基化的和唾液酸化的蛋白质的方法。参见例如Savinova等人,Applied Biochem&Microbiol.51(8):827-33(2015)。

如本文所用，“聚乙二醇化”是指多肽具有一个或多个缔合或者共价或非共价附接的聚乙二醇(PEG)部分。

在一些实施方案中，TrkA ECD多肽被糖基化。在一些实施方案中，TrkA ECD多肽包含附接至N连接的糖基化位点的至少一个聚糖部分。在一些实施方案中，TrkA ECD多肽被唾液酸化。在一些实施方案中，TrkA ECD多肽被聚乙二醇化。在一些实施方案中，TrkA ECD多肽在聚糖处被聚乙二醇化。在一些实施方案中，TrkA ECD多肽在伯胺处被聚乙二醇化。在一些实施方案中，TrkA ECD多肽在N末端α胺处被聚乙二醇化。在一些实施方案中，TrkA ECD多肽被糖基化、唾液酸化和/或聚乙二醇化。

示例性变体IgG Fc多肽和融合分子

包含TrkA多肽的连续多肽可以包含融合配偶体，如野生型或变体IgG Fc多肽。

如本文所用，“融合分子”是指包含一个或多个“融合配偶体”的分子。在一些实施方案中，融合配偶体是共价连接(“融合”)的。如果两个融合配偶体均是多肽，则融合配偶体多肽可以是连续氨基酸序列(即，连续多肽)的一部分。第一融合配偶体多肽可以连接至第二融合配偶体的N末端或C末端。在一些实施方案中，融合配偶体由编码两个融合配偶体的编码序列翻译为单个多肽。融合配偶体可以通过其他手段，如除了肽键之外的化学连接而共价连接。可以使用许多已知的将多肽与其他分子(例如，融合配偶体)共价连接的方法。在其他实施方案中，融合配偶体通过“接头”融合，所述接头由至少一个氨基酸或化学部分构成。

在一些实施方案中，融合配偶体是白蛋白、白蛋白结合片段或免疫球蛋白分子的片段。融合配偶体可以包含寡聚化结构域，如重链免疫球蛋白的Fc结构域。在一些实施方案中，融合配偶体包含至少一种TrkA ECD多肽和一种IgG Fc多肽。在一些实施方案中，融合配偶体还包含一种或多种其他治疗性多肽，如NGFR ECD多肽。在一些实施方案中，TrkA ECD多肽可以连接至IgG Fc多肽的N末端或C末端。

本文中的术语“连续多肽”用于意指氨基酸的不间断序列。连续多肽通常从单个连续DNA序列翻译。它可以通过基因工程来制得，例如，通过从第一蛋白质的DNA序列中去除终止密码子，然后在框内附加第二蛋白质的DNA序列，使得DNA序列表达为单一蛋白质。通常，这是通过将cDNA与现有基因一起框内克隆至表达载体中来完成的。

“接头”是指连接第一多肽与第二多肽的一个或多个氨基酸残基。

在一些实施方案中，接头是柔性非结构性接头。在一些实施方案中，接头是富含甘氨酸、富含丝氨酸、或富含甘氨酸和丝氨酸的接头。在一些实施方案中，接头包含100％、至少95％、至少90％、或至少85％的丝氨酸和/或甘氨酸氨基酸残基。在一些实施方案中，接头是富含甘氨酸、富含丝氨酸或富含GS的柔性非结构性接头。在一些实施方案中，接头包含氨基酸G(Gly)和/或S(Ser)。例如，接头可以包含G或G的重复序列(例如，GG、GGG等)；GS或GS的重复序列(例如，GSGS(SEQ ID NO:143)、GSGSGS(SEQ ID NO:144)等)；GGS或GGS的重复序列(例如，GGSGGS(SEQ ID NO:145)、GGSGGSGGS(SEQ ID NO:146)等)；GGGS(SEQ ID NO:147)或GGGS(SEQ ID NO:147)的重复序列(例如，GGGSGGGS(SEQ ID NO:148)、GGGSGGGSGGGS(SEQID NO:149)等)；GSS或GSS的重复序列(例如，GSSGSS(SEQ ID NO:150)、GSSGSSGSS(SEQ IDNO:151)等)；GGSS(SEQ ID NO:152)或GGSS(SEQ ID NO:152)的重复(例如，GGSSGGSS(SEQID NO:153)、GGSSGGSSGGSS(SEQ ID NO:157)等)；SGGG(SEQ ID NO:158)或SGGG(SEQ IDNO:158)的重复序列(例如SGGGSGGGS(SEQ ID NO:156))。

如本文所用，“延伸部分”是指在C末端或N末端连接至多肽的一个或多个氨基酸残基。

在一些实施方案中，延伸部分是柔性的。在一些实施方案中，延伸部分向多肽增加柔性，而不干扰多肽的生物活性。在一些实施方案中，延伸部分增加多肽的溶解度。在一些实施方案中，延伸部分包含一个或多个甘氨酸残基。在一些实施方案中，延伸部分包含一个甘氨酸残基、两个甘氨酸残基、三个甘氨酸残基、四个甘氨酸残基、五个甘氨酸残基、六个甘氨酸残基、七个甘氨酸残基、八个甘氨酸残基或更多个甘氨酸残基。

如本文所用，“变体IgG Fc”是这样的IgG Fc多肽，其与参考IgG Fc多肽的不同之处在于单个或多个氨基酸取代、缺失和/或添加，并且基本上保留了参考IgG Fc多肽的至少一种生物活性。

“可结晶片段多肽”或“Fc多肽”是抗体分子中与效应分子和细胞相互作用的部分。其包含免疫球蛋白重链的C末端部分。如本文所用，Fc多肽包括具有完整Fc多肽的一种或多种生物活性的Fc结构域的片段。在一些实施方案中，Fc多肽的生物活性是结合FcRn的能力。在一些实施方案中，Fc多肽的生物活性是结合C1q的能力。在一些实施方案中，Fc多肽的生物活性是结合CD16的能力。在一些实施方案中，Fc多肽的生物活性是结合蛋白A的能力。Fc多肽的“效应子功能”是任何抗体响应于刺激而全部或部分执行的作用或活性，并且可以包括补体结合和/或ADCC(抗体依赖性细胞毒性)诱导。

术语“IgX Fc”或“IgX Fc多肽”是指源自特定抗体同种型(例如，IgG、IgA、IgD、IgE、IgM等)的Fc多肽，其中“X”表示抗体同种型。因此，“IgG Fc”表示Fc多肽源自γ链，“IgAFc”表示Fc多肽源自α链，“IgD Fc”表示Fc多肽源自δ链，“IgE Fc”表示Fc多肽源自ε链，“IgMFc”表示Fc多肽源自μ链等。在一些实施方案中，IgG Fc多肽包含铰链、CH2和CH3，但不包含CH1或CL。在一些实施方案中，IgG Fc多肽包含CH2和CH3，但不包含CH1、铰链或CL。在一些实施方案中，IgG Fc多肽包含CH1、铰链、CH2、CH3，具有或不具有CL。在一些实施方案中，IgGFc多肽包含CH1、铰链、CH2和CH3，具有或不具有CL1。在一些实施方案中，Fc多肽(如IgG Fc多肽)缺少一个或多个C末端氨基酸，如1至20、1至15、1至10、1至5或1至2个氨基酸，同时保留生物活性。在一些实施方案中，生物活性是结合FcRn的能力。Fc多肽的“效应子功能”是任何抗体响应于刺激而全部或部分执行的作用或活性，并且可以包括补体结合和/或ADCC(抗体依赖性细胞毒性)诱导。“IgX-NFc”或“IgGXN Fc”表示Fc多肽源自抗体同种型的特定子类(如犬类IgG子类IgG-A、IgG-B、IgG-C或IgG-D；猫类IgG子类IgG1a、IgG1b或IgG2；或马类IgG子类IgG1、IgG2、IgG3、IgG4、IgG5、IgG6或IgG7等)，其中“N”表示子类。

“铰链”是指Fc多肽或变体Fc多肽的任何部分，所述任何部分富含脯氨酸并且包含位于全长重链恒定区的CH1与CH2之间的至少一个半胱氨酸残基。

在一些实施方案中，铰链能够在同一铰链区内(同一Fc多肽内)与单独Fc多肽的铰链区或与单独Fc多肽形成二硫键。在一些实施方案中，铰链包含至少一个、至少两个、至少三个、至少四个、至少五个、至少六个、至少七个、至少八个、至少九个或至少十个脯氨酸残基。

在一些实施方案中，IgX或IgXN区源自诸如狗、猫或马等伴生动物。在一些实施方案中，IgG区分离自犬类γ重链，如IgGA、IgGB、IgGC或IgGD。在一些情况下，IgG Fc区分离自猫类γ重链，如IgG1、IgG2a或IgG2b。在其他情况下，IgG区分离自马类γ重链，如IgG1、IgG2、IgG3、IgG4、IgG5、IgG6或IgG7。包含IgGA、IgGB、IgGC或IgGD的Fc区的多肽可以在重组生产系统中提供更高的表达水平。

在一些实施方案中，IgX Fc多肽或IgX-N Fc多肽源自诸如狗、猫或马等伴生动物。在一些实施方案中，IgG Fc多肽分离自犬类γ重链，如IgG-A、IgG-B、IgG-C或IgG-D。在一些情况下，IgG Fc多肽分离自猫类γ重链，如IgG1a、IgG1b或IgG2。在其他情况下，IgG Fc多肽分离自马类γ重链，如IgG1、IgG2、IgG3、IgG4、IgG5、IgG6或IgG7。

除非另外说明，否则术语“IgX Fc”和“IgX Fc多肽”包括野生型IgX Fc多肽和变体IgX Fc多肽。

在一些实施方案中，野生型IgG Fc多肽包含以下的氨基酸序列：SEQ ID NO:34、SEQ ID NO:35、SEQ ID NO:36、SEQ ID NO:37、SEQ ID NO:38、SEQ ID NO:39、SEQ ID NO:70、SEQ ID NO:71、SEQ ID NO:72、SEQ ID NO:73、SEQ ID NO:74、SEQ ID NO:75、SEQ IDNO:76、SEQ ID NO:77、SEQ ID NO:86、SEQ ID NO:87、SEQ ID NO:88、SEQ ID NO:89或SEQID NO:90。

“变体Fc多肽”是如下的Fc多肽，其与参考多肽的不同之处在于单个或多个非天然氨基酸取代、缺失和/或添加。在一些实施方案中，变体Fc多肽保留了参考Fc多肽的至少一种生物活性。在一些实施方案中，变体Fc多肽(例如，变体犬类IgG-A Fc、变体犬类IgG-CFc、变体犬类IgG-D Fc、变体马类IgG2 Fc、变体马类IgG5 Fc、或变体马类IgG6 Fc)具有参考Fc多肽基本上缺乏的活性。例如，在一些实施方案中，变体犬类IgG-A Fc、变体犬类IgG-CFc、变体犬类IgG-D Fc、变体马类IgG2 Fc、变体马类IgG5 Fc或变体马类IgG6 Fc结合蛋白A。

在一些实施方案中，变体IgG Fc多肽包含伴生动物物种的变体IgG Fc多肽。在一些实施方案中，变体IgG Fc多肽包含变体犬类IgG Fc多肽、变体马类IgG Fc多肽或猫类IgGFc多肽。

具有修饰的蛋白A结合的示例性变体IgG Fc多肽

在一些实施方案中，变体IgG Fc多肽具有修饰的蛋白A结合亲和力。在一些实施方案中，变体IgG Fc多肽具有增加的与蛋白A的结合亲和力。在一些实施方案中，变体IgG Fc多肽可以使用蛋白A柱色谱来纯化。

在一些实施方案中，变体IgG Fc多肽包含在对应于SEQ ID NO:34的位置21、位置23、位置25、位置80、位置205和/或位置207的位置处的氨基酸取代。在一些实施方案中，变体IgG Fc多肽包含在对应于SEQ ID NO:37的位置21、位置23和/或位置24的位置处的氨基酸取代。在一些实施方案中，变体IgG Fc多肽包含在对应于SEQ ID NO:39的位置21、位置23、位置25、位置80和/或位置207的位置处的氨基酸取代。

在一些实施方案中，变体IgG Fc多肽包含在对应于SEQ ID NO:71的位置15和/或位置203的位置处的氨基酸取代。在一些实施方案中，变体IgG Fc多肽包含在对应于SEQ IDNO:75的位置199和/或位置200的位置处的氨基酸取代。在一些实施方案中，变体IgG Fc多肽包含在对应于SEQ ID NO:76的位置199、位置200、位置201和/或202的位置处的氨基酸取代。

在一些实施方案中，变体IgG Fc多肽包含在SEQ ID NO:34的位置21、位置23、位置25、位置80、位置205和/或位置207处的氨基酸取代。在一些实施方案中，变体IgG Fc多肽包含在SEQ ID NO:37的位置21、位置23和/或位置24处的氨基酸取代。在一些实施方案中，变体IgG Fc多肽包含在SEQ ID NO:39的位置21、位置23、位置25、位置80和/或位置207处的氨基酸取代。

在一些实施方案中，变体IgG Fc多肽包含在SEQ ID NO:71的位置15和/或位置203处的氨基酸取代。在一些实施方案中，变体IgG Fc多肽包含在SEQ ID NO:75的位置199和/或位置200处的氨基酸取代。在一些实施方案中，变体IgG Fc多肽包含在SEQ ID NO:76的位置199、位置200、位置201和/或位置202处的氨基酸取代。

在一些实施方案中，变体IgG Fc多肽包含在对应于SEQ ID NO:34的位置21的位置处的苏氨酸、在对应于SEQ ID NO:34的位置23的位置处的亮氨酸、在对应于SEQ ID NO:34的位置25的位置处的丙氨酸、在对应于SEQ ID NO:34的位置80的位置处的甘氨酸、在对应于SEQ ID NO:34的位置205的位置处的丙氨酸和/或在对应于SEQ ID NO:34的位置207的位置处的组氨酸。在一些实施方案中，变体IgG Fc多肽包含在对应于SEQ ID NO:37的位置21的位置处的苏氨酸、在对应于SEQ ID NO:37的位置23的位置处的亮氨酸和/或在对应于SEQID NO:37的位置24的位置处的异亮氨酸。在一些实施方案中，变体IgG Fc多肽包含在对应于SEQ ID NO:39的位置21的位置处的苏氨酸、在对应于SEQ ID NO:39的位置23的位置处的亮氨酸、在对应于SEQ ID NO:39的位置25的位置处的丙氨酸、在对应于SEQ ID NO:39的位置80的位置处的甘氨酸和/或在对应于SEQ ID NO:39的位置207的位置处的组氨酸。

在一些实施方案中，变体IgG Fc多肽包含在对应于SEQ ID NO:71的位置15的位置处的苏氨酸或缬氨酸和/或在对应于SEQ ID NO:71的位置203的位置处的酪氨酸或缬氨酸。在一些实施方案中，变体IgG Fc多肽包含在对应于SEQ ID NO:75的位置199的位置处的亮氨酸和/或在对应于SEQ ID NO:75的位置200的位置处的组氨酸。在一些实施方案中，变体IgG Fc多肽包含在对应于SEQ ID NO:76的位置199的位置处的异亮氨酸、在对应于SEQ IDNO:76的位置200的位置处的组氨酸、在对应于SEQ ID NO:76的位置201的位置处的天冬酰胺和/或在对应于SEQ ID NO:76的位置202的位置处的组氨酸。

在一些实施方案中，变体IgG Fc多肽包含在SEQ ID NO:34的位置21处的苏氨酸、在SEQ ID NO:34的位置23处的亮氨酸、在SEQ ID NO:34的位置25处的丙氨酸、在SEQ IDNO:34的位置80处的甘氨酸、在SEQ ID NO:34的位置205处的丙氨酸和/或在SEQ ID NO:34的位置207处的组氨酸。在一些实施方案中，变体IgG Fc多肽包含在SEQ ID NO:47的位置21处的苏氨酸、在SEQ ID NO:47的位置23处的亮氨酸和/或在SEQ ID NO:47的位置24处的异亮氨酸。在一些实施方案中，变体IgG Fc多肽在SEQ ID NO:39的位置21处的苏氨酸、在SEQID NO:39的位置23处的亮氨酸、在SEQ ID NO:39的位置25处的丙氨酸、在SEQ ID NO:39的位置80处的甘氨酸和/或在SEQ ID NO:39的位置207处的组氨酸。

在一些实施方案中，变体IgG Fc多肽包含在SEQ ID NO:71的位置15处的苏氨酸或缬氨酸和/或在SEQ ID NO:71的位置203处的酪氨酸或缬氨酸。在一些实施方案中，变体IgGFc多肽包含在SEQ ID NO:75的位置199处的亮氨酸和/或在SEQ ID NO:75的位置200处的组氨酸。在一些实施方案中，变体IgG Fc多肽包含在SEQ ID NO:76的位置199处的异亮氨酸、在SEQ ID NO:76的位置200处的组氨酸、在SEQ ID NO:76的位置201处的天冬酰胺和/或在SEQ ID NO:76的位置202处的组氨酸。

具有修饰的CD16结合的示例性变体IgG Fc多肽

在一些实施方案中，变体IgG Fc多肽具有修饰的CD16结合亲和力。在一些实施方案中，变体IgG Fc多肽具有降低的对CD16的结合亲和力。在一些实施方案中，变体IgG Fc可以具有降低的ADCC免疫应答。

在一些实施方案中，变体IgG Fc多肽包含在对应于SEQ ID NO:35的位置5、位置38、位置39、位置97和/或位置98的位置处的氨基酸取代。在一些实施方案中，变体IgG Fc多肽包含在对应于SEQ ID NO:37的位置5、位置38、位置39、位置97和/或位置98的位置处的氨基酸取代。

在一些实施方案中，变体IgG Fc多肽包含在SEQ ID NO:35的位置5、位置38、位置39、位置97和/或位置98处的氨基酸取代。在一些实施方案中，变体IgG Fc多肽包含在SEQID NO:37的位置5、位置38、位置39、位置97和/或位置98处的氨基酸取代。

在一些实施方案中，变体IgG Fc多肽包含在对应于SEQ ID NO:36的位置5的位置处的脯氨酸、在对应于其位置38的位置处的甘氨酸、在对应于其位置39的位置处的精氨酸、在对应于其位置97的位置处的异亮氨酸和/或在对应于其位置98的位置处的甘氨酸。在一些实施方案中，变体IgG Fc多肽包含在对应于SEQ ID NO:37的位置5的位置处的脯氨酸、在对应于其位置38的位置处的甘氨酸、在对应于其位置39的位置处的精氨酸、在对应于其位置97的位置处的异亮氨酸和/或在对应于其位置98的位置处的甘氨酸。

在一些实施方案中，变体IgG Fc多肽包含在SEQ ID NO:35的位置5处的脯氨酸、位置38处的甘氨酸、位置39处的精氨酸、位置97处的异亮氨酸和/或位置98处的甘氨酸。在一些实施方案中，变体IgG Fc多肽包含在SEQ ID NO:37的位置5处的脯氨酸、位置38处的甘氨酸、位置39处的精氨酸、位置97处的异亮氨酸和/或位置98处的甘氨酸。

具有修饰的C1q结合的示例性变体IgG Fc多肽

在一些实施方案中，变体IgG Fc多肽具有修饰的C1q结合亲和力。在一些实施方案中，变体IgG Fc多肽具有降低的对C1q的结合亲和力。在一些实施方案中，变体IgG Fc多肽可以具有降低的补体结合。在一些实施方案中，变体IgG Fc可以具有降低的补体介导的免疫应答。

在一些实施方案中，变体IgG Fc多肽包含在对应于SEQ ID NO:35的位置93的位置处的氨基酸取代。在一些实施方案中，变体IgG Fc多肽包含在对应于SEQ ID NO:37的位置93的位置处的氨基酸取代。在一些实施方案中，变体IgG Fc多肽包含在对应于SEQ ID NO:70的位置87的位置处的氨基酸取代。在一些实施方案中，变体IgG Fc多肽包含在对应于SEQID NO:73的位置87的位置处的氨基酸取代。在一些实施方案中，变体IgG Fc多肽包含在对应于SEQ ID NO:74的位置87的位置处的氨基酸取代。在一些实施方案中，变体IgG Fc多肽包含在对应于SEQ ID NO:77的位置87的位置处的氨基酸取代。在一些实施方案中，变体IgGFc多肽包含在对应于SEQ ID NO:86、SEQ ID NO:87、SEQ ID NO:88或SEQ ID NO:89的位置198的位置处的氨基酸取代。

在一些实施方案中，变体IgG Fc多肽包含在SEQ ID NO:35的位置93处的氨基酸取代。在一些实施方案中，变体IgG Fc多肽包含在SEQ ID NO:37的位置93处的氨基酸取代。在一些实施方案中，变体IgG Fc多肽包含在SEQ ID NO:70的位置87处的氨基酸取代。在一些实施方案中，变体IgG Fc多肽包含在SEQ ID NO:73的位置87处的氨基酸取代。在一些实施方案中，变体IgG Fc多肽包含在SEQ ID NO:74的位置87处的氨基酸取代。在一些实施方案中，变体IgG Fc多肽包含在SEQ ID NO:77的位置87处的氨基酸取代。在一些实施方案中，变体IgG Fc多肽包含在SEQ ID NO:86、SEQ ID NO:87、SEQ ID NO:88或SEQ ID NO:89的位置198处的氨基酸取代。

在一些实施方案中，变体IgG Fc多肽包含在对应于SEQ ID NO:35的位置93的位置处的精氨酸。在一些实施方案中，变体IgG Fc多肽包含在对应于SEQ ID NO:37的位置93的位置处的精氨酸。在一些实施方案中，变体IgG Fc多肽包含在对应于SEQ ID NO:70的位置87的位置处的丝氨酸。在一些实施方案中，变体IgG Fc多肽包含在对应于SEQ ID NO:73的位置87的位置处的丝氨酸取代。在一些实施方案中，变体IgG Fc多肽包含在对应于SEQ IDNO:74的位置87的位置处的丝氨酸。在一些实施方案中，变体IgG Fc多肽包含在对应于SEQID NO:77的位置87的位置处的丝氨酸。在一些实施方案中，变体IgG Fc多肽包含在对应于SEQ ID NO:86、SEQ ID NO:87、SEQ ID NO:88或SEQ ID NO:89的位置198的位置处的丙氨酸。

在一些实施方案中，变体IgG Fc多肽包含在SEQ ID NO:35的位置93处的精氨酸。在一些实施方案中，变体IgG Fc多肽包含在SEQ ID NO:37的位置93处的氨基酸取代。在一些实施方案中，变体IgG Fc多肽包含在SEQ ID NO:70的位置87处的丝氨酸。在一些实施方案中，变体IgG Fc多肽包含在SEQ ID NO:73的位置87处的丝氨酸。在一些实施方案中，变体IgG Fc多肽包含在SEQ ID NO:74的位置87处的丝氨酸。在一些实施方案中，变体IgG Fc多肽包含在SEQ ID NO:77的位置87处的丝氨酸。在一些实施方案中，变体IgG Fc多肽包含在SEQ ID NO:86、SEQ ID NO:87、SEQ ID NO:88或SEQ ID NO:89的位置198处的丙氨酸。

具有修饰的FcRn结合的示例性变体IgG Fc多肽

在一些实施方案中，变体IgG Fc多肽具有修饰的新生儿受体(FcRn)结合亲和力。在一些实施方案中，变体IgG Fc多肽具有增加的对FcRn的结合亲和力。

在一些实施方案中，变体IgG Fc多肽以比野生型IgG Fc多肽更大的亲和力与FcRn结合，所述亲和力是通过生物膜层干涉法、表面等离子体共振或任何蛋白质-蛋白质相互作用工具在约5.0至约6.5范围内的pH下，如在约5.0的pH、约5.2的pH、约5.5的pH、约6.0的pH、约6.2的pH或约6.5的pH下测量的。

在一些实施方案中，变体IgG Fc多肽以小于5x10^-6M、小于1x10^-6M、小于5x10^-7M、小于1x10^-7M、小于5x10^-8M、小于1x10^-8M、小于5x10^-9M、小于1x10^-9M、小于5x10^-10M、小于1x10^{- 10}M、小于5x10^-11M、小于1x10^-11M、小于5x10^-12M或小于1x10^-12M的解离常数(Kd)与FcRn结合，所述解离常数是通过生物膜层干涉法、表面等离子体共振或任何蛋白质-蛋白质相互作用工具在约5.0至约6.5范围内的pH下，如在约5.0的pH、约5.5的pH、约6.0的pH或约6.5的pH下测量的。

在一些实施方案中，连续多肽包含能够以相对于野生型Fc多肽增加的亲和力与FcRn结合的变体IgG Fc多肽，并且其中所述连续多肽相对于包含野生型Fc多肽的连续多肽具有增加的血清半衰期。

在一些实施方案中，变体IgG Fc多肽包含在对应于SEQ ID NO:34、SEQ ID NO:35、SEQ ID NO:37、SEQ ID NO:39、SEQ ID NO:70、SEQ ID NO:71、SEQ ID NO:73、SEQ ID NO:74、SEQ ID NO:75、SEQ ID NO:76、SEQ ID NO:77、SEQ ID NO:86、SEQ ID NO:88或SEQ IDNO:90的位置23的位置处的酪氨酸或苯丙氨酸。在一些实施方案中，变体IgG Fc多肽包含在对应于SEQ ID NO:34、SEQ ID NO:35、SEQ ID NO:37、SEQ ID NO:39、SEQ ID NO:70、SEQ IDNO:71、SEQ ID NO:73、SEQ ID NO:74、SEQ ID NO:75、SEQ ID NO:76、SEQ ID NO:77、SEQ IDNO:86、SEQ ID NO:88或SEQ ID NO:90的位置82的位置处的酪氨酸。在一些实施方案中，变体IgG Fc多肽包含在对应于SEQ ID NO:35、SEQ ID NO:37、SEQ ID NO:70、SEQ ID NO:71、SEQ ID NO:73、SEQ ID NO:74、SEQ ID NO:75、SEQ ID NO:76、SEQ ID NO:77、SEQ ID NO:86、SEQ ID NO:88或SEQ ID NO:90的位置82的位置处的酪氨酸和在对应于其位置207的位置处的组氨酸。在一些实施方案中，变体IgG Fc多肽包含在对应于SEQ ID NO:35、SEQ IDNO:37、SEQ ID NO:70、SEQ ID NO:71、SEQ ID NO:73、SEQ ID NO:74、SEQ ID NO:75、SEQ IDNO:76、SEQ ID NO:77、SEQ ID NO:86、SEQ ID NO:88或SEQ ID NO:90的位置82的位置处的酪氨酸和在对应于其位置207的位置处的酪氨酸。在一些实施方案中，变体IgG Fc多肽包含在对应于SEQ ID NO:35、SEQ ID NO:37、SEQ ID NO:70、SEQ ID NO:71、SEQ ID NO:73、SEQID NO:74、SEQ ID NO:75、SEQ ID NO:76、SEQ ID NO:77、SEQ ID NO:86、SEQ ID NO:88或SEQ ID NO:90的位置207的位置处的酪氨酸。在一些实施方案中，变体IgG Fc多肽包含在对应于SEQ ID NO:34或SEQ ID NO:39的位置82的位置处的酪氨酸和在对应于其位置208的位置处的组氨酸。在一些实施方案中，变体IgG Fc多肽包含在对应于SEQ ID NO:34或SEQ IDNO:39的位置82的位置处的酪氨酸和在对应于其位置208的位置处的酪氨酸。在一些实施方案中，变体IgG Fc多肽包含在对应于SEQ ID NO:34或SEQ ID NO:39的位置208的位置处的酪氨酸。

在一些实施方案中，变体IgG Fc多肽包含在SEQ ID NO:34、SEQ ID NO:35、SEQ IDNO:37、SEQ ID NO:39、SEQ ID NO:70、SEQ ID NO:71、SEQ ID NO:73、SEQ ID NO:74、SEQ IDNO:75、SEQ ID NO:76、SEQ ID NO:77、SEQ ID NO:86、SEQ ID NO:88或SEQ ID NO:90的位置23处的酪氨酸或苯丙氨酸。在一些实施方案中，变体IgG Fc多肽包含在SEQ ID NO:34、SEQID NO:35、SEQ ID NO:37、SEQ ID NO:39、SEQ ID NO:70、SEQ ID NO:71、SEQ ID NO:73、SEQID NO:74、SEQ ID NO:75、SEQ ID NO:76、SEQ ID NO:77、SEQ ID NO:86、SEQ ID NO:88或SEQ ID NO:90的位置82处的酪氨酸。在一些实施方案中，变体IgG Fc多肽包含在SEQ IDNO:35、SEQ ID NO:37、SEQ ID NO:70、SEQ ID NO:71、SEQ ID NO:73、SEQ ID NO:74、SEQ IDNO:75、SEQ ID NO:76、SEQ ID NO:77、SEQ ID NO:86、SEQ ID NO:88或SEQ ID NO:90的位置82处的酪氨酸和位置207处的组氨酸。在一些实施方案中，变体IgG Fc多肽包含在SEQ IDNO:35、SEQ ID NO:37、SEQ ID NO:70、SEQ ID NO:71、SEQ ID NO:73、SEQ ID NO:74、SEQ IDNO:75、SEQ ID NO:76、SEQ ID NO:77、SEQ ID NO:86、SEQ ID NO:88或SEQ ID NO:90的位置82处的酪氨酸和位置207处的酪氨酸。在一些实施方案中，变体IgG Fc多肽包含在SEQ IDNO:35、SEQ ID NO:37、SEQ ID NO:70、SEQ ID NO:71、SEQ ID NO:73、SEQ ID NO:74、SEQ IDNO:75、SEQ ID NO:76、SEQ ID NO:77、SEQ ID NO:86、SEQ ID NO:88或SEQ ID NO:90的位置207处的酪氨酸。在一些实施方案中，变体IgG Fc多肽包含在SEQ ID NO:34或SEQ ID NO:39的位置82处的酪氨酸和位置208处的组氨酸。在一些实施方案中，变体IgG Fc多肽包含在SEQ ID NO:34或SEQ ID NO:39的位置82处的酪氨酸和位置208处的酪氨酸。在一些实施方案中，变体IgG Fc多肽包含在SEQ ID NO:34或SEQ ID NO:39的位置208处的酪氨酸。

具有修饰的链间二硫键的示例性变体IgG Fc多肽

在一些实施方案中，变体猫类IgG Fc多肽相对于野生型猫类IgG Fc多肽具有至少一个另外的链间二硫键。在一些实施方案中，变体猫类IgG Fc多肽在铰链区中具有至少一个另外的链间二硫键。在一些实施方案中，具有至少一个另外的链间二硫键的变体猫类IgG2 Fc多肽相对于野生型猫类IgG Fc多肽具有增加的链间稳定性。在一些实施方案中，变体IgG多肽相对于野生型IgG Fc多肽具有对铰链区的至少一个氨基酸修饰。在一些实施方案中，野生型IgG Fc多肽是野生型猫类或马类IgG Fc多肽。在一些实施方案中，变体IgG Fc多肽包含来自不同同种型的IgG Fc多肽的铰链区或铰链区的一部分。在一些实施方案中，变体IgG Fc多肽包含来自野生型猫类IgG-1a Fc多肽、来自野生型猫类IgG-1b Fc多肽或来自野生型马类IgG1 Fc多肽的铰链区。在一些实施方案中，变体IgG2 Fc多肽相对于野生型IgG Fc多肽具有增加的重组产生和/或增加的铰链二硫化物形成。在一些实施方案中，增加的重组产生和/或增加的铰链二硫化物形成可以在还原和/或非还原条件下通过SDS-PAGE分析来确定。

在一些实施方案中，变体IgG Fc多肽包含在对应于SEQ ID NO:90的位置8、位置9、位置10、位置11、位置12、位置13、位置14、位置15或位置16的位置处的半胱氨酸。在一些实施方案中，变体IgG Fc多肽包含在SEQ ID NO:90的位置8、位置9、位置10、位置11、位置12、位置13、位置14、位置15或位置16处的半胱氨酸。

在一些实施方案中，变体IgG Fc多肽包含在对应于SEQ ID NO:86、SEQ ID NO:87、SEQ ID NO:88、SEQ ID NO:89或SEQ ID NO:90的位置16的位置处的氨基酸取代。在一些实施方案中，变体IgG Fc多肽包含在对应于SEQ ID NO:72的位置3的位置处和/或在对应于其位置20的位置处的氨基酸取代。

在一些实施方案中，变体IgG Fc多肽包含在SEQ ID NO:86、SEQ ID NO:87、SEQ IDNO:88、SEQ ID NO:89或SEQ ID NO:90的位置16处的氨基酸取代。在一些实施方案中，变体IgG Fc多肽包含在SEQ ID NO:72的位置3处和/或在对应于其位置20的位置处的氨基酸取代。

在一些实施方案中，变体IgG Fc多肽包含在对应于SEQ ID NO:86、SEQ ID NO:87、SEQ ID NO:88、SEQ ID NO:89或SEQ ID NO:90的位置16的位置处的脯氨酸。在一些实施方案中，变体IgG Fc多肽包含在对应于SEQ ID NO:72的位置3的位置处的丝氨酸和/或在对应于其位置20的位置处的脯氨酸。

在一些实施方案中，变体IgG Fc多肽包含在SEQ ID NO:86、SEQ ID NO:87、SEQ IDNO:88、SEQ ID NO:89或SEQ ID NO:90的位置16处的脯氨酸。在一些实施方案中，变体IgGFc多肽包含在SEQ ID NO:72的位置3处的丝氨酸和/或位置20处的脯氨酸。

在一些实施方案中，变体IgG Fc多肽包含以下的氨基酸序列：SEQ ID NO:40、SEQID NO:41、SEQ ID NO:42、SEQ ID NO:43、SEQ ID NO:44、SEQ ID NO:45、SEQ ID NO:46、SEQID NO:47、SEQ ID NO:48、SEQ ID NO:49、SEQ ID NO:50、SEQ ID NO:51、SEQ ID NO:52、SEQID NO:53、SEQ ID NO:54、SEQ ID NO:55、SEQ ID NO:56、SEQ ID NO:57、SEQ ID NO:58、SEQID NO:59、SEQ ID NO:60、SEQ ID NO:61、SEQ ID NO:62、SEQ ID NO:63、SEQ ID NO:64、SEQID NO:65、SEQ ID NO:66、SEQ ID NO:67、SEQ ID NO:68、SEQ ID NO:69、SEQ ID NO:78、SEQID NO:79、SEQ ID NO:80、SEQ ID NO:81、SEQ ID NO:82、SEQ ID NO:83、SEQ ID NO:84、SEQID NO:85、SEQ ID NO:91、SEQ ID NO:92、SEQ ID NO:93、SEQ ID NO:94、SEQ ID NO:95、SEQID NO:96、SEQ ID NO:97、SEQ ID NO:98、SEQ ID NO:99、SEQ ID NO:100、SEQ ID NO:101、SEQ ID NO:102、SEQ ID NO:103、SEQ ID NO:104、SEQ ID NO:105、SEQ ID NO:106、SEQ IDNO:107、SEQ ID NO:108、SEQ ID NO:109、SEQ ID NO:197、SEQ ID NO:198、SEQ ID NO:199、SEQ ID NO:200、SEQ ID NO:201、SEQ ID NO:202、SEQ ID NO:203、SEQ ID NO:204、SEQ IDNO:205、SEQ ID NO:206、SEQ ID NO:207、SEQ ID NO:208、SEQ ID NO:209和/或SEQ ID NO:210。

在一些实施方案中，可以基于以下式制备包含至少一种TrkA ECD多肽(例如，ECDv1、v2、v3和/或v4)和本文所述的野生型或变体犬类、猫类或马类IgG Fc多肽的连续多肽：

式(I)：TrkA ECD 1-L1-Fc；

式(II)：Fc-L1-TrkA ECD 1；

式(III)：TrkA ECD 1-L1-Fc-L2-TrkA ECD 2；

式(IV)：TrkA ECD 1-L1-TrkA ECD 2-L2-Fc；或

式(V)：Fc-L1-TrkA ECD 1-L2-TrkA ECD 2，

其中TrkA ECD 1是第一TrkA ECD多肽，TrkA ECD 2是第二TrkA ECD多肽(例如，相同的TrkA ECD多肽或不同的TrkA ECD多肽)，L1和L2是任选的接头；并且Fc是伴生动物物种的野生型或变体IgG Fc多肽。任选地，连续多肽包含信号序列。式I-V的示例性构建体可以包含在任何TrkA ECD 1或TrkA ECD 2之后或之前的第三、第四或第五等TrkA ECD。第三、第四或第五等TrkA ECD可以是与TrkA ECD 1或TrkA ECD 2相同的TrkA ECD多肽或不同的TrkA ECD多肽。

例如，连续多肽可以包含至少一种犬类TrkA ECD多肽(例如，SEQ ID NO:2、3、4、5、25、26或27)和野生型犬类IgG多肽(例如，SEQ ID NO:34、35、36、37、38或39)、变体犬类IgG-A Fc多肽(例如，SEQ ID NO:40、43、199或200)、变体犬类IgG-B Fc多肽(例如，SEQ ID NO:46、48、49、50、51、52、53、54、55、64、65、66、67、197、198、203、204、205、206、207、208、209或210)、变体犬类IgG-C Fc多肽(例如，SEQ ID NO:41、44、47、56、57、58、59、60、61、52、63、68或69)或变体犬类IgG-D Fc多肽(例如，SEQ ID NO:42、45、201或202)，如本文所述。

连续多肽可以包含至少一种猫类TrkA ECD多肽(例如，SEQ ID NO:7、8、9、10、28、29或30)和野生型猫类IgG Fc多肽(例如，86、87、88、89或90)、变体猫类IgG1a Fc多肽(例如，SEQ ID NO:91、92、96或97)、变体猫类IgG1b Fc多肽(例如，SEQ ID NO:93、94、98或99)或变体猫类IgG2 Fc多肽(例如，SEQ ID NO:95、100或107)，如本文所述。

连续多肽可以包含至少一种马类TrkA ECD多肽(例如，SEQ ID NO:12、13、14、15、31、32或33)和野生型马类IgG Fc多肽(例如，SEQ ID NO:70、71、72、73、74、75、76或77)、变体马类IgG1Fc多肽(例如，SEQ ID NO:82)、变体马类IgG2 Fc多肽(例如，SEQ ID NO:78、79、101、102、103、104、105、106、108或109)、变体马类IgG3 Fc多肽(例如，SEQ ID NO:83)、变体马类IgG4 Fc多肽(例如，SEQ ID NO:84)、变体马类IgG5 Fc多肽(例如，SEQ ID NO:80)、变体马类IgG6 Fc多肽(例如，SEQ ID NO:81)或变体马类IgG7 Fc多肽(例如，SEQ ID NO:85)。

在一些实施方案中，包含TrkA ECD多肽的连续多肽还可以包含至少一种NGFR ECD多肽。在一些实施方案中，NGFR ECD多肽包含SEQ ID NO:135、SEQ ID NO:137和/或SEQ IDNO:139的氨基酸序列。

在一些实施方案中，连续多肽包含以下的氨基酸序列：SEQ ID NO:16、SEQ ID NO:17、SEQ ID NO:18、SEQ ID NO:19、SEQ ID NO:20、SEQ ID NO:21、SEQ ID NO:22、SEQ IDNO:23、SEQ ID NO:24、SEQ ID NO:110、SEQ ID NO:111、SEQ ID NO:112、SEQ ID NO:113、SEQ ID NO:114、SEQ ID NO:115、SEQ ID NO:116、SEQ ID NO:117、SEQ ID NO:118、SEQ IDNO:119、SEQ ID NO:120、SEQ ID NO:121、SEQ ID NO:122、SEQ ID NO:123、SEQ ID NO:124、SEQ ID NO:125、SEQ ID NO:126、SEQ ID NO:127、SEQ ID NO:128、SEQ ID NO:129、SEQ IDNO:130、SEQ ID NO:131、SEQ ID NO:132、SEQ ID NO:133、SEQ ID NO:140、SEQ ID NO:141、SEQ ID NO:142、SEQ ID NO:159、SEQ ID NO:160、SEQ ID NO:161、SEQ ID NO:162、SEQ IDNO:163、SEQ ID NO:164、SEQ ID NO:165、SEQ ID NO:166、SEQ ID NO:167、SEQ ID NO:168、SEQ ID NO:169、SEQ ID NO:170、SEQ ID NO:171、SEQ ID NO:172、SEQ ID NO:173、SEQ IDNO:174、SEQ ID NO:175、SEQ ID NO:176、SEQ ID NO:177、SEQ ID NO:178、SEQ ID NO:179、SEQ ID NO:180、SEQ ID NO:181、SEQ ID NO:182、SEQ ID NO:183、SEQ ID NO:184、SEQ IDNO:185、SEQ ID NO:186、SEQ ID NO:187、SEQ ID NO:188、SEQ ID NO:189、SEQ ID NO:190、SEQ ID NO:191、SEQ ID NO:192、SEQ ID NO:193、SEQ ID NO:194、SEQ ID NO:211、SEQ IDNO:212、SEQ ID NO:213、SEQ ID NO:214、SEQ ID NO:215、SEQ ID NO:216、SEQ ID NO:217、SEQ ID NO:218、SEQ ID NO:219、SEQ ID NO:220、SEQ ID NO:221、SEQ ID NO:222、SEQ IDNO:223、SEQ ID NO:224、SEQ ID NO:225、SEQ ID NO:226、SEQ ID NO:227、SEQ ID NO:228、SEQ ID NO:229、SEQ ID NO:230、SEQ ID NO:231、SEQ ID NO:232、SEQ ID NO:233、SEQ IDNO:234、SEQ ID NO:235、SEQ ID NO:236、SEQ ID NO:237、SEQ ID NO:238、SEQ ID NO:239、SEQ ID NO:240、SEQ ID NO:241、SEQ ID NO:242、SEQ ID NO:243、SEQ ID NO:244、SEQ IDNO:245、SEQ ID NO:246。

可以使用以下形式进一步构建分子：R-(接头)-Fc-TrkA。R可以是任何蛋白质，如TNFR、IL13R、IL4R、IL17R等。双特异性形式可以提供另外的治疗益处。

也可以将TrkA与抗体，例如与IgG重链C末端融合。抗体可以是抗TNF、抗CGRP、抗IL17、抗IL4R、抗EGFR等。抗体融合体可以对治疗具有增强的效果。

示例性TrkA ECD多肽表达和产生

提供具有或不具有信号序列的编码TrkA多肽的全部或部分(例如，细胞外结构域)的多核苷酸序列。如果在核酸分子的构建中不使用同源信号序列(即，TRKA的信号序列)，则可以使用另一信号序列，例如，PCT US06/02951中所述的信号序列中的任何一种。

通常，将编码目的多肽(如TrkA多肽)的核苷酸序列插入到适合于在所选宿主细胞中表达的表达载体中。

“载体”是可用于将DNA序列从一种生物体转移至另一种生物体或用于表达目的基因的质粒。载体通常包括复制起点和调节目的基因表达的调节序列，并且可以携带或可以不携带选择性标记基因，如抗生素抗性基因。载体适用于要在其中表达它的宿主细胞。当目的基因存在于载体中时，载体可以称为“重组载体”。

“宿主细胞”是指可以是或已经是载体或分离的多核苷酸的受体的细胞。宿主细胞可以是原核细胞或真核细胞。示例性真核细胞包括哺乳动物细胞，如灵长类动物或非灵长类动物细胞；真菌细胞，如酵母；植物细胞；和昆虫细胞。非限制性示例性哺乳动物细胞包括但不限于NS0细胞、PER.细胞(Crucell)、293细胞和CHO细胞，及其衍生物，如293-6E、DG44、CHO-S和CHO-K细胞。宿主细胞包括单个宿主细胞的后代，并且由于天然的、偶然的或故意的突变，所述后代可能不一定与原始亲本细胞完全相同(在形态方面或基因组DNA互补序列方面)。宿主细胞包括在体内用编码本文提供的一个或多个氨基酸序列的一个或多个多核苷酸转染的细胞。

如本文所用，术语“分离的”是指已经与通常在自然界中发现或产生的至少一些组分分离的分子。例如，当多肽与产生它的细胞的至少一些组分分离时，称其为“分离的”。当多肽在表达后由细胞分泌时，将含有所述多肽的上清液与产生它的细胞物理分离，认为是“分离”所述多肽。类似地，当多核苷酸不是通常在自然界中发现的较大的多核苷酸(如在DNA多核苷酸的情况下的基因组DNA或线粒体DNA)的一部分时，或例如在RNA多核苷酸的情况下与产生它的细胞的至少一些组分分离时，称多核苷酸为“分离的”。因此，包含在宿主细胞内的载体中的DNA多核苷酸可称为“分离的”。

在一些实施方案中，使用色谱(如尺寸排阻色谱、离子交换色谱、蛋白质A柱色谱、疏水相互作用色谱和CHT色谱)分离TrkA多肽。

术语“标记”和“可检测标记”意指与TrkA多肽附接以使其可检测的部分。在一些实施方案中，标记是可以产生可通过视觉或仪器手段检测的信号的可检测标记物，例如，掺入放射性标记的氨基酸或将生物素基部分附接到多肽，所述生物素基部分可以通过加标记的抗生物素蛋白(例如，含有可以通过光学方法或比色法检测的荧光标记物或酶活性的链霉亲和素)检测。用于多肽的标记的例子包括但不限于以下：放射性同位素或放射性核素(例如，³H、¹⁴C、³⁵S、⁹⁰Y、⁹⁹Tc、¹¹¹In、¹²⁵I、¹³¹I、¹⁷⁷Lu、¹⁶⁶Ho或¹⁵³Sm)；色原、荧光标记(例如，FITC、罗丹明、镧系元素磷光体)、酶标记(例如，辣根过氧化物酶、萤光素酶、碱性磷酸酶)；化学发光标记物；生物素基团；由第二报吿分子识别的预定多肽表位(例如，亮氨酸拉链对序列、第二抗体的结合位点、金属结合结构域、表位标签)；和诸如钆螯合物等磁性剂。通常用于免疫测定的标记的代表性例子包括产生光的部分，例如吖啶鎓化合物；和产生荧光的部分，例如荧光素。在这方面，所述部分本身可以未被可检测地标记，但在与又另一种部分反应时可能变得可检测。

作为诱饵受体陷阱的示例性TrkA多肽

本发明的TRKA多肽可以充当诱饵受体用于捕获NGF并抑制其与细胞表面上的NGF和TRKA的相互作用。诱饵受体(如本发明的那些)以高亲和力和特异性识别其配体，但在结构上不能传导信号。它们与野生型受体竞争配体结合并参与配体/受体相互作用，从而调节功能受体的活性或数量和/或受体下游的细胞活性。诱饵受体可以充当激动剂配体的分子陷阱且从而抑制配体诱导的受体激活。

如本文所用，“NGF”是指由细胞中NGF的表达和加工产生的任何天然NGF。除非另外指明，否则所述术语包括来自任何脊椎动物来源的NGF，所述脊椎动物包括哺乳动物如灵长类动物(例如，人和食蟹猴)和啮齿动物(例如，小鼠和大鼠)和伴生动物(例如，狗、猫和马类)。所述术语还包括天然存在的NGF变体，例如剪接变体或等位基因变体。

本发明提供了作为治疗剂的TrkA ECD多肽。本发明的TrkA ECD多肽与本文更详细描述的NGF(其已被证明与慢性疼痛或炎性疼痛相关)结合。在各种实施方案中，TrkA多肽可以以高亲和力结合NGF。在各种实施方案中，TrkA多肽可以干扰NGF信号传导。

术语“亲和力”意指在分子(例如，受体)的单个结合位点与其结合配偶体(例如，配体)之间的非共价相互作用的总和的强度。分子X对其配偶体Y的亲和力通常可以由解离常数(K_D)表示。亲和力可以通过本领域中已知的常用方法来测量，所述常用方法例如免疫印迹、ELISA KD、KinEx A、生物膜层干涉法(BLI)或表面等离子体共振装置。

术语“K_D”、“K_d”、“Kd”或“Kd值”可互换用于指受体融合体-配体相互作用的平衡解离常数。在一些实施方案中，根据供应商说明书，使用诸如系统(Pall ForteBioLLC，加利福尼亚州弗里蒙特)等的生物传感器，通过使用生物膜层干涉测定来测量融合分子与其配体的K_d。简而言之，将生物素化的抗原与传感器尖端结合，并且监测融合分子的缔合持续90秒，并且监测解离持续600秒。用于稀释和结合步骤的缓冲液是20mM磷酸盐、150mMNaCl，pH 7.2。减去仅缓冲液的空白曲线以校正任何漂移。使用ForteBio数据分析软件将数据拟合至2:1结合模型以确定缔合速率常数(k_on)、解离速率常数(k_off)和K_d。平衡解离常数(K_d)计算为k_off/k_on的比率。术语“kon”是指分子X与其配偶体Y的缔合的速率常数，而术语“koff”是指分子X或配偶体Y与分子X/配偶体Y复合物解离的速率常数。

术语与物质“结合”是本领域熟知的术语，并且确定这种结合的方法也是本领域熟知的。如果分子与特定细胞或物质反应，与特定细胞或物质缔合或者具有对特定细胞或物质的亲和力，并且所述反应、缔合或亲和力可通过本领域中已知的一种或多种方法(如免疫印迹、ELISA KD、KinEx A、生物膜层干涉法(BLI)、表面等离子体共振装置等)来检测，则称所述分子展现“结合”。

“表面等离子体共振”表示光学现象，其允许通过检测生物传感器基质内蛋白质浓度的变化来分析实时生物特异性相互作用，例如使用BIAcore^TM系统(BIAcoreInternational AB,a GE Healthcare公司,乌普萨拉,瑞典以及皮斯卡塔韦,新泽西州)。有关进一步说明，请参见Jonsson等人(1993)Ann.Biol.Clin.51:19-26。

“生物膜层干涉法”是指光学分析技术，其分析在生物传感器尖端和内部参考层上从固定化蛋白质层反射的光的干涉图案。与生物传感器尖端结合的分子数量的变化引起可以实时测量的干涉图案的偏移。用于生物膜层干涉法的非限制性示例性装置是系统(Pall ForteBio LLC)。参见例如Abdiche等人,2008,Anal.Biochem.377:209-277。

在一些实施方案中，TrkA多肽以通过生物膜层干涉法测量的小于5x10^-6M、小于1x10^-6M、小于5x10^-7M、小于1x10^-7M、小于5x10^-8M、小于1x10^-8M、小于5x10^-9M、小于1x10^-9M、小于5x10^-10M、小于1x10^-10M、小于5x10^-11M、小于1x10^-11M、小于5x10^-12M或小于1x10^-12M的解离常数(Kd)与犬类NGF、猫类NGF、马类NGF或人NGF结合。在一些实施例中，TRKA多肽以通过生物膜层干涉法测量的如下Kd与犬类NGF、猫类NGF、或马类NGF结合：在5x10^-6M与1x10^-6M之间、在5x10^-6M与5x10^-7M之间、在5x10^-6M与1x10^-7M之间、在5x10^-6M与5x10^-8M、5x10^-6M与1x10^-8M之间、在5x10^-6M与5x10^-9M之间、在5x10^-6M与1x10^-9M之间、在5x10^-6M与5x10^-10M之间、在5x10^-6M与1x10^-10M之间、在5x10^-6M与5x10^-11M之间、在5x10^-6M与1x10^-11M之间、在5x10^-6M与5x10^-12M之间、在5x10^-6M与1x10^-12M之间、在1x10^-6M与5x10^-7M之间、在1x10^-6M与1x10^-7M之间、在1x10^-6M与5x10^-8M、1x10^-6M与1x10^-8M之间、在1x10^-6M与5x10^-9M之间、在1x10^-6M与1x10^-9M之间、在1x10^-6M与5x10^-10M之间、在1x10^-6M与1x10^-10M之间、在1x10^-6M与5x10^-11M之间、在1x10^-6M与1x10^-11M之间、在1x10^-6M与5x10^-12M之间、在1x10^-6M与1x10^-12M之间、在5x10^-7M与1x10^-7M之间、在5x10^-7M与5x10^-8M、5x10^-7M与1x10^-8M之间、在5x10^-7M与5x10^-9M之间、在5x10^-7M与1x10^-9M之间、在5x10^-7M与5x10^-10M之间、在5x10^-7M与1x10^-10M之间、在5x10^-7M与5x10^{- 11}M之间、在5x10^-7M与1x10^-11M之间、在5x10^-7M与5x10^-12M之间、在5x10^-7M与1x10^-12M之间、在1x10^-7M与5x10^-8M,1x10^-7M与1x10^-8M之间、在1x10^-7M与5x10^-9M之间、在1x10^-7M与1x10^-9M之间、在1x10^-7M与5x10^-10M之间、在1x10^-7M与1x10^-10M之间、在1x10^-7M与5x10^-11M之间、在1x10^{- 7}M与1x10^-11M之间、在1x10^-7M与5x10^-12M之间、在1x10^-7M与1x10^-12M之间、在5x10^-8M与1x10^-8M之间、在5x10^-8M与5x10^-9M之间、在5x10^-8M与1x10^-9M之间、在5x10^-8M与5x10^-10M之间、在5x10^-8M与1x10^-10M之间、在5x10^-8M与5x10^-11M之间、在5x10^-8M与1x10^-11M之间、在5x10^-8M与5x10^{- 12}M之间、在5x10^-8M与1x10^-12M、1x10^-8M与5x10^-9M之间、在1x10^-8M与1x10^-9M之间、在1x10^-8M与5x10^-10M之间、在1x10^-8M与1x10^-10M之间、在1x10^-8M与5x10^-11M之间、在1x10^-8M与1x10^-11M之间、在1x10^-8M与5x10^-12M之间、在1x10^-8M与1x10^-12M之间、在5x10^-9M与1x10^-9M之间、在5x10^{- 9}M与5x10^-10M之间、在5x10^-9M与1x10^-10M之间、在5x10^-9M与5x10^-11M之间、在5x10^-9M与1x10^{- 11}M之间、在5x10^-9M与5x10^-12M之间、在5x10^-9M与1x10^-12M之间、在1x10^-9M与5x10^-10M之间、在1x10^-9M与1x10^-10M之间、在1x10^-9M与5x10^-11M之间、在1x10^-9M与1x10^-11M之间、在1x10^-9M与5x10^-12M之间、在1x10^-9M与1x10^-12M之间、在5x10^-10M与1x10^-10M之间、在5x10^-10M与5x10^-11M之间、在1x10^-10M与5x10^-11M、1x10^-10M与1x10^-11M之间、在1x10^-10M与5x10^-12M之间、在1x10^-10M与1x10^-12M之间、在5x10^-11M与1x10^-12M之间、在5x10^-11M与5x10^-12M之间、在5x10^-11M与1x10^-12M之间、在1x10^-11M与5x10^-12M或在1x10^-11M与1x10^-12M之间。在一些实施方案中，TRKA多肽与犬类NGF、猫类NGF和/或马类NGF结合。

“降低”或“抑制”意指与参考相比使活性、功能或量减少、降低或停滞。在一些实施方案中，“降低”或“抑制”意指引起总体减少20％或更多的能力。在一些实施方案中，“降低”或“抑制”意指引起总体减少50％或更多的能力。在一些实施方案中，“降低”或“抑制”意指引起总体减少75％、85％、90％、95％或更多的能力。在一些实施方案中，在相同的时间段内，相对于对照剂量(如安慰剂)，上述量在一段时间内被抑制或减少。如本文所用，“参考”是指用于比较目的的任何样品、标准或水平。可以从健康或非患病样品中获得参考。在一些例子中，从伴生动物的未患病或未处理样品中获得参考。在一些例子中，从特定物种的一种或多种健康动物而不是被测试或治疗的动物获得参考。

如本文所用，术语“显著降低”表示在数值与参考数值之间的足够高的降低程度，使得本领域技术人员将认为在由所述值测量的生物学特征的背景下这两个值之间的差异具有统计学显著性。在一些实施方案中，与参考值相比，显著降低的数值降低大于约10％、15％、20％、25％、30％、35％、40％、45％、50％、60％、70％、80％、90％或100％中的任何一个。

在一些实施方案中，与不存在融合分子时的NGF信号传导相比，TrkA多肽可以将伴生动物物种中的NGF信号传导降低至少10％、至少15％、至少20％、至少25％、至少30％、至少35％、至少40、至少45％、至少50％、至少60％、至少70％、至少80％、至少90％或100％。在一些实施方案中，信号传导通过NGF依赖性TF-1细胞增殖的降低来测量。在一些实施方案中，NGF信号传导的降低或增殖的降低在10％与15％之间、10％与20％之间、10％与25％之间、10％与30％之间、10％与35％之间、10％与40％之间、10％与45％之间、10％与50％之间、10％与60％之间、10％与70％之间、10％与80％之间、10％与90％之间、10％与100％之间、15％与20％之间、15％与25％之间、15％与30％之间、15％与35％之间、15％与40％之间、15％与45％之间、15％与50％之间、15％与60％之间、15％与70％之间、15％与80％之间、15％与90％之间、15％与100％之间、20％与25％之间、20％与30％之间、20％与35％之间、20％与40％之间、20％与45％之间、20％与50％之间、20％与60％之间、20％与70％之间、20％与80％之间、20％与90％之间、20％与100％之间、25％与30％之间、25％与35％之间、25％与40％之间、25％与45％之间、25％与50％之间、25％与60％之间、25％与70％之间、25％与80％之间、25％与90％之间、25％与100％之间、30％与35％之间、30％与40％之间、30％与45％之间、30％与50％之间、30％与60％之间、30％与70％之间、30％与80％之间、30％与90％之间、30％与100％之间、35％与40％之间、35％与45％之间、35％与50％之间、35％与60％之间、35％与70％之间、35％与80％之间、35％与90％之间、35％与100％之间、40％与45％之间、40％与50％之间、40％与60％之间、40％与70％之间、40％与80％之间、40％与90％之间、40％与100％之间、45％与50％之间、45％与60％之间、45％与70％之间、45％与80％之间、45％与90％之间、45％与100％之间、50％与60％之间、50％与70％之间、50％与80％之间、50％与90％之间、50％与100％之间、60％与70％之间、60％与80％之间、60％与90％之间、60％与100％之间、70％与80％之间、70％与90％之间、70％与100％之间、80％与90％之间、80％与100％之间或90％与100％之间。

示例性药物组合物

术语“药物配制品”和“药物组合物”是指呈使得一种或多种活性成分的生物活性有效的形式，并且不含对所述配制品所施用的受试者具有不可接受的毒性的其他组分的制剂。

“药学上可接受的载体”是指本领域常规的无毒固体、半固体或液体填充剂、稀释剂、包封材料、配制辅助剂或载体，其与共同构成用于施用于受试者的“药物组合物”的治疗剂一起使用。药学上可接受的载体在使用的剂量和浓度下对接受者无毒，并且与配制品的其他成分相容。药学上可接受的载体适用于所用配制品。药学上可接受的载体的例子包括氧化铝；硬脂酸铝；卵磷脂；诸如人血清白蛋白、犬类或其他动物白蛋白等的血清蛋白；诸如磷酸盐、柠檬酸盐、氨丁三醇或HEPES缓冲液等的缓冲液；甘氨酸；山梨酸；山梨酸钾；饱和植物脂肪酸的偏甘油酯混合物；水；盐或诸如硫酸鱼精蛋白、磷酸氢二钠、磷酸氢钾、氯化钠、锌盐、胶体二氧化硅或三硅酸镁等的电解质；聚乙烯吡咯烷酮，纤维素基物质；聚乙二醇；蔗糖；甘露糖醇；或包括但不限于精氨酸的氨基酸。

所述药物组合物可以以冻干形式储存。因此，在一些实施方案中，所述制备方法包括冻干步骤。然后可以在施用于狗、猫或马之前，将冻干的组合物重新配制，通常作为适用于肠胃外施用的水性组合物。在其他实施方案中，特别是当融合分子对热变性和氧化变性而言高度稳定时，药物组合物可以作为液体储存，即作为水性组合物储存，其可以直接或在适当稀释的情况下施用于狗、猫或马。可以用无菌注射用水(WFI)重构冻干的组合物。可以包括抑菌试剂，如苯甲醇。因此，本发明提供了固体或液体形式的药物组合物。

当施用时，所述药物组合物的pH可以在约pH 5至约pH 8的范围内。如果本发明的组合物用于治疗目的，则它们是无菌的。无菌可以通过本领域已知的几种方法中的任何一种来实现，包括通过无菌过滤膜(例如0.2微米膜)过滤。可以使用或不使用抗细菌剂来维持无菌。

TrkA多肽和药物组合物的示例性用途

TrkA多肽或包含本发明的TrkA多肽的药物组合物可用于治疗NGF诱导的病症。如本文所用，“NGF诱导的病症”意指与NGF的水平升高或分布改变相关、由其引起或表征的疾病。此类NGF诱导的病症包括但不限于骨关节炎疼痛、癌症疼痛、下背痛。在一些实施方案中，NGF诱导的病症是慢性疼痛或炎性疼痛。NGF诱导的病症可以在伴生动物中展现出来，所述伴生动物包括但不限于犬类、猫类或马类。

如本文所用，“治疗”是用于获得有益或期望的临床结果的途径。如本文所用，“治疗”包括哺乳动物(包括伴生动物)中疾病治疗剂的任何施用或应用。出于本公开文本的目的，有益或期望的临床结果包括但不限于以下中的任何一个或多个：减轻一种或多种症状，降低疾病程度，预防或延迟疾病的传播，预防或延迟疾病的复发，延迟或减缓疾病的进展，改善疾病状态，抑制疾病或疾病进展，抑制或减缓疾病或疾病进展，停滞疾病发展和缓解(无论是部分还是全部)。“治疗”还涵盖降低增殖性疾病的病理后果。本文提供的方法考虑了这些治疗方面中的任何一个或多个。与上述一致，术语治疗不需要百分之百地去除所述障碍的所有方面。

在一些实施方案中，可以根据本文的方法使用TrkA多肽或包含它的药物组合物来治疗NGF诱导的病症。在一些实施方案中，将TrkA多肽或药物组合物施用于伴生动物如犬类、猫类或马类，以治疗NGF诱导的病症。

物质/分子、激动剂或拮抗剂的“治疗有效量”可根据诸如待治疗的疾病类型，疾病状态，疾病的严重程度和病程，治疗目的的类型，任何既往治疗，临床病史，对先前治疗的反应，主治兽医的判断，动物的年龄、性别和体重，以及物质/分子、激动剂或拮抗剂在动物中引起期望反应的能力等因素而变化。治疗有效量也是治疗有益效果超过物质/分子、激动剂或拮抗剂的任何毒性或有害作用的量。治疗有效量可以按一次或多次施用来递送。“治疗有效量”是指在必要的剂量和持续必要的时间段的情况下能有效实现所需治疗或预防结果的量。

在一些实施方案中，TrkA多肽或包含TrkA多肽的药物组合物是肠胃外施用的，通过皮下施用、静脉输注或肌内注射进行。在一些实施方案中，TrkA多肽或包含TrkA多肽的药物组合物作为推注或通过在一段时间中连续输注来施用。在一些实施方案中，TrkA多肽或包含TrkA多肽的药物组合物是通过肌内、腹膜内、脑脊髓内、皮下、动脉内、滑膜内、鞘内或吸入途径施用的。

可以将本文所述的TrkA多肽以在每剂量0.1mg/kg体重至100mg/kg体重范围内的量来施用。在一些实施方案中，可以将TrkA融合体以每剂量0.5mg/kg体重至50mg/kg体重范围内的量施用。在一些实施方案中，可以将TrkA融合体以每剂量1mg/kg体重至10mg/kg体重范围内的量施用。在一些实施方案中，可以将融合分子以0.5mg/kg体重至100mg/kg体重范围内、1mg/kg体重至100mg/kg体重范围内、5mg/kg体重至100mg/kg体重范围内、10mg/kg体重至100mg/kg体重范围内、20mg/kg体重至100mg/kg体重范围内、50mg/kg体重至100mg/kg体重范围内、1mg/kg体重至10mg/kg体重范围内、5mg/kg体重至10mg/kg体重范围内、0.5mg/kg体重至10mg/kg体重范围内或5mg/kg体重至50mg/kg体重范围内的量施用。

可以将TrkA多肽或包含TrkA多肽的药物组合物一次或经过一系列治疗施用于伴生动物。例如，可以将TrkA多肽或包含TrkA的药物组合物施用至少一次、多于一次、至少两次、至少三次、至少四次或至少五次。

在一些实施方案中，将所述剂量每周施用一次，持续至少连续两周或三周，并且在一些实施方案中，该治疗周期重复两次或更多次，任选地穿插有一周或多周未治疗。在其他实施方案中，将所述治疗有效剂量每天施用一次，持续连续二至五天，并且在一些实施方案中，该治疗周期重复两次或更多次，任选地穿插有一天或多天未治疗。

与一种或多种其他治疗剂“组合”施用包括以任何顺序同时(并行)和连续或依序施用。术语“并行”在本文中用于指两种或更多种治疗剂的施用，其中至少部分施用在时间上重叠或者一种治疗剂的施用相对于另一种治疗剂的施用在很短的时间内发生。例如，以不超过约指定分钟数的时间间隔施用所述两种或更多种治疗剂。术语“依序”在本文中用于指两种或更多种治疗剂的施用，其中在中断施用一种或多种药剂后继续施用一种或多种其他药剂，或者其中在施用一种或多种药剂之前施用一种或多种其他药剂。例如，以超过约指定分钟数的时间间隔施用所述两种或更多种治疗剂。如本文所用，术语“与......结合”是指除了一种治疗模式之外还施用另一种治疗模式。因此，“与……结合”是指在向动物施用一种治疗模式之前、期间或之后施用另一种治疗模式。

在一些实施方案中，所述方法包括与TrkA多肽或包含TrkA多肽的药物组合物组合施用NGF激酶抑制剂、PI3K抑制剂、ras抑制剂和/或磷脂酶C途径抑制剂。在一些实施方案中，所述方法还包括施用一种或多种疼痛治疗药物，如皮质类固醇、非甾体抗炎药(NSAID)、环氧合酶抑制剂、阿片类物质和/或大麻素。

本文提供了在允许与NGF结合的条件下，向细胞暴露TrkA多肽或包含TrkA多肽的药物组合物的方法。在一些实施方案中，将所述细胞离体暴露于TrkA多肽或药物组合物。在一些实施方案中，将所述细胞在体内暴露于TrkA多肽或药物组合物。在一些实施方案中，将细胞暴露于TrkA多肽。在一些实施方案中，在以下条件下将细胞暴露于TrkA多肽或所述药物组合物：所述条件允许所述融合分子与细胞外NGF结合。在一些实施方案中，可以将细胞通过本文所述的任何一种或多种施用方法在体内暴露于TrkA多肽或所述药物组合物，所述施用方法包括但不限于腹膜内、肌内、静脉注射至受试者体内。在一些实施方案中，可以通过以下方式将细胞离体暴露于TrkA多肽或所述药物组合物：将所述细胞暴露于包含所述融合分子或所述药物组合物的培养基。在一些实施方案中，在将所述细胞暴露于包含所述融合分子或所述药物组合物的培养基之前，可以使用本领域技术人员理解的任何数量的方法(如电穿孔细胞或将细胞暴露于含有氯化钙的溶液)影响细胞膜的渗透性。

在一些实施方案中，所述暴露导致所述细胞的NGF信号传导功能的降低。在一些实施方案中，与不存在TrkA多肽时的NGF信号传导功能相比，TrkA多肽可以将细胞中的NGF信号传导降低至少10％、至少15％、至少20％、至少25％、至少30％、至少35％、至少40、至少45％、至少50％、至少60％、至少70％、至少80％、至少90％或100％。在一些实施方案中，NGF信号传导的降低或TF-1增殖的降低在10％与15％之间、10％与20％之间、10％与25％之间、10％与30％之间、10％与35％之间、10％与40％之间、10％与45％之间、10％与50％之间、10％与60％之间、10％与70％之间、10％与80％之间、10％与90％之间、10％与100％之间、15％与20％之间、15％与25％之间、15％与30％之间、15％与35％之间、15％与40％之间、15％与45％之间、15％与50％之间、15％与60％之间、15％与70％之间、15％与80％之间、15％与90％之间、15％与100％之间、20％与25％之间、20％与30％之间、20％与35％之间、20％与40％之间、20％与45％之间、20％与50％之间、20％与60％之间、20％与70％之间、20％与80％之间、20％与90％之间、20％与100％之间、25％与30％之间、25％与35％之间、25％与40％之间、25％与45％之间、25％与50％之间、25％与60％之间、25％与70％之间、25％与80％之间、25％与90％之间、25％与100％之间、30％与35％之间、30％与40％之间、30％与45％之间、30％与50％之间、30％与60％之间、30％与70％之间、30％与80％之间、30％与90％之间、30％与100％之间、35％与40％之间、35％与45％之间、35％与50％之间、35％与60％之间、35％与70％之间、35％与80％之间、35％与90％之间、35％与100％之间、40％与45％之间、40％与50％之间、40％与60％之间、40％与70％之间、40％与80％之间、40％与90％之间、40％与100％之间、45％与50％之间、45％与60％之间、45％与70％之间、45％与80％之间、45％与90％之间、45％与100％之间、50％与60％之间、50％与70％之间、50％与80％之间、50％与90％之间、50％与100％之间、60％与70％之间、60％与80％之间、60％与90％之间、60％与100％之间、70％与80％之间、70％与90％之间、70％与100％之间、80％与90％之间、80％与100％之间或90％与100％之间。

本文提供了使用TrkA多肽和多核苷酸用于检测、诊断和监测NGF诱导的病症的方法。本文提供了确定伴生动物是否将对TrkA多肽疗法有反应的方法。在一些实施方案中，所述方法包括使用TrkA多肽检测动物是否具有表达NGF的细胞。在一些实施方案中，所述检测方法包括使样品与抗体、多肽或多核苷酸接触，并且确定结合水平是否不同于参考或对照样品(如对照)的结合水平。在一些实施方案中，所述方法可以用于确定本文所述的TrkA多肽是否是对受试动物而言适当的治疗。

在一些实施方案中，样品是生物样品。术语“生物样品”意指来自活物或以前的活物的一定量的物质。在一些实施方案中，生物样品是细胞或细胞/组织裂解物。在一些实施方案中，生物样品包括但不限于血液(例如，全血)、血浆、血清、尿液、滑液和上皮细胞。

在一些实施方案中，使细胞或细胞/组织裂解物与TrkA多肽接触，并测定TrkA多肽与细胞之间的结合。当测试细胞与相同组织类型的参考细胞相比显示出结合活性时，它可以指示受试者将受益于用TrkA多肽的治疗。在一些实施方案中，测试细胞来自伴生动物的组织。

可以使用本领域已知的用于检测特异性抗体-抗原结合的各种方法。可以进行的示例性免疫测定包括荧光偏振免疫测定(FPIA)、荧光免疫测定(FIA)、酶免疫测定(EIA)、比浊法抑制免疫测定(NIA)、酶联免疫吸附测定(ELISA)和放射免疫测定(RIA)。可以将指示剂部分或标记基团附接到主题抗体上并且进行选择以便满足所述方法的通常由测定设备的可用性和相容的免疫测定程序决定的各种应用的需要。适当的标记包括但不限于放射性核素(例如¹²⁵I、¹³¹I、³⁵S、³H或³²P)、酶(例如，碱性磷酸酶、辣根过氧化物酶、萤光素酶或p-乳糖苷酶)、荧光部分或蛋白质(例如，荧光素、罗丹明、藻红蛋白、GFP或BFP)或发光部分(例如，由Quantum Dot Corporation，帕洛阿尔托，加利福尼亚州提供的Qdot^TM纳米颗粒)。用于进行上述各种免疫测定的一般技术是本领域普通技术人员已知的。

出于诊断目的，可以用可检测部分标记TrkA多肽，所述可检测部分包括但不限于放射性同位素、荧光标记和本领域已知的各种酶-底物标记。将标记与多肽缀合的方法是本领域已知的。在一些实施方案中，TrkA多肽不需要被标记，并且可以例如使用与TrkA多肽结合的抗体检测其存在。在一些实施方案中，TRKA多肽可以用于任何已知的测定方法，如竞争性结合测定、直接和间接夹心测定和免疫沉淀测定中。Zola,Monoclonal Antibodies:AManual of Techniques,第147-158页(CRC Press,Inc.1987)。抗NGF抗体和多肽也可以用于体内诊断测定，如体内成像。通常，用放射性核素(如¹¹¹In、⁹⁹Tc、¹⁴C、¹³¹I、¹²⁵I、³H或任何其他放射性核素标记(包括本文概述的那些))标记抗体或多肽，使得可以用免疫闪烁成像术定位目的细胞或组织。使用本领域熟知的技术，TRKA多肽还可以用作病理学中的染色试剂。

在一些实施方案中，TrkA多肽用于诊断剂并且TrkA多肽用作治疗剂。在一些实施方案中，第一TrkA多肽和第二TrkA多肽是不同的。

以下实施例说明了本公开文本的具体方面，并不旨在以任何方式限制本公开文本。

实施例

实施例1

TrkA的细胞外结构域

鉴定出负责结合犬类、猫类和马类NGF的犬类、猫类和马类TrkA的细胞外结构域并对其定义边界。从相应的全长多肽序列(分别为SEQ ID NO:1、SEQ ID NO:6和SEQ ID NO:11)鉴定出犬类TrkA(SEQ ID NO:2)、猫类TrkA(SEQ ID NO:7)和马类TrkA(SEQ ID NO:12)的全长细胞外结构域(ECD v1)。鉴定出假定保留NGF结合的犬类TrkA、猫类TrkA和马类TrkA的示例性截短型细胞外结构域多肽(示例性ECD v2、v3和v4)(例如，SEQ ID NO:3、4和5(犬类TrkA ECD v2、v3和v4)；SEQ ID NO:8、9和10(猫类TrkA ECD v2、v3和v4)；和SEQ ID NO:13、14和15(马类TrkA ECD v2、v3和v4)。

实施例2

来自CHO细胞的TrkA ECD多肽的设计、表达、纯化和稳定性

为了增强体内半衰期、NGF结合亲合力和纯化，将示例性TrkA ECD融合至用接头桥接的IgG Fc多肽。优选地，IgG Fc多肽可以结合蛋白A。

设计、化学合成编码信号序列、犬类TrkA ECD v2(SEQ ID NO:3)或犬类TrkA ECDv3(SEQ ID NO:4)、接头和野生型犬类IgG-B Fc多肽的核苷酸序列，并将其插入到适合于转染至CHO宿主细胞中的表达载体中。此外，类似地设计、合成编码以下的单独核苷酸序列，并将其克隆至表达载体中：(1)信号序列、猫类TrkA ECD v2(SEQ ID NO:8)或猫类TrkA ECDv3(SEQ ID NO:9)、接头和野生型猫类IgG-2Fc多肽；和(2)信号序列、马类TrkA ECD v2(SEQID NO:13)或马类TrkA ECD v3(SEQ ID NO:14)以及变体马类IgG-2Fc多肽(SEQ ID NO:104；蛋白A+、C1q-、CD16-)。在转染至CHO细胞中并培养后，通过单步蛋白A柱色谱将融合蛋白(分别为SEQ ID NO:16、17、19、20、22和23)从培养基中纯化出来。

使用差示扫描荧光测定法来评估TrkA ECD v2和TrkA ECD v3在不同pH下的稳定性，如通过平均熔点温度所反映的(下表6)。在该实施例中，比较了上文制备的马类TrkAECD v2和马类TrkA ECD v3融合多肽(SEQ ID NO:22和SEQ ID NO:23)。在测试的pH中，在热稳定性方面，马类TrkA ECD v3(SEQ ID NO:23)比马类TrkA ECD v2(SEQ ID NO:22)稍微更稳定。

表6.

实施例3

NGF结合活性的证明

考虑了实施例2中制备的犬类、猫类和马类TrkA ECD v2和v3融合多肽(SEQ IDNO:16、17、19、20、22和23)与可商购的人NGF的结合活性。使用生物传感器Octet进行如下结合分析。简而言之，将人NGF(Sino Biological,Inc.；目录号11050-HNAC)生物素化。通过广泛透析从生物素化的NGF中去除游离的未反应的生物素。在链霉亲和素传感器尖端上捕获生物素化的NGF。监测NGF与TrkA-Fc(25ug/mL)的缔合持续600秒。监测解离持续600秒。减去仅缓冲液空白曲线以校正任何漂移。使用ForteBio^TM数据分析软件将数据拟合至1:1结合模型以确定k_on、k_off和Kd。用于稀释和所有结合步骤的缓冲液是：20mM磷酸盐，150mM NaCl，pH7.2。

图1和图2是示出犬类、猫类和马类TrkA ECD v2和v3融合多肽均结合NGF的传感图。图1示出了比较犬类和猫类TrkA v2和v3与NGF的结合亲和力的传感图。不相关的犬类和猫类IgG-Fc融合蛋白用作阴性对照。图2示出了比较马类TrkA v2和v3与NGF的结合亲和力的传感图。在三个物种中，所有TrkA ECD和NGF的Kd在1x10^-9M范围内。

实施例4

TrkA ECD-IgG Fc多肽的细胞功能活性

将TF1细胞(ATCC目录号CRL-2003)(一种在细胞表面表达NGF受体的人红白血病细胞系)用于增殖测定。在不存在其他必要的生长因子(例如，红细胞生成素、IL3或GM-CSF)时，重组人NGF刺激TF-1细胞的细胞增殖。参见Kitamura,T.等人,“Establishment andcharacterization of a unique human cell line that proliferates dependently onGM-CSF,IL-3,or erythropoietin.”J.Cell Physiol.140(2):323-34(1989)；rndsystems.com/prod ucts/recombinant-human-beta-ngf-protein_256-gf#product-details。使细胞在RP MI1640(Gibco，目录号11875)中生长，所述RPMI1640补充有10％热灭活的胎牛血清(Sigma，目录号2868)和2nM/ml人GM-CSF(R&D System，目录号215-GM-010)。将指数生长期时的细胞用PBS洗涤，重悬于不含GM-C SF的上述培养基中，且铺板在96孔板中。将马类TrkA ECD v2-变体马类IgG2 Fc(SEQ ID NO:22；蛋白A+、C1q-、CD16-)以一系列稀释液添加，之后以10ng/ml添加NGF(Sino Biological,Inc.；目录号11050-HNAC)。不相关的单克隆抗体用作阴性对照。

将细胞以100μl的总体积在37℃、5％CO₂中孵育48小时。在孵育结束时，将细胞在室温中冷却并通过使用CellTiter-发光法细胞活力测定(Promega，目录号G7570)测量细胞ATP含量来分析增殖/活力。在该测定中，将100μl预混合试剂A和B添加至每个孔中。在定轨摇床上振荡大约2分钟后，裂解细胞。在细胞中出现的Mg2+和ATP的存在下，通过萤光素酶催化荧光素的单氧化，从而产生与细胞中的ATP量成比例的发光信号。ATP的量正比于在培养物中存在的细胞的数目。将板在室温下孵育10分钟以稳定发光信号，并且使用Synergy HT微板读数器(Biotek，威努斯基，佛蒙特州)检测发光。使用4参数逻辑拟合分析数据，并证明TrkA ECD-IgG Fc多肽在该TF1细胞增殖测定中中和了NGF活性。TrkA ECD-Fc多肽的IC50是5.4nM。参见图3。

实施例5

对TrkA ECD多肽的N连接的糖基化工程化

为了进一步增强TrkA ECD多肽的药代动力学，可以将另外的N连接的糖基化位点引入野生型犬类TrkA、猫类TrkA和马类TrkA中。例如，可以将一个、两个、三个或四个另外的N连接的糖基化位点在非重叠位置处引入TrkA ECD氨基酸序列中。N连接的糖基化位点可以具有Asn-Xaa-Ser/Thr的共有序列，其中Xaa是除脯氨酸外的任何氨基酸。添加一个或多个糖基化位点可以增加TrkA ECD多肽的分子大小，提供更多唾液酸化位点，和/或改善所述多肽在动物血清中的半衰期。

TrkA ECD多肽可以由哺乳动物细胞在增强唾液酸化的条件下产生。此外，TrkAECD多肽可以通过胺缀合或在聚糖上进一步聚乙二醇化或聚唾液酸化。例如，可以将化学聚唾液酸化引入糖基化位点。

表7列出犬类TrkA ECD v2、v3和v4的氨基酸取代，其可以用于产生一个或多个另外的N连接的糖基化位点。

表7.

*X指示除脯氨酸外的任何氨基酸(如E、V、A、I等)。

表8列出猫类TrkA ECD v2、v3和v4的氨基酸取代，其可以用于产生一个或多个另外的N连接的糖基化位点。

表8.

*X指示除脯氨酸外的任何氨基酸(如E、V、A、I等)。

表9列出马类TrkA ECD v2、v3和v4的氨基酸取代，其可以用于产生一个或多个另外的N连接的糖基化位点。

表9.

*X指示除脯氨酸外的任何氨基酸(如E、V、A、I等)。

实施例6

TrkA ECD分子内二硫化物

为了增加TrkA ECD多肽的稳定性，通过三维蛋白质建模和分析来鉴定用于另外的分子内二硫化物结合的合适位置。另外的二硫化物结合可以防止TrkA ECD多肽解折叠并增强蛋白酶抗性，从而导致增强的产物保质期稳定性和增强的体内药代动力学。例如，可以将半胱氨酸残基在SEQ ID NO:3、4、8、9、13或14的氨基酸位置7和89处并入犬类、猫类或马类TrkA ECD v2或v3中(V7C和A89C(对于犬类或猫类序列)或D89C(对于马类序列))。也可以将半胱氨酸残基在SEQ ID NO:5、10或15的氨基酸位置5和87处并入犬类、猫类或马类TrkAECD v4中(V5C和A87C(对于犬类或猫类序列)或D87C(对于马类序列))。具有另外的二硫化物对的示例性TrkA ECD多肽包括SEQ ID NO:25、26、27、28、29、30、31、32和33。

实施例7

包含TrkA ECD和IgG Fc的示例性连续多肽

可以设计、表达和纯化包含犬类、猫类或马类TrkA ECD v1、v2、v3或v4多肽(例如，SEQ ID NO:2、3、4、5、7、8、9、10、12、13、14、15、25、26、27、28、29、30、31、32或33)和相应伴生动物的野生型IgG Fc多肽或变体IgG Fc多肽的连续多肽用于表征。优选将与具有蛋白A结合、与C1q的降低或不可测量结合(例如，以降低CDC功能)和/或与CD16的降低或不可测量结合(例如，以降低ADCC功能)的IgG Fc多肽连接的TrkA ECD用于施用于患有NGF诱导的疼痛的伴生动物。示例性野生型犬类、猫类和马类IgG Fc多肽包含SEQ ID NO:33-39、70-77或86-90的氨基酸序列。示例性变体犬类、猫类和马类IgG Fc多肽包含诸如实施例8至11中描述的那些的氨基酸序列(例如，SEQ ID NO:40-69、78-85或91-109)。

可以基于以下式制备包含至少一种TrkA ECD多肽(例如，ECD v1、v2、v3和/或v4)和本文所述的野生型或变体犬类、猫类或马类IgG Fc多肽的连续多肽：

式(I)：TrkA ECD 1-L1-Fc；

式(II)：Fc-L1-TrkA ECD 1；

式(III)：TrkA ECD 1-L1-Fc-L2-TrkA ECD 2；

式(IV)：TrkA ECD 1-L1-TrkA ECD 2-L2-Fc；或

式(V)：Fc-L1-TrkA ECD 1-L2-TrkA ECD 2，

其中TrkA ECD 1是第一TrkA ECD多肽，TrkA ECD 2是第二TrkA ECD多肽(例如，相同的TrkA ECD多肽或不同的TrkA ECD多肽)，L1和L2是任选的接头；并且Fc是伴生动物物种的野生型或变体IgG Fc多肽。任选地，连续多肽包含信号序列。式I-V的示例性构建体可以包含在任何TrkA ECD 1或TrkA ECD 2之后或之前的第三、第四或第五等TrkA ECD。第三、第四或第五等TrkA ECD可以是与TrkA ECD 1或TrkA ECD 2相同的TrkA ECD多肽或不同的TrkA ECD多肽。

例如，连续多肽可以包含至少一种犬类TrkA ECD多肽(例如，SEQ ID NO:2、3、4、5、25、26或27)和野生型犬类IgG多肽(例如，SEQ ID NO:34、35、36、37、38或39)、变体犬类IgG-A Fc多肽(例如，SEQ ID NO:40、43、199或200)、变体犬类IgG-B Fc多肽(例如，SEQ ID NO:46、48、49、50、51、52、53、54、55、64、65、66、67、197、198、203、204、205、206、207、208、209或210)、变体犬类IgG-C Fc多肽(例如，SEQ ID NO:41、44、47、56、57、58、59、60、61、52、63、68或69)或变体犬类IgG-DFc多肽(例如，SEQ ID NO:42、45、201或202)，如本文所述。

连续多肽可以包含至少一种猫类TrkA ECD多肽(例如，SEQ ID NO:7、8、9、10、28、29或30)和野生型猫类IgG Fc多肽(例如，86、87、88、89或90)、变体猫类IgG1a Fc多肽(例如，SEQ ID NO:91、92、96或97)、变体猫类IgG1b Fc多肽(例如，SEQ ID NO:93、94、98或99)或变体猫类IgG2Fc多肽(例如，SEQ ID NO:95、100或107)，如本文所述。

连续多肽可以包含至少一种马类TrkA ECD多肽(例如，SEQ ID NO:12、13、14、15、31、32或33)和野生型马类IgG Fc多肽(例如，SEQ ID NO:70、71、72、73、74、75、76或77)、变体马类IgG1Fc多肽(例如，SEQ ID NO:82)、变体马类IgG2 Fc多肽(例如，SEQ ID NO:78、79、101、102、103、104、105、106、108或109)、变体马类IgG3 Fc多肽(例如，SEQ ID NO:83)、变体马类IgG4 Fc多肽(例如，SEQ ID NO:84)、变体马类IgG5 Fc多肽(例如，SEQ ID NO:80)、变体马类IgG6 Fc多肽(例如，SEQ ID NO:81)或变体马类IgG7 Fc多肽(例如，SEQ ID NO:85)。

接头可以是柔性非结构性接头，如富含甘氨酸和/或丝氨酸的接头。可以将柔性延伸部分添加至连续多肽的C末端。延伸部分可以包含一个、两个、三个、四个、五个、六个、七个、八个或更多个甘氨酸残基。

包含TrkA ECD的连续多肽还可以包含NGFR多肽的至少一个ECD，如SEQ ID NO:135、SEQ ID NO:137或SEQ ID NO:139。

可以使用蛋白A柱(蛋白A亲和树脂，Repligen)亲和纯化包含具有蛋白A结合的Fc IgG多肽的连续多肽。还可以经由其他色谱方法分离连续多肽，所述其他色谱方法如离子交换柱色谱、疏水相互作用柱色谱、混合模式柱色谱(如CHT)或多峰模式柱色谱(如CaptoMMC)。可以应用低pH或其他病毒灭活和病毒去除步骤。可以将纯化的蛋白质与赋形剂混合，并通过过滤灭菌以制备本发明的药物组合物。

可以通过HPLC凝胶过滤和/或在不存在和存在还原剂(DTT)的情况下的SDS-PAGE分析来评估所得蛋白质的二聚化、聚集和/或硫化物连接的存在。

实施例8

用于增加的蛋白A结合和/或降低的补体结合

和/或降低的CD16结合的变体犬类IgG Fc多肽

使用蛋白A亲和力纯化抗体是成熟的过程。然而，在犬类IgG的四种亚型中，只有IgG-B Fc(例如，SEQ ID NO:35或SEQ ID NO:36)具有蛋白A结合亲和力。犬类IgG-A Fc(例如，SEQ ID NO:34)、IgG-C Fc(例如，SEQ ID NO:37或SEQ ID NO:38)和IgG-D Fc(例如，SEQID NO:39)具有弱的或无可测量的蛋白A结合亲和力。设计了变体犬类IgG-A Fc、IgG-C Fc和IgG-D Fc多肽以用于改变蛋白A结合。

此外，犬类IgG-B Fc和IgG-C Fc具有补体活性并且结合至C1q，而犬类IgG-A Fc和IgG-D Fc具有弱的或无可测量的对C1q的结合亲和力。为了潜在地降低C1q结合和/或潜在地降低补体介导的免疫应答，设计了变体犬类IgG-B Fc和IgG-C Fc多肽。

此外，犬类IgG-B Fc和IgG-C Fc具有CD16结合活性。为了潜在地降低CD16与IgG-BFc和IgG-C Fc的结合，和/或潜在地降低ADCC，设计了变体犬类IgG-B Fc和IgG-C Fc多肽。

下表10汇总了犬类IgG Fc亚型的蛋白A、C1q和CD16结合特征。值得注意的是，野生型犬类IgG Fc亚型均不结合蛋白A并且缺乏C1q结合和/或CD16结合。

表10.

(-)表示低的或无可测量的结合活性。

使用三维蛋白质建模和蛋白质序列分析，鉴定了可能与蛋白A接触的犬类IgG-BFc的序列。使用两种途径来设计变体犬类IgG-A、IgG-C和IgG-D Fc多肽以用于增加蛋白A结合。对于第一种途径，将变体犬类IgG-A、IgG-C和IgG-D Fc多肽设计为具有与犬类IgG-B Fc相同的蛋白A结合基序序列(例如，分别为SEQ ID NO:40、SEQ ID NO:41和SEQ ID NO:42)。对于第二种途径，将变体犬类IgG-A Fc I(21)T/Q(207)H(SEQ ID NO:43)、变体犬类IgG-CFc I(21)T(SEQ ID NO:44)和变体犬类IgG-D Fc I(21)T/Q(207)H(SEQ ID NO:45)设计为在蛋白A结合区具有一个或两个氨基酸取代以对应于犬类IgG-B Fc序列。

此外，可以制备具有增加的蛋白A结合的变体犬类IgG-A Fc、IgG-C Fc和IgG-D Fc多肽，其具有表11中列出的一个或多个氨基酸取代。

表11.

*列出的氨基酸位置是相对于所指示的SEQ ID NO.。

为了潜在地降低C1q与犬类IgG-B Fc和IgG-C Fc的结合，和/或潜在地降低补体介导的免疫应答，可以制备变体犬类IgG-B Fc和IgG-C Fc多肽，其分别在对应于SEQ ID NO:35或SEQ ID NO:37的位置93的氨基酸位置处具有用除Lys外的任何氨基酸对Lys的氨基酸取代。这些氨基酸取代在犬类IgG-B Fc和IgG-C Fc与犬类IgG-A Fc和IgG-D Fc(了解它们未展现出补体活性)相比的蛋白质序列分析和3-D结构建模之后鉴定出。例如，可以制备变体犬类IgG-B Fc K(93)R(SEQ ID NO:46)和变体犬类IgG-C Fc K(93)R(SEQ ID NO:47)。与包含野生型犬类IgG-B Fc的融合蛋白相比，观察到人C1q与包含变体犬类IgG-B Fc K(93)R的融合蛋白之间的结合降低。

为了潜在地降低CD16与IgG-B Fc和IgG-C Fc的结合，和/或潜在地降低ADCC，可以制备具有表12中列出的一个或多个氨基酸取代的变体犬类IgG-B Fc和IgG-C Fc多肽(例如，SEQ ID NO:48、SEQ ID NO:49、SEQ ID NO:50、SEQ ID NO:51、SEQ ID NO:52、SEQ IDNO:53、SEQ ID NO:54、SEQ ID NO:55、SEQ ID NO:56、SEQ ID NO:57、SEQ ID NO:58、SEQ IDNO:59、SEQ ID NO:60、SEQ ID NO:61和/或SEQ ID NO:62)。所述一个或多个氨基酸取代在犬类IgG-B和IgG-C与IgG-A和IgG-D(了解它们未展现出ADCC活性)相比的蛋白质序列分析和3-D结构建模之后鉴定出。

表12.

*列出的氨基酸位置是相对于所指示的SEQ ID NO.。

由于野生型犬类IgG-C Fc缺乏蛋白A结合并且具有C1q结合，因此可以通过将表11中列出的一个或多个氨基酸取代与K(93)R取代或K(93)X取代(其中X是除Lys外的任何氨基酸)组合来制备结合蛋白A并且具有降低的与C1q的结合的双重变体犬类IgG-C Fc(例如，SEQ ID NO:63)。可以通过将表12中列出的一个或多个氨基酸取代与K(93)R取代或K(93)R取代(其中X是除Lys外的任何氨基酸)组合来制备具有降低的与C1q的结合和降低的与CD16的结合的双重变体犬类IgG-B Fc或双重变体犬类IgG-C Fc(例如，SEQ ID NO:65、SEQ IDNO:66、SEQ ID NO:67、SEQ ID NO:68和/或SEQ ID NO:69)。可以通过将表11中列出的一个或多个氨基酸取代和表12中列出的一个或多个氨基酸取代与K(93)R取代或K(93)X取代(其中X是除Lys外的任何氨基酸)组合来制备结合蛋白A并且具有降低的与C1q和CD16的结合的三重变体犬类IgG-C Fc。

可以确定任何变体犬类IgG Fc与蛋白A、CD16和/或C1q的结合，并且将其与另一种IgG Fc(例如，相应的野生型犬类IgG Fc、另一种野生型或变体犬类IgG Fc、或另一种伴生动物的野生型或变体IgG Fc等)与蛋白A、CD16和/或C1q的结合进行比较。

结合分析可以使用Octet生物传感器进行。简言之，可以将靶分子(例如，蛋白A、C1q、CD16等)生物素化并去除游离的未反应的生物素(例如，通过透析)。在链霉亲和素传感器尖端上捕获生物素化的靶分子。监测靶分子与各种浓度(例如，10μg/mL)的IgG Fc多肽的缔合持续指定的时间或直到达到稳定状态。监测解离持续指定的时间或直到达到稳定状态。可以减去仅缓冲液的空白曲线以校正任何漂移。使用ForteBio^TM数据分析软件将数据拟合至1:1结合模型以确定k_on、k_off和K_d。

实施例9

用于增加的蛋白A结合

和/或降低的补体结合的变体马类IgG Fc多肽

在马类IgG的七种亚型中，IgG1 Fc(例如，SEQ ID NO:70)、IgG3 Fc(例如，SEQ IDNO:73)、IgG4 Fc(例如，SEQ ID NO:74)、IgG7 Fc(例如，SEQ ID NO:77)具有蛋白A结合亲和力。马类IgG2 Fc(例如，SEQ ID NO:71或SEQ ID NO:72)、IgG5 Fc(例如，SEQ ID NO:75)和IgG6 Fc(例如，SEQ ID NO:76)具有弱或无可测量的蛋白A结合亲和力。设计了变体马类IgG2 Fc、IgG5 Fc和IgG6 Fc多肽以用于改变蛋白A结合。

此外，马类IgG2 Fc、IgG5 Fc和IgG6 Fc具有弱的或无可测量的对C1q的结合亲和力，而马类IgG1 Fc、IgG3 Fc、IgG4 Fc和IgG7 Fc结合至C1q。为了潜在地降低C1q结合和/或潜在地降低补体介导的免疫应答，设计了变体马类IgG1 Fc、IgG3 Fc、IgG4 Fc和IgG7 Fc多肽。

下表13汇总了马类IgG Fc亚型的蛋白A和C1q结合特征。值得注意的是，没有一种野生型马类IgG Fc亚型缺乏C1q结合并且结合蛋白A。

表13.

(-)表示低的或无可测量的结合活性。

使用三维蛋白质建模和蛋白质序列分析，鉴定了可能与蛋白A接触的马类IgG1Fc、IgG3 Fc、IgG4 Fc和IgG7 Fc的序列。可以制备具有增加的蛋白A结合的变体马类IgG2Fc、IgG5 Fc和IgG6 Fc多肽，其具有表14中列出的一个或多个氨基酸取代。

表14.

*列出的氨基酸位置是相对于所指示的SEQ ID NO.

例如，将变体马类IgG2 Fc、IgG5 Fc和IgG6 Fc多肽设计为在蛋白A结合区中具有一个或多个氨基酸取代，以与结合蛋白A的野生型马类IgG Fc的氨基酸序列相对应。可以制备具有增加的蛋白A结合的变体马类IgG2 Fc F(203)Y(SEQ ID NO:78)；变体马类IgG2 FcA(15)T/F(203)Y(SEQ ID NO:79)；变体马类IgG5 Fc V(199)L/E(200)Y(SEQ ID NO:80)；和变体马类IgG6Fc I(199)L/R(200)H/H(201)N/T(202)H(SEQ ID NO:81)。

为了潜在地降低C1q与马类IgG1 Fc、IgG3 Fc、IgG4 Fc和IgG7 Fc的结合，和/或潜在地降低补体介导的免疫应答，可以制备变体犬类IgG1 Fc、IgG3 Fc、IgG4 Fc和IgG7 Fc多肽，其分别在对应于SEQ ID NO:70、SEQ ID NO:73、SEQ ID NO:74、SEQ ID NO:77的位置87的氨基酸位置处具有用除Lys外的任何氨基酸对Lys的氨基酸取代。这些氨基酸取代在马类IgG1 Fc、IgG3 Fc、IgG4 Fc和IgG7 Fc与马类IgG2 Fc、IgG5 Fc和IgG6 Fc(了解它们未展现出补体活性)相比的蛋白质序列分析和3-D结构建模之后鉴定出。例如，可以制备变体马类IgG1 Fc K(87)S(SEQ ID NO:82)、变体马类IgG3 Fc K(87)S(SEQ ID NO:83)、变体马类IgG4 Fc K(87)S(SEQ ID NO:84)和变体马类IgG7 Fc K(87)S(SEQ ID NO:85)。

可以确定任何变体马类IgG Fc与蛋白A和/或C1q的结合，并且将其与另一种IgGFc(例如，相应的野生型马类IgG Fc、另一种野生型或变体马类IgG Fc、或另一种伴生动物的野生型或变体IgG Fc等)与蛋白A和/或C1q的结合进行比较。可以使用实施例8中描述的结合测定。

实施例10

用于减少补体结合的变体猫类IgG Fc多肽

猫类IgG、IgG1a Fc(SEQ ID NO:86或SEQ ID NO:87)、IgG1b Fc(SEQ ID NO:88或SEQ ID NO:89)和IgG2 Fc(SEQ ID NO:90)的三种亚型中的每一种都具有蛋白A结合亲和力。然而，只有猫类IgG2 Fc具有弱的或无可测量的对C1q的结合亲和力，而猫类IgG1a Fc、IgG1b Fc结合至C1q。为了潜在地降低C1q结合和/或潜在地降低补体介导的免疫应答，设计了变体猫类IgG1a Fc和IgG1b Fc多肽。

下表15汇总了猫类IgG Fc亚型的蛋白A和C1q结合特征。值得注意的是，没有一种野生型马类IgG Fc亚型缺乏C1q结合并且结合蛋白A。

表15.

(-)表示低的或无可测量的结合活性。

为了潜在地降低C1q与猫类IgG1a Fc和IgG1b Fc的结合，和/或潜在地降低补体介导的免疫应答，可以制备变体猫类IgG1a Fc和IgG1b Fc多肽，其在对应于SEQ ID NO:86、SEQ ID NO:87、SEQ ID NO:88或SEQ ID NO:89的位置198的氨基酸位置处具有用除Pro外的任何氨基酸对Pro的氨基酸取代。这些氨基酸取代在猫类IgG1a Fc和IgG1b Fc与猫类IgG2Fc(了解其未展现出补体活性)相比的蛋白质序列分析和3-D结构建模之后鉴定出。例如，可以制备变体猫类IgG1a Fc P(198)A(例如，SEQ ID NO:91或SEQ ID NO:92)和变体猫类IgG1b Fc P(198)A(例如，SEQ ID NO:93或SEQ ID NO:94)。

可以确定任何变体猫类IgG Fc与C1q的结合，并且将其与另一种IgG Fc(例如，相应的野生型猫类IgG Fc、另一种野生型或变体猫类IgG Fc、或另一种伴生动物的野生型或变体IgG Fc等)与C1q的结合进行比较。可以使用实施例8中描述的结合测定。

实施例11

用于增加和/或增强二硫化物形成的变体IgG Fc多肽

使用若干种直系同源铰链结构的三维蛋白质建模分析来确定用于修饰猫类IgG2铰链以增加二硫化物形成的大致位置。为了增加猫类IgG2铰链处的二硫化物形成，可以通过用半胱氨酸取代氨基酸来修饰铰链序列。例如，可以通过在对应于SEQ ID NO:90的位置14的氨基酸位置处用半胱氨酸取代甘氨酸来制备具有修饰铰链的变体猫类IgG2 Fc(SEQID NO:95)。可以制备具有修饰铰链的其他变体猫类IgG2 Fc多肽，所述修饰铰链包含在对应于SEQ ID NO:90的位置8、位置9、位置10、位置11、位置12、位置13、位置15或位置16的氨基酸位置处的半胱氨酸。

使用对若干种直系同源铰链结构的另外三维蛋白质建模分析来修饰猫类和马类IgG铰链以增强二硫化物形成。为了增强猫类IgG铰链处的二硫化物形成，可以通过以下方式来修饰铰链序列：在对应于野生型或变体猫类IgG1a(例如，SEQ ID NO:86或SEQ ID NO:87)、猫类IgG1b(例如，SEQ ID NO:88或SEQ ID NO:89)、或猫类IgG2(例如，SEQ ID NO:90)的位置16的位置处用脯氨酸取代赖氨酸(例如，K16P)。具有修饰铰链的变体猫类IgG多肽的氨基酸序列的例子包括SEQ ID NO:96、SEQ ID NO:97、SEQ ID NO:98、SEQ ID NO:99和SEQID NO:100。

为了增强马类IgG铰链处的二硫化物形成，可以通过以下方式来修饰铰链序列：在对应于具有铰链的野生型或变体马类IgG(例如，IgG2 Fc(SEQ ID NO:72))的位置3的位置处用丝氨酸取代半胱氨酸和/或在对应于具有铰链的马类IgG(例如，IgG2 Fc(SEQ ID NO:72)的位置20的位置处用脯氨酸取代谷氨酰胺(例如，C3S和/或Q20P)。具有修饰铰链的变体马类IgG多肽的氨基酸序列的例子包括SEQ ID NO:101、SEQ ID NO:102、SEQ ID NO:103、SEQ ID NO:104、SEQ ID NO:105和SEQ ID NO:106。

可以将上述氨基酸取代掺入至本文所述的野生型或变体Fc多肽的铰链中。

使用三维蛋白质建模来设计猫类和马类变体IgG Fc多肽，其包含来自不同IgG同种型的铰链区的序列以用于增强重组产生和改善铰链二硫化物形成。可以制备包含来自猫类IgG1a或IgG1b的铰链区的序列的变体猫类IgG2 Fc多肽(例如，SEQ ID NO:107)。此外，可以制备包含来自马类IgG1铰链区的序列的变体马类IgG2 Fc多肽(例如，SEQ ID NO:108和SEQ ID NO:109)。

可以确定变体IgG Fc多肽的重组产生的水平和/或铰链二硫化物形成的水平，并且通过在还原和非还原条件下的SDS-PAGE分析将其与另一种IgG Fc(例如，相同或不同同种型的相应野生型IgG Fc，或另一种伴生动物的野生型或变体IgG Fc)的所述水平进行比较。

实施例12

TrkA-Fc缓冲液配制品

分析了各种缓冲液配制品中犬类TrkA-Fc的热稳定性。考虑了含有20mM磷酸钠(pH6.2、6.6、7.2和7.6)、20mM柠檬酸钠(pH 4.4、5.2、5.8和6.4)、20mM组氨酸(pH 5.5、6.0和6.5)和20mM乙酸钠(pH 5.2)的缓冲液。在所有缓冲液中使用终浓度为40mM或140mM的氯化钠。通过差示扫描荧光技术从20℃至95℃一式两份测量每种缓冲液中浓度为6μg/μL的示例性犬类TrkA-Fc多肽(SEQ ID NO:126)的熔解温度(Tm 1和Tm 2)。表16列出了测试的各种缓冲液中犬类TrkA的平均Tm值。

表16.

*来自一个样品的结果

含有较低浓度的柠檬酸钠、组氨酸或乙酸钠缓冲液和在5与6之间的pH的配制品6A、7B、9A和12B对于TrkA ECD融合多肽可能是更希望的。

使用配制品6A、7B、9A、12B和PBS(pH 7.2)来研究在45℃下应激下储存3天的示例性犬类TrkA-Fc多肽(SEQ ID NO:126)样品的稳定性。通过HPLC凝胶过滤分析评价五个样品的聚集状态，并且没有鉴定出明显的聚集。然后将五个样品在55℃下再储存一天。在PBS(pH7.2)中储存的样品中观察到明显的聚集，但在配制品6A、7B、9A和12B中储存的样品中未观察到。

实施例13

在用TrkA-Fc多肽的情况下NGF的体内减少

NGF水平在患有各种类型的慢性关节炎的人患者的滑液中是升高的。参见Aloe L等人,“Nerve growth factor in the synovial fluid of patients with chronicarthritis,”Arthritis Rheum.1992,35(3):351-5。在大鼠MIA诱导的骨关节炎模型中测试犬类TrkA-Fc多肽对NGF水平的影响。

所述研究方案由机构动物伦理委员会(Institutional Animal EthicsCommittee)(IAEC)审查和批准(批准号：B-070)。将雄性斯普拉-道来(Sprague Dawley)大鼠用异氟醚麻醉，并通过右膝(骨关节炎)的髌下韧带给予3mg碘乙酸单钠(Sigma，目录号I2512，圣路易，密苏里州)的单次关节内注射。将MIA溶解在生理盐水中并使用30号、0.5英寸针头以50μl的体积施用。参见Combe R等人,“The monosodium iodoacetate model ofosteoarthritis:a model of chronic nociceptive pain in rats？”NeurosciLett.2004,370(2-3):236-40。向对照大鼠注射等体积的盐水并使其恢复。从程序中恢复后，将动物以三只为一组返回至笼中，使用12h光照/黑暗循环并随意进食和饮水。

在MIA注射后第8、15和22天，进行犬类TrkA-Fc多肽(1mg/kg(第3组)和10mg/kg(第4组))的每周一次施用。在第28天，测量滑膜NGF水平。治疗组汇总在下表17中。

表17.

在完成行为和膝关节直径测量后，收集来自每个治疗组的3-4只大鼠的膝关节样品。收集膝关节内软组织的修剪样品(同侧膝关节外侧囊的滑膜和前部)并将其切碎成约2mm大小的小块，在PBS中充分冲洗，并在液氮中冷冻直至使用。将组织样品压碎成粉末，并且在具有蛋白酶抑制剂(cOmplete^TM，不含EDTA的蛋白酶抑制剂混合物，目录号4693132001，Sigma-Aldrich)的200-μl裂解试剂(CelLytic^TMMT细胞裂解试剂(C3228)，Sigma-Aldrich)中匀浆。将样品在4℃下以14,000rpm离心10min，且然后收集上清液用于测定。使用ELISA试剂盒(Millipore，特曼库拉，加利福尼亚州)测量NGF的浓度。使用BCA蛋白质测定试剂盒(目录号BCA1-1KT，Sigma，美国)测量所有样品中的总蛋白质浓度。

图4示出了四个动物组中每一个的滑膜中NGF的浓度。与未经治疗的MIA诱导对照组(第2组)相比，接受犬类TrkA-Fc多肽的MIA诱导动物组(第3组和第4组)显示出滑膜中NGF浓度的剂量依赖性降低。由于仍在研究中的原因，在该实验中，经治疗的动物并未显示疼痛的相应减少，如已经基于已公布的涉及使用NGF抗体和TrkA-IgG融合分子治疗动物的疼痛的研究所预期的那样。参见Ro LS等人,“Effect of NGF and anti-NGF on neuropathicpain in rats following chronic constriction injury of the sciatic nerve.”Pain.1999,79(2-3):265-74；Gearing D等人,“A fully caninised anti-NGF monoclonalantibody for pain relief in dogs.”BMC Vet Res.2013,9:226doi:10.1186/1746-6148-9-226；Gearing D等人,“In vitro and in vivo characterization of a fullyfelinized therapeutic anti-nerve growth factor monoclonal antibody for thetreatment of pain in cats.”J Vet Intern Med.2016,30(4):1129-37；McMahon SB等人,“The biological effects of endogenous nerve growth factor on adult sensoryneurons revealed by a trkA-IgG fusion molecule.”Nat Med.1995,1(8):774-80。

实施例14

筛选具有增强的犬类FcRn/B2M结合的变体犬类IgG-B多肽

将具有聚His标签的犬类FcRn(SEQ ID NO:195)和犬类B2M(SEQ ID NO:196)异源二聚体复合物在HEK细胞中瞬时表达，并且使用Ni-NTA色谱纯化。

对犬类IgG-B Fc噬菌体文库进行了针对表达、生物物理特性和亲和力的快速筛选(FASEBA)。简而言之，将犬类IgG-B Fc多肽的开放阅读框亚克隆至质粒pFASEBA中。基于犬类IgG-B/犬类FcRn/犬类B2M复合物的三维蛋白质建模，犬类IgG-B的十二个氨基酸位置被鉴定为可能参与IgG-B与FcRn/B2M之间的结合。鉴定出的犬类IgG-B的十二个位置是SEQ IDNO:35或SEQ ID NO:36的Thr(21)、Leu(22)、Leu(23)、Ile(24)、Ala(25)、Thr(27)、Gly(80)、His(81)、Gln(82)、Leu(85)、Met(201)和Asn(207)。

制备了犬类IgG-B Fc的十二个单位点NNK突变文库，使得每个文库都应包括变体IgG-B Fc多肽，所述变体IgG-B Fc多肽在十二个位点中的每一个处都具有被取代的20种可能氨基酸中的每一种。在pH 6.0下针对犬类FcRn/B2M复合物淘选每个噬菌体文库。在三轮淘选之后，将总共53个Fc噬菌体克隆鉴定为可能具有增强的FcRn/B2M结合，并且通过测序鉴定了突变。

对表达具有SASA标签的53种变体犬类IgG-B Fc多肽中的每一种的单个大肠杆菌(E.coli)菌落进行培养，并诱导其表达Fc多肽。将含有变体犬类IgG-B Fc多肽的细胞培养基暴露于板或Biacore芯片上的固定化BSA。将结合有变体犬类IgG-B Fc多肽的板或芯片暴露于可溶性犬类FcRn/B2M复合物，以筛选pH 6下的缓慢解离速率(koff)。鉴定了与野生型IgG-B Fc多肽相比，展现出的与犬类FcRn/B2M复合物的koff较慢的每种变体IgG-B Fc多肽。鉴定出四种先导变体犬类IgG-B多肽：L(23)Y(SEQ ID NO:198；“Y00”)；L(23)F(SEQ IDNO:197；“F00”)；L(23)M；以及L(23)S。

进一步研究了每种先导变体犬类IgG-B多肽的koff。将生物素化的犬类FcRn/B2M复合物固定在Biacore芯片上，并且使用Biacore T200在pH 6.0下暴露于作为分析物的每种变体犬类IgG-B多肽。野生型犬类IgG-B Fc多肽的koff(1/s)是1.22x10^-1；变体犬类IgG-BFc多肽L(23)Y(“Y00”)的koff(1/s)是1.38x10^-2；变体IgG-B Fc多肽L(23)F(“F00”)的koff(1/s)是6.31x10^-2和8.47x10^-2；变体犬类IgG-B多肽L(23)M的koff(1/s)是1.26x10^-1；并且变体犬类IgG-B多肽L(23)S的koff(1/s)是2.41x10^-1。

使用Biacore T200进行了结合分析。简而言之，将具有SASA标签的先导变体犬类IgG-B Fc多肽各自固定至S系列传感器芯片CM5上。在25℃下监测每种变体IgG-B Fc多肽与各种浓度的犬类FcRn/B2M复合物(12.5、25、50、100和200nM)的缔合，直到达到稳态。使用10mM HEPES、500mM NaCl、3mM EDTA、0.005％Tween-20的运行缓冲液(pH 6.0)。使用仅缓冲液空白曲线作为对照。结果呈现于图5至图9中。野生型犬类IgG-B Fc多肽的稳态Kd是1.25x10^-6(图5)；变体犬类IgG-B Fc多肽L(23)Y(“Y00”)的稳态Kd是1.13x10^-7(图6)；变体犬类IgG-B Fc多肽L(23)F(“F00”)的稳态Kd是3.67x10^-7(图7)；并且变体犬类IgG-B Fc多肽L(23)M的稳态Kd是4.06x10^-7(图8)；并且变体犬类IgG-B Fc多肽YTE的稳态Kd是8.62x10^-8(图9)。

实施例15

犬类IgG中的Phe突变增强犬类FcRn相互作用

在嵌合抗体的背景下评价变体犬类Fc多肽对FcRn的亲和力。表达了与犬类κ轻链融合的抗体可变轻链和与包含SEQ ID NO:199(F00；蛋白A+；C1q-；CD16-)或SEQ ID NO:200(蛋白A+；C1q+；CD16+)的变体犬类IgG-A Fc多肽和与包含SEQ ID NO:201(F00；蛋白A+；C1q-；CD16-)或SEQ ID NO:202(蛋白A+；C1q+；CD16+)的变体犬类IgG-D Fc多肽融合的可变重链。

使用生物传感器OctetRed如下进行了结合分析。简而言之，在链霉抗生物素蛋白传感器尖端上捕获生物素化的TNFα。20μg/mL的抗体的缔合是与TNFα结合。然后将复合物用于在pH 6.0下与犬类FcRn(50μg/mL)结合。在pH 7.2下进行解离。

与不具有Phe突变的嵌合变体犬类IgG-A(图10，C)和不具有Phe突变的IgG-D(图10，D)相比，Phe突变增强了在低pH(pH6.0、20mM柠檬酸钠、140mM NaCl)下的犬类FcRn结合，如通过嵌合变体犬类IgG-A“F00”抗体(图10，A)和IgG-D“F00”抗体(图10，B)的结合概况所示的。具有Phe突变的嵌合变体犬类IgG-A和IgG-D抗体(图10，A和B)在低pH(pH 6.0)下展现出增强的与犬类FcRn的缔合，并且在中性pH(PBS pH 7.2)下展现出快速解离。在嵌合变体犬类IgG-B“F00”抗体的情况下也观察到类似的增强的结合概况。

实施例16

犬类IgG中Phe突变的药代动力学

使用斯普拉-道来大鼠进行了药代动力学分析。向大鼠皮下施用2mg/kg的嵌合变体犬类IgG-A“F00”抗体和不具有Phe突变的嵌合变体犬类IgG-A(每组两只大鼠)。在注射前以及注射后0.5、1、6、24、48、72、168、216和336小时从大鼠收集血清样品。通过ELISA如下测定了血清样品中的犬类嵌合抗体浓度。

将捕获抗体(1μg/mL，在PBS中)包被在96孔Maxisorp板上，每孔具有100μl。将板在4℃下孵育过夜并用PBST(含有0.05％Tween-20的PBS)洗涤五次。将每个孔用在PBST中的200μl 5％BSA封闭，并将板在室温下孵育1小时。用PBST洗涤板五次。将对照抗体的稀释液(1,000ng/mL至0.1ng/mL)一式两份添加至板中，并与不含对照抗体的空白孔一起用于产生标准曲线。在5％BSA-PBST中按10倍、20倍和40倍稀释度制备血清样品并将其添加至板中。将板在室温下孵育1小时并用PBST洗涤5次。将100μl的在5％BSA-PBST中的HRP缀合的抗体(Bio-Rad，目录号HCA204P)以0.25μg/mL添加到每个孔中。将板在室温下孵育1小时并用PBST洗涤5次。将100μl QuantaBlu(Thermo Scientific，目录号15169)添加至每个孔中。孵育10-15分钟后，在325nm/420nm(发射/激发)下测量荧光。根据标准曲线计算血清样品中抗TNFα的滴度。

IgG-A的AUC_0-336h是150970，而IgG-A“F00”是848924ng/mL*h(图11)。终末半衰期估计分别为33小时和152小时。因此，单个Phe突变显著改善了抗体在大鼠中的药代动力学特征。

实施例17

犬类、猫类和马类IgG Fc中的Phe突变

使用三维蛋白质结构分析对犬类IgG-A、IgG-B、IgG-C和IgG-D Fc中的Phe突变与FcRn之间的相互作用进行了建模。Phe的芳族侧链显现与犬类FcRn在“WPE”基序的Pro疏水环(π-CH)处具有疏水相互作用。此外，Phe疏水侧链可以与同一“WPE”基序的Pro旁边的Glu侧链直接接触。如果Glu侧链去质子化为带负电荷(如在中性pH下)，则该相互作用可能会产生能量损耗。因此，可能需要一定水平的Glu残基质子化以使芳族化合物与Glu-H的相互作用最小化。这可以解释为什么具有Phe突变的变体IgG与FcRn之间的相互作用在中性pH下降低。基于蛋白质结构分析，相互作用在犬类IgG-A、IgG-B、IgG-C和IgG-D Fc之间显现是保守的。

此外，对在复合时猫类IgG1a和IgG2 Fc中的Phe突变与猫类FcRn之间的相互作用进行建模。在犬类IgG Fc的情况下观察到的相同的相互作用显现对于猫类IgG Fc是保守的。

还对复合时马类IgG1、IgG2、IgG3、IgG4、IgG5、IgG6和IgG7 Fc中的Phe突变与马类FcRn之间的相互作用进行建模。马类IgG Fc显现维持了相同的相互作用。

实施例18

其他示例性变体犬类IgG Fc增强犬类FcRn相互作用

在嵌合抗体的背景下评价另外的变体犬类Fc多肽对FcRn的亲和力。表达了与犬类κ轻链融合的抗体可变轻链和与野生型IgG-B Fc多肽(包含SEQ ID NO:35)、变体犬类IgG-BFc多肽0Y0(包含SEQ ID NO:203)、变体犬类IgG-B Fc多肽0YH(包含SEQ ID NO:204)、变体犬类IgG-B Fc多肽0YY(包含SEQ ID NO:205)以及变体犬类IgG-B Fc多肽00Y(包含SEQ IDNO:206)融合的可变重链序列。

使用生物传感器OctetRed如下进行了结合分析。简而言之，在链霉亲和素传感器尖端上捕获生物素化的靶标。20μg/mL的抗体的缔合是与生物素化的靶标结合。然后将复合物用于在pH 6.0下与犬类FcRn(50μg/mL)结合。在pH 7.2下进行解离。

与嵌合野生型犬类IgG-B抗体相比，每种嵌合变体犬类IgG-B抗体在pH 6.0下均展现出增强的与犬类FcRn的结合，并且各自在中性pH下具有相当可观的解离速率(图12)。

实施例19

变体犬类IgG Fc延长抗体在犬类体内的半衰期

在嵌合抗体的背景下评价针对FcRn的变体犬类Fc多肽的体内半衰期。表达了与犬类κ轻链融合的抗体可变轻链和与野生型IgG-B Fc多肽(包含SEQ ID NO:35)、变体犬类IgG-B Fc多肽YTE(包含SEQ ID NO:207)、变体犬类IgG-B Fc多肽0Y0(包含SEQ ID NO:203)、变体犬类IgG-B Fc多肽F00(包含SEQ ID NO:197)、变体犬类IgG-B Fc多肽0YH(包含SEQ ID NO:204)和变体犬类IgG-B Fc多肽Y00(包含SEQ ID NO:198)融合的可变重链，并将其在PBS(pH 7.2)中纯化至40mg/mL。

在Absorption Systems加利福尼亚州公司进行犬类药代动力学。从纽约州NorthRose的Marshall Bioresources获得雄性比格犬(约8-14kg)。共使用12只狗用于研究，每组n＝2只狗。将六种抗体以4mg/Kg皮下施用于狗。在注射前和注射后6、24、48、72、96、120、144、168、216、264、336、504和672小时收集血清样品。如所述通过ELISA确定犬类嵌合抗体浓度。将在144小时和336小时的时间之间的Cp转换为Ln[Cp]，然后拟合至Ln[Cp]_t＝-k*t+Ln[Cp]_144h形式的线性方程。然后从斜率k计算终末半衰期，如下表18中列出的。犬类IgG-BFc中的0Y0、F00、0YH和Y00突变大大改善了抗体在狗体内的半衰期。

表18：变体犬类IgG Fc对狗体内抗体半衰期的影响

*NR：结果不可靠。

序列表

<110> 金德雷德生物科学股份有限公司

<120> 医用NGF拮抗剂

<130> 01157-0018-00PCT

<150> US 62/821,438

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Thr Glu Phe Leu Glu Pro Ala Ala Asn Glu Thr Val Arg His Gly Cys

50 55 60

Leu Arg Leu Asn Gln Pro Thr His Val Asn Asn Gly Asn Tyr Thr Leu

65 70 75 80

Leu Ala Ala Asn Pro Ser Gly Arg Ala Ala Ala Ser Val Leu Ala Ala

85 90 95

Phe Met Asp Asn Pro Phe Glu Phe Asn Pro Glu Asp Pro Ile Pro Val

100 105 110

Ser Phe Ser Pro Val Asp Ser Asn Ser Thr Ser Gly Asp

115 120 125

<210> 9

<211> 101

<212> PRT

<213> 人工序列

<220>

<223> 合成的: 示例性猫类TrkA ECD (v3)

<400> 9

Val Ser Phe Pro Ala Ser Val Gln Leu His Ala Ala Val Glu Leu His

1 5 10 15

His Trp Cys Ile Pro Phe Ser Val Asp Gly Gln Pro Ala Pro Ser Leu

20 25 30

Arg Trp Leu Phe Asn Gly Ser Val Leu Asn Glu Thr Ser Phe Ile Phe

35 40 45

Thr Glu Phe Leu Glu Pro Ala Ala Asn Glu Thr Val Arg His Gly Cys

50 55 60

Leu Arg Leu Asn Gln Pro Thr His Val Asn Asn Gly Asn Tyr Thr Leu

65 70 75 80

Leu Ala Ala Asn Pro Ser Gly Arg Ala Ala Ala Ser Val Leu Ala Ala

85 90 95

Phe Met Asp Asn Pro

100

<210> 10

<211> 99

<212> PRT

<213> 人工序列

<220>

<223> 合成的: 示例性猫类TrkA ECD (v4)

<400> 10

Phe Pro Ala Ser Val Gln Leu His Ala Ala Val Glu Leu His His Trp

1 5 10 15

Cys Ile Pro Phe Ser Val Asp Gly Gln Pro Ala Pro Ser Leu Arg Trp

20 25 30

Leu Phe Asn Gly Ser Val Leu Asn Glu Thr Ser Phe Ile Phe Thr Glu

35 40 45

Phe Leu Glu Pro Ala Ala Asn Glu Thr Val Arg His Gly Cys Leu Arg

50 55 60

Leu Asn Gln Pro Thr His Val Asn Asn Gly Asn Tyr Thr Leu Leu Ala

65 70 75 80

Ala Asn Pro Ser Gly Arg Ala Ala Ala Ser Val Leu Ala Ala Phe Met

85 90 95

Asp Asn Pro

<210> 11

<211> 796

<212> PRT

<213> 家马(Equus caballus)

<220>

<221> 尚未归类的特征

<223> 马类TrkA

<400> 11

Met Leu Arg Gly Gly Arg Arg Gly Gln Leu Gly Trp His Gly Arg Ala

1 5 10 15

Thr Gly Pro Gly Ser Leu Leu Ala Trp Leu Met Leu Ala Ser Ala Gly

20 25 30

Ala Ala Pro Cys Pro Asp Ala Cys Cys Pro His Gly Pro Ser Gly Leu

35 40 45

Arg Cys Thr Gln Pro Gly Ala Leu Asp Ser Leu Arg His Leu Pro Gly

50 55 60

Ala Glu Asn Leu Thr Glu Leu Tyr Ile Glu Asn Gln Gln Asn Leu Gln

65 70 75 80

Arg Leu Glu Arg Asn Asp Leu Arg Gly Leu Gly Glu Leu Arg Asn Leu

85 90 95

Thr Ile Val Lys Ser Gly Leu His Phe Val Ala Pro Asp Ala Phe His

100 105 110

Phe Thr Pro Arg Leu Ser Arg Leu Asn Leu Ser Phe Asn Ala Leu Lys

115 120 125

Ser Leu Ser Trp Lys Thr Val Gln Gly Leu Ser Leu Gln Gln Leu Val

130 135 140

Leu Leu Gly Asn Pro Leu Asp Cys Ser Cys Ala Leu Arg Trp Leu Gln

145 150 155 160

Arg Trp Glu Glu Glu Gly Leu Gly Gly Val Arg Glu Gln Lys Leu Gln

165 170 175

Cys His Gln Gln Gly Pro Leu Ala Leu Met Ser Asn Thr Asn Cys Gly

180 185 190

Val Pro Leu Leu Lys Val Gln Val Pro Asn Ala Ser Val Asp Val Gly

195 200 205

Asp Asn Val Trp Leu Gln Cys Gln Val Glu Gly Gln Gly Leu Glu Gln

210 215 220

Ala Gly Trp Ile Leu Thr Glu Leu Glu Glu Ser Ala Thr Val Met Gln

225 230 235 240

Ser Gly Gly Leu Pro Ser Leu Gly Leu Thr Leu Ala Asn Val Thr Ser

245 250 255

Asp Leu Asn Arg Lys Asn Val Thr Cys Trp Ala Glu Asn Asp Val Gly

260 265 270

Arg Ala Glu Val Ser Val Gln Val Asn Val Ser Phe Pro Ala Ser Val

275 280 285

His Leu Gln Thr Ala Val Glu Gln His His Trp Cys Ile Pro Phe Ser

290 295 300

Val Asp Gly Gln Pro Ala Pro Thr Leu Arg Trp Leu Phe Asn Gly Ser

305 310 315 320

Val Leu Asn Glu Thr Ser Phe Ile Phe Thr Glu Phe Leu Glu Ser Ala

325 330 335

Ala Asn Glu Thr Met Arg His Gly Cys Leu Arg Leu Asn Gln Pro Thr

340 345 350

His Val Asn Asn Gly Asn Tyr Thr Leu Leu Ala Thr Asn Pro Tyr Gly

355 360 365

Gln Asp Ser Ala Ser Val Met Val Ala Phe Met Asp Asn Pro Phe Glu

370 375 380

Phe Asn Pro Glu Asp Pro Ile Pro Val Ser Phe Ser Pro Val Asp Thr

385 390 395 400

Asn Ser Thr Ser Arg Asp Pro Val Glu Lys Lys Asp Glu Thr His Phe

405 410 415

Gly Val Ser Val Ala Val Gly Leu Ala Val Phe Ala Cys Leu Phe Leu

420 425 430

Ser Thr Leu Phe Leu Val Leu Asn Lys Cys Gly Arg Arg Asn Lys Phe

435 440 445

Gly Ile Asn Arg Pro Ala Val Leu Ala Pro Glu Asp Gly Leu Ala Met

450 455 460

Ser Leu His Phe Met Thr Leu Gly Gly Ser Ser Leu Ser Pro Thr Glu

465 470 475 480

Gly Lys Gly Ser Gly Leu Gln Gly His Ile Ile Glu Asn Pro Gln Tyr

485 490 495

Phe Ser Asp Ala Cys Val His His Ile Lys Arg Arg Asp Ile Val Leu

500 505 510

Lys Trp Glu Leu Gly Glu Gly Ala Phe Gly Lys Val Phe Leu Ala Glu

515 520 525

Cys His Asn Leu Leu Pro Glu Gln Asp Lys Met Leu Val Ala Val Lys

530 535 540

Ala Leu Lys Glu Val Ser Glu Ser Ala Arg Gln Asp Phe Gln Arg Glu

545 550 555 560

Ala Glu Leu Leu Thr Met Leu Gln His Gln His Ile Val Arg Phe Phe

565 570 575

Gly Val Cys Thr Glu Gly Arg Pro Leu Leu Met Val Phe Glu Tyr Met

580 585 590

Arg His Gly Asp Leu Asn Arg Phe Leu Arg Ser His Gly Pro Asp Ala

595 600 605

Lys Leu Leu Ala Gly Gly Glu Asp Val Ala Pro Gly Pro Leu Gly Leu

610 615 620

Gly Gln Leu Leu Ala Val Ala Ser Gln Val Ala Ala Gly Met Val Tyr

625 630 635 640

Leu Ala Gly Leu His Phe Val His Arg Asp Leu Ala Thr Arg Asn Cys

645 650 655

Leu Val Gly Gln Gly Leu Val Val Lys Ile Gly Asp Phe Gly Met Ser

660 665 670

Arg Asp Ile Tyr Ser Thr Asp Tyr Tyr Arg Val Gly Gly Arg Thr Met

675 680 685

Leu Pro Ile Arg Trp Met Pro Pro Glu Ser Ile Leu Tyr Arg Lys Phe

690 695 700

Thr Thr Glu Ser Asp Val Trp Ser Phe Gly Val Val Leu Trp Glu Ile

705 710 715 720

Phe Thr Tyr Gly Lys Gln Pro Trp Tyr Gln Leu Ser Asn Thr Glu Ala

725 730 735

Ile Glu Cys Ile Thr Gln Gly Arg Glu Leu Glu Arg Pro Arg Ala Cys

740 745 750

Pro Pro Glu Val Tyr Ala Ile Met Arg Gly Cys Trp Gln Arg Glu Pro

755 760 765

Gln Gln Arg His Ser Ile Lys Asp Val His Ala Arg Leu Gln Ala Leu

770 775 780

Val Gln Ala Pro Pro Val Tyr Leu Asp Val Leu Gly

785 790 795

<210> 12

<211> 417

<212> PRT

<213> 人工序列

<220>

<223> 合成的: 示例性马类TrkA ECD (v1)

<400> 12

Met Leu Arg Gly Gly Arg Arg Gly Gln Leu Gly Trp His Gly Arg Ala

1 5 10 15

Thr Gly Pro Gly Ser Leu Leu Ala Trp Leu Met Leu Ala Ser Ala Gly

20 25 30

Ala Ala Pro Cys Pro Asp Ala Cys Cys Pro His Gly Pro Ser Gly Leu

35 40 45

Arg Cys Thr Gln Pro Gly Ala Leu Asp Ser Leu Arg His Leu Pro Gly

50 55 60

Ala Glu Asn Leu Thr Glu Leu Tyr Ile Glu Asn Gln Gln Asn Leu Gln

65 70 75 80

Arg Leu Glu Arg Asn Asp Leu Arg Gly Leu Gly Glu Leu Arg Asn Leu

85 90 95

Thr Ile Val Lys Ser Gly Leu His Phe Val Ala Pro Asp Ala Phe His

100 105 110

Phe Thr Pro Arg Leu Ser Arg Leu Asn Leu Ser Phe Asn Ala Leu Lys

115 120 125

Ser Leu Ser Trp Lys Thr Val Gln Gly Leu Ser Leu Gln Gln Leu Val

130 135 140

Leu Leu Gly Asn Pro Leu Asp Cys Ser Cys Ala Leu Arg Trp Leu Gln

145 150 155 160

Arg Trp Glu Glu Glu Gly Leu Gly Gly Val Arg Glu Gln Lys Leu Gln

165 170 175

Cys His Gln Gln Gly Pro Leu Ala Leu Met Ser Asn Thr Asn Cys Gly

180 185 190

Val Pro Leu Leu Lys Val Gln Val Pro Asn Ala Ser Val Asp Val Gly

195 200 205

Asp Asn Val Trp Leu Gln Cys Gln Val Glu Gly Gln Gly Leu Glu Gln

210 215 220

Ala Gly Trp Ile Leu Thr Glu Leu Glu Glu Ser Ala Thr Val Met Gln

225 230 235 240

Ser Gly Gly Leu Pro Ser Leu Gly Leu Thr Leu Ala Asn Val Thr Ser

245 250 255

Asp Leu Asn Arg Lys Asn Val Thr Cys Trp Ala Glu Asn Asp Val Gly

260 265 270

Arg Ala Glu Val Ser Val Gln Val Asn Val Ser Phe Pro Ala Ser Val

275 280 285

His Leu Gln Thr Ala Val Glu Gln His His Trp Cys Ile Pro Phe Ser

290 295 300

Val Asp Gly Gln Pro Ala Pro Thr Leu Arg Trp Leu Phe Asn Gly Ser

305 310 315 320

Val Leu Asn Glu Thr Ser Phe Ile Phe Thr Glu Phe Leu Glu Ser Ala

325 330 335

Ala Asn Glu Thr Met Arg His Gly Cys Leu Arg Leu Asn Gln Pro Thr

340 345 350

His Val Asn Asn Gly Asn Tyr Thr Leu Leu Ala Thr Asn Pro Tyr Gly

355 360 365

Gln Asp Ser Ala Ser Val Met Val Ala Phe Met Asp Asn Pro Phe Glu

370 375 380

Phe Asn Pro Glu Asp Pro Ile Pro Val Ser Phe Ser Pro Val Asp Thr

385 390 395 400

Asn Ser Thr Ser Arg Asp Pro Val Glu Lys Lys Asp Glu Thr His Phe

405 410 415

Gly

<210> 13

<211> 125

<212> PRT

<213> 人工序列

<220>

<223> 合成的: 示例性马类TrkA ECD (v2)

<400> 13

Val Ser Phe Pro Ala Ser Val His Leu Gln Thr Ala Val Glu Gln His

1 5 10 15

His Trp Cys Ile Pro Phe Ser Val Asp Gly Gln Pro Ala Pro Thr Leu

20 25 30

Arg Trp Leu Phe Asn Gly Ser Val Leu Asn Glu Thr Ser Phe Ile Phe

35 40 45

Thr Glu Phe Leu Glu Ser Ala Ala Asn Glu Thr Met Arg His Gly Cys

50 55 60

Leu Arg Leu Asn Gln Pro Thr His Val Asn Asn Gly Asn Tyr Thr Leu

65 70 75 80

Leu Ala Thr Asn Pro Tyr Gly Gln Asp Ser Ala Ser Val Met Val Ala

85 90 95

Phe Met Asp Asn Pro Phe Glu Phe Asn Pro Glu Asp Pro Ile Pro Val

100 105 110

Ser Phe Ser Pro Val Asp Thr Asn Ser Thr Ser Arg Asp

115 120 125

<210> 14

<211> 101

<212> PRT

<213> 人工序列

<220>

<223> 合成的: 示例性马类TrkA ECD (v3)

<400> 14

Val Ser Phe Pro Ala Ser Val His Leu Gln Thr Ala Val Glu Gln His

1 5 10 15

His Trp Cys Ile Pro Phe Ser Val Asp Gly Gln Pro Ala Pro Thr Leu

20 25 30

Arg Trp Leu Phe Asn Gly Ser Val Leu Asn Glu Thr Ser Phe Ile Phe

35 40 45

Thr Glu Phe Leu Glu Ser Ala Ala Asn Glu Thr Met Arg His Gly Cys

50 55 60

Leu Arg Leu Asn Gln Pro Thr His Val Asn Asn Gly Asn Tyr Thr Leu

65 70 75 80

Leu Ala Thr Asn Pro Tyr Gly Gln Asp Ser Ala Ser Val Met Val Ala

85 90 95

Phe Met Asp Asn Pro

100

<210> 15

<211> 99

<212> PRT

<213> 人工序列

<220>

<223> 合成的: 示例性马类TrkA ECD (v4)

<400> 15

Phe Pro Ala Ser Val His Leu Gln Thr Ala Val Glu Gln His His Trp

1 5 10 15

Cys Ile Pro Phe Ser Val Asp Gly Gln Pro Ala Pro Thr Leu Arg Trp

20 25 30

Leu Phe Asn Gly Ser Val Leu Asn Glu Thr Ser Phe Ile Phe Thr Glu

35 40 45

Phe Leu Glu Ser Ala Ala Asn Glu Thr Met Arg His Gly Cys Leu Arg

50 55 60

Leu Asn Gln Pro Thr His Val Asn Asn Gly Asn Tyr Thr Leu Leu Ala

65 70 75 80

Thr Asn Pro Tyr Gly Gln Asp Ser Ala Ser Val Met Val Ala Phe Met

85 90 95

Asp Asn Pro

<210> 16

<211> 384

<212> PRT

<213> 人工序列

<220>

<223> 合成的: 具有信号序列的示例性犬类TrkA ECD v2 - 野生型犬类

IgG-B Fc 蛋白A+ C1q + CD16 +

<400> 16

Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp

1 5 10 15

Leu Arg Gly Ala Arg Cys Val Ser Phe Pro Ala Ser Val Gln Leu His

20 25 30

Glu Ala Val Glu Leu His His Trp Cys Ile Pro Phe Ser Val Asp Gly

35 40 45

Gln Pro Ala Pro Ser Leu Arg Trp Leu Phe Asn Gly Ser Val Leu Asn

50 55 60

Glu Thr Ser Phe Ile Phe Thr Glu Phe Leu Glu Pro Val Ala Asn Glu

65 70 75 80

Thr Val Arg His Gly Cys Leu Arg Leu Asn Gln Pro Thr His Val Asn

85 90 95

Asn Gly Asn Tyr Thr Leu Leu Ala Ala Asn Pro Ser Gly Arg Ala Ala

100 105 110

Ala Phe Val Met Ala Ala Phe Met Asp Asn Pro Phe Glu Phe Asn Pro

115 120 125

Glu Asp Pro Ile Pro Val Ser Phe Ser Pro Val Asp Thr Asn Ser Thr

130 135 140

Ser Gly Asp Ser Gly Gly Gly Ser Gly Gly Gly Ser Arg Pro Pro Asp

145 150 155 160

Cys Pro Lys Cys Pro Ala Pro Glu Met Leu Gly Gly Pro Ser Val Phe

165 170 175

Ile Phe Pro Pro Lys Pro Lys Asp Thr Leu Leu Ile Ala Arg Thr Pro

180 185 190

Glu Val Thr Cys Val Val Val Asp Leu Asp Pro Glu Asp Pro Glu Val

195 200 205

Gln Ile Ser Trp Phe Val Asp Gly Lys Gln Met Gln Thr Ala Lys Thr

210 215 220

Gln Pro Arg Glu Glu Gln Phe Asn Gly Thr Tyr Arg Val Val Ser Val

225 230 235 240

Leu Pro Ile Gly His Gln Asp Trp Leu Lys Gly Lys Gln Phe Thr Cys

245 250 255

Lys Val Asn Asn Lys Ala Leu Pro Ser Pro Ile Glu Arg Thr Ile Ser

260 265 270

Lys Ala Arg Gly Gln Ala His Gln Pro Ser Val Tyr Val Leu Pro Pro

275 280 285

Ser Arg Glu Glu Leu Ser Lys Asn Thr Val Ser Leu Thr Cys Leu Ile

290 295 300

Lys Asp Phe Phe Pro Pro Asp Ile Asp Val Glu Trp Gln Ser Asn Gly

305 310 315 320

Gln Gln Glu Pro Glu Ser Lys Tyr Arg Thr Thr Pro Pro Gln Leu Asp

325 330 335

Glu Asp Gly Ser Tyr Phe Leu Tyr Ser Lys Leu Ser Val Asp Lys Ser

340 345 350

Arg Trp Gln Arg Gly Asp Thr Phe Ile Cys Ala Val Met His Glu Ala

355 360 365

Leu His Asn His Tyr Thr Gln Glu Ser Leu Ser His Ser Pro Gly Lys

370 375 380

<210> 17

<211> 360

<212> PRT

<213> 人工序列

<220>

<223> 合成的: 具有信号序列的示例性犬类TrkA ECD v3 - 野生型犬类

IgG-B Fc 蛋白A+ C1q + CD16 +

<400> 17

Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp

1 5 10 15

Leu Arg Gly Ala Arg Cys Val Ser Phe Pro Ala Ser Val Gln Leu His

20 25 30

Glu Ala Val Glu Leu His His Trp Cys Ile Pro Phe Ser Val Asp Gly

35 40 45

Gln Pro Ala Pro Ser Leu Arg Trp Leu Phe Asn Gly Ser Val Leu Asn

50 55 60

Glu Thr Ser Phe Ile Phe Thr Glu Phe Leu Glu Pro Val Ala Asn Glu

65 70 75 80

Thr Val Arg His Gly Cys Leu Arg Leu Asn Gln Pro Thr His Val Asn

85 90 95

Asn Gly Asn Tyr Thr Leu Leu Ala Ala Asn Pro Ser Gly Arg Ala Ala

100 105 110

Ala Phe Val Met Ala Ala Phe Met Asp Asn Pro Ser Gly Gly Gly Ser

115 120 125

Gly Gly Gly Ser Arg Pro Pro Asp Cys Pro Lys Cys Pro Ala Pro Glu

130 135 140

Met Leu Gly Gly Pro Ser Val Phe Ile Phe Pro Pro Lys Pro Lys Asp

145 150 155 160

Thr Leu Leu Ile Ala Arg Thr Pro Glu Val Thr Cys Val Val Val Asp

165 170 175

Leu Asp Pro Glu Asp Pro Glu Val Gln Ile Ser Trp Phe Val Asp Gly

180 185 190

Lys Gln Met Gln Thr Ala Lys Thr Gln Pro Arg Glu Glu Gln Phe Asn

195 200 205

Gly Thr Tyr Arg Val Val Ser Val Leu Pro Ile Gly His Gln Asp Trp

210 215 220

Leu Lys Gly Lys Gln Phe Thr Cys Lys Val Asn Asn Lys Ala Leu Pro

225 230 235 240

Ser Pro Ile Glu Arg Thr Ile Ser Lys Ala Arg Gly Gln Ala His Gln

245 250 255

Pro Ser Val Tyr Val Leu Pro Pro Ser Arg Glu Glu Leu Ser Lys Asn

260 265 270

Thr Val Ser Leu Thr Cys Leu Ile Lys Asp Phe Phe Pro Pro Asp Ile

275 280 285

Asp Val Glu Trp Gln Ser Asn Gly Gln Gln Glu Pro Glu Ser Lys Tyr

290 295 300

Arg Thr Thr Pro Pro Gln Leu Asp Glu Asp Gly Ser Tyr Phe Leu Tyr

305 310 315 320

Ser Lys Leu Ser Val Asp Lys Ser Arg Trp Gln Arg Gly Asp Thr Phe

325 330 335

Ile Cys Ala Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Glu

340 345 350

Ser Leu Ser His Ser Pro Gly Lys

355 360

<210> 18

<211> 358

<212> PRT

<213> 人工序列

<220>

<223> 合成的: 具有信号序列的示例性犬类TrkA ECD v4 - 野生型犬类

IgG-B Fc 蛋白A+ C1q + CD16 +

<400> 18

Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp

1 5 10 15

Leu Arg Gly Ala Arg Cys Phe Pro Ala Ser Val Gln Leu His Glu Ala

20 25 30

Val Glu Leu His His Trp Cys Ile Pro Phe Ser Val Asp Gly Gln Pro

35 40 45

Ala Pro Ser Leu Arg Trp Leu Phe Asn Gly Ser Val Leu Asn Glu Thr

50 55 60

Ser Phe Ile Phe Thr Glu Phe Leu Glu Pro Val Ala Asn Glu Thr Val

65 70 75 80

Arg His Gly Cys Leu Arg Leu Asn Gln Pro Thr His Val Asn Asn Gly

85 90 95

Asn Tyr Thr Leu Leu Ala Ala Asn Pro Ser Gly Arg Ala Ala Ala Phe

100 105 110

Val Met Ala Ala Phe Met Asp Asn Pro Ser Gly Gly Gly Ser Gly Gly

115 120 125

Gly Ser Arg Pro Pro Asp Cys Pro Lys Cys Pro Ala Pro Glu Met Leu

130 135 140

Gly Gly Pro Ser Val Phe Ile Phe Pro Pro Lys Pro Lys Asp Thr Leu

145 150 155 160

Leu Ile Ala Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Leu Asp

165 170 175

Pro Glu Asp Pro Glu Val Gln Ile Ser Trp Phe Val Asp Gly Lys Gln

180 185 190

Met Gln Thr Ala Lys Thr Gln Pro Arg Glu Glu Gln Phe Asn Gly Thr

195 200 205

Tyr Arg Val Val Ser Val Leu Pro Ile Gly His Gln Asp Trp Leu Lys

210 215 220

Gly Lys Gln Phe Thr Cys Lys Val Asn Asn Lys Ala Leu Pro Ser Pro

225 230 235 240

Ile Glu Arg Thr Ile Ser Lys Ala Arg Gly Gln Ala His Gln Pro Ser

245 250 255

Val Tyr Val Leu Pro Pro Ser Arg Glu Glu Leu Ser Lys Asn Thr Val

260 265 270

Ser Leu Thr Cys Leu Ile Lys Asp Phe Phe Pro Pro Asp Ile Asp Val

275 280 285

Glu Trp Gln Ser Asn Gly Gln Gln Glu Pro Glu Ser Lys Tyr Arg Thr

290 295 300

Thr Pro Pro Gln Leu Asp Glu Asp Gly Ser Tyr Phe Leu Tyr Ser Lys

305 310 315 320

Leu Ser Val Asp Lys Ser Arg Trp Gln Arg Gly Asp Thr Phe Ile Cys

325 330 335

Ala Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Glu Ser Leu

340 345 350

Ser His Ser Pro Gly Lys

355

<210> 19

<211> 393

<212> PRT

<213> 人工序列

<220>

<223> 合成的: 具有信号序列的示例性猫类TrkA ECD v2 - 野生型猫类

IgG2 Fc 蛋白A + C1q - CD16 -

<400> 19

Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp

1 5 10 15

Leu Arg Gly Ala Arg Cys Val Ser Phe Pro Ala Ser Val Gln Leu His

20 25 30

Ala Ala Val Glu Leu His His Trp Cys Ile Pro Phe Ser Val Asp Gly

35 40 45

Gln Pro Ala Pro Ser Leu Arg Trp Leu Phe Asn Gly Ser Val Leu Asn

50 55 60

Glu Thr Ser Phe Ile Phe Thr Glu Phe Leu Glu Pro Ala Ala Asn Glu

65 70 75 80

Thr Val Arg His Gly Cys Leu Arg Leu Asn Gln Pro Thr His Val Asn

85 90 95

Asn Gly Asn Tyr Thr Leu Leu Ala Ala Asn Pro Ser Gly Arg Ala Ala

100 105 110

Ala Ser Val Leu Ala Ala Phe Met Asp Asn Pro Phe Glu Phe Asn Pro

115 120 125

Glu Asp Pro Ile Pro Val Ser Phe Ser Pro Val Asp Ser Asn Ser Thr

130 135 140

Ser Gly Asp Ser Gly Gly Gly Ser Gly Gly Gly Ser Pro Lys Thr Ala

145 150 155 160

Ser Thr Ile Glu Ser Lys Thr Gly Glu Gly Pro Lys Cys Pro Val Pro

165 170 175

Glu Ile Pro Gly Ala Pro Ser Val Phe Ile Phe Pro Pro Lys Pro Lys

180 185 190

Asp Thr Leu Ser Ile Ser Arg Thr Pro Glu Val Thr Cys Leu Val Val

195 200 205

Asp Leu Gly Pro Asp Asp Ser Asn Val Gln Ile Thr Trp Phe Val Asp

210 215 220

Asn Thr Glu Met His Thr Ala Lys Thr Arg Pro Arg Glu Glu Gln Phe

225 230 235 240

Asn Ser Thr Tyr Arg Val Val Ser Val Leu Pro Ile Leu His Gln Asp

245 250 255

Trp Leu Lys Gly Lys Glu Phe Lys Cys Lys Val Asn Ser Lys Ser Leu

260 265 270

Pro Ser Ala Met Glu Arg Thr Ile Ser Lys Ala Lys Gly Gln Pro His

275 280 285

Glu Pro Gln Val Tyr Val Leu Pro Pro Thr Gln Glu Glu Leu Ser Glu

290 295 300

Asn Lys Val Ser Val Thr Cys Leu Ile Lys Gly Phe His Pro Pro Asp

305 310 315 320

Ile Ala Val Glu Trp Glu Ile Thr Gly Gln Pro Glu Pro Glu Asn Asn

325 330 335

Tyr Gln Thr Thr Pro Pro Gln Leu Asp Ser Asp Gly Thr Tyr Phe Leu

340 345 350

Tyr Ser Arg Leu Ser Val Asp Arg Ser His Trp Gln Arg Gly Asn Thr

355 360 365

Tyr Thr Cys Ser Val Ser His Glu Ala Leu His Ser His His Thr Gln

370 375 380

Lys Ser Leu Thr Gln Ser Pro Gly Lys

385 390

<210> 20

<211> 369

<212> PRT

<213> 人工序列

<220>

<223> 合成的: 具有信号序列的示例性猫类TrkA ECD v3 - 野生型猫类

IgG2 Fc 蛋白A + C1q - CD16 -

<400> 20

Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp

1 5 10 15

Leu Arg Gly Ala Arg Cys Val Ser Phe Pro Ala Ser Val Gln Leu His

20 25 30

Ala Ala Val Glu Leu His His Trp Cys Ile Pro Phe Ser Val Asp Gly

35 40 45

Gln Pro Ala Pro Ser Leu Arg Trp Leu Phe Asn Gly Ser Val Leu Asn

50 55 60

Glu Thr Ser Phe Ile Phe Thr Glu Phe Leu Glu Pro Ala Ala Asn Glu

65 70 75 80

Thr Val Arg His Gly Cys Leu Arg Leu Asn Gln Pro Thr His Val Asn

85 90 95

Asn Gly Asn Tyr Thr Leu Leu Ala Ala Asn Pro Ser Gly Arg Ala Ala

100 105 110

Ala Ser Val Leu Ala Ala Phe Met Asp Asn Pro Ser Gly Gly Gly Ser

115 120 125

Gly Gly Gly Ser Pro Lys Thr Ala Ser Thr Ile Glu Ser Lys Thr Gly

130 135 140

Glu Gly Pro Lys Cys Pro Val Pro Glu Ile Pro Gly Ala Pro Ser Val

145 150 155 160

Phe Ile Phe Pro Pro Lys Pro Lys Asp Thr Leu Ser Ile Ser Arg Thr

165 170 175

Pro Glu Val Thr Cys Leu Val Val Asp Leu Gly Pro Asp Asp Ser Asn

180 185 190

Val Gln Ile Thr Trp Phe Val Asp Asn Thr Glu Met His Thr Ala Lys

195 200 205

Thr Arg Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser

210 215 220

Val Leu Pro Ile Leu His Gln Asp Trp Leu Lys Gly Lys Glu Phe Lys

225 230 235 240

Cys Lys Val Asn Ser Lys Ser Leu Pro Ser Ala Met Glu Arg Thr Ile

245 250 255

Ser Lys Ala Lys Gly Gln Pro His Glu Pro Gln Val Tyr Val Leu Pro

260 265 270

Pro Thr Gln Glu Glu Leu Ser Glu Asn Lys Val Ser Val Thr Cys Leu

275 280 285

Ile Lys Gly Phe His Pro Pro Asp Ile Ala Val Glu Trp Glu Ile Thr

290 295 300

Gly Gln Pro Glu Pro Glu Asn Asn Tyr Gln Thr Thr Pro Pro Gln Leu

305 310 315 320

Asp Ser Asp Gly Thr Tyr Phe Leu Tyr Ser Arg Leu Ser Val Asp Arg

325 330 335

Ser His Trp Gln Arg Gly Asn Thr Tyr Thr Cys Ser Val Ser His Glu

340 345 350

Ala Leu His Ser His His Thr Gln Lys Ser Leu Thr Gln Ser Pro Gly

355 360 365

Lys

<210> 21

<211> 367

<212> PRT

<213> 人工序列

<220>

<223> 合成的: 具有信号序列的示例性猫类TrkA ECD v4 - 野生型猫类

IgG2 Fc 蛋白A + C1q - CD16 -

<400> 21

Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp

1 5 10 15

Leu Arg Gly Ala Arg Cys Phe Pro Ala Ser Val Gln Leu His Ala Ala

20 25 30

Val Glu Leu His His Trp Cys Ile Pro Phe Ser Val Asp Gly Gln Pro

35 40 45

Ala Pro Ser Leu Arg Trp Leu Phe Asn Gly Ser Val Leu Asn Glu Thr

50 55 60

Ser Phe Ile Phe Thr Glu Phe Leu Glu Pro Ala Ala Asn Glu Thr Val

65 70 75 80

Arg His Gly Cys Leu Arg Leu Asn Gln Pro Thr His Val Asn Asn Gly

85 90 95

Asn Tyr Thr Leu Leu Ala Ala Asn Pro Ser Gly Arg Ala Ala Ala Ser

100 105 110

Val Leu Ala Ala Phe Met Asp Asn Pro Ser Gly Gly Gly Ser Gly Gly

115 120 125

Gly Ser Pro Lys Thr Ala Ser Thr Ile Glu Ser Lys Thr Gly Glu Gly

130 135 140

Pro Lys Cys Pro Val Pro Glu Ile Pro Gly Ala Pro Ser Val Phe Ile

145 150 155 160

Phe Pro Pro Lys Pro Lys Asp Thr Leu Ser Ile Ser Arg Thr Pro Glu

165 170 175

Val Thr Cys Leu Val Val Asp Leu Gly Pro Asp Asp Ser Asn Val Gln

180 185 190

Ile Thr Trp Phe Val Asp Asn Thr Glu Met His Thr Ala Lys Thr Arg

195 200 205

Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu

210 215 220

Pro Ile Leu His Gln Asp Trp Leu Lys Gly Lys Glu Phe Lys Cys Lys

225 230 235 240

Val Asn Ser Lys Ser Leu Pro Ser Ala Met Glu Arg Thr Ile Ser Lys

245 250 255

Ala Lys Gly Gln Pro His Glu Pro Gln Val Tyr Val Leu Pro Pro Thr

260 265 270

Gln Glu Glu Leu Ser Glu Asn Lys Val Ser Val Thr Cys Leu Ile Lys

275 280 285

Gly Phe His Pro Pro Asp Ile Ala Val Glu Trp Glu Ile Thr Gly Gln

290 295 300

Pro Glu Pro Glu Asn Asn Tyr Gln Thr Thr Pro Pro Gln Leu Asp Ser

305 310 315 320

Asp Gly Thr Tyr Phe Leu Tyr Ser Arg Leu Ser Val Asp Arg Ser His

325 330 335

Trp Gln Arg Gly Asn Thr Tyr Thr Cys Ser Val Ser His Glu Ala Leu

340 345 350

His Ser His His Thr Gln Lys Ser Leu Thr Gln Ser Pro Gly Lys

355 360 365

<210> 22

<211> 389

<212> PRT

<213> 人工序列

<220>

<223> 合成的: 具有信号序列的示例性马类TrkA ECD v2 - 变体马类

IgG2 Fc 蛋白A + C1q - CD16 -

<400> 22

Met Glu Thr Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro

1 5 10 15

Gly Ser Thr Gly Val Ser Phe Pro Ala Ser Val His Leu Gln Thr Ala

20 25 30

Val Glu Gln His His Trp Cys Ile Pro Phe Ser Val Asp Gly Gln Pro

35 40 45

Ala Pro Thr Leu Arg Trp Leu Phe Asn Gly Ser Val Leu Asn Glu Thr

50 55 60

Ser Phe Ile Phe Thr Glu Phe Leu Glu Ser Ala Ala Asn Glu Thr Met

65 70 75 80

Arg His Gly Cys Leu Arg Leu Asn Gln Pro Thr His Val Asn Asn Gly

85 90 95

Asn Tyr Thr Leu Leu Ala Thr Asn Pro Tyr Gly Gln Asp Ser Ala Ser

100 105 110

Val Met Val Ala Phe Met Asp Asn Pro Phe Glu Phe Asn Pro Glu Asp

115 120 125

Pro Ile Pro Val Ser Phe Ser Pro Val Asp Thr Asn Ser Thr Ser Arg

130 135 140

Asp Pro Pro Cys Val Leu Ser Ala Glu Gly Val Ile Pro Ile Pro Ser

145 150 155 160

Val Pro Lys Pro Gln Cys Pro Pro Tyr Thr His Ser Lys Phe Leu Gly

165 170 175

Gly Pro Ser Val Phe Ile Phe Pro Pro Asn Pro Lys Asp Thr Leu Met

180 185 190

Ile Ser Arg Thr Pro Val Val Thr Cys Val Val Val Asn Leu Ser Asp

195 200 205

Gln Tyr Pro Asp Val Gln Phe Ser Trp Tyr Val Asp Asn Thr Glu Val

210 215 220

His Ser Ala Ile Thr Lys Gln Arg Glu Ala Gln Phe Asn Ser Thr Tyr

225 230 235 240

Arg Val Val Ser Val Leu Pro Ile Gln His Gln Asp Trp Leu Ser Gly

245 250 255

Lys Glu Phe Lys Cys Ser Val Thr Asn Val Gly Val Pro Gln Pro Ile

260 265 270

Ser Arg Ala Ile Ser Arg Gly Lys Gly Pro Ser Arg Val Pro Gln Val

275 280 285

Tyr Val Leu Pro Pro His Pro Asp Glu Leu Ala Lys Ser Lys Val Ser

290 295 300

Val Thr Cys Leu Val Lys Asp Phe Tyr Pro Pro Asp Ile Ser Val Glu

305 310 315 320

Trp Gln Ser Asn Arg Trp Pro Glu Leu Glu Gly Lys Tyr Ser Thr Thr

325 330 335

Pro Ala Gln Leu Asp Gly Asp Gly Ser Tyr Phe Leu Tyr Ser Lys Leu

340 345 350

Ser Leu Glu Thr Ser Arg Trp Gln Gln Val Glu Ser Phe Thr Cys Ala

355 360 365

Val Met His Glu Ala Leu His Asn His Tyr Thr Lys Thr Asp Ile Ser

370 375 380

Glu Ser Leu Gly Lys

385

<210> 23

<211> 365

<212> PRT

<213> 人工序列

<220>

<223> 合成的: 具有信号序列的示例性马类TrkA ECD v3 - 变体马类

IgG2 Fc 蛋白A + C1q - CD16 -

<400> 23

Met Glu Thr Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro

1 5 10 15

Gly Ser Thr Gly Val Ser Phe Pro Ala Ser Val His Leu Gln Thr Ala

20 25 30

Val Glu Gln His His Trp Cys Ile Pro Phe Ser Val Asp Gly Gln Pro

35 40 45

Ala Pro Thr Leu Arg Trp Leu Phe Asn Gly Ser Val Leu Asn Glu Thr

50 55 60

Ser Phe Ile Phe Thr Glu Phe Leu Glu Ser Ala Ala Asn Glu Thr Met

65 70 75 80

Arg His Gly Cys Leu Arg Leu Asn Gln Pro Thr His Val Asn Asn Gly

85 90 95

Asn Tyr Thr Leu Leu Ala Thr Asn Pro Tyr Gly Gln Asp Ser Ala Ser

100 105 110

Val Met Val Ala Phe Met Asp Asn Pro Pro Pro Cys Val Leu Ser Ala

115 120 125

Glu Gly Val Ile Pro Ile Pro Ser Val Pro Lys Pro Gln Cys Pro Pro

130 135 140

Tyr Thr His Ser Lys Phe Leu Gly Gly Pro Ser Val Phe Ile Phe Pro

145 150 155 160

Pro Asn Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Val Val Thr

165 170 175

Cys Val Val Val Asn Leu Ser Asp Gln Tyr Pro Asp Val Gln Phe Ser

180 185 190

Trp Tyr Val Asp Asn Thr Glu Val His Ser Ala Ile Thr Lys Gln Arg

195 200 205

Glu Ala Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Pro Ile

210 215 220

Gln His Gln Asp Trp Leu Ser Gly Lys Glu Phe Lys Cys Ser Val Thr

225 230 235 240

Asn Val Gly Val Pro Gln Pro Ile Ser Arg Ala Ile Ser Arg Gly Lys

245 250 255

Gly Pro Ser Arg Val Pro Gln Val Tyr Val Leu Pro Pro His Pro Asp

260 265 270

Glu Leu Ala Lys Ser Lys Val Ser Val Thr Cys Leu Val Lys Asp Phe

275 280 285

Tyr Pro Pro Asp Ile Ser Val Glu Trp Gln Ser Asn Arg Trp Pro Glu

290 295 300

Leu Glu Gly Lys Tyr Ser Thr Thr Pro Ala Gln Leu Asp Gly Asp Gly

305 310 315 320

Ser Tyr Phe Leu Tyr Ser Lys Leu Ser Leu Glu Thr Ser Arg Trp Gln

325 330 335

Gln Val Glu Ser Phe Thr Cys Ala Val Met His Glu Ala Leu His Asn

340 345 350

His Tyr Thr Lys Thr Asp Ile Ser Glu Ser Leu Gly Lys

355 360 365

<210> 24

<211> 363

<212> PRT

<213> 人工序列

<220>

<223> 合成的: 具有信号序列的示例性马类TrkA ECD v4 - 变体马类

IgG2 Fc 蛋白A + C1q - CD16 -

<400> 24

Met Glu Thr Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro

1 5 10 15

Gly Ser Thr Gly Phe Pro Ala Ser Val His Leu Gln Thr Ala Val Glu

20 25 30

Gln His His Trp Cys Ile Pro Phe Ser Val Asp Gly Gln Pro Ala Pro

35 40 45

Thr Leu Arg Trp Leu Phe Asn Gly Ser Val Leu Asn Glu Thr Ser Phe

50 55 60

Ile Phe Thr Glu Phe Leu Glu Ser Ala Ala Asn Glu Thr Met Arg His

65 70 75 80

Gly Cys Leu Arg Leu Asn Gln Pro Thr His Val Asn Asn Gly Asn Tyr

85 90 95

Thr Leu Leu Ala Thr Asn Pro Tyr Gly Gln Asp Ser Ala Ser Val Met

100 105 110

Val Ala Phe Met Asp Asn Pro Pro Pro Cys Val Leu Ser Ala Glu Gly

115 120 125

Val Ile Pro Ile Pro Ser Val Pro Lys Pro Gln Cys Pro Pro Tyr Thr

130 135 140

His Ser Lys Phe Leu Gly Gly Pro Ser Val Phe Ile Phe Pro Pro Asn

145 150 155 160

Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Val Val Thr Cys Val

165 170 175

Val Val Asn Leu Ser Asp Gln Tyr Pro Asp Val Gln Phe Ser Trp Tyr

180 185 190

Val Asp Asn Thr Glu Val His Ser Ala Ile Thr Lys Gln Arg Glu Ala

195 200 205

Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Pro Ile Gln His

210 215 220

Gln Asp Trp Leu Ser Gly Lys Glu Phe Lys Cys Ser Val Thr Asn Val

225 230 235 240

Gly Val Pro Gln Pro Ile Ser Arg Ala Ile Ser Arg Gly Lys Gly Pro

245 250 255

Ser Arg Val Pro Gln Val Tyr Val Leu Pro Pro His Pro Asp Glu Leu

260 265 270

Ala Lys Ser Lys Val Ser Val Thr Cys Leu Val Lys Asp Phe Tyr Pro

275 280 285

Pro Asp Ile Ser Val Glu Trp Gln Ser Asn Arg Trp Pro Glu Leu Glu

290 295 300

Gly Lys Tyr Ser Thr Thr Pro Ala Gln Leu Asp Gly Asp Gly Ser Tyr

305 310 315 320

Phe Leu Tyr Ser Lys Leu Ser Leu Glu Thr Ser Arg Trp Gln Gln Val

325 330 335

Glu Ser Phe Thr Cys Ala Val Met His Glu Ala Leu His Asn His Tyr

340 345 350

Thr Lys Thr Asp Ile Ser Glu Ser Leu Gly Lys

355 360

<210> 25

<211> 125

<212> PRT

<213> 人工序列

<220>

<223> 合成的: 示例性犬类TrkA ECD (v2) 额外的二硫化物

<400> 25

Val Ser Phe Pro Ala Ser Cys Gln Leu His Glu Ala Val Glu Leu His

1 5 10 15

His Trp Cys Ile Pro Phe Ser Val Asp Gly Gln Pro Ala Pro Ser Leu

20 25 30

Arg Trp Leu Phe Asn Gly Ser Val Leu Asn Glu Thr Ser Phe Ile Phe

35 40 45

Thr Glu Phe Leu Glu Pro Val Ala Asn Glu Thr Val Arg His Gly Cys

50 55 60

Leu Arg Leu Asn Gln Pro Thr His Val Asn Asn Gly Asn Tyr Thr Leu

65 70 75 80

Leu Ala Ala Asn Pro Ser Gly Arg Cys Ala Ala Phe Val Met Ala Ala

85 90 95

Phe Met Asp Asn Pro Phe Glu Phe Asn Pro Glu Asp Pro Ile Pro Val

100 105 110

Ser Phe Ser Pro Val Asp Thr Asn Ser Thr Ser Gly Asp

115 120 125

<210> 26

<211> 101

<212> PRT

<213> 人工序列

<220>

<223> 合成的: 示例性犬类TrkA ECD (v3) 额外的二硫化物

<400> 26

Val Ser Phe Pro Ala Ser Cys Gln Leu His Glu Ala Val Glu Leu His

1 5 10 15

His Trp Cys Ile Pro Phe Ser Val Asp Gly Gln Pro Ala Pro Ser Leu

20 25 30

Arg Trp Leu Phe Asn Gly Ser Val Leu Asn Glu Thr Ser Phe Ile Phe

35 40 45

Thr Glu Phe Leu Glu Pro Val Ala Asn Glu Thr Val Arg His Gly Cys

50 55 60

Leu Arg Leu Asn Gln Pro Thr His Val Asn Asn Gly Asn Tyr Thr Leu

65 70 75 80

Leu Ala Ala Asn Pro Ser Gly Arg Cys Ala Ala Phe Val Met Ala Ala

85 90 95

Phe Met Asp Asn Pro

100

<210> 27

<211> 99

<212> PRT

<213> 人工序列

<220>

<223> 合成的: 示例性犬类TrkA ECD (v4) 额外的二硫化物

<400> 27

Phe Pro Ala Ser Cys Gln Leu His Glu Ala Val Glu Leu His His Trp

1 5 10 15

Cys Ile Pro Phe Ser Val Asp Gly Gln Pro Ala Pro Ser Leu Arg Trp

20 25 30

Leu Phe Asn Gly Ser Val Leu Asn Glu Thr Ser Phe Ile Phe Thr Glu

35 40 45

Phe Leu Glu Pro Val Ala Asn Glu Thr Val Arg His Gly Cys Leu Arg

50 55 60

Leu Asn Gln Pro Thr His Val Asn Asn Gly Asn Tyr Thr Leu Leu Ala

65 70 75 80

Ala Asn Pro Ser Gly Arg Cys Ala Ala Phe Val Met Ala Ala Phe Met

85 90 95

Asp Asn Pro

<210> 28

<211> 125

<212> PRT

<213> 人工序列

<220>

<223> 合成的: 示例性猫类TrkA ECD (v2) 额外的二硫化物

<400> 28

Val Ser Phe Pro Ala Ser Cys Gln Leu His Ala Ala Val Glu Leu His

1 5 10 15

His Trp Cys Ile Pro Phe Ser Val Asp Gly Gln Pro Ala Pro Ser Leu

20 25 30

Arg Trp Leu Phe Asn Gly Ser Val Leu Asn Glu Thr Ser Phe Ile Phe

35 40 45

Thr Glu Phe Leu Glu Pro Ala Ala Asn Glu Thr Val Arg His Gly Cys

50 55 60

Leu Arg Leu Asn Gln Pro Thr His Val Asn Asn Gly Asn Tyr Thr Leu

65 70 75 80

Leu Ala Ala Asn Pro Ser Gly Arg Cys Ala Ala Ser Val Leu Ala Ala

85 90 95

Phe Met Asp Asn Pro Phe Glu Phe Asn Pro Glu Asp Pro Ile Pro Val

100 105 110

Ser Phe Ser Pro Val Asp Ser Asn Ser Thr Ser Gly Asp

115 120 125

<210> 29

<211> 101

<212> PRT

<213> 人工序列

<220>

<223> 合成的: 示例性猫类TrkA ECD (v3) 额外的二硫化物

<400> 29

Val Ser Phe Pro Ala Ser Cys Gln Leu His Ala Ala Val Glu Leu His

1 5 10 15

His Trp Cys Ile Pro Phe Ser Val Asp Gly Gln Pro Ala Pro Ser Leu

20 25 30

Arg Trp Leu Phe Asn Gly Ser Val Leu Asn Glu Thr Ser Phe Ile Phe

35 40 45

Thr Glu Phe Leu Glu Pro Ala Ala Asn Glu Thr Val Arg His Gly Cys

50 55 60

Leu Arg Leu Asn Gln Pro Thr His Val Asn Asn Gly Asn Tyr Thr Leu

65 70 75 80

Leu Ala Ala Asn Pro Ser Gly Arg Cys Ala Ala Ser Val Leu Ala Ala

85 90 95

Phe Met Asp Asn Pro

100

<210> 30

<211> 99

<212> PRT

<213> 人工序列

<220>

<223> 合成的: 示例性猫类TrkA ECD (v4) 额外的二硫化物

<400> 30

Phe Pro Ala Ser Cys Gln Leu His Ala Ala Val Glu Leu His His Trp

1 5 10 15

Cys Ile Pro Phe Ser Val Asp Gly Gln Pro Ala Pro Ser Leu Arg Trp

20 25 30

Leu Phe Asn Gly Ser Val Leu Asn Glu Thr Ser Phe Ile Phe Thr Glu

35 40 45

Phe Leu Glu Pro Ala Ala Asn Glu Thr Val Arg His Gly Cys Leu Arg

50 55 60

Leu Asn Gln Pro Thr His Val Asn Asn Gly Asn Tyr Thr Leu Leu Ala

65 70 75 80

Ala Asn Pro Ser Gly Arg Cys Ala Ala Ser Val Leu Ala Ala Phe Met

85 90 95

Asp Asn Pro

<210> 31

<211> 125

<212> PRT

<213> 人工序列

<220>

<223> 合成的: 示例性马类TrkA ECD (v2) 额外的二硫化物

<400> 31

Val Ser Phe Pro Ala Ser Cys His Leu Gln Thr Ala Val Glu Gln His

1 5 10 15

His Trp Cys Ile Pro Phe Ser Val Asp Gly Gln Pro Ala Pro Thr Leu

20 25 30

Arg Trp Leu Phe Asn Gly Ser Val Leu Asn Glu Thr Ser Phe Ile Phe

35 40 45

Thr Glu Phe Leu Glu Ser Ala Ala Asn Glu Thr Met Arg His Gly Cys

50 55 60

Leu Arg Leu Asn Gln Pro Thr His Val Asn Asn Gly Asn Tyr Thr Leu

65 70 75 80

Leu Ala Thr Asn Pro Tyr Gly Gln Cys Ser Ala Ser Val Met Val Ala

85 90 95

Phe Met Asp Asn Pro Phe Glu Phe Asn Pro Glu Asp Pro Ile Pro Val

100 105 110

Ser Phe Ser Pro Val Asp Thr Asn Ser Thr Ser Arg Asp

115 120 125

<210> 32

<211> 101

<212> PRT

<213> 人工序列

<220>

<223> 合成的: 示例性马类TrkA ECD (v3) 额外的二硫化物

<400> 32

Val Ser Phe Pro Ala Ser Cys His Leu Gln Thr Ala Val Glu Gln His

1 5 10 15

His Trp Cys Ile Pro Phe Ser Val Asp Gly Gln Pro Ala Pro Thr Leu

20 25 30

Arg Trp Leu Phe Asn Gly Ser Val Leu Asn Glu Thr Ser Phe Ile Phe

35 40 45

Thr Glu Phe Leu Glu Ser Ala Ala Asn Glu Thr Met Arg His Gly Cys

50 55 60

Leu Arg Leu Asn Gln Pro Thr His Val Asn Asn Gly Asn Tyr Thr Leu

65 70 75 80

Leu Ala Thr Asn Pro Tyr Gly Gln Cys Ser Ala Ser Val Met Val Ala

85 90 95

Phe Met Asp Asn Pro

100

<210> 33

<211> 99

<212> PRT

<213> 人工序列

<220>

<223> 合成的: 示例性马类TrkA ECD (v4) 额外的二硫化物

<400> 33

Phe Pro Ala Ser Cys His Leu Gln Thr Ala Val Glu Gln His His Trp

1 5 10 15

Cys Ile Pro Phe Ser Val Asp Gly Gln Pro Ala Pro Thr Leu Arg Trp

20 25 30

Leu Phe Asn Gly Ser Val Leu Asn Glu Thr Ser Phe Ile Phe Thr Glu

35 40 45

Phe Leu Glu Ser Ala Ala Asn Glu Thr Met Arg His Gly Cys Leu Arg

50 55 60

Leu Asn Gln Pro Thr His Val Asn Asn Gly Asn Tyr Thr Leu Leu Ala

65 70 75 80

Thr Asn Pro Tyr Gly Gln Cys Ser Ala Ser Val Met Val Ala Phe Met

85 90 95

Asp Asn Pro

<210> 34

<211> 221

<212> PRT

<213> 人工序列

<220>

<223> 合成的: 示例性野生型犬类IgG-A Fc 蛋白A - C1q

- CD16 -

<400> 34

Pro Val Pro Glu Pro Leu Gly Gly Pro Ser Val Leu Ile Phe Pro Pro

1 5 10 15

Lys Pro Lys Asp Ile Leu Arg Ile Thr Arg Thr Pro Glu Val Thr Cys

20 25 30

Val Val Leu Asp Leu Gly Arg Glu Asp Pro Glu Val Gln Ile Ser Trp

35 40 45

Phe Val Asp Gly Lys Glu Val His Thr Ala Lys Thr Gln Ser Arg Glu

50 55 60

Gln Gln Phe Asn Gly Thr Tyr Arg Val Val Ser Val Leu Pro Ile Glu

65 70 75 80

His Gln Asp Trp Leu Thr Gly Lys Glu Phe Lys Cys Arg Val Asn His

85 90 95

Ile Asp Leu Pro Ser Pro Ile Glu Arg Thr Ile Ser Lys Ala Arg Gly

100 105 110

Arg Ala His Lys Pro Ser Val Tyr Val Leu Pro Pro Ser Pro Lys Glu

115 120 125

Leu Ser Ser Ser Asp Thr Val Ser Ile Thr Cys Leu Ile Lys Asp Phe

130 135 140

Tyr Pro Pro Asp Ile Asp Val Glu Trp Gln Ser Asn Gly Gln Gln Glu

145 150 155 160

Pro Glu Arg Lys His Arg Met Thr Pro Pro Gln Leu Asp Glu Asp Gly

165 170 175

Ser Tyr Phe Leu Tyr Ser Lys Leu Ser Val Asp Lys Ser Arg Trp Gln

180 185 190

Gln Gly Asp Pro Phe Thr Cys Ala Val Met His Glu Thr Leu Gln Asn

195 200 205

His Tyr Thr Asp Leu Ser Leu Ser His Ser Pro Gly Lys

210 215 220

<210> 35

<211> 220

<212> PRT

<213> 人工序列

<220>

<223> 合成的: 示例性野生型犬类IgG-B Fc 蛋白A + C1q

+ CD16 +

<400> 35

Pro Ala Pro Glu Met Leu Gly Gly Pro Ser Val Phe Ile Phe Pro Pro

1 5 10 15

Lys Pro Lys Asp Thr Leu Leu Ile Ala Arg Thr Pro Glu Val Thr Cys

20 25 30

Val Val Val Asp Leu Asp Pro Glu Asp Pro Glu Val Gln Ile Ser Trp

35 40 45

Phe Val Asp Gly Lys Gln Met Gln Thr Ala Lys Thr Gln Pro Arg Glu

50 55 60

Glu Gln Phe Asn Gly Thr Tyr Arg Val Val Ser Val Leu Pro Ile Gly

65 70 75 80

His Gln Asp Trp Leu Lys Gly Lys Gln Phe Thr Cys Lys Val Asn Asn

85 90 95

Lys Ala Leu Pro Ser Pro Ile Glu Arg Thr Ile Ser Lys Ala Arg Gly

100 105 110

Gln Ala His Gln Pro Ser Val Tyr Val Leu Pro Pro Ser Arg Glu Glu

115 120 125

Leu Ser Lys Asn Thr Val Ser Leu Thr Cys Leu Ile Lys Asp Phe Phe

130 135 140

Pro Pro Asp Ile Asp Val Glu Trp Gln Ser Asn Gly Gln Gln Glu Pro

145 150 155 160

Glu Ser Lys Tyr Arg Thr Thr Pro Pro Gln Leu Asp Glu Asp Gly Ser

165 170 175

Tyr Phe Leu Tyr Ser Lys Leu Ser Val Asp Lys Ser Arg Trp Gln Arg

180 185 190

Gly Asp Thr Phe Ile Cys Ala Val Met His Glu Ala Leu His Asn His

195 200 205

Tyr Thr Gln Glu Ser Leu Ser His Ser Pro Gly Lys

210 215 220

<210> 36

<211> 237

<212> PRT

<213> 人工序列

<220>

<223> 合成的: 具有铰链的示例性野生型犬类IgG-B Fc

蛋白A + C1q + CD16 +

<400> 36

Pro Lys Arg Glu Asn Gly Arg Val Pro Arg Pro Pro Asp Cys Pro Lys

1 5 10 15

Cys Pro Ala Pro Glu Met Leu Gly Gly Pro Ser Val Phe Ile Phe Pro

20 25 30

Pro Lys Pro Lys Asp Thr Leu Leu Ile Ala Arg Thr Pro Glu Val Thr

35 40 45

Cys Val Val Val Asp Leu Asp Pro Glu Asp Pro Glu Val Gln Ile Ser

50 55 60

Trp Phe Val Asp Gly Lys Gln Met Gln Thr Ala Lys Thr Gln Pro Arg

65 70 75 80

Glu Glu Gln Phe Asn Gly Thr Tyr Arg Val Val Ser Val Leu Pro Ile

85 90 95

Gly His Gln Asp Trp Leu Lys Gly Lys Gln Phe Thr Cys Lys Val Asn

100 105 110

Asn Lys Ala Leu Pro Ser Pro Ile Glu Arg Thr Ile Ser Lys Ala Arg

115 120 125

Gly Gln Ala His Gln Pro Ser Val Tyr Val Leu Pro Pro Ser Arg Glu

130 135 140

Glu Leu Ser Lys Asn Thr Val Ser Leu Thr Cys Leu Ile Lys Asp Phe

145 150 155 160

Phe Pro Pro Asp Ile Asp Val Glu Trp Gln Ser Asn Gly Gln Gln Glu

165 170 175

Pro Glu Ser Lys Tyr Arg Thr Thr Pro Pro Gln Leu Asp Glu Asp Gly

180 185 190

Ser Tyr Phe Leu Tyr Ser Lys Leu Ser Val Asp Lys Ser Arg Trp Gln

195 200 205

Arg Gly Asp Thr Phe Ile Cys Ala Val Met His Glu Ala Leu His Asn

210 215 220

His Tyr Thr Gln Glu Ser Leu Ser His Ser Pro Gly Lys

225 230 235

<210> 37

<211> 220

<212> PRT

<213> 人工序列

<220>

<223> 合成的: 示例性野生型犬类IgG-C Fc 蛋白A - C1q

+ CD16 +

<400> 37

Pro Gly Cys Gly Leu Leu Gly Gly Pro Ser Val Phe Ile Phe Pro Pro

1 5 10 15

Lys Pro Lys Asp Ile Leu Val Thr Ala Arg Thr Pro Thr Val Thr Cys

20 25 30

Val Val Val Asp Leu Asp Pro Glu Asn Pro Glu Val Gln Ile Ser Trp

35 40 45

Phe Val Asp Ser Lys Gln Val Gln Thr Ala Asn Thr Gln Pro Arg Glu

50 55 60

Glu Gln Ser Asn Gly Thr Tyr Arg Val Val Ser Val Leu Pro Ile Gly

65 70 75 80

His Gln Asp Trp Leu Ser Gly Lys Gln Phe Lys Cys Lys Val Asn Asn

85 90 95

Lys Ala Leu Pro Ser Pro Ile Glu Glu Ile Ile Ser Lys Thr Pro Gly

100 105 110

Gln Ala His Gln Pro Asn Val Tyr Val Leu Pro Pro Ser Arg Asp Glu

115 120 125

Met Ser Lys Asn Thr Val Thr Leu Thr Cys Leu Val Lys Asp Phe Phe

130 135 140

Pro Pro Glu Ile Asp Val Glu Trp Gln Ser Asn Gly Gln Gln Glu Pro

145 150 155 160

Glu Ser Lys Tyr Arg Met Thr Pro Pro Gln Leu Asp Glu Asp Gly Ser

165 170 175

Tyr Phe Leu Tyr Ser Lys Leu Ser Val Asp Lys Ser Arg Trp Gln Arg

180 185 190

Gly Asp Thr Phe Ile Cys Ala Val Met His Glu Ala Leu His Asn His

195 200 205

Tyr Thr Gln Ile Ser Leu Ser His Ser Pro Gly Lys

210 215 220

<210> 38

<211> 235

<212> PRT

<213> 人工序列

<220>

<223> 合成的: 具有铰链的示例性野生型犬类IgG-C Fc

蛋白A - C1q + CD16 +

<400> 38

Ala Lys Glu Cys Glu Cys Lys Cys Asn Cys Asn Asn Cys Pro Cys Pro

1 5 10 15

Gly Cys Gly Leu Leu Gly Gly Pro Ser Val Phe Ile Phe Pro Pro Lys

20 25 30

Pro Lys Asp Ile Leu Val Thr Ala Arg Thr Pro Thr Val Thr Cys Val

35 40 45

Val Val Asp Leu Asp Pro Glu Asn Pro Glu Val Gln Ile Ser Trp Phe

50 55 60

Val Asp Ser Lys Gln Val Gln Thr Ala Asn Thr Gln Pro Arg Glu Glu

65 70 75 80

Gln Ser Asn Gly Thr Tyr Arg Val Val Ser Val Leu Pro Ile Gly His

85 90 95

Gln Asp Trp Leu Ser Gly Lys Gln Phe Lys Cys Lys Val Asn Asn Lys

100 105 110

Ala Leu Pro Ser Pro Ile Glu Glu Ile Ile Ser Lys Thr Pro Gly Gln

115 120 125

Ala His Gln Pro Asn Val Tyr Val Leu Pro Pro Ser Arg Asp Glu Met

130 135 140

Ser Lys Asn Thr Val Thr Leu Thr Cys Leu Val Lys Asp Phe Phe Pro

145 150 155 160

Pro Glu Ile Asp Val Glu Trp Gln Ser Asn Gly Gln Gln Glu Pro Glu

165 170 175

Ser Lys Tyr Arg Met Thr Pro Pro Gln Leu Asp Glu Asp Gly Ser Tyr

180 185 190

Phe Leu Tyr Ser Lys Leu Ser Val Asp Lys Ser Arg Trp Gln Arg Gly

195 200 205

Asp Thr Phe Ile Cys Ala Val Met His Glu Ala Leu His Asn His Tyr

210 215 220

Thr Gln Ile Ser Leu Ser His Ser Pro Gly Lys

225 230 235

<210> 39

<211> 221

<212> PRT

<213> 人工序列

<220>

<223> 合成的: 示例性野生型犬类IgG-D Fc 蛋白A - C1q

- CD16 -

<400> 39

Pro Val Pro Glu Ser Leu Gly Gly Pro Ser Val Phe Ile Phe Pro Pro

1 5 10 15

Lys Pro Lys Asp Ile Leu Arg Ile Thr Arg Thr Pro Glu Ile Thr Cys

20 25 30

Val Val Leu Asp Leu Gly Arg Glu Asp Pro Glu Val Gln Ile Ser Trp

35 40 45

Phe Val Asp Gly Lys Glu Val His Thr Ala Lys Thr Gln Pro Arg Glu

50 55 60

Gln Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Pro Ile Glu

65 70 75 80

His Gln Asp Trp Leu Thr Gly Lys Glu Phe Lys Cys Arg Val Asn His

85 90 95

Ile Gly Leu Pro Ser Pro Ile Glu Arg Thr Ile Ser Lys Ala Arg Gly

100 105 110

Gln Ala His Gln Pro Ser Val Tyr Val Leu Pro Pro Ser Pro Lys Glu

115 120 125

Leu Ser Ser Ser Asp Thr Val Thr Leu Thr Cys Leu Ile Lys Asp Phe

130 135 140

Phe Pro Pro Glu Ile Asp Val Glu Trp Gln Ser Asn Gly Gln Pro Glu

145 150 155 160

Pro Glu Ser Lys Tyr His Thr Thr Ala Pro Gln Leu Asp Glu Asp Gly

165 170 175

Ser Tyr Phe Leu Tyr Ser Lys Leu Ser Val Asp Lys Ser Arg Trp Gln

180 185 190

Gln Gly Asp Thr Phe Thr Cys Ala Val Met His Glu Ala Leu Gln Asn

195 200 205

His Tyr Thr Asp Leu Ser Leu Ser His Ser Pro Gly Lys

210 215 220

<210> 40

<211> 221

<212> PRT

<213> 人工序列

<220>

<223> 合成的: 示例性变体犬类IgG-A Fc C1q - CD16 -

蛋白A + I(21)T R(23)L T(25)A E(80)G T(205)A Q(207)H

<400> 40

Pro Val Pro Glu Pro Leu Gly Gly Pro Ser Val Leu Ile Phe Pro Pro

1 5 10 15

Lys Pro Lys Asp Thr Leu Leu Ile Ala Arg Thr Pro Glu Val Thr Cys

20 25 30

Val Val Leu Asp Leu Gly Arg Glu Asp Pro Glu Val Gln Ile Ser Trp

35 40 45

Phe Val Asp Gly Lys Glu Val His Thr Ala Lys Thr Gln Ser Arg Glu

50 55 60

Gln Gln Phe Asn Gly Thr Tyr Arg Val Val Ser Val Leu Pro Ile Gly

65 70 75 80

His Gln Asp Trp Leu Thr Gly Lys Glu Phe Lys Cys Arg Val Asn His

85 90 95

Ile Asp Leu Pro Ser Pro Ile Glu Arg Thr Ile Ser Lys Ala Arg Gly

100 105 110

Arg Ala His Lys Pro Ser Val Tyr Val Leu Pro Pro Ser Pro Lys Glu

115 120 125

Leu Ser Ser Ser Asp Thr Val Ser Ile Thr Cys Leu Ile Lys Asp Phe

130 135 140

Tyr Pro Pro Asp Ile Asp Val Glu Trp Gln Ser Asn Gly Gln Gln Glu

145 150 155 160

Pro Glu Arg Lys His Arg Met Thr Pro Pro Gln Leu Asp Glu Asp Gly

165 170 175

Ser Tyr Phe Leu Tyr Ser Lys Leu Ser Val Asp Lys Ser Arg Trp Gln

180 185 190

Gln Gly Asp Pro Phe Thr Cys Ala Val Met His Glu Ala Leu His Asn

195 200 205

His Tyr Thr Asp Leu Ser Leu Ser His Ser Pro Gly Lys

210 215 220

<210> 41

<211> 220

<212> PRT

<213> 人工序列

<220>

<223> 合成的: 示例性变体犬类IgG-C Fc C1q + 蛋白A +

I(21)T V(23)L T(24)I

<400> 41

Pro Gly Cys Gly Leu Leu Gly Gly Pro Ser Val Phe Ile Phe Pro Pro

1 5 10 15

Lys Pro Lys Asp Thr Leu Leu Ile Ala Arg Thr Pro Thr Val Thr Cys

20 25 30

Val Val Val Asp Leu Asp Pro Glu Asn Pro Glu Val Gln Ile Ser Trp

35 40 45

Phe Val Asp Ser Lys Gln Val Gln Thr Ala Asn Thr Gln Pro Arg Glu

50 55 60

Glu Gln Ser Asn Gly Thr Tyr Arg Val Val Ser Val Leu Pro Ile Gly

65 70 75 80

His Gln Asp Trp Leu Ser Gly Lys Gln Phe Lys Cys Lys Val Asn Asn

85 90 95

Lys Ala Leu Pro Ser Pro Ile Glu Glu Ile Ile Ser Lys Thr Pro Gly

100 105 110

Gln Ala His Gln Pro Asn Val Tyr Val Leu Pro Pro Ser Arg Asp Glu

115 120 125

Met Ser Lys Asn Thr Val Thr Leu Thr Cys Leu Val Lys Asp Phe Phe

130 135 140

Pro Pro Glu Ile Asp Val Glu Trp Gln Ser Asn Gly Gln Gln Glu Pro

145 150 155 160

Glu Ser Lys Tyr Arg Met Thr Pro Pro Gln Leu Asp Glu Asp Gly Ser

165 170 175

Tyr Phe Leu Tyr Ser Lys Leu Ser Val Asp Lys Ser Arg Trp Gln Arg

180 185 190

Gly Asp Thr Phe Ile Cys Ala Val Met His Glu Ala Leu His Asn His

195 200 205

Tyr Thr Gln Ile Ser Leu Ser His Ser Pro Gly Lys

210 215 220

<210> 42

<211> 221

<212> PRT

<213> 人工序列

<220>

<223> 合成的: 示例性变体犬类IgG-D Fc C1q - CD16 -

蛋白A + I(21)T R(23)L T(25)A E(80)G Q(207)H

<400> 42

Pro Val Pro Glu Ser Leu Gly Gly Pro Ser Val Phe Ile Phe Pro Pro

1 5 10 15

Lys Pro Lys Asp Thr Leu Leu Ile Ala Arg Thr Pro Glu Ile Thr Cys

20 25 30

Val Val Leu Asp Leu Gly Arg Glu Asp Pro Glu Val Gln Ile Ser Trp

35 40 45

Phe Val Asp Gly Lys Glu Val His Thr Ala Lys Thr Gln Pro Arg Glu

50 55 60

Gln Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Pro Ile Gly

65 70 75 80

His Gln Asp Trp Leu Thr Gly Lys Glu Phe Lys Cys Arg Val Asn His

85 90 95

Ile Gly Leu Pro Ser Pro Ile Glu Arg Thr Ile Ser Lys Ala Arg Gly

100 105 110

Gln Ala His Gln Pro Ser Val Tyr Val Leu Pro Pro Ser Pro Lys Glu

115 120 125

Leu Ser Ser Ser Asp Thr Val Thr Leu Thr Cys Leu Ile Lys Asp Phe

130 135 140

Phe Pro Pro Glu Ile Asp Val Glu Trp Gln Ser Asn Gly Gln Pro Glu

145 150 155 160

Pro Glu Ser Lys Tyr His Thr Thr Ala Pro Gln Leu Asp Glu Asp Gly

165 170 175

Ser Tyr Phe Leu Tyr Ser Lys Leu Ser Val Asp Lys Ser Arg Trp Gln

180 185 190

Gln Gly Asp Thr Phe Thr Cys Ala Val Met His Glu Ala Leu His Asn

195 200 205

His Tyr Thr Asp Leu Ser Leu Ser His Ser Pro Gly Lys

210 215 220

<210> 43

<211> 221

<212> PRT

<213> 人工序列

<220>

<223> 合成的: 示例性变体犬类IgG-A Fc C1q - CD16 -

蛋白A + I(21)T Q(207)H

<400> 43

Pro Val Pro Glu Pro Leu Gly Gly Pro Ser Val Leu Ile Phe Pro Pro

1 5 10 15

Lys Pro Lys Asp Thr Leu Arg Ile Thr Arg Thr Pro Glu Val Thr Cys

20 25 30

Val Val Leu Asp Leu Gly Arg Glu Asp Pro Glu Val Gln Ile Ser Trp

35 40 45

Phe Val Asp Gly Lys Glu Val His Thr Ala Lys Thr Gln Ser Arg Glu

50 55 60

Gln Gln Phe Asn Gly Thr Tyr Arg Val Val Ser Val Leu Pro Ile Glu

65 70 75 80

His Gln Asp Trp Leu Thr Gly Lys Glu Phe Lys Cys Arg Val Asn His

85 90 95

Ile Asp Leu Pro Ser Pro Ile Glu Arg Thr Ile Ser Lys Ala Arg Gly

100 105 110

Arg Ala His Lys Pro Ser Val Tyr Val Leu Pro Pro Ser Pro Lys Glu

115 120 125

Leu Ser Ser Ser Asp Thr Val Ser Ile Thr Cys Leu Ile Lys Asp Phe

130 135 140

Tyr Pro Pro Asp Ile Asp Val Glu Trp Gln Ser Asn Gly Gln Gln Glu

145 150 155 160

Pro Glu Arg Lys His Arg Met Thr Pro Pro Gln Leu Asp Glu Asp Gly

165 170 175

Ser Tyr Phe Leu Tyr Ser Lys Leu Ser Val Asp Lys Ser Arg Trp Gln

180 185 190

Gln Gly Asp Pro Phe Thr Cys Ala Val Met His Glu Thr Leu His Asn

195 200 205

His Tyr Thr Asp Leu Ser Leu Ser His Ser Pro Gly Lys

210 215 220

<210> 44

<211> 220

<212> PRT

<213> 人工序列

<220>

<223> 合成的: 示例性变体犬类IgG-C Fc C1q + 蛋白A +

I(21)T

<400> 44

Pro Gly Cys Gly Leu Leu Gly Gly Pro Ser Val Phe Ile Phe Pro Pro

1 5 10 15

Lys Pro Lys Asp Thr Leu Val Thr Ala Arg Thr Pro Thr Val Thr Cys

20 25 30

Val Val Val Asp Leu Asp Pro Glu Asn Pro Glu Val Gln Ile Ser Trp

35 40 45

Phe Val Asp Ser Lys Gln Val Gln Thr Ala Asn Thr Gln Pro Arg Glu

50 55 60

Glu Gln Ser Asn Gly Thr Tyr Arg Val Val Ser Val Leu Pro Ile Gly

65 70 75 80

His Gln Asp Trp Leu Ser Gly Lys Gln Phe Lys Cys Lys Val Asn Asn

85 90 95

Lys Ala Leu Pro Ser Pro Ile Glu Glu Ile Ile Ser Lys Thr Pro Gly

100 105 110

Gln Ala His Gln Pro Asn Val Tyr Val Leu Pro Pro Ser Arg Asp Glu

115 120 125

Met Ser Lys Asn Thr Val Thr Leu Thr Cys Leu Val Lys Asp Phe Phe

130 135 140

Pro Pro Glu Ile Asp Val Glu Trp Gln Ser Asn Gly Gln Gln Glu Pro

145 150 155 160

Glu Ser Lys Tyr Arg Met Thr Pro Pro Gln Leu Asp Glu Asp Gly Ser

165 170 175

Tyr Phe Leu Tyr Ser Lys Leu Ser Val Asp Lys Ser Arg Trp Gln Arg

180 185 190

Gly Asp Thr Phe Ile Cys Ala Val Met His Glu Ala Leu His Asn His

195 200 205

Tyr Thr Gln Ile Ser Leu Ser His Ser Pro Gly Lys

210 215 220

<210> 45

<211> 221

<212> PRT

<213> 人工序列

<220>

<223> 合成的: 示例性变体犬类IgG-D Fc C1q - 蛋白A +

I(21)T Q(207)H

<400> 45

Pro Val Pro Glu Ser Leu Gly Gly Pro Ser Val Phe Ile Phe Pro Pro

1 5 10 15

Lys Pro Lys Asp Thr Leu Arg Ile Thr Arg Thr Pro Glu Ile Thr Cys

20 25 30

Val Val Leu Asp Leu Gly Arg Glu Asp Pro Glu Val Gln Ile Ser Trp

35 40 45

Phe Val Asp Gly Lys Glu Val His Thr Ala Lys Thr Gln Pro Arg Glu

50 55 60

Gln Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Pro Ile Glu

65 70 75 80

His Gln Asp Trp Leu Thr Gly Lys Glu Phe Lys Cys Arg Val Asn His

85 90 95

Ile Gly Leu Pro Ser Pro Ile Glu Arg Thr Ile Ser Lys Ala Arg Gly

100 105 110

Gln Ala His Gln Pro Ser Val Tyr Val Leu Pro Pro Ser Pro Lys Glu

115 120 125

Leu Ser Ser Ser Asp Thr Val Thr Leu Thr Cys Leu Ile Lys Asp Phe

130 135 140

Phe Pro Pro Glu Ile Asp Val Glu Trp Gln Ser Asn Gly Gln Pro Glu

145 150 155 160

Pro Glu Ser Lys Tyr His Thr Thr Ala Pro Gln Leu Asp Glu Asp Gly

165 170 175

Ser Tyr Phe Leu Tyr Ser Lys Leu Ser Val Asp Lys Ser Arg Trp Gln

180 185 190

Gln Gly Asp Thr Phe Thr Cys Ala Val Met His Glu Ala Leu His Asn

195 200 205

His Tyr Thr Asp Leu Ser Leu Ser His Ser Pro Gly Lys

210 215 220

<210> 46

<211> 220

<212> PRT

<213> 人工序列

<220>

<223> 合成的: 示例性变体犬类IgG-B Fc 蛋白A + C1q -

K(93)R

<400> 46

Pro Ala Pro Glu Met Leu Gly Gly Pro Ser Val Phe Ile Phe Pro Pro

1 5 10 15

Lys Pro Lys Asp Thr Leu Leu Ile Ala Arg Thr Pro Glu Val Thr Cys

20 25 30

Val Val Val Asp Leu Asp Pro Glu Asp Pro Glu Val Gln Ile Ser Trp

35 40 45

Phe Val Asp Gly Lys Gln Met Gln Thr Ala Lys Thr Gln Pro Arg Glu

50 55 60

Glu Gln Phe Asn Gly Thr Tyr Arg Val Val Ser Val Leu Pro Ile Gly

65 70 75 80

His Gln Asp Trp Leu Lys Gly Lys Gln Phe Thr Cys Arg Val Asn Asn

85 90 95

Lys Ala Leu Pro Ser Pro Ile Glu Arg Thr Ile Ser Lys Ala Arg Gly

100 105 110

Gln Ala His Gln Pro Ser Val Tyr Val Leu Pro Pro Ser Arg Glu Glu

115 120 125

Leu Ser Lys Asn Thr Val Ser Leu Thr Cys Leu Ile Lys Asp Phe Phe

130 135 140

Pro Pro Asp Ile Asp Val Glu Trp Gln Ser Asn Gly Gln Gln Glu Pro

145 150 155 160

Glu Ser Lys Tyr Arg Thr Thr Pro Pro Gln Leu Asp Glu Asp Gly Ser

165 170 175

Tyr Phe Leu Tyr Ser Lys Leu Ser Val Asp Lys Ser Arg Trp Gln Arg

180 185 190

Gly Asp Thr Phe Ile Cys Ala Val Met His Glu Ala Leu His Asn His

195 200 205

Tyr Thr Gln Glu Ser Leu Ser His Ser Pro Gly Lys

210 215 220

<210> 47

<211> 220

<212> PRT

<213> 人工序列

<220>

<223> 合成的: 示例性变体犬类IgG-C Fc 蛋白A - C1q -

CD16 + K(93)R

<400> 47

Pro Gly Cys Gly Leu Leu Gly Gly Pro Ser Val Phe Ile Phe Pro Pro

1 5 10 15

Lys Pro Lys Asp Ile Leu Val Thr Ala Arg Thr Pro Thr Val Thr Cys

20 25 30

Val Val Val Asp Leu Asp Pro Glu Asn Pro Glu Val Gln Ile Ser Trp

35 40 45

Phe Val Asp Ser Lys Gln Val Gln Thr Ala Asn Thr Gln Pro Arg Glu

50 55 60

Glu Gln Ser Asn Gly Thr Tyr Arg Val Val Ser Val Leu Pro Ile Gly

65 70 75 80

His Gln Asp Trp Leu Ser Gly Lys Gln Phe Lys Cys Arg Val Asn Asn

85 90 95

Lys Ala Leu Pro Ser Pro Ile Glu Glu Ile Ile Ser Lys Thr Pro Gly

100 105 110

Gln Ala His Gln Pro Asn Val Tyr Val Leu Pro Pro Ser Arg Asp Glu

115 120 125

Met Ser Lys Asn Thr Val Thr Leu Thr Cys Leu Val Lys Asp Phe Phe

130 135 140

Pro Pro Glu Ile Asp Val Glu Trp Gln Ser Asn Gly Gln Gln Glu Pro

145 150 155 160

Glu Ser Lys Tyr Arg Met Thr Pro Pro Gln Leu Asp Glu Asp Gly Ser

165 170 175

Tyr Phe Leu Tyr Ser Lys Leu Ser Val Asp Lys Ser Arg Trp Gln Arg

180 185 190

Gly Asp Thr Phe Ile Cys Ala Val Met His Glu Ala Leu His Asn His

195 200 205

Tyr Thr Gln Ile Ser Leu Ser His Ser Pro Gly Lys

210 215 220

<210> 48

<211> 220

<212> PRT

<213> 人工序列

<220>

<223> 合成的: 示例性变体犬类IgG-B Fc 蛋白A + C1q +

CD16 - M(5)P

<400> 48

Pro Ala Pro Glu Pro Leu Gly Gly Pro Ser Val Phe Ile Phe Pro Pro

1 5 10 15

Lys Pro Lys Asp Thr Leu Leu Ile Ala Arg Thr Pro Glu Val Thr Cys

20 25 30

Val Val Val Asp Leu Asp Pro Glu Asp Pro Glu Val Gln Ile Ser Trp

35 40 45

Phe Val Asp Gly Lys Gln Met Gln Thr Ala Lys Thr Gln Pro Arg Glu

50 55 60

Glu Gln Phe Asn Gly Thr Tyr Arg Val Val Ser Val Leu Pro Ile Gly

65 70 75 80

His Gln Asp Trp Leu Lys Gly Lys Gln Phe Thr Cys Lys Val Asn Asn

85 90 95

Lys Ala Leu Pro Ser Pro Ile Glu Arg Thr Ile Ser Lys Ala Arg Gly

100 105 110

Gln Ala His Gln Pro Ser Val Tyr Val Leu Pro Pro Ser Arg Glu Glu

115 120 125

Leu Ser Lys Asn Thr Val Ser Leu Thr Cys Leu Ile Lys Asp Phe Phe

130 135 140

Pro Pro Asp Ile Asp Val Glu Trp Gln Ser Asn Gly Gln Gln Glu Pro

145 150 155 160

Glu Ser Lys Tyr Arg Thr Thr Pro Pro Gln Leu Asp Glu Asp Gly Ser

165 170 175

Tyr Phe Leu Tyr Ser Lys Leu Ser Val Asp Lys Ser Arg Trp Gln Arg

180 185 190

Gly Asp Thr Phe Ile Cys Ala Val Met His Glu Ala Leu His Asn His

195 200 205

Tyr Thr Gln Glu Ser Leu Ser His Ser Pro Gly Lys

210 215 220

<210> 49

<211> 220

<212> PRT

<213> 人工序列

<220>

<223> 合成的: 示例性变体犬类IgG-B Fc 蛋白A + C1q +

CD16 - P(39)R

<400> 49

Pro Ala Pro Glu Met Leu Gly Gly Pro Ser Val Phe Ile Phe Pro Pro

1 5 10 15

Lys Pro Lys Asp Thr Leu Leu Ile Ala Arg Thr Pro Glu Val Thr Cys

20 25 30

Val Val Val Asp Leu Asp Arg Glu Asp Pro Glu Val Gln Ile Ser Trp

35 40 45

Phe Val Asp Gly Lys Gln Met Gln Thr Ala Lys Thr Gln Pro Arg Glu

50 55 60

Glu Gln Phe Asn Gly Thr Tyr Arg Val Val Ser Val Leu Pro Ile Gly

65 70 75 80

His Gln Asp Trp Leu Lys Gly Lys Gln Phe Thr Cys Lys Val Asn Asn

85 90 95

Lys Ala Leu Pro Ser Pro Ile Glu Arg Thr Ile Ser Lys Ala Arg Gly

100 105 110

Gln Ala His Gln Pro Ser Val Tyr Val Leu Pro Pro Ser Arg Glu Glu

115 120 125

Leu Ser Lys Asn Thr Val Ser Leu Thr Cys Leu Ile Lys Asp Phe Phe

130 135 140

Pro Pro Asp Ile Asp Val Glu Trp Gln Ser Asn Gly Gln Gln Glu Pro

145 150 155 160

Glu Ser Lys Tyr Arg Thr Thr Pro Pro Gln Leu Asp Glu Asp Gly Ser

165 170 175

Tyr Phe Leu Tyr Ser Lys Leu Ser Val Asp Lys Ser Arg Trp Gln Arg

180 185 190

Gly Asp Thr Phe Ile Cys Ala Val Met His Glu Ala Leu His Asn His

195 200 205

Tyr Thr Gln Glu Ser Leu Ser His Ser Pro Gly Lys

210 215 220

<210> 50

<211> 220

<212> PRT

<213> 人工序列

<220>

<223> 合成的: 示例性变体犬类IgG-B Fc 蛋白A + C1q +

CD16 - D(38)G

<400> 50

Pro Ala Pro Glu Met Leu Gly Gly Pro Ser Val Phe Ile Phe Pro Pro

1 5 10 15

Lys Pro Lys Asp Thr Leu Leu Ile Ala Arg Thr Pro Glu Val Thr Cys

20 25 30

Val Val Val Asp Leu Gly Pro Glu Asp Pro Glu Val Gln Ile Ser Trp

35 40 45

Phe Val Asp Gly Lys Gln Met Gln Thr Ala Lys Thr Gln Pro Arg Glu

50 55 60

Glu Gln Phe Asn Gly Thr Tyr Arg Val Val Ser Val Leu Pro Ile Gly

65 70 75 80

His Gln Asp Trp Leu Lys Gly Lys Gln Phe Thr Cys Lys Val Asn Asn

85 90 95

Lys Ala Leu Pro Ser Pro Ile Glu Arg Thr Ile Ser Lys Ala Arg Gly

100 105 110

Gln Ala His Gln Pro Ser Val Tyr Val Leu Pro Pro Ser Arg Glu Glu

115 120 125

Leu Ser Lys Asn Thr Val Ser Leu Thr Cys Leu Ile Lys Asp Phe Phe

130 135 140

Pro Pro Asp Ile Asp Val Glu Trp Gln Ser Asn Gly Gln Gln Glu Pro

145 150 155 160

Glu Ser Lys Tyr Arg Thr Thr Pro Pro Gln Leu Asp Glu Asp Gly Ser

165 170 175

Tyr Phe Leu Tyr Ser Lys Leu Ser Val Asp Lys Ser Arg Trp Gln Arg

180 185 190

Gly Asp Thr Phe Ile Cys Ala Val Met His Glu Ala Leu His Asn His

195 200 205

Tyr Thr Gln Glu Ser Leu Ser His Ser Pro Gly Lys

210 215 220

<210> 51

<211> 220

<212> PRT

<213> 人工序列

<220>

<223> 合成的: 示例性变体犬类IgG-B Fc 蛋白A + C1q +

CD16 - D(38)G P(39)R

<400> 51

Pro Ala Pro Glu Met Leu Gly Gly Pro Ser Val Phe Ile Phe Pro Pro

1 5 10 15

Lys Pro Lys Asp Thr Leu Leu Ile Ala Arg Thr Pro Glu Val Thr Cys

20 25 30

Val Val Val Asp Leu Gly Arg Glu Asp Pro Glu Val Gln Ile Ser Trp

35 40 45

Phe Val Asp Gly Lys Gln Met Gln Thr Ala Lys Thr Gln Pro Arg Glu

50 55 60

Glu Gln Phe Asn Gly Thr Tyr Arg Val Val Ser Val Leu Pro Ile Gly

65 70 75 80

His Gln Asp Trp Leu Lys Gly Lys Gln Phe Thr Cys Lys Val Asn Asn

85 90 95

Lys Ala Leu Pro Ser Pro Ile Glu Arg Thr Ile Ser Lys Ala Arg Gly

100 105 110

Gln Ala His Gln Pro Ser Val Tyr Val Leu Pro Pro Ser Arg Glu Glu

115 120 125

Leu Ser Lys Asn Thr Val Ser Leu Thr Cys Leu Ile Lys Asp Phe Phe

130 135 140

Pro Pro Asp Ile Asp Val Glu Trp Gln Ser Asn Gly Gln Gln Glu Pro

145 150 155 160

Glu Ser Lys Tyr Arg Thr Thr Pro Pro Gln Leu Asp Glu Asp Gly Ser

165 170 175

Tyr Phe Leu Tyr Ser Lys Leu Ser Val Asp Lys Ser Arg Trp Gln Arg

180 185 190

Gly Asp Thr Phe Ile Cys Ala Val Met His Glu Ala Leu His Asn His

195 200 205

Tyr Thr Gln Glu Ser Leu Ser His Ser Pro Gly Lys

210 215 220

<210> 52

<211> 220

<212> PRT

<213> 人工序列

<220>

<223> 合成的: 示例性变体犬类IgG-B Fc 蛋白A + C1q +

CD16 - K(97)I

<400> 52

Pro Ala Pro Glu Met Leu Gly Gly Pro Ser Val Phe Ile Phe Pro Pro

1 5 10 15

Lys Pro Lys Asp Thr Leu Leu Ile Ala Arg Thr Pro Glu Val Thr Cys

20 25 30

Val Val Val Asp Leu Asp Pro Glu Asp Pro Glu Val Gln Ile Ser Trp

35 40 45

Phe Val Asp Gly Lys Gln Met Gln Thr Ala Lys Thr Gln Pro Arg Glu

50 55 60

Glu Gln Phe Asn Gly Thr Tyr Arg Val Val Ser Val Leu Pro Ile Gly

65 70 75 80

His Gln Asp Trp Leu Lys Gly Lys Gln Phe Thr Cys Lys Val Asn Asn

85 90 95

Ile Ala Leu Pro Ser Pro Ile Glu Arg Thr Ile Ser Lys Ala Arg Gly

100 105 110

Gln Ala His Gln Pro Ser Val Tyr Val Leu Pro Pro Ser Arg Glu Glu

115 120 125

Leu Ser Lys Asn Thr Val Ser Leu Thr Cys Leu Ile Lys Asp Phe Phe

130 135 140

Pro Pro Asp Ile Asp Val Glu Trp Gln Ser Asn Gly Gln Gln Glu Pro

145 150 155 160

Glu Ser Lys Tyr Arg Thr Thr Pro Pro Gln Leu Asp Glu Asp Gly Ser

165 170 175

Tyr Phe Leu Tyr Ser Lys Leu Ser Val Asp Lys Ser Arg Trp Gln Arg

180 185 190

Gly Asp Thr Phe Ile Cys Ala Val Met His Glu Ala Leu His Asn His

195 200 205

Tyr Thr Gln Glu Ser Leu Ser His Ser Pro Gly Lys

210 215 220

<210> 53

<211> 220

<212> PRT

<213> 人工序列

<220>

<223> 合成的: 示例性变体犬类IgG-B Fc 蛋白A + C1q +

CD16 - A(98)G

<400> 53

Pro Ala Pro Glu Met Leu Gly Gly Pro Ser Val Phe Ile Phe Pro Pro

1 5 10 15

Lys Pro Lys Asp Thr Leu Leu Ile Ala Arg Thr Pro Glu Val Thr Cys

20 25 30

Val Val Val Asp Leu Asp Pro Glu Asp Pro Glu Val Gln Ile Ser Trp

35 40 45

Phe Val Asp Gly Lys Gln Met Gln Thr Ala Lys Thr Gln Pro Arg Glu

50 55 60

Glu Gln Phe Asn Gly Thr Tyr Arg Val Val Ser Val Leu Pro Ile Gly

65 70 75 80

His Gln Asp Trp Leu Lys Gly Lys Gln Phe Thr Cys Lys Val Asn Asn

85 90 95

Lys Gly Leu Pro Ser Pro Ile Glu Arg Thr Ile Ser Lys Ala Arg Gly

100 105 110

Gln Ala His Gln Pro Ser Val Tyr Val Leu Pro Pro Ser Arg Glu Glu

115 120 125

Leu Ser Lys Asn Thr Val Ser Leu Thr Cys Leu Ile Lys Asp Phe Phe

130 135 140

Pro Pro Asp Ile Asp Val Glu Trp Gln Ser Asn Gly Gln Gln Glu Pro

145 150 155 160

Glu Ser Lys Tyr Arg Thr Thr Pro Pro Gln Leu Asp Glu Asp Gly Ser

165 170 175

Tyr Phe Leu Tyr Ser Lys Leu Ser Val Asp Lys Ser Arg Trp Gln Arg

180 185 190

Gly Asp Thr Phe Ile Cys Ala Val Met His Glu Ala Leu His Asn His

195 200 205

Tyr Thr Gln Glu Ser Leu Ser His Ser Pro Gly Lys

210 215 220

<210> 54

<211> 220

<212> PRT

<213> 人工序列

<220>

<223> 合成的: 示例性变体犬类IgG-B Fc 蛋白A + C1q +

CD16 - D(38)G K(97)I A(98)G

<400> 54

Pro Ala Pro Glu Met Leu Gly Gly Pro Ser Val Phe Ile Phe Pro Pro

1 5 10 15

Lys Pro Lys Asp Thr Leu Leu Ile Ala Arg Thr Pro Glu Val Thr Cys

20 25 30

Val Val Val Asp Leu Gly Pro Glu Asp Pro Glu Val Gln Ile Ser Trp

35 40 45

Phe Val Asp Gly Lys Gln Met Gln Thr Ala Lys Thr Gln Pro Arg Glu

50 55 60

Glu Gln Phe Asn Gly Thr Tyr Arg Val Val Ser Val Leu Pro Ile Gly

65 70 75 80

His Gln Asp Trp Leu Lys Gly Lys Gln Phe Thr Cys Lys Val Asn Asn

85 90 95

Ile Gly Leu Pro Ser Pro Ile Glu Arg Thr Ile Ser Lys Ala Arg Gly

100 105 110

Gln Ala His Gln Pro Ser Val Tyr Val Leu Pro Pro Ser Arg Glu Glu

115 120 125

Leu Ser Lys Asn Thr Val Ser Leu Thr Cys Leu Ile Lys Asp Phe Phe

130 135 140

Pro Pro Asp Ile Asp Val Glu Trp Gln Ser Asn Gly Gln Gln Glu Pro

145 150 155 160

Glu Ser Lys Tyr Arg Thr Thr Pro Pro Gln Leu Asp Glu Asp Gly Ser

165 170 175

Tyr Phe Leu Tyr Ser Lys Leu Ser Val Asp Lys Ser Arg Trp Gln Arg

180 185 190

Gly Asp Thr Phe Ile Cys Ala Val Met His Glu Ala Leu His Asn His

195 200 205

Tyr Thr Gln Glu Ser Leu Ser His Ser Pro Gly Lys

210 215 220

<210> 55

<211> 220

<212> PRT

<213> 人工序列

<220>

<223> 合成的: 示例性变体犬类IgG-B Fc 蛋白A + C1q +

CD16 - M(5)P P(39)R

<400> 55

Pro Ala Pro Glu Pro Leu Gly Gly Pro Ser Val Phe Ile Phe Pro Pro

1 5 10 15

Lys Pro Lys Asp Thr Leu Leu Ile Ala Arg Thr Pro Glu Val Thr Cys

20 25 30

Val Val Val Asp Leu Asp Arg Glu Asp Pro Glu Val Gln Ile Ser Trp

35 40 45

Phe Val Asp Gly Lys Gln Met Gln Thr Ala Lys Thr Gln Pro Arg Glu

50 55 60

Glu Gln Phe Asn Gly Thr Tyr Arg Val Val Ser Val Leu Pro Ile Gly

65 70 75 80

His Gln Asp Trp Leu Lys Gly Lys Gln Phe Thr Cys Lys Val Asn Asn

85 90 95

Lys Ala Leu Pro Ser Pro Ile Glu Arg Thr Ile Ser Lys Ala Arg Gly

100 105 110

Gln Ala His Gln Pro Ser Val Tyr Val Leu Pro Pro Ser Arg Glu Glu

115 120 125

Leu Ser Lys Asn Thr Val Ser Leu Thr Cys Leu Ile Lys Asp Phe Phe

130 135 140

Pro Pro Asp Ile Asp Val Glu Trp Gln Ser Asn Gly Gln Gln Glu Pro

145 150 155 160

Glu Ser Lys Tyr Arg Thr Thr Pro Pro Gln Leu Asp Glu Asp Gly Ser

165 170 175

Tyr Phe Leu Tyr Ser Lys Leu Ser Val Asp Lys Ser Arg Trp Gln Arg

180 185 190

Gly Asp Thr Phe Ile Cys Ala Val Met His Glu Ala Leu His Asn His

195 200 205

Tyr Thr Gln Glu Ser Leu Ser His Ser Pro Gly Lys

210 215 220

<210> 56

<211> 220

<212> PRT

<213> 人工序列

<220>

<223> 合成的: 示例性变体犬类IgG-C Fc 蛋白A - C1q +

CD16 - L(5)P

<400> 56

Pro Gly Cys Gly Pro Leu Gly Gly Pro Ser Val Phe Ile Phe Pro Pro

1 5 10 15

Lys Pro Lys Asp Ile Leu Val Thr Ala Arg Thr Pro Thr Val Thr Cys

20 25 30

Val Val Val Asp Leu Asp Pro Glu Asn Pro Glu Val Gln Ile Ser Trp

35 40 45

Phe Val Asp Ser Lys Gln Val Gln Thr Ala Asn Thr Gln Pro Arg Glu

50 55 60

Glu Gln Ser Asn Gly Thr Tyr Arg Val Val Ser Val Leu Pro Ile Gly

65 70 75 80

His Gln Asp Trp Leu Ser Gly Lys Gln Phe Lys Cys Lys Val Asn Asn

85 90 95

Lys Ala Leu Pro Ser Pro Ile Glu Glu Ile Ile Ser Lys Thr Pro Gly

100 105 110

Gln Ala His Gln Pro Asn Val Tyr Val Leu Pro Pro Ser Arg Asp Glu

115 120 125

Met Ser Lys Asn Thr Val Thr Leu Thr Cys Leu Val Lys Asp Phe Phe

130 135 140

Pro Pro Glu Ile Asp Val Glu Trp Gln Ser Asn Gly Gln Gln Glu Pro

145 150 155 160

Glu Ser Lys Tyr Arg Met Thr Pro Pro Gln Leu Asp Glu Asp Gly Ser

165 170 175

Tyr Phe Leu Tyr Ser Lys Leu Ser Val Asp Lys Ser Arg Trp Gln Arg

180 185 190

Gly Asp Thr Phe Ile Cys Ala Val Met His Glu Ala Leu His Asn His

195 200 205

Tyr Thr Gln Ile Ser Leu Ser His Ser Pro Gly Lys

210 215 220

<210> 57

<211> 220

<212> PRT

<213> 人工序列

<220>

<223> 合成的: 示例性变体犬类IgG-C Fc 蛋白A - C1q +

CD16 - P(39)R

<400> 57

Pro Gly Cys Gly Leu Leu Gly Gly Pro Ser Val Phe Ile Phe Pro Pro

1 5 10 15

Lys Pro Lys Asp Ile Leu Val Thr Ala Arg Thr Pro Thr Val Thr Cys

20 25 30

Val Val Val Asp Leu Asp Arg Glu Asn Pro Glu Val Gln Ile Ser Trp

35 40 45

Phe Val Asp Ser Lys Gln Val Gln Thr Ala Asn Thr Gln Pro Arg Glu

50 55 60

Glu Gln Ser Asn Gly Thr Tyr Arg Val Val Ser Val Leu Pro Ile Gly

65 70 75 80

His Gln Asp Trp Leu Ser Gly Lys Gln Phe Lys Cys Lys Val Asn Asn

85 90 95

Lys Ala Leu Pro Ser Pro Ile Glu Glu Ile Ile Ser Lys Thr Pro Gly

100 105 110

Gln Ala His Gln Pro Asn Val Tyr Val Leu Pro Pro Ser Arg Asp Glu

115 120 125

Met Ser Lys Asn Thr Val Thr Leu Thr Cys Leu Val Lys Asp Phe Phe

130 135 140

Pro Pro Glu Ile Asp Val Glu Trp Gln Ser Asn Gly Gln Gln Glu Pro

145 150 155 160

Glu Ser Lys Tyr Arg Met Thr Pro Pro Gln Leu Asp Glu Asp Gly Ser

165 170 175

Tyr Phe Leu Tyr Ser Lys Leu Ser Val Asp Lys Ser Arg Trp Gln Arg

180 185 190

Gly Asp Thr Phe Ile Cys Ala Val Met His Glu Ala Leu His Asn His

195 200 205

Tyr Thr Gln Ile Ser Leu Ser His Ser Pro Gly Lys

210 215 220

<210> 58

<211> 220

<212> PRT

<213> 人工序列

<220>

<223> 合成的: 示例性变体犬类IgG-C Fc 蛋白A - C1q +

CD16 - D(38)G

<400> 58

Pro Gly Cys Gly Leu Leu Gly Gly Pro Ser Val Phe Ile Phe Pro Pro

1 5 10 15

Lys Pro Lys Asp Ile Leu Val Thr Ala Arg Thr Pro Thr Val Thr Cys

20 25 30

Val Val Val Asp Leu Gly Pro Glu Asn Pro Glu Val Gln Ile Ser Trp

35 40 45

Phe Val Asp Ser Lys Gln Val Gln Thr Ala Asn Thr Gln Pro Arg Glu

50 55 60

Glu Gln Ser Asn Gly Thr Tyr Arg Val Val Ser Val Leu Pro Ile Gly

65 70 75 80

His Gln Asp Trp Leu Ser Gly Lys Gln Phe Lys Cys Lys Val Asn Asn

85 90 95

Lys Ala Leu Pro Ser Pro Ile Glu Glu Ile Ile Ser Lys Thr Pro Gly

100 105 110

Gln Ala His Gln Pro Asn Val Tyr Val Leu Pro Pro Ser Arg Asp Glu

115 120 125

Met Ser Lys Asn Thr Val Thr Leu Thr Cys Leu Val Lys Asp Phe Phe

130 135 140

Pro Pro Glu Ile Asp Val Glu Trp Gln Ser Asn Gly Gln Gln Glu Pro

145 150 155 160

Glu Ser Lys Tyr Arg Met Thr Pro Pro Gln Leu Asp Glu Asp Gly Ser

165 170 175

Tyr Phe Leu Tyr Ser Lys Leu Ser Val Asp Lys Ser Arg Trp Gln Arg

180 185 190

Gly Asp Thr Phe Ile Cys Ala Val Met His Glu Ala Leu His Asn His

195 200 205

Tyr Thr Gln Ile Ser Leu Ser His Ser Pro Gly Lys

210 215 220

<210> 59

<211> 220

<212> PRT

<213> 人工序列

<220>

<223> 合成的: 示例性变体犬类IgG-C Fc 蛋白A - C1q +

CD16 - K(97)I

<400> 59

Pro Gly Cys Gly Leu Leu Gly Gly Pro Ser Val Phe Ile Phe Pro Pro

1 5 10 15

Lys Pro Lys Asp Ile Leu Val Thr Ala Arg Thr Pro Thr Val Thr Cys

20 25 30

Val Val Val Asp Leu Asp Pro Glu Asn Pro Glu Val Gln Ile Ser Trp

35 40 45

Phe Val Asp Ser Lys Gln Val Gln Thr Ala Asn Thr Gln Pro Arg Glu

50 55 60

Glu Gln Ser Asn Gly Thr Tyr Arg Val Val Ser Val Leu Pro Ile Gly

65 70 75 80

His Gln Asp Trp Leu Ser Gly Lys Gln Phe Lys Cys Lys Val Asn Asn

85 90 95

Ile Ala Leu Pro Ser Pro Ile Glu Glu Ile Ile Ser Lys Thr Pro Gly

100 105 110

Gln Ala His Gln Pro Asn Val Tyr Val Leu Pro Pro Ser Arg Asp Glu

115 120 125

Met Ser Lys Asn Thr Val Thr Leu Thr Cys Leu Val Lys Asp Phe Phe

130 135 140

Pro Pro Glu Ile Asp Val Glu Trp Gln Ser Asn Gly Gln Gln Glu Pro

145 150 155 160

Glu Ser Lys Tyr Arg Met Thr Pro Pro Gln Leu Asp Glu Asp Gly Ser

165 170 175

Tyr Phe Leu Tyr Ser Lys Leu Ser Val Asp Lys Ser Arg Trp Gln Arg

180 185 190

Gly Asp Thr Phe Ile Cys Ala Val Met His Glu Ala Leu His Asn His

195 200 205

Tyr Thr Gln Ile Ser Leu Ser His Ser Pro Gly Lys

210 215 220

<210> 60

<211> 220

<212> PRT

<213> 人工序列

<220>

<223> 合成的: 示例性变体犬类IgG-C Fc 蛋白A - C1q +

CD16 - A(98)G

<400> 60

Pro Gly Cys Gly Leu Leu Gly Gly Pro Ser Val Phe Ile Phe Pro Pro

1 5 10 15

Lys Pro Lys Asp Ile Leu Val Thr Ala Arg Thr Pro Thr Val Thr Cys

20 25 30

Val Val Val Asp Leu Asp Pro Glu Asn Pro Glu Val Gln Ile Ser Trp

35 40 45

Phe Val Asp Ser Lys Gln Val Gln Thr Ala Asn Thr Gln Pro Arg Glu

50 55 60

Glu Gln Ser Asn Gly Thr Tyr Arg Val Val Ser Val Leu Pro Ile Gly

65 70 75 80

His Gln Asp Trp Leu Ser Gly Lys Gln Phe Lys Cys Lys Val Asn Asn

85 90 95

Lys Gly Leu Pro Ser Pro Ile Glu Glu Ile Ile Ser Lys Thr Pro Gly

100 105 110

Gln Ala His Gln Pro Asn Val Tyr Val Leu Pro Pro Ser Arg Asp Glu

115 120 125

Met Ser Lys Asn Thr Val Thr Leu Thr Cys Leu Val Lys Asp Phe Phe

130 135 140

Pro Pro Glu Ile Asp Val Glu Trp Gln Ser Asn Gly Gln Gln Glu Pro

145 150 155 160

Glu Ser Lys Tyr Arg Met Thr Pro Pro Gln Leu Asp Glu Asp Gly Ser

165 170 175

Tyr Phe Leu Tyr Ser Lys Leu Ser Val Asp Lys Ser Arg Trp Gln Arg

180 185 190

Gly Asp Thr Phe Ile Cys Ala Val Met His Glu Ala Leu His Asn His

195 200 205

Tyr Thr Gln Ile Ser Leu Ser His Ser Pro Gly Lys

210 215 220

<210> 61

<211> 220

<212> PRT

<213> 人工序列

<220>

<223> 合成的: 示例性变体犬类IgG-C Fc 蛋白A - C1q +

CD16 - L(5)P P(39)R

<400> 61

Pro Gly Cys Gly Pro Leu Gly Gly Pro Ser Val Phe Ile Phe Pro Pro

1 5 10 15

Lys Pro Lys Asp Ile Leu Val Thr Ala Arg Thr Pro Thr Val Thr Cys

20 25 30

Val Val Val Asp Leu Asp Arg Glu Asn Pro Glu Val Gln Ile Ser Trp

35 40 45

Phe Val Asp Ser Lys Gln Val Gln Thr Ala Asn Thr Gln Pro Arg Glu

50 55 60

Glu Gln Ser Asn Gly Thr Tyr Arg Val Val Ser Val Leu Pro Ile Gly

65 70 75 80

His Gln Asp Trp Leu Ser Gly Lys Gln Phe Lys Cys Lys Val Asn Asn

85 90 95

Lys Ala Leu Pro Ser Pro Ile Glu Glu Ile Ile Ser Lys Thr Pro Gly

100 105 110

Gln Ala His Gln Pro Asn Val Tyr Val Leu Pro Pro Ser Arg Asp Glu

115 120 125

Met Ser Lys Asn Thr Val Thr Leu Thr Cys Leu Val Lys Asp Phe Phe

130 135 140

Pro Pro Glu Ile Asp Val Glu Trp Gln Ser Asn Gly Gln Gln Glu Pro

145 150 155 160

Glu Ser Lys Tyr Arg Met Thr Pro Pro Gln Leu Asp Glu Asp Gly Ser

165 170 175

Tyr Phe Leu Tyr Ser Lys Leu Ser Val Asp Lys Ser Arg Trp Gln Arg

180 185 190

Gly Asp Thr Phe Ile Cys Ala Val Met His Glu Ala Leu His Asn His

195 200 205

Tyr Thr Gln Ile Ser Leu Ser His Ser Pro Gly Lys

210 215 220

<210> 62

<211> 220

<212> PRT

<213> 人工序列

<220>

<223> 合成的: 示例性变体犬类IgG-C Fc 蛋白A - C1q +

CD16 - D(38)G K(97)I A(98)G

<400> 62

Pro Gly Cys Gly Leu Leu Gly Gly Pro Ser Val Phe Ile Phe Pro Pro

1 5 10 15

Lys Pro Lys Asp Ile Leu Val Thr Ala Arg Thr Pro Thr Val Thr Cys

20 25 30

Val Val Val Asp Leu Gly Pro Glu Asn Pro Glu Val Gln Ile Ser Trp

35 40 45

Phe Val Asp Ser Lys Gln Val Gln Thr Ala Asn Thr Gln Pro Arg Glu

50 55 60

Glu Gln Ser Asn Gly Thr Tyr Arg Val Val Ser Val Leu Pro Ile Gly

65 70 75 80

His Gln Asp Trp Leu Ser Gly Lys Gln Phe Lys Cys Lys Val Asn Asn

85 90 95

Ile Gly Leu Pro Ser Pro Ile Glu Glu Ile Ile Ser Lys Thr Pro Gly

100 105 110

Gln Ala His Gln Pro Asn Val Tyr Val Leu Pro Pro Ser Arg Asp Glu

115 120 125

Met Ser Lys Asn Thr Val Thr Leu Thr Cys Leu Val Lys Asp Phe Phe

130 135 140

Pro Pro Glu Ile Asp Val Glu Trp Gln Ser Asn Gly Gln Gln Glu Pro

145 150 155 160

Glu Ser Lys Tyr Arg Met Thr Pro Pro Gln Leu Asp Glu Asp Gly Ser

165 170 175

Tyr Phe Leu Tyr Ser Lys Leu Ser Val Asp Lys Ser Arg Trp Gln Arg

180 185 190

Gly Asp Thr Phe Ile Cys Ala Val Met His Glu Ala Leu His Asn His

195 200 205

Tyr Thr Gln Ile Ser Leu Ser His Ser Pro Gly Lys

210 215 220

<210> 63

<211> 220

<212> PRT

<213> 人工序列

<220>

<223> 合成的: 示例性变体犬类IgG-C Fc C1q - K(93)R

蛋白A + I(21)T V(23)L T(24)I

<400> 63

Pro Gly Cys Gly Leu Leu Gly Gly Pro Ser Val Phe Ile Phe Pro Pro

1 5 10 15

Lys Pro Lys Asp Thr Leu Leu Ile Ala Arg Thr Pro Thr Val Thr Cys

20 25 30

Val Val Val Asp Leu Asp Pro Glu Asn Pro Glu Val Gln Ile Ser Trp

35 40 45

Phe Val Asp Ser Lys Gln Val Gln Thr Ala Asn Thr Gln Pro Arg Glu

50 55 60

Glu Gln Ser Asn Gly Thr Tyr Arg Val Val Ser Val Leu Pro Ile Gly

65 70 75 80

His Gln Asp Trp Leu Ser Gly Lys Gln Phe Lys Cys Arg Val Asn Asn

85 90 95

Lys Ala Leu Pro Ser Pro Ile Glu Glu Ile Ile Ser Lys Thr Pro Gly

100 105 110

Gln Ala His Gln Pro Asn Val Tyr Val Leu Pro Pro Ser Arg Asp Glu

115 120 125

Met Ser Lys Asn Thr Val Thr Leu Thr Cys Leu Val Lys Asp Phe Phe

130 135 140

Pro Pro Glu Ile Asp Val Glu Trp Gln Ser Asn Gly Gln Gln Glu Pro

145 150 155 160

Glu Ser Lys Tyr Arg Met Thr Pro Pro Gln Leu Asp Glu Asp Gly Ser

165 170 175

Tyr Phe Leu Tyr Ser Lys Leu Ser Val Asp Lys Ser Arg Trp Gln Arg

180 185 190

Gly Asp Thr Phe Ile Cys Ala Val Met His Glu Ala Leu His Asn His

195 200 205

Tyr Thr Gln Ile Ser Leu Ser His Ser Pro Gly Lys

210 215 220

<210> 64

<211> 220

<212> PRT

<213> 人工序列

<220>

<223> 合成的: 示例性变体犬类IgG-B Fc 蛋白A + C1q -

CD16 - K(93)R K(97)I A(98)G

<400> 64

Pro Ala Pro Glu Met Leu Gly Gly Pro Ser Val Phe Ile Phe Pro Pro

1 5 10 15

Lys Pro Lys Asp Thr Leu Leu Ile Ala Arg Thr Pro Glu Val Thr Cys

20 25 30

Val Val Val Asp Leu Asp Pro Glu Asp Pro Glu Val Gln Ile Ser Trp

35 40 45

Phe Val Asp Gly Lys Gln Met Gln Thr Ala Lys Thr Gln Pro Arg Glu

50 55 60

Glu Gln Phe Asn Gly Thr Tyr Arg Val Val Ser Val Leu Pro Ile Gly

65 70 75 80

His Gln Asp Trp Leu Lys Gly Lys Gln Phe Thr Cys Arg Val Asn Asn

85 90 95

Ile Gly Leu Pro Ser Pro Ile Glu Arg Thr Ile Ser Lys Ala Arg Gly

100 105 110

Gln Ala His Gln Pro Ser Val Tyr Val Leu Pro Pro Ser Arg Glu Glu

115 120 125

Leu Ser Lys Asn Thr Val Ser Leu Thr Cys Leu Ile Lys Asp Phe Phe

130 135 140

Pro Pro Asp Ile Asp Val Glu Trp Gln Ser Asn Gly Gln Gln Glu Pro

145 150 155 160

Glu Ser Lys Tyr Arg Thr Thr Pro Pro Gln Leu Asp Glu Asp Gly Ser

165 170 175

Tyr Phe Leu Tyr Ser Lys Leu Ser Val Asp Lys Ser Arg Trp Gln Arg

180 185 190

Gly Asp Thr Phe Ile Cys Ala Val Met His Glu Ala Leu His Asn His

195 200 205

Tyr Thr Gln Glu Ser Leu Ser His Ser Pro Gly Lys

210 215 220

<210> 65

<211> 220

<212> PRT

<213> 人工序列

<220>

<223> 合成的: 示例性变体犬类IgG-B Fc 蛋白A + C1q -

CD16 - D(38)G K(93)R K(97)I A(98)G

<400> 65

Pro Ala Pro Glu Met Leu Gly Gly Pro Ser Val Phe Ile Phe Pro Pro

1 5 10 15

Lys Pro Lys Asp Thr Leu Leu Ile Ala Arg Thr Pro Glu Val Thr Cys

20 25 30

Val Val Val Asp Leu Gly Pro Glu Asp Pro Glu Val Gln Ile Ser Trp

35 40 45

Phe Val Asp Gly Lys Gln Met Gln Thr Ala Lys Thr Gln Pro Arg Glu

50 55 60

Glu Gln Phe Asn Gly Thr Tyr Arg Val Val Ser Val Leu Pro Ile Gly

65 70 75 80

His Gln Asp Trp Leu Lys Gly Lys Gln Phe Thr Cys Arg Val Asn Asn

85 90 95

Ile Gly Leu Pro Ser Pro Ile Glu Arg Thr Ile Ser Lys Ala Arg Gly

100 105 110

Gln Ala His Gln Pro Ser Val Tyr Val Leu Pro Pro Ser Arg Glu Glu

115 120 125

Leu Ser Lys Asn Thr Val Ser Leu Thr Cys Leu Ile Lys Asp Phe Phe

130 135 140

Pro Pro Asp Ile Asp Val Glu Trp Gln Ser Asn Gly Gln Gln Glu Pro

145 150 155 160

Glu Ser Lys Tyr Arg Thr Thr Pro Pro Gln Leu Asp Glu Asp Gly Ser

165 170 175

Tyr Phe Leu Tyr Ser Lys Leu Ser Val Asp Lys Ser Arg Trp Gln Arg

180 185 190

Gly Asp Thr Phe Ile Cys Ala Val Met His Glu Ala Leu His Asn His

195 200 205

Tyr Thr Gln Glu Ser Leu Ser His Ser Pro Gly Lys

210 215 220

<210> 66

<211> 220

<212> PRT

<213> 人工序列

<220>

<223> 合成的: 示例性变体犬类IgG-B Fc 蛋白A + C1q -

CD16 - M(5)P P(39)R K(93)R

<400> 66

Pro Ala Pro Glu Pro Leu Gly Gly Pro Ser Val Phe Ile Phe Pro Pro

1 5 10 15

Lys Pro Lys Asp Thr Leu Leu Ile Ala Arg Thr Pro Glu Val Thr Cys

20 25 30

Val Val Val Asp Leu Asp Arg Glu Asp Pro Glu Val Gln Ile Ser Trp

35 40 45

Phe Val Asp Gly Lys Gln Met Gln Thr Ala Lys Thr Gln Pro Arg Glu

50 55 60

Glu Gln Phe Asn Gly Thr Tyr Arg Val Val Ser Val Leu Pro Ile Gly

65 70 75 80

His Gln Asp Trp Leu Lys Gly Lys Gln Phe Thr Cys Arg Val Asn Asn

85 90 95

Lys Ala Leu Pro Ser Pro Ile Glu Arg Thr Ile Ser Lys Ala Arg Gly

100 105 110

Gln Ala His Gln Pro Ser Val Tyr Val Leu Pro Pro Ser Arg Glu Glu

115 120 125

Leu Ser Lys Asn Thr Val Ser Leu Thr Cys Leu Ile Lys Asp Phe Phe

130 135 140

Pro Pro Asp Ile Asp Val Glu Trp Gln Ser Asn Gly Gln Gln Glu Pro

145 150 155 160

Glu Ser Lys Tyr Arg Thr Thr Pro Pro Gln Leu Asp Glu Asp Gly Ser

165 170 175

Tyr Phe Leu Tyr Ser Lys Leu Ser Val Asp Lys Ser Arg Trp Gln Arg

180 185 190

Gly Asp Thr Phe Ile Cys Ala Val Met His Glu Ala Leu His Asn His

195 200 205

Tyr Thr Gln Glu Ser Leu Ser His Ser Pro Gly Lys

210 215 220

<210> 67

<211> 220

<212> PRT

<213> 人工序列

<220>

<223> 合成的: 示例性变体犬类IgG-B Fc 蛋白A + C1q -

CD16 - M(5)P D(38)G P(39)R K(93)R

<400> 67

Pro Ala Pro Glu Pro Leu Gly Gly Pro Ser Val Phe Ile Phe Pro Pro

1 5 10 15

Lys Pro Lys Asp Thr Leu Leu Ile Ala Arg Thr Pro Glu Val Thr Cys

20 25 30

Val Val Val Asp Leu Gly Arg Glu Asp Pro Glu Val Gln Ile Ser Trp

35 40 45

Phe Val Asp Gly Lys Gln Met Gln Thr Ala Lys Thr Gln Pro Arg Glu

50 55 60

Glu Gln Phe Asn Gly Thr Tyr Arg Val Val Ser Val Leu Pro Ile Gly

65 70 75 80

His Gln Asp Trp Leu Lys Gly Lys Gln Phe Thr Cys Arg Val Asn Asn

85 90 95

Lys Ala Leu Pro Ser Pro Ile Glu Arg Thr Ile Ser Lys Ala Arg Gly

100 105 110

Gln Ala His Gln Pro Ser Val Tyr Val Leu Pro Pro Ser Arg Glu Glu

115 120 125

Leu Ser Lys Asn Thr Val Ser Leu Thr Cys Leu Ile Lys Asp Phe Phe

130 135 140

Pro Pro Asp Ile Asp Val Glu Trp Gln Ser Asn Gly Gln Gln Glu Pro

145 150 155 160

Glu Ser Lys Tyr Arg Thr Thr Pro Pro Gln Leu Asp Glu Asp Gly Ser

165 170 175

Tyr Phe Leu Tyr Ser Lys Leu Ser Val Asp Lys Ser Arg Trp Gln Arg

180 185 190

Gly Asp Thr Phe Ile Cys Ala Val Met His Glu Ala Leu His Asn His

195 200 205

Tyr Thr Gln Glu Ser Leu Ser His Ser Pro Gly Lys

210 215 220

<210> 68

<211> 220

<212> PRT

<213> 人工序列

<220>

<223> 合成的: 示例性变体犬类IgG-C Fc 蛋白A - C1q -

CD16 - D(38)G K(93)R K(97)I A(98)G

<400> 68

Pro Gly Cys Gly Leu Leu Gly Gly Pro Ser Val Phe Ile Phe Pro Pro

1 5 10 15

Lys Pro Lys Asp Ile Leu Val Thr Ala Arg Thr Pro Thr Val Thr Cys

20 25 30

Val Val Val Asp Leu Gly Pro Glu Asn Pro Glu Val Gln Ile Ser Trp

35 40 45

Phe Val Asp Ser Lys Gln Val Gln Thr Ala Asn Thr Gln Pro Arg Glu

50 55 60

Glu Gln Ser Asn Gly Thr Tyr Arg Val Val Ser Val Leu Pro Ile Gly

65 70 75 80

His Gln Asp Trp Leu Ser Gly Lys Gln Phe Lys Cys Arg Val Asn Asn

85 90 95

Ile Gly Leu Pro Ser Pro Ile Glu Glu Ile Ile Ser Lys Thr Pro Gly

100 105 110

Gln Ala His Gln Pro Asn Val Tyr Val Leu Pro Pro Ser Arg Asp Glu

115 120 125

Met Ser Lys Asn Thr Val Thr Leu Thr Cys Leu Val Lys Asp Phe Phe

130 135 140

Pro Pro Glu Ile Asp Val Glu Trp Gln Ser Asn Gly Gln Gln Glu Pro

145 150 155 160

Glu Ser Lys Tyr Arg Met Thr Pro Pro Gln Leu Asp Glu Asp Gly Ser

165 170 175

Tyr Phe Leu Tyr Ser Lys Leu Ser Val Asp Lys Ser Arg Trp Gln Arg

180 185 190

Gly Asp Thr Phe Ile Cys Ala Val Met His Glu Ala Leu His Asn His

195 200 205

Tyr Thr Gln Ile Ser Leu Ser His Ser Pro Gly Lys

210 215 220

<210> 69

<211> 220

<212> PRT

<213> 人工序列

<220>

<223> 合成的: 示例性变体犬类IgG-C Fc 蛋白A - C1q -

CD16 - M(5)P P(39)R K(93)R

<400> 69

Pro Gly Cys Gly Pro Leu Gly Gly Pro Ser Val Phe Ile Phe Pro Pro

1 5 10 15

Lys Pro Lys Asp Ile Leu Val Thr Ala Arg Thr Pro Thr Val Thr Cys

20 25 30

Val Val Val Asp Leu Asp Arg Glu Asn Pro Glu Val Gln Ile Ser Trp

35 40 45

Phe Val Asp Ser Lys Gln Val Gln Thr Ala Asn Thr Gln Pro Arg Glu

50 55 60

Glu Gln Ser Asn Gly Thr Tyr Arg Val Val Ser Val Leu Pro Ile Gly

65 70 75 80

His Gln Asp Trp Leu Ser Gly Lys Gln Phe Lys Cys Arg Val Asn Asn

85 90 95

Lys Ala Leu Pro Ser Pro Ile Glu Glu Ile Ile Ser Lys Thr Pro Gly

100 105 110

Gln Ala His Gln Pro Asn Val Tyr Val Leu Pro Pro Ser Arg Asp Glu

115 120 125

Met Ser Lys Asn Thr Val Thr Leu Thr Cys Leu Val Lys Asp Phe Phe

130 135 140

Pro Pro Glu Ile Asp Val Glu Trp Gln Ser Asn Gly Gln Gln Glu Pro

145 150 155 160

Glu Ser Lys Tyr Arg Met Thr Pro Pro Gln Leu Asp Glu Asp Gly Ser

165 170 175

Tyr Phe Leu Tyr Ser Lys Leu Ser Val Asp Lys Ser Arg Trp Gln Arg

180 185 190

Gly Asp Thr Phe Ile Cys Ala Val Met His Glu Ala Leu His Asn His

195 200 205

Tyr Thr Gln Ile Ser Leu Ser His Ser Pro Gly Lys

210 215 220

<210> 70

<211> 214

<212> PRT

<213> 人工序列

<220>

<223> 合成的: 示例性野生型马类IgG1 Fc 蛋白A + C1q +

<400> 70

Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Asn Pro Lys Asp Thr Leu

1 5 10 15

Met Ile Thr Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser

20 25 30

Gln Glu Asn Pro Asp Val Lys Phe Asn Trp Tyr Met Asp Gly Val Glu

35 40 45

Val Arg Thr Ala Thr Thr Arg Pro Lys Glu Glu Gln Phe Asn Ser Thr

50 55 60

Tyr Arg Val Val Ser Val Leu Arg Ile Gln His Gln Asp Trp Leu Ser

65 70 75 80

Gly Lys Glu Phe Lys Cys Lys Val Asn Asn Gln Ala Leu Pro Gln Pro

85 90 95

Ile Glu Arg Thr Ile Thr Lys Thr Lys Gly Arg Ser Gln Glu Pro Gln

100 105 110

Val Tyr Val Leu Ala Pro His Pro Asp Glu Ser Lys Lys Ser Lys Val

115 120 125

Ser Val Thr Cys Leu Val Lys Asp Phe Tyr Pro Pro Glu Ile Asn Ile

130 135 140

Glu Trp Gln Ser Asn Gly Gln Pro Glu Leu Glu Thr Lys Tyr Ser Thr

145 150 155 160

Thr Gln Ala Gln Gln Asp Ser Asp Gly Ser Tyr Phe Leu Tyr Ser Lys

165 170 175

Leu Ser Val Asp Arg Asn Arg Trp Gln Gln Gly Thr Thr Phe Thr Cys

180 185 190

Gly Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Asn Val

195 200 205

Ser Lys Asn Pro Gly Lys

210

<210> 71

<211> 214

<212> PRT

<213> 人工序列

<220>

<223> 合成的: 示例性野生型马类IgG2 Fc 蛋白A - C1q -

<400> 71

Gly Gly Pro Ser Val Phe Ile Phe Pro Pro Asn Pro Lys Asp Ala Leu

1 5 10 15

Met Ile Ser Arg Thr Pro Val Val Thr Cys Val Val Val Asn Leu Ser

20 25 30

Asp Gln Tyr Pro Asp Val Gln Phe Ser Trp Tyr Val Asp Asn Thr Glu

35 40 45

Val His Ser Ala Ile Thr Lys Gln Arg Glu Ala Gln Phe Asn Ser Thr

50 55 60

Tyr Arg Val Val Ser Val Leu Pro Ile Gln His Gln Asp Trp Leu Ser

65 70 75 80

Gly Lys Glu Phe Lys Cys Ser Val Thr Asn Val Gly Val Pro Gln Pro

85 90 95

Ile Ser Arg Ala Ile Ser Arg Gly Lys Gly Pro Ser Arg Val Pro Gln

100 105 110

Val Tyr Val Leu Pro Pro His Pro Asp Glu Leu Ala Lys Ser Lys Val

115 120 125

Ser Val Thr Cys Leu Val Lys Asp Phe Tyr Pro Pro Asp Ile Ser Val

130 135 140

Glu Trp Gln Ser Asn Arg Trp Pro Glu Leu Glu Gly Lys Tyr Ser Thr

145 150 155 160

Thr Pro Ala Gln Leu Asp Gly Asp Gly Ser Tyr Phe Leu Tyr Ser Lys

165 170 175

Leu Ser Leu Glu Thr Ser Arg Trp Gln Gln Val Glu Ser Phe Thr Cys

180 185 190

Ala Val Met His Glu Ala Leu His Asn His Phe Thr Lys Thr Asp Ile

195 200 205

Ser Glu Ser Leu Gly Lys

210

<210> 72

<211> 244

<212> PRT

<213> 人工序列

<220>

<223> 合成的: 具有铰链的示例性野生型马类IgG2 Fc 蛋白

A - C1q -

<400> 72

Pro Pro Cys Val Leu Ser Ala Glu Gly Val Ile Pro Ile Pro Ser Val

1 5 10 15

Pro Lys Pro Gln Cys Pro Pro Tyr Thr His Ser Lys Phe Leu Gly Gly

20 25 30

Pro Ser Val Phe Ile Phe Pro Pro Asn Pro Lys Asp Ala Leu Met Ile

35 40 45

Ser Arg Thr Pro Val Val Thr Cys Val Val Val Asn Leu Ser Asp Gln

50 55 60

Tyr Pro Asp Val Gln Phe Ser Trp Tyr Val Asp Asn Thr Glu Val His

65 70 75 80

Ser Ala Ile Thr Lys Gln Arg Glu Ala Gln Phe Asn Ser Thr Tyr Arg

85 90 95

Val Val Ser Val Leu Pro Ile Gln His Gln Asp Trp Leu Ser Gly Lys

100 105 110

Glu Phe Lys Cys Ser Val Thr Asn Val Gly Val Pro Gln Pro Ile Ser

115 120 125

Arg Ala Ile Ser Arg Gly Lys Gly Pro Ser Arg Val Pro Gln Val Tyr

130 135 140

Val Leu Pro Pro His Pro Asp Glu Leu Ala Lys Ser Lys Val Ser Val

145 150 155 160

Thr Cys Leu Val Lys Asp Phe Tyr Pro Pro Asp Ile Ser Val Glu Trp

165 170 175

Gln Ser Asn Arg Trp Pro Glu Leu Glu Gly Lys Tyr Ser Thr Thr Pro

180 185 190

Ala Gln Leu Asp Gly Asp Gly Ser Tyr Phe Leu Tyr Ser Lys Leu Ser

195 200 205

Leu Glu Thr Ser Arg Trp Gln Gln Val Glu Ser Phe Thr Cys Ala Val

210 215 220

Met His Glu Ala Leu His Asn His Phe Thr Lys Thr Asp Ile Ser Glu

225 230 235 240

Ser Leu Gly Lys

<210> 73

<211> 214

<212> PRT

<213> 人工序列

<220>

<223> 合成的: 示例性野生型马类IgG3 Fc 蛋白A + C1q+

<400> 73

Gly Gly Pro Ser Val Phe Ile Phe Pro Pro Lys Pro Lys Asp Val Leu

1 5 10 15

Met Ile Thr Arg Met Pro Glu Val Thr Cys Leu Val Val Asp Val Ser

20 25 30

His Asp Ser Ser Asp Val Leu Phe Thr Trp Tyr Val Asp Gly Thr Glu

35 40 45

Val Lys Thr Ala Lys Thr Met Pro Asn Glu Glu Gln Asn Asn Ser Thr

50 55 60

Tyr Arg Val Val Ser Val Leu Arg Ile Gln His Gln Asp Trp Leu Asn

65 70 75 80

Gly Lys Lys Phe Lys Cys Lys Val Asn Asn Gln Ala Leu Pro Ala Pro

85 90 95

Val Glu Arg Thr Ile Ser Lys Ala Thr Gly Gln Thr Arg Val Pro Gln

100 105 110

Val Tyr Val Leu Ala Pro His Pro Asp Glu Leu Ser Lys Asn Lys Val

115 120 125

Ser Val Thr Cys Leu Val Lys Asp Phe Tyr Pro Pro Asp Ile Thr Val

130 135 140

Glu Trp Gln Ser Asn Glu His Pro Glu Pro Glu Gly Lys Tyr Arg Thr

145 150 155 160

Thr Glu Ala Gln Lys Asp Ser Asp Gly Ser Tyr Phe Leu Tyr Ser Lys

165 170 175

Leu Thr Val Glu Lys Asp Arg Trp Gln Gln Gly Thr Thr Phe Thr Cys

180 185 190

Val Val Met His Glu Ala Leu His Asn His Val Met Gln Lys Asn Ile

195 200 205

Ser Lys Asn Pro Gly Lys

210

<210> 74

<211> 214

<212> PRT

<213> 人工序列

<220>

<223> 合成的: 示例性野生型马类IgG4 Fc 蛋白A + C1q +

<400> 74

Val Gly Pro Ser Val Phe Ile Phe Pro Pro Lys Pro Lys Asp Val Leu

1 5 10 15

Met Ile Ser Arg Thr Pro Thr Val Thr Cys Val Val Val Asp Val Gly

20 25 30

His Asp Phe Pro Asp Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu

35 40 45

Thr His Thr Ala Thr Thr Glu Pro Lys Gln Glu Gln Phe Asn Ser Thr

50 55 60

Tyr Arg Val Val Ser Val Leu Pro Ile Gln His Lys Asp Trp Leu Ser

65 70 75 80

Gly Lys Glu Phe Lys Cys Lys Val Asn Asn Lys Ala Leu Pro Ala Pro

85 90 95

Val Glu Arg Thr Ile Ser Ala Pro Thr Gly Gln Pro Arg Glu Pro Gln

100 105 110

Val Tyr Val Leu Ala Pro His Arg Asp Glu Leu Ser Lys Asn Lys Val

115 120 125

Ser Val Thr Cys Leu Val Lys Asp Phe Tyr Pro Pro Asp Ile Asp Ile

130 135 140

Glu Trp Lys Ser Asn Gly Gln Pro Glu Pro Glu Thr Lys Tyr Ser Thr

145 150 155 160

Thr Pro Ala Gln Leu Asp Ser Asp Gly Ser Tyr Phe Leu Tyr Ser Lys

165 170 175

Leu Thr Val Glu Thr Asn Arg Trp Gln Gln Gly Thr Thr Phe Thr Cys

180 185 190

Ala Val Met His Glu Ala Leu His Asn His Tyr Thr Glu Lys Ser Val

195 200 205

Ser Lys Ser Pro Gly Lys

210

<210> 75

<211> 214

<212> PRT

<213> 人工序列

<220>

<223> 合成的: 示例性野生型马类IgG5 Fc 蛋白A - C1q -

<400> 75

Gly Gly Pro Ser Val Phe Ile Phe Pro Pro Lys Pro Lys Asp Val Leu

1 5 10 15

Met Ile Ser Arg Lys Pro Glu Val Thr Cys Val Val Val Asp Leu Gly

20 25 30

His Asp Asp Pro Asp Val Gln Phe Thr Trp Phe Val Asp Gly Val Glu

35 40 45

Thr His Thr Ala Thr Thr Glu Pro Lys Glu Glu Gln Phe Asn Ser Thr

50 55 60

Tyr Arg Val Val Ser Val Leu Pro Ile Gln His Gln Asp Trp Leu Ser

65 70 75 80

Gly Lys Glu Phe Lys Cys Ser Val Thr Ser Lys Ala Leu Pro Ala Pro

85 90 95

Val Glu Arg Thr Ile Ser Lys Ala Lys Gly Gln Leu Arg Val Pro Gln

100 105 110

Val Tyr Val Leu Ala Pro His Pro Asp Glu Leu Ala Lys Asn Thr Val

115 120 125

Ser Val Thr Cys Leu Val Lys Asp Phe Tyr Pro Pro Glu Ile Asp Val

130 135 140

Glu Trp Gln Ser Asn Glu His Pro Glu Pro Glu Gly Lys Tyr Ser Thr

145 150 155 160

Thr Pro Ala Gln Leu Asn Ser Asp Gly Ser Tyr Phe Leu Tyr Ser Lys

165 170 175

Leu Ser Val Glu Thr Ser Arg Trp Lys Gln Gly Glu Ser Phe Thr Cys

180 185 190

Gly Val Met His Glu Ala Val Glu Asn His Tyr Thr Gln Lys Asn Val

195 200 205

Ser His Ser Pro Gly Lys

210

<210> 76

<211> 214

<212> PRT

<213> 人工序列

<220>

<223> 合成的: 示例性野生型马类IgG6 Fc 蛋白A - C1q -

<400> 76

Gly Arg Pro Ser Val Phe Ile Phe Pro Pro Asn Pro Lys Asp Thr Leu

1 5 10 15

Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser

20 25 30

Gln Glu Asn Pro Asp Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu

35 40 45

Ala His Thr Ala Thr Thr Lys Ala Lys Glu Lys Gln Asp Asn Ser Thr

50 55 60

Tyr Arg Val Val Ser Val Leu Pro Ile Gln His Gln Asp Trp Arg Arg

65 70 75 80

Gly Lys Glu Phe Lys Cys Lys Val Asn Asn Arg Ala Leu Pro Ala Pro

85 90 95

Val Glu Arg Thr Ile Thr Lys Ala Lys Gly Glu Leu Gln Asp Pro Gln

100 105 110

Val Tyr Ile Leu Ala Pro His Pro Asp Glu Val Thr Lys Asn Thr Val

115 120 125

Ser Val Thr Cys Leu Val Lys Asp Phe Tyr Pro Pro Asp Ile Asn Val

130 135 140

Glu Trp Gln Ser Asn Glu Glu Pro Glu Pro Glu Val Lys Tyr Ser Thr

145 150 155 160

Thr Pro Ala Gln Leu Asp Gly Asp Gly Ser Tyr Phe Leu Tyr Ser Lys

165 170 175

Leu Thr Val Glu Thr Asp Arg Trp Glu Gln Gly Glu Ser Phe Thr Cys

180 185 190

Val Val Met His Glu Ala Ile Arg His Thr Tyr Arg Gln Lys Ser Ile

195 200 205

Thr Asn Phe Pro Gly Lys

210

<210> 77

<211> 214

<212> PRT

<213> 人工序列

<220>

<223> 合成的: 示例性野生型马类IgG7 Fc 蛋白A + C1q +

<400> 77

Val Gly Pro Ser Val Phe Ile Phe Pro Pro Lys Pro Lys Asp Val Leu

1 5 10 15

Met Ile Ser Arg Thr Pro Thr Val Thr Cys Val Val Val Asp Val Gly

20 25 30

His Asp Phe Pro Asp Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu

35 40 45

Thr His Thr Ala Thr Thr Glu Pro Lys Gln Glu Gln Asn Asn Ser Thr

50 55 60

Tyr Arg Val Val Ser Ile Leu Ala Ile Gln His Lys Asp Trp Leu Ser

65 70 75 80

Gly Lys Glu Phe Lys Cys Lys Val Asn Asn Gln Ala Leu Pro Ala Pro

85 90 95

Val Gln Lys Thr Ile Ser Lys Pro Thr Gly Gln Pro Arg Glu Pro Gln

100 105 110

Val Tyr Val Leu Ala Pro His Pro Asp Glu Leu Ser Lys Asn Lys Val

115 120 125

Ser Val Thr Cys Leu Val Lys Asp Phe Tyr Pro Pro Asp Ile Asp Ile

130 135 140

Glu Trp Lys Ser Asn Gly Gln Pro Glu Pro Glu Thr Lys Tyr Ser Thr

145 150 155 160

Thr Pro Ala Gln Leu Asp Gly Asp Gly Ser Tyr Phe Leu Tyr Ser Lys

165 170 175

Leu Thr Val Glu Thr Asn Arg Trp Gln Gln Gly Thr Thr Phe Thr Cys

180 185 190

Ala Val Met His Glu Ala Leu His Asn His Tyr Thr Glu Lys Ser Val

195 200 205

Ser Lys Ser Pro Gly Lys

210

<210> 78

<211> 214

<212> PRT

<213> 人工序列

<220>

<223> 合成的: 示例性变体马类IgG2 Fc C1q - 蛋白A +

F(203)Y

<400> 78

Gly Gly Pro Ser Val Phe Ile Phe Pro Pro Asn Pro Lys Asp Ala Leu

1 5 10 15

Met Ile Ser Arg Thr Pro Val Val Thr Cys Val Val Val Asn Leu Ser

20 25 30

Asp Gln Tyr Pro Asp Val Gln Phe Ser Trp Tyr Val Asp Asn Thr Glu

35 40 45

Val His Ser Ala Ile Thr Lys Gln Arg Glu Ala Gln Phe Asn Ser Thr

50 55 60

Tyr Arg Val Val Ser Val Leu Pro Ile Gln His Gln Asp Trp Leu Ser

65 70 75 80

Gly Lys Glu Phe Lys Cys Ser Val Thr Asn Val Gly Val Pro Gln Pro

85 90 95

Ile Ser Arg Ala Ile Ser Arg Gly Lys Gly Pro Ser Arg Val Pro Gln

100 105 110

Val Tyr Val Leu Pro Pro His Pro Asp Glu Leu Ala Lys Ser Lys Val

115 120 125

Ser Val Thr Cys Leu Val Lys Asp Phe Tyr Pro Pro Asp Ile Ser Val

130 135 140

Glu Trp Gln Ser Asn Arg Trp Pro Glu Leu Glu Gly Lys Tyr Ser Thr

145 150 155 160

Thr Pro Ala Gln Leu Asp Gly Asp Gly Ser Tyr Phe Leu Tyr Ser Lys

165 170 175

Leu Ser Leu Glu Thr Ser Arg Trp Gln Gln Gly Glu Ser Phe Thr Cys

180 185 190

Ala Val Met His Glu Ala Leu His Asn His Tyr Thr Lys Thr Asp Ile

195 200 205

Ser Glu Ser Leu Gly Lys

210

<210> 79

<211> 214

<212> PRT

<213> 人工序列

<220>

<223> 合成的: 示例性变体马类IgG2 Fc C1q - 蛋白A +

A(15)T F(203)Y

<400> 79

Gly Gly Pro Ser Val Phe Ile Phe Pro Pro Asn Pro Lys Asp Thr Leu

1 5 10 15

Met Ile Ser Arg Thr Pro Val Val Thr Cys Val Val Val Asn Leu Ser

20 25 30

Asp Gln Tyr Pro Asp Val Gln Phe Ser Trp Tyr Val Asp Asn Thr Glu

35 40 45

Val His Ser Ala Ile Thr Lys Gln Arg Glu Ala Gln Phe Asn Ser Thr

50 55 60

Tyr Arg Val Val Ser Val Leu Pro Ile Gln His Gln Asp Trp Leu Ser

65 70 75 80

Gly Lys Glu Phe Lys Cys Ser Val Thr Asn Val Gly Val Pro Gln Pro

85 90 95

Ile Ser Arg Ala Ile Ser Arg Gly Lys Gly Pro Ser Arg Val Pro Gln

100 105 110

Val Tyr Val Leu Pro Pro His Pro Asp Glu Leu Ala Lys Ser Lys Val

115 120 125

Ser Val Thr Cys Leu Val Lys Asp Phe Tyr Pro Pro Asp Ile Ser Val

130 135 140

Glu Trp Gln Ser Asn Arg Trp Pro Glu Leu Glu Gly Lys Tyr Ser Thr

145 150 155 160

Thr Pro Ala Gln Leu Asp Gly Asp Gly Ser Tyr Phe Leu Tyr Ser Lys

165 170 175

Leu Ser Leu Glu Thr Ser Arg Trp Gln Gln Val Glu Ser Phe Thr Cys

180 185 190

Ala Val Met His Glu Ala Leu His Asn His Tyr Thr Lys Thr Asp Ile

195 200 205

Ser Glu Ser Leu Gly Lys

210

<210> 80

<211> 214

<212> PRT

<213> 人工序列

<220>

<223> 合成的: 示例性变体马类IgG5 Fc C1q - 蛋白A +

V(199)L E(200)H

<400> 80

Gly Gly Pro Ser Val Phe Ile Phe Pro Pro Lys Pro Lys Asp Val Leu

1 5 10 15

Met Ile Ser Arg Lys Pro Glu Val Thr Cys Val Val Val Asp Leu Gly

20 25 30

His Asp Asp Pro Asp Val Gln Phe Thr Trp Phe Val Asp Gly Val Glu

35 40 45

Thr His Thr Ala Thr Thr Glu Pro Lys Glu Glu Gln Phe Asn Ser Thr

50 55 60

Tyr Arg Val Val Ser Val Leu Pro Ile Gln His Gln Asp Trp Leu Ser

65 70 75 80

Gly Lys Glu Phe Lys Cys Ser Val Thr Ser Lys Ala Leu Pro Ala Pro

85 90 95

Val Glu Arg Thr Ile Ser Lys Ala Lys Gly Gln Leu Arg Val Pro Gln

100 105 110

Val Tyr Val Leu Ala Pro His Pro Asp Glu Leu Ala Lys Asn Thr Val

115 120 125

Ser Val Thr Cys Leu Val Lys Asp Phe Tyr Pro Pro Glu Ile Asp Val

130 135 140

Glu Trp Gln Ser Asn Glu His Pro Glu Pro Glu Gly Lys Tyr Ser Thr

145 150 155 160

Thr Pro Ala Gln Leu Asn Ser Asp Gly Ser Tyr Phe Leu Tyr Ser Lys

165 170 175

Leu Ser Val Glu Thr Ser Arg Trp Lys Gln Gly Glu Ser Phe Thr Cys

180 185 190

Gly Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Asn Val

195 200 205

Ser His Ser Pro Gly Lys

210

<210> 81

<211> 214

<212> PRT

<213> 人工序列

<220>

<223> 合成的: 示例性变体马类IgG6 Fc C1q - 蛋白A +

I(199)L R(200)H H(201)N T(202)H

<400> 81

Gly Arg Pro Ser Val Phe Ile Phe Pro Pro Asn Pro Lys Asp Thr Leu

1 5 10 15

Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser

20 25 30

Gln Glu Asn Pro Asp Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu

35 40 45

Ala His Thr Ala Thr Thr Lys Ala Lys Glu Lys Gln Asp Asn Ser Thr

50 55 60

Tyr Arg Val Val Ser Val Leu Pro Ile Gln His Gln Asp Trp Arg Arg

65 70 75 80

Gly Lys Glu Phe Lys Cys Lys Val Asn Asn Arg Ala Leu Pro Ala Pro

85 90 95

Val Glu Arg Thr Ile Thr Lys Ala Lys Gly Glu Leu Gln Asp Pro Gln

100 105 110

Val Tyr Ile Leu Ala Pro His Pro Asp Glu Val Thr Lys Asn Thr Val

115 120 125

Ser Val Thr Cys Leu Val Lys Asp Phe Tyr Pro Pro Asp Ile Asn Val

130 135 140

Glu Trp Gln Ser Asn Glu Glu Pro Glu Pro Glu Val Lys Tyr Ser Thr

145 150 155 160

Thr Pro Ala Gln Leu Asp Gly Asp Gly Ser Tyr Phe Leu Tyr Ser Lys

165 170 175

Leu Thr Val Glu Thr Asp Arg Trp Glu Gln Gly Glu Ser Phe Thr Cys

180 185 190

Val Val Met His Glu Ala Leu His Asn His Tyr Arg Gln Lys Ser Ile

195 200 205

Thr Asn Phe Pro Gly Lys

210

<210> 82

<211> 214

<212> PRT

<213> 人工序列

<220>

<223> 合成的: 示例性变体马类IgG1 Fc 蛋白A + C1q -

K(87)S

<400> 82

Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Asn Pro Lys Asp Thr Leu

1 5 10 15

Met Ile Thr Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser

20 25 30

Gln Glu Asn Pro Asp Val Lys Phe Asn Trp Tyr Met Asp Gly Val Glu

35 40 45

Val Arg Thr Ala Thr Thr Arg Pro Lys Glu Glu Gln Phe Asn Ser Thr

50 55 60

Tyr Arg Val Val Ser Val Leu Arg Ile Gln His Gln Asp Trp Leu Ser

65 70 75 80

Gly Lys Glu Phe Lys Cys Ser Val Asn Asn Gln Ala Leu Pro Gln Pro

85 90 95

Ile Glu Arg Thr Ile Thr Lys Thr Lys Gly Arg Ser Gln Glu Pro Gln

100 105 110

Val Tyr Val Leu Ala Pro His Pro Asp Glu Ser Lys Lys Ser Lys Val

115 120 125

Ser Val Thr Cys Leu Val Lys Asp Phe Tyr Pro Pro Glu Ile Asn Ile

130 135 140

Glu Trp Gln Ser Asn Gly Gln Pro Glu Leu Glu Thr Lys Tyr Ser Thr

145 150 155 160

Thr Gln Ala Gln Gln Asp Ser Asp Gly Ser Tyr Phe Leu Tyr Ser Lys

165 170 175

Leu Ser Val Asp Arg Asn Arg Trp Gln Gln Gly Thr Thr Phe Thr Cys

180 185 190

Gly Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Asn Val

195 200 205

Ser Lys Asn Pro Gly Lys

210

<210> 83

<211> 214

<212> PRT

<213> 人工序列

<220>

<223> 合成的: 示例性变体马类IgG3 Fc 蛋白A + C1q -

K(87)S

<400> 83

Gly Gly Pro Ser Val Phe Ile Phe Pro Pro Lys Pro Lys Asp Val Leu

1 5 10 15

Met Ile Thr Arg Met Pro Glu Val Thr Cys Leu Val Val Asp Val Ser

20 25 30

His Asp Ser Ser Asp Val Leu Phe Thr Trp Tyr Val Asp Gly Thr Glu

35 40 45

Val Lys Thr Ala Lys Thr Met Pro Asn Glu Glu Gln Asn Asn Ser Thr

50 55 60

Tyr Arg Val Val Ser Val Leu Arg Ile Gln His Gln Asp Trp Leu Asn

65 70 75 80

Gly Lys Lys Phe Lys Cys Ser Val Asn Asn Gln Ala Leu Pro Ala Pro

85 90 95

Val Glu Arg Thr Ile Ser Lys Ala Thr Gly Gln Thr Arg Val Pro Gln

100 105 110

Val Tyr Val Leu Ala Pro His Pro Asp Glu Leu Ser Lys Asn Lys Val

115 120 125

Ser Val Thr Cys Leu Val Lys Asp Phe Tyr Pro Pro Asp Ile Thr Val

130 135 140

Glu Trp Gln Ser Asn Glu His Pro Glu Pro Glu Gly Lys Tyr Arg Thr

145 150 155 160

Thr Glu Ala Gln Lys Asp Ser Asp Gly Ser Tyr Phe Leu Tyr Ser Lys

165 170 175

Leu Thr Val Glu Lys Asp Arg Trp Gln Gln Gly Thr Thr Phe Thr Cys

180 185 190

Val Val Met His Glu Ala Leu His Asn His Val Met Gln Lys Asn Ile

195 200 205

Ser Lys Asn Pro Gly Lys

210

<210> 84

<211> 214

<212> PRT

<213> 人工序列

<220>

<223> 合成的: 示例性变体马类IgG4 Fc 蛋白A + C1q -

K(87)S

<400> 84

Val Gly Pro Ser Val Phe Ile Phe Pro Pro Lys Pro Lys Asp Val Leu

1 5 10 15

Met Ile Ser Arg Thr Pro Thr Val Thr Cys Val Val Val Asp Val Gly

20 25 30

His Asp Phe Pro Asp Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu

35 40 45

Thr His Thr Ala Thr Thr Glu Pro Lys Gln Glu Gln Phe Asn Ser Thr

50 55 60

Tyr Arg Val Val Ser Val Leu Pro Ile Gln His Lys Asp Trp Leu Ser

65 70 75 80

Gly Lys Glu Phe Lys Cys Ser Val Asn Asn Lys Ala Leu Pro Ala Pro

85 90 95

Val Glu Arg Thr Ile Ser Ala Pro Thr Gly Gln Pro Arg Glu Pro Gln

100 105 110

Val Tyr Val Leu Ala Pro His Arg Asp Glu Leu Ser Lys Asn Lys Val

115 120 125

Ser Val Thr Cys Leu Val Lys Asp Phe Tyr Pro Pro Asp Ile Asp Ile

130 135 140

Glu Trp Lys Ser Asn Gly Gln Pro Glu Pro Glu Thr Lys Tyr Ser Thr

145 150 155 160

Thr Pro Ala Gln Leu Asp Ser Asp Gly Ser Tyr Phe Leu Tyr Ser Lys

165 170 175

Leu Thr Val Glu Thr Asn Arg Trp Gln Gln Gly Thr Thr Phe Thr Cys

180 185 190

Ala Val Met His Glu Ala Leu His Asn His Tyr Thr Glu Lys Ser Val

195 200 205

Ser Lys Ser Pro Gly Lys

210

<210> 85

<211> 214

<212> PRT

<213> 人工序列

<220>

<223> 合成的: 示例性变体马类IgG7 Fc 蛋白A + C1q -

K(87)S

<400> 85

Val Gly Pro Ser Val Phe Ile Phe Pro Pro Lys Pro Lys Asp Val Leu

1 5 10 15

Met Ile Ser Arg Thr Pro Thr Val Thr Cys Val Val Val Asp Val Gly

20 25 30

His Asp Phe Pro Asp Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu

35 40 45

Thr His Thr Ala Thr Thr Glu Pro Lys Gln Glu Gln Asn Asn Ser Thr

50 55 60

Tyr Arg Val Val Ser Ile Leu Ala Ile Gln His Lys Asp Trp Leu Ser

65 70 75 80

Gly Lys Glu Phe Lys Cys Ser Val Asn Asn Gln Ala Leu Pro Ala Pro

85 90 95

Val Gln Lys Thr Ile Ser Lys Pro Thr Gly Gln Pro Arg Glu Pro Gln

100 105 110

Val Tyr Val Leu Ala Pro His Pro Asp Glu Leu Ser Lys Asn Lys Val

115 120 125

Ser Val Thr Cys Leu Val Lys Asp Phe Tyr Pro Pro Asp Ile Asp Ile

130 135 140

Glu Trp Lys Ser Asn Gly Gln Pro Glu Pro Glu Thr Lys Tyr Ser Thr

145 150 155 160

Thr Pro Ala Gln Leu Asp Gly Asp Gly Ser Tyr Phe Leu Tyr Ser Lys

165 170 175

Leu Thr Val Glu Thr Asn Arg Trp Gln Gln Gly Thr Thr Phe Thr Cys

180 185 190

Ala Val Met His Glu Ala Leu His Asn His Tyr Thr Glu Lys Ser Val

195 200 205

Ser Lys Ser Pro Gly Lys

210

<210> 86

<211> 237

<212> PRT

<213> 人工序列

<220>

<223> 合成的: 示例性野生型猫类IgG1a Fc 蛋白A + C1q +

<400> 86

Arg Lys Thr Asp His Pro Pro Gly Pro Lys Thr Gly Glu Gly Pro Lys

1 5 10 15

Cys Pro Pro Pro Glu Met Leu Gly Gly Pro Ser Ile Phe Ile Phe Pro

20 25 30

Pro Lys Pro Lys Asp Thr Leu Ser Ile Ser Arg Thr Pro Glu Val Thr

35 40 45

Cys Leu Val Val Asp Leu Gly Pro Asp Asp Ser Asp Val Gln Ile Thr

50 55 60

Trp Phe Val Asp Asn Thr Gln Val Tyr Thr Ala Lys Thr Ser Pro Arg

65 70 75 80

Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Pro Ile

85 90 95

Leu His Gln Asp Trp Leu Lys Gly Lys Glu Phe Lys Cys Lys Val Asn

100 105 110

Ser Lys Ser Leu Pro Ser Pro Ile Glu Arg Thr Ile Ser Lys Ala Lys

115 120 125

Gly Gln Pro His Glu Pro Gln Val Tyr Val Leu Pro Pro Ala Gln Glu

130 135 140

Glu Leu Ser Glu Asn Lys Val Ser Val Thr Cys Leu Ile Lys Ser Phe

145 150 155 160

His Pro Pro Asp Ile Ala Val Glu Trp Glu Ile Thr Gly Gln Pro Glu

165 170 175

Pro Glu Asn Asn Tyr Arg Thr Thr Pro Pro Gln Leu Asp Ser Asp Gly

180 185 190

Thr Tyr Phe Val Tyr Ser Lys Leu Ser Val Asp Arg Ser His Trp Gln

195 200 205

Arg Gly Asn Thr Tyr Thr Cys Ser Val Ser His Glu Ala Leu His Ser

210 215 220

His His Thr Gln Lys Ser Leu Thr Gln Ser Pro Gly Lys

225 230 235

<210> 87

<211> 237

<212> PRT

<213> 人工序列

<220>

<223> 合成的: 示例性野生型猫类IgG1a Fc 蛋白A + C1q +

<400> 87

Arg Lys Thr Asp His Pro Pro Gly Pro Lys Pro Cys Asp Cys Pro Lys

1 5 10 15

Cys Pro Pro Pro Glu Met Leu Gly Gly Pro Ser Ile Phe Ile Phe Pro

20 25 30

Pro Lys Pro Lys Asp Thr Leu Ser Ile Ser Arg Thr Pro Glu Val Thr

35 40 45

Cys Leu Val Val Asp Leu Gly Pro Asp Asp Ser Asp Val Gln Ile Thr

50 55 60

Trp Phe Val Asp Asn Thr Gln Val Tyr Thr Ala Lys Thr Ser Pro Arg

65 70 75 80

Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Pro Ile

85 90 95

Leu His Gln Asp Trp Leu Lys Gly Lys Glu Phe Lys Cys Lys Val Asn

100 105 110

Ser Lys Ser Leu Pro Ser Pro Ile Glu Arg Thr Ile Ser Lys Ala Lys

115 120 125

Gly Gln Pro His Glu Pro Gln Val Tyr Val Leu Pro Pro Ala Gln Glu

130 135 140

Glu Leu Ser Glu Asn Lys Val Ser Val Thr Cys Leu Ile Lys Ser Phe

145 150 155 160

His Pro Pro Asp Ile Ala Val Glu Trp Glu Ile Thr Gly Gln Pro Glu

165 170 175

Pro Glu Asn Asn Tyr Arg Thr Thr Pro Pro Gln Leu Asp Ser Asp Gly

180 185 190

Thr Tyr Phe Val Tyr Ser Lys Leu Ser Val Asp Arg Ser His Trp Gln

195 200 205

Arg Gly Asn Thr Tyr Thr Cys Ser Val Ser His Glu Ala Leu His Ser

210 215 220

His His Thr Gln Lys Ser Leu Thr Gln Ser Pro Gly Lys

225 230 235

<210> 88

<211> 237

<212> PRT

<213> 人工序列

<220>

<223> 合成的: 示例性野生型猫类IgG1b Fc 蛋白A + C1q +

<400> 88

Arg Lys Thr Asp His Pro Pro Gly Pro Lys Thr Gly Glu Gly Pro Lys

1 5 10 15

Cys Pro Pro Pro Glu Met Leu Gly Gly Pro Ser Ile Phe Ile Phe Pro

20 25 30

Pro Lys Pro Lys Asp Thr Leu Ser Ile Ser Arg Thr Pro Glu Val Thr

35 40 45

Cys Leu Val Val Asp Leu Gly Pro Asp Asp Ser Asp Val Gln Ile Thr

50 55 60

Trp Phe Val Asp Asn Thr Gln Val Tyr Thr Ala Lys Thr Ser Pro Arg

65 70 75 80

Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Pro Ile

85 90 95

Leu His Gln Asp Trp Leu Lys Gly Lys Glu Phe Lys Cys Lys Val Asn

100 105 110

Ser Lys Ser Leu Pro Ser Pro Ile Glu Arg Thr Ile Ser Lys Asp Lys

115 120 125

Gly Gln Pro His Glu Pro Gln Val Tyr Val Leu Pro Pro Ala Gln Glu

130 135 140

Glu Leu Ser Glu Asn Lys Val Ser Val Thr Cys Leu Ile Glu Gly Phe

145 150 155 160

Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ile Thr Gly Gln Pro Glu

165 170 175

Pro Glu Asn Asn Tyr Arg Thr Thr Pro Pro Gln Leu Asp Ser Asp Gly

180 185 190

Thr Tyr Phe Leu Tyr Ser Arg Leu Ser Val Asp Arg Ser Arg Trp Gln

195 200 205

Arg Gly Asn Thr Tyr Thr Cys Ser Val Ser His Glu Ala Leu His Ser

210 215 220

His His Thr Gln Lys Ser Leu Thr Gln Ser Pro Gly Lys

225 230 235

<210> 89

<211> 237

<212> PRT

<213> 人工序列

<220>

<223> 合成的: 示例性野生型猫类IgG1b Fc 蛋白A + C1q +

<400> 89

Arg Lys Thr Asp His Pro Pro Gly Pro Lys Pro Cys Asp Cys Pro Lys

1 5 10 15

Cys Pro Pro Pro Glu Met Leu Gly Gly Pro Ser Ile Phe Ile Phe Pro

20 25 30

Pro Lys Pro Lys Asp Thr Leu Ser Ile Ser Arg Thr Pro Glu Val Thr

35 40 45

Cys Leu Val Val Asp Leu Gly Pro Asp Asp Ser Asp Val Gln Ile Thr

50 55 60

Trp Phe Val Asp Asn Thr Gln Val Tyr Thr Ala Lys Thr Ser Pro Arg

65 70 75 80

Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Pro Ile

85 90 95

Leu His Gln Asp Trp Leu Lys Gly Lys Glu Phe Lys Cys Lys Val Asn

100 105 110

Ser Lys Ser Leu Pro Ser Pro Ile Glu Arg Thr Ile Ser Lys Asp Lys

115 120 125

Gly Gln Pro His Glu Pro Gln Val Tyr Val Leu Pro Pro Ala Gln Glu

130 135 140

Glu Leu Ser Glu Asn Lys Val Ser Val Thr Cys Leu Ile Glu Gly Phe

145 150 155 160

Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ile Thr Gly Gln Pro Glu

165 170 175

Pro Glu Asn Asn Tyr Arg Thr Thr Pro Pro Gln Leu Asp Ser Asp Gly

180 185 190

Thr Tyr Phe Leu Tyr Ser Arg Leu Ser Val Asp Arg Ser Arg Trp Gln

195 200 205

Arg Gly Asn Thr Tyr Thr Cys Ser Val Ser His Glu Ala Leu His Ser

210 215 220

His His Thr Gln Lys Ser Leu Thr Gln Ser Pro Gly Lys

225 230 235

<210> 90

<211> 237

<212> PRT

<213> 人工序列

<220>

<223> 合成的: 示例性野生型猫类IgG2 Fc 蛋白A + C1q -

<400> 90

Pro Lys Thr Ala Ser Thr Ile Glu Ser Lys Thr Gly Glu Gly Pro Lys

1 5 10 15

Cys Pro Val Pro Glu Ile Pro Gly Ala Pro Ser Val Phe Ile Phe Pro

20 25 30

Pro Lys Pro Lys Asp Thr Leu Ser Ile Ser Arg Thr Pro Glu Val Thr

35 40 45

Cys Leu Val Val Asp Leu Gly Pro Asp Asp Ser Asn Val Gln Ile Thr

50 55 60

Trp Phe Val Asp Asn Thr Glu Met His Thr Ala Lys Thr Arg Pro Arg

65 70 75 80

Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Pro Ile

85 90 95

Leu His Gln Asp Trp Leu Lys Gly Lys Glu Phe Lys Cys Lys Val Asn

100 105 110

Ser Lys Ser Leu Pro Ser Ala Met Glu Arg Thr Ile Ser Lys Ala Lys

115 120 125

Gly Gln Pro His Glu Pro Gln Val Tyr Val Leu Pro Pro Thr Gln Glu

130 135 140

Glu Leu Ser Glu Asn Lys Val Ser Val Thr Cys Leu Ile Lys Gly Phe

145 150 155 160

His Pro Pro Asp Ile Ala Val Glu Trp Glu Ile Thr Gly Gln Pro Glu

165 170 175

Pro Glu Asn Asn Tyr Gln Thr Thr Pro Pro Gln Leu Asp Ser Asp Gly

180 185 190

Thr Tyr Phe Leu Tyr Ser Arg Leu Ser Val Asp Arg Ser His Trp Gln

195 200 205

Arg Gly Asn Thr Tyr Thr Cys Ser Val Ser His Glu Ala Leu His Ser

210 215 220

His His Thr Gln Lys Ser Leu Thr Gln Ser Pro Gly Lys

225 230 235

<210> 91

<211> 237

<212> PRT

<213> 人工序列

<220>

<223> 合成的: 示例性变体猫类IgG1a Fc 蛋白A + C1q -

P(198)A

<400> 91

Arg Lys Thr Asp His Pro Pro Gly Pro Lys Pro Cys Asp Cys Pro Lys

1 5 10 15

Cys Pro Pro Pro Glu Met Leu Gly Gly Pro Ser Ile Phe Ile Phe Pro

20 25 30

Pro Lys Pro Lys Asp Thr Leu Ser Ile Ser Arg Thr Pro Glu Val Thr

35 40 45

Cys Leu Val Val Asp Leu Gly Pro Asp Asp Ser Asp Val Gln Ile Thr

50 55 60

Trp Phe Val Asp Asn Thr Gln Val Tyr Thr Ala Lys Thr Ser Pro Arg

65 70 75 80

Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Pro Ile

85 90 95

Leu His Gln Asp Trp Leu Lys Gly Lys Glu Phe Lys Cys Lys Val Asn

100 105 110

Ser Lys Ser Leu Pro Ser Pro Ile Glu Arg Thr Ile Ser Lys Ala Lys

115 120 125

Gly Gln Pro His Glu Pro Gln Val Tyr Val Leu Pro Pro Ala Gln Glu

130 135 140

Glu Leu Ser Glu Asn Lys Val Ser Val Thr Cys Leu Ile Lys Ser Phe

145 150 155 160

His Pro Pro Asp Ile Ala Val Glu Trp Glu Ile Thr Gly Gln Pro Glu

165 170 175

Pro Glu Asn Asn Tyr Arg Thr Thr Pro Pro Gln Leu Asp Ser Asp Gly

180 185 190

Thr Tyr Phe Val Tyr Ser Lys Leu Ser Val Asp Arg Ser His Trp Gln

195 200 205

Arg Gly Asn Thr Tyr Thr Cys Ser Val Ser His Glu Ala Leu His Ser

210 215 220

His His Thr Gln Lys Ser Leu Thr Gln Ser Pro Gly Lys

225 230 235

<210> 92

<211> 237

<212> PRT

<213> 人工序列

<220>

<223> 合成的: 示例性变体猫类IgG1a Fc 蛋白A + C1q -

P(198)A

<400> 92

Arg Lys Thr Asp His Pro Pro Gly Pro Lys Thr Gly Glu Gly Pro Lys

1 5 10 15

Cys Pro Pro Pro Glu Met Leu Gly Gly Pro Ser Ile Phe Ile Phe Pro

20 25 30

Pro Lys Pro Lys Asp Thr Leu Ser Ile Ser Arg Thr Pro Glu Val Thr

35 40 45

Cys Leu Val Val Asp Leu Gly Pro Asp Asp Ser Asp Val Gln Ile Thr

50 55 60

Trp Phe Val Asp Asn Thr Gln Val Tyr Thr Ala Lys Thr Ser Pro Arg

65 70 75 80

Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Pro Ile

85 90 95

Leu His Gln Asp Trp Leu Lys Gly Lys Glu Phe Lys Cys Lys Val Asn

100 105 110

Ser Lys Ser Leu Pro Ser Pro Ile Glu Arg Thr Ile Ser Lys Ala Lys

115 120 125

Gly Gln Pro His Glu Pro Gln Val Tyr Val Leu Pro Pro Ala Gln Glu

130 135 140

Glu Leu Ser Glu Asn Lys Val Ser Val Thr Cys Leu Ile Lys Ser Phe

145 150 155 160

His Pro Pro Asp Ile Ala Val Glu Trp Glu Ile Thr Gly Gln Pro Glu

165 170 175

Pro Glu Asn Asn Tyr Arg Thr Thr Pro Pro Gln Leu Asp Ser Asp Gly

180 185 190

Thr Tyr Phe Val Tyr Ser Lys Leu Ser Val Asp Arg Ser His Trp Gln

195 200 205

Arg Gly Asn Thr Tyr Thr Cys Ser Val Ser His Glu Ala Leu His Ser

210 215 220

His His Thr Gln Lys Ser Leu Thr Gln Ser Pro Gly Lys

225 230 235

<210> 93

<211> 237

<212> PRT

<213> 人工序列

<220>

<223> 合成的: 示例性变体猫类IgG1b Fc 蛋白A + C1q -

P(198)A

<400> 93

Arg Lys Thr Asp His Pro Pro Gly Pro Lys Pro Cys Asp Cys Pro Lys

1 5 10 15

Cys Pro Pro Pro Glu Met Leu Gly Gly Pro Ser Ile Phe Ile Phe Pro

20 25 30

Pro Lys Pro Lys Asp Thr Leu Ser Ile Ser Arg Thr Pro Glu Val Thr

35 40 45

Cys Leu Val Val Asp Leu Gly Pro Asp Asp Ser Asp Val Gln Ile Thr

50 55 60

Trp Phe Val Asp Asn Thr Gln Val Tyr Thr Ala Lys Thr Ser Pro Arg

65 70 75 80

Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Pro Ile

85 90 95

Leu His Gln Asp Trp Leu Lys Gly Lys Glu Phe Lys Cys Lys Val Asn

100 105 110

Ser Lys Ser Leu Pro Ser Pro Ile Glu Arg Thr Ile Ser Lys Asp Lys

115 120 125

Gly Gln Pro His Glu Pro Gln Val Tyr Val Leu Pro Pro Ala Gln Glu

130 135 140

Glu Leu Ser Glu Asn Lys Val Ser Val Thr Cys Leu Ile Glu Gly Phe

145 150 155 160

Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ile Thr Gly Gln Pro Glu

165 170 175

Pro Glu Asn Asn Tyr Arg Thr Thr Pro Pro Gln Leu Asp Ser Asp Gly

180 185 190

Thr Tyr Phe Leu Tyr Ser Arg Leu Ser Val Asp Arg Ser Arg Trp Gln

195 200 205

Arg Gly Asn Thr Tyr Thr Cys Ser Val Ser His Glu Ala Leu His Ser

210 215 220

His His Thr Gln Lys Ser Leu Thr Gln Ser Pro Gly Lys

225 230 235

<210> 94

<211> 237

<212> PRT

<213> 人工序列

<220>

<223> 合成的: 示例性变体猫类IgG1b Fc 蛋白A + C1q -

P(198)A

<400> 94

Arg Lys Thr Asp His Pro Pro Gly Pro Lys Thr Gly Glu Gly Pro Lys

1 5 10 15

Cys Pro Pro Pro Glu Met Leu Gly Gly Pro Ser Ile Phe Ile Phe Pro

20 25 30

Pro Lys Pro Lys Asp Thr Leu Ser Ile Ser Arg Thr Pro Glu Val Thr

35 40 45

Cys Leu Val Val Asp Leu Gly Pro Asp Asp Ser Asp Val Gln Ile Thr

50 55 60

Trp Phe Val Asp Asn Thr Gln Val Tyr Thr Ala Lys Thr Ser Pro Arg

65 70 75 80

Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Pro Ile

85 90 95

Leu His Gln Asp Trp Leu Lys Gly Lys Glu Phe Lys Cys Lys Val Asn

100 105 110

Ser Lys Ser Leu Pro Ser Pro Ile Glu Arg Thr Ile Ser Lys Asp Lys

115 120 125

Gly Gln Pro His Glu Pro Gln Val Tyr Val Leu Pro Pro Ala Gln Glu

130 135 140

Glu Leu Ser Glu Asn Lys Val Ser Val Thr Cys Leu Ile Glu Gly Phe

145 150 155 160

Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ile Thr Gly Gln Pro Glu

165 170 175

Pro Glu Asn Asn Tyr Arg Thr Thr Pro Pro Gln Leu Asp Ser Asp Gly

180 185 190

Thr Tyr Phe Leu Tyr Ser Arg Leu Ser Val Asp Arg Ser Arg Trp Gln

195 200 205

Arg Gly Asn Thr Tyr Thr Cys Ser Val Ser His Glu Ala Leu His Ser

210 215 220

His His Thr Gln Lys Ser Leu Thr Gln Ser Pro Gly Lys

225 230 235

<210> 95

<211> 237

<212> PRT

<213> 人工序列

<220>

<223> 合成的: 示例性变体猫类IgG2 Fc 铰链 Cys G(14)C

<400> 95

Pro Lys Thr Ala Ser Thr Ile Glu Ser Lys Thr Gly Glu Cys Pro Lys

1 5 10 15

Cys Pro Val Pro Glu Ile Pro Gly Ala Pro Ser Val Phe Ile Phe Pro

20 25 30

Pro Lys Pro Lys Asp Thr Leu Ser Ile Ser Arg Thr Pro Glu Val Thr

35 40 45

Cys Leu Val Val Asp Leu Gly Pro Asp Asp Ser Asn Val Gln Ile Thr

50 55 60

Trp Phe Val Asp Asn Thr Glu Met His Thr Ala Lys Thr Arg Pro Arg

65 70 75 80

Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Pro Ile

85 90 95

Leu His Gln Asp Trp Leu Lys Gly Lys Glu Phe Lys Cys Lys Val Asn

100 105 110

Ser Lys Ser Leu Pro Ser Ala Met Glu Arg Thr Ile Ser Lys Ala Lys

115 120 125

Gly Gln Pro His Glu Pro Gln Val Tyr Val Leu Pro Pro Thr Gln Glu

130 135 140

Glu Leu Ser Glu Asn Lys Val Ser Val Thr Cys Leu Ile Lys Gly Phe

145 150 155 160

His Pro Pro Asp Ile Ala Val Glu Trp Glu Ile Thr Gly Gln Pro Glu

165 170 175

Pro Glu Asn Asn Tyr Gln Thr Thr Pro Pro Gln Leu Asp Ser Asp Gly

180 185 190

Thr Tyr Phe Leu Tyr Ser Arg Leu Ser Val Asp Arg Ser His Trp Gln

195 200 205

Arg Gly Asn Thr Tyr Thr Cys Ser Val Ser His Glu Ala Leu His Ser

210 215 220

His His Thr Gln Lys Ser Leu Thr Gln Ser Pro Gly Lys

225 230 235

<210> 96

<211> 237

<212> PRT

<213> 人工序列

<220>

<223> 合成的: 具有修饰铰链的示例性变体猫类IgG1a Fc

K(16)P

<400> 96

Arg Lys Thr Asp His Pro Pro Gly Pro Lys Thr Gly Glu Gly Pro Pro

1 5 10 15

Cys Pro Pro Pro Glu Met Leu Gly Gly Pro Ser Ile Phe Ile Phe Pro

20 25 30

Pro Lys Pro Lys Asp Thr Leu Ser Ile Ser Arg Thr Pro Glu Val Thr

35 40 45

Cys Leu Val Val Asp Leu Gly Pro Asp Asp Ser Asp Val Gln Ile Thr

50 55 60

Trp Phe Val Asp Asn Thr Gln Val Tyr Thr Ala Lys Thr Ser Pro Arg

65 70 75 80

Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Pro Ile

85 90 95

Leu His Gln Asp Trp Leu Lys Gly Lys Glu Phe Lys Cys Lys Val Asn

100 105 110

Ser Lys Ser Leu Pro Ser Pro Ile Glu Arg Thr Ile Ser Lys Ala Lys

115 120 125

Gly Gln Pro His Glu Pro Gln Val Tyr Val Leu Pro Pro Ala Gln Glu

130 135 140

Glu Leu Ser Glu Asn Lys Val Ser Val Thr Cys Leu Ile Lys Ser Phe

145 150 155 160

His Pro Pro Asp Ile Ala Val Glu Trp Glu Ile Thr Gly Gln Pro Glu

165 170 175

Pro Glu Asn Asn Tyr Arg Thr Thr Pro Pro Gln Leu Asp Ser Asp Gly

180 185 190

Thr Tyr Phe Val Tyr Ser Lys Leu Ser Val Asp Arg Ser His Trp Gln

195 200 205

Arg Gly Asn Thr Tyr Thr Cys Ser Val Ser His Glu Ala Leu His Ser

210 215 220

His His Thr Gln Lys Ser Leu Thr Gln Ser Pro Gly Lys

225 230 235

<210> 97

<211> 237

<212> PRT

<213> 人工序列

<220>

<223> 合成的: 具有修饰铰链的示例性变体猫类IgG1a Fc

K(16)P

<400> 97

Arg Lys Thr Asp His Pro Pro Gly Pro Lys Pro Cys Asp Cys Pro Pro

1 5 10 15

Cys Pro Pro Pro Glu Met Leu Gly Gly Pro Ser Ile Phe Ile Phe Pro

20 25 30

Pro Lys Pro Lys Asp Thr Leu Ser Ile Ser Arg Thr Pro Glu Val Thr

35 40 45

Cys Leu Val Val Asp Leu Gly Pro Asp Asp Ser Asp Val Gln Ile Thr

50 55 60

Trp Phe Val Asp Asn Thr Gln Val Tyr Thr Ala Lys Thr Ser Pro Arg

65 70 75 80

Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Pro Ile

85 90 95

Leu His Gln Asp Trp Leu Lys Gly Lys Glu Phe Lys Cys Lys Val Asn

100 105 110

Ser Lys Ser Leu Pro Ser Pro Ile Glu Arg Thr Ile Ser Lys Ala Lys

115 120 125

Gly Gln Pro His Glu Pro Gln Val Tyr Val Leu Pro Pro Ala Gln Glu

130 135 140

Glu Leu Ser Glu Asn Lys Val Ser Val Thr Cys Leu Ile Lys Ser Phe

145 150 155 160

His Pro Pro Asp Ile Ala Val Glu Trp Glu Ile Thr Gly Gln Pro Glu

165 170 175

Pro Glu Asn Asn Tyr Arg Thr Thr Pro Pro Gln Leu Asp Ser Asp Gly

180 185 190

Thr Tyr Phe Val Tyr Ser Lys Leu Ser Val Asp Arg Ser His Trp Gln

195 200 205

Arg Gly Asn Thr Tyr Thr Cys Ser Val Ser His Glu Ala Leu His Ser

210 215 220

His His Thr Gln Lys Ser Leu Thr Gln Ser Pro Gly Lys

225 230 235

<210> 98

<211> 237

<212> PRT

<213> 人工序列

<220>

<223> 合成的: 具有修饰铰链的示例性变体猫类IgG1b Fc

K(16)P

<400> 98

Arg Lys Thr Asp His Pro Pro Gly Pro Lys Thr Gly Glu Gly Pro Pro

1 5 10 15

Cys Pro Pro Pro Glu Met Leu Gly Gly Pro Ser Ile Phe Ile Phe Pro

20 25 30

Pro Lys Pro Lys Asp Thr Leu Ser Ile Ser Arg Thr Pro Glu Val Thr

35 40 45

Cys Leu Val Val Asp Leu Gly Pro Asp Asp Ser Asp Val Gln Ile Thr

50 55 60

Trp Phe Val Asp Asn Thr Gln Val Tyr Thr Ala Lys Thr Ser Pro Arg

65 70 75 80

Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Pro Ile

85 90 95

Leu His Gln Asp Trp Leu Lys Gly Lys Glu Phe Lys Cys Lys Val Asn

100 105 110

Ser Lys Ser Leu Pro Ser Pro Ile Glu Arg Thr Ile Ser Lys Asp Lys

115 120 125

Gly Gln Pro His Glu Pro Gln Val Tyr Val Leu Pro Pro Ala Gln Glu

130 135 140

Glu Leu Ser Glu Asn Lys Val Ser Val Thr Cys Leu Ile Glu Gly Phe

145 150 155 160

Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ile Thr Gly Gln Pro Glu

165 170 175

Pro Glu Asn Asn Tyr Arg Thr Thr Pro Pro Gln Leu Asp Ser Asp Gly

180 185 190

Thr Tyr Phe Leu Tyr Ser Arg Leu Ser Val Asp Arg Ser Arg Trp Gln

195 200 205

Arg Gly Asn Thr Tyr Thr Cys Ser Val Ser His Glu Ala Leu His Ser

210 215 220

His His Thr Gln Lys Ser Leu Thr Gln Ser Pro Gly Lys

225 230 235

<210> 99

<211> 237

<212> PRT

<213> 人工序列

<220>

<223> 合成的: 具有修饰铰链的示例性变体猫类IgG1b Fc

K(16)P

<400> 99

Arg Lys Thr Asp His Pro Pro Gly Pro Lys Pro Cys Asp Cys Pro Pro

1 5 10 15

Cys Pro Pro Pro Glu Met Leu Gly Gly Pro Ser Ile Phe Ile Phe Pro

20 25 30

Pro Lys Pro Lys Asp Thr Leu Ser Ile Ser Arg Thr Pro Glu Val Thr

35 40 45

Cys Leu Val Val Asp Leu Gly Pro Asp Asp Ser Asp Val Gln Ile Thr

50 55 60

Trp Phe Val Asp Asn Thr Gln Val Tyr Thr Ala Lys Thr Ser Pro Arg

65 70 75 80

Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Pro Ile

85 90 95

Leu His Gln Asp Trp Leu Lys Gly Lys Glu Phe Lys Cys Lys Val Asn

100 105 110

Ser Lys Ser Leu Pro Ser Pro Ile Glu Arg Thr Ile Ser Lys Asp Lys

115 120 125

Gly Gln Pro His Glu Pro Gln Val Tyr Val Leu Pro Pro Ala Gln Glu

130 135 140

Glu Leu Ser Glu Asn Lys Val Ser Val Thr Cys Leu Ile Glu Gly Phe

145 150 155 160

Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ile Thr Gly Gln Pro Glu

165 170 175

Pro Glu Asn Asn Tyr Arg Thr Thr Pro Pro Gln Leu Asp Ser Asp Gly

180 185 190

Thr Tyr Phe Leu Tyr Ser Arg Leu Ser Val Asp Arg Ser Arg Trp Gln

195 200 205

Arg Gly Asn Thr Tyr Thr Cys Ser Val Ser His Glu Ala Leu His Ser

210 215 220

His His Thr Gln Lys Ser Leu Thr Gln Ser Pro Gly Lys

225 230 235

<210> 100

<211> 237

<212> PRT

<213> 人工序列

<220>

<223> 合成的: 具有修饰铰链的示例性变体猫类IgG2 Fc

K(16)P

<400> 100

Pro Lys Thr Ala Ser Thr Ile Glu Ser Lys Thr Gly Glu Gly Pro Pro

1 5 10 15

Cys Pro Val Pro Glu Ile Pro Gly Ala Pro Ser Val Phe Ile Phe Pro

20 25 30

Pro Lys Pro Lys Asp Thr Leu Ser Ile Ser Arg Thr Pro Glu Val Thr

35 40 45

Cys Leu Val Val Asp Leu Gly Pro Asp Asp Ser Asn Val Gln Ile Thr

50 55 60

Trp Phe Val Asp Asn Thr Glu Met His Thr Ala Lys Thr Arg Pro Arg

65 70 75 80

Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Pro Ile

85 90 95

Leu His Gln Asp Trp Leu Lys Gly Lys Glu Phe Lys Cys Lys Val Asn

100 105 110

Ser Lys Ser Leu Pro Ser Ala Met Glu Arg Thr Ile Ser Lys Ala Lys

115 120 125

Gly Gln Pro His Glu Pro Gln Val Tyr Val Leu Pro Pro Thr Gln Glu

130 135 140

Glu Leu Ser Glu Asn Lys Val Ser Val Thr Cys Leu Ile Lys Gly Phe

145 150 155 160

His Pro Pro Asp Ile Ala Val Glu Trp Glu Ile Thr Gly Gln Pro Glu

165 170 175

Pro Glu Asn Asn Tyr Gln Thr Thr Pro Pro Gln Leu Asp Ser Asp Gly

180 185 190

Thr Tyr Phe Leu Tyr Ser Arg Leu Ser Val Asp Arg Ser His Trp Gln

195 200 205

Arg Gly Asn Thr Tyr Thr Cys Ser Val Ser His Glu Ala Leu His Ser

210 215 220

His His Thr Gln Lys Ser Leu Thr Gln Ser Pro Gly Lys

225 230 235

<210> 101

<211> 244

<212> PRT

<213> 人工序列

<220>

<223> 合成的: 具有修饰铰链的示例性变体马类IgG2 Fc

蛋白A - C1q - Q(20)P

<400> 101

Pro Pro Cys Val Leu Ser Ala Glu Gly Val Ile Pro Ile Pro Ser Val

1 5 10 15

Pro Lys Pro Pro Cys Pro Pro Tyr Thr His Ser Lys Phe Leu Gly Gly

20 25 30

Pro Ser Val Phe Ile Phe Pro Pro Asn Pro Lys Asp Ala Leu Met Ile

35 40 45

Ser Arg Thr Pro Val Val Thr Cys Val Val Val Asn Leu Ser Asp Gln

50 55 60

Tyr Pro Asp Val Gln Phe Ser Trp Tyr Val Asp Asn Thr Glu Val His

65 70 75 80

Ser Ala Ile Thr Lys Gln Arg Glu Ala Gln Phe Asn Ser Thr Tyr Arg

85 90 95

Val Val Ser Val Leu Pro Ile Gln His Gln Asp Trp Leu Ser Gly Lys

100 105 110

Glu Phe Lys Cys Ser Val Thr Asn Val Gly Val Pro Gln Pro Ile Ser

115 120 125

Arg Ala Ile Ser Arg Gly Lys Gly Pro Ser Arg Val Pro Gln Val Tyr

130 135 140

Val Leu Pro Pro His Pro Asp Glu Leu Ala Lys Ser Lys Val Ser Val

145 150 155 160

Thr Cys Leu Val Lys Asp Phe Tyr Pro Pro Asp Ile Ser Val Glu Trp

165 170 175

Gln Ser Asn Arg Trp Pro Glu Leu Glu Gly Lys Tyr Ser Thr Thr Pro

180 185 190

Ala Gln Leu Asp Gly Asp Gly Ser Tyr Phe Leu Tyr Ser Lys Leu Ser

195 200 205

Leu Glu Thr Ser Arg Trp Gln Gln Val Glu Ser Phe Thr Cys Ala Val

210 215 220

Met His Glu Ala Leu His Asn His Phe Thr Lys Thr Asp Ile Ser Glu

225 230 235 240

Ser Leu Gly Lys

<210> 102

<211> 244

<212> PRT

<213> 人工序列

<220>

<223> 合成的: 具有修饰铰链的示例性变体马类IgG2 Fc

蛋白A - C1q - C(3)S

<400> 102

Pro Pro Ser Val Leu Ser Ala Glu Gly Val Ile Pro Ile Pro Ser Val

1 5 10 15

Pro Lys Pro Gln Cys Pro Pro Tyr Thr His Ser Lys Phe Leu Gly Gly

20 25 30

Pro Ser Val Phe Ile Phe Pro Pro Asn Pro Lys Asp Ala Leu Met Ile

35 40 45

Ser Arg Thr Pro Val Val Thr Cys Val Val Val Asn Leu Ser Asp Gln

50 55 60

Tyr Pro Asp Val Gln Phe Ser Trp Tyr Val Asp Asn Thr Glu Val His

65 70 75 80

Ser Ala Ile Thr Lys Gln Arg Glu Ala Gln Phe Asn Ser Thr Tyr Arg

85 90 95

Val Val Ser Val Leu Pro Ile Gln His Gln Asp Trp Leu Ser Gly Lys

100 105 110

Glu Phe Lys Cys Ser Val Thr Asn Val Gly Val Pro Gln Pro Ile Ser

115 120 125

Arg Ala Ile Ser Arg Gly Lys Gly Pro Ser Arg Val Pro Gln Val Tyr

130 135 140

Val Leu Pro Pro His Pro Asp Glu Leu Ala Lys Ser Lys Val Ser Val

145 150 155 160

Thr Cys Leu Val Lys Asp Phe Tyr Pro Pro Asp Ile Ser Val Glu Trp

165 170 175

Gln Ser Asn Arg Trp Pro Glu Leu Glu Gly Lys Tyr Ser Thr Thr Pro

180 185 190

Ala Gln Leu Asp Gly Asp Gly Ser Tyr Phe Leu Tyr Ser Lys Leu Ser

195 200 205

Leu Glu Thr Ser Arg Trp Gln Gln Val Glu Ser Phe Thr Cys Ala Val

210 215 220

Met His Glu Ala Leu His Asn His Phe Thr Lys Thr Asp Ile Ser Glu

225 230 235 240

Ser Leu Gly Lys

<210> 103

<211> 244

<212> PRT

<213> 人工序列

<220>

<223> 合成的: 具有修饰铰链的示例性变体马类IgG2 Fc

蛋白A - C1q - C(3)S Q(20)P

<400> 103

Pro Pro Ser Val Leu Ser Ala Glu Gly Val Ile Pro Ile Pro Ser Val

1 5 10 15

Pro Lys Pro Pro Cys Pro Pro Tyr Thr His Ser Lys Phe Leu Gly Gly

20 25 30

Pro Ser Val Phe Ile Phe Pro Pro Asn Pro Lys Asp Ala Leu Met Ile

35 40 45

Ser Arg Thr Pro Val Val Thr Cys Val Val Val Asn Leu Ser Asp Gln

50 55 60

Tyr Pro Asp Val Gln Phe Ser Trp Tyr Val Asp Asn Thr Glu Val His

65 70 75 80

Ser Ala Ile Thr Lys Gln Arg Glu Ala Gln Phe Asn Ser Thr Tyr Arg

85 90 95

Val Val Ser Val Leu Pro Ile Gln His Gln Asp Trp Leu Ser Gly Lys

100 105 110

Glu Phe Lys Cys Ser Val Thr Asn Val Gly Val Pro Gln Pro Ile Ser

115 120 125

Arg Ala Ile Ser Arg Gly Lys Gly Pro Ser Arg Val Pro Gln Val Tyr

130 135 140

Val Leu Pro Pro His Pro Asp Glu Leu Ala Lys Ser Lys Val Ser Val

145 150 155 160

Thr Cys Leu Val Lys Asp Phe Tyr Pro Pro Asp Ile Ser Val Glu Trp

165 170 175

Gln Ser Asn Arg Trp Pro Glu Leu Glu Gly Lys Tyr Ser Thr Thr Pro

180 185 190

Ala Gln Leu Asp Gly Asp Gly Ser Tyr Phe Leu Tyr Ser Lys Leu Ser

195 200 205

Leu Glu Thr Ser Arg Trp Gln Gln Val Glu Ser Phe Thr Cys Ala Val

210 215 220

Met His Glu Ala Leu His Asn His Phe Thr Lys Thr Asp Ile Ser Glu

225 230 235 240

Ser Leu Gly Lys

<210> 104

<211> 244

<212> PRT

<213> 人工序列

<220>

<223> 合成的: 具有铰链的示例性变体马类IgG2 Fc 蛋白A

+ C1q - A(45)T F(233)Y

<400> 104

Pro Pro Cys Val Leu Ser Ala Glu Gly Val Ile Pro Ile Pro Ser Val

1 5 10 15

Pro Lys Pro Gln Cys Pro Pro Tyr Thr His Ser Lys Phe Leu Gly Gly

20 25 30

Pro Ser Val Phe Ile Phe Pro Pro Asn Pro Lys Asp Thr Leu Met Ile

35 40 45

Ser Arg Thr Pro Val Val Thr Cys Val Val Val Asn Leu Ser Asp Gln

50 55 60

Tyr Pro Asp Val Gln Phe Ser Trp Tyr Val Asp Asn Thr Glu Val His

65 70 75 80

Ser Ala Ile Thr Lys Gln Arg Glu Ala Gln Phe Asn Ser Thr Tyr Arg

85 90 95

Val Val Ser Val Leu Pro Ile Gln His Gln Asp Trp Leu Ser Gly Lys

100 105 110

Glu Phe Lys Cys Ser Val Thr Asn Val Gly Val Pro Gln Pro Ile Ser

115 120 125

Arg Ala Ile Ser Arg Gly Lys Gly Pro Ser Arg Val Pro Gln Val Tyr

130 135 140

Val Leu Pro Pro His Pro Asp Glu Leu Ala Lys Ser Lys Val Ser Val

145 150 155 160

Thr Cys Leu Val Lys Asp Phe Tyr Pro Pro Asp Ile Ser Val Glu Trp

165 170 175

Gln Ser Asn Arg Trp Pro Glu Leu Glu Gly Lys Tyr Ser Thr Thr Pro

180 185 190

Ala Gln Leu Asp Gly Asp Gly Ser Tyr Phe Leu Tyr Ser Lys Leu Ser

195 200 205

Leu Glu Thr Ser Arg Trp Gln Gln Val Glu Ser Phe Thr Cys Ala Val

210 215 220

Met His Glu Ala Leu His Asn His Tyr Thr Lys Thr Asp Ile Ser Glu

225 230 235 240

Ser Leu Gly Lys

<210> 105

<211> 244

<212> PRT

<213> 人工序列

<220>

<223> 合成的: 具有修饰铰链的示例性变体马类IgG2 Fc

蛋白A + C1q - Q(20)P A(45)T F(233)Y

<400> 105

Pro Pro Cys Val Leu Ser Ala Glu Gly Val Ile Pro Ile Pro Ser Val

1 5 10 15

Pro Lys Pro Pro Cys Pro Pro Tyr Thr His Ser Lys Phe Leu Gly Gly

20 25 30

Pro Ser Val Phe Ile Phe Pro Pro Asn Pro Lys Asp Thr Leu Met Ile

35 40 45

Ser Arg Thr Pro Val Val Thr Cys Val Val Val Asn Leu Ser Asp Gln

50 55 60

Tyr Pro Asp Val Gln Phe Ser Trp Tyr Val Asp Asn Thr Glu Val His

65 70 75 80

Ser Ala Ile Thr Lys Gln Arg Glu Ala Gln Phe Asn Ser Thr Tyr Arg

85 90 95

Val Val Ser Val Leu Pro Ile Gln His Gln Asp Trp Leu Ser Gly Lys

100 105 110

Glu Phe Lys Cys Ser Val Thr Asn Val Gly Val Pro Gln Pro Ile Ser

115 120 125

Arg Ala Ile Ser Arg Gly Lys Gly Pro Ser Arg Val Pro Gln Val Tyr

130 135 140

Val Leu Pro Pro His Pro Asp Glu Leu Ala Lys Ser Lys Val Ser Val

145 150 155 160

Thr Cys Leu Val Lys Asp Phe Tyr Pro Pro Asp Ile Ser Val Glu Trp

165 170 175

Gln Ser Asn Arg Trp Pro Glu Leu Glu Gly Lys Tyr Ser Thr Thr Pro

180 185 190

Ala Gln Leu Asp Gly Asp Gly Ser Tyr Phe Leu Tyr Ser Lys Leu Ser

195 200 205

Leu Glu Thr Ser Arg Trp Gln Gln Val Glu Ser Phe Thr Cys Ala Val

210 215 220

Met His Glu Ala Leu His Asn His Tyr Thr Lys Thr Asp Ile Ser Glu

225 230 235 240

Ser Leu Gly Lys

<210> 106

<211> 244

<212> PRT

<213> 人工序列

<220>

<223> 合成的: 具有修饰铰链的示例性变体马类IgG2 Fc

蛋白A + C1q - C(3)S Q(20)P A(45)T F(233)Y

<400> 106

Pro Pro Ser Val Leu Ser Ala Glu Gly Val Ile Pro Ile Pro Ser Val

1 5 10 15

Pro Lys Pro Pro Cys Pro Pro Tyr Thr His Ser Lys Phe Leu Gly Gly

20 25 30

Pro Ser Val Phe Ile Phe Pro Pro Asn Pro Lys Asp Thr Leu Met Ile

35 40 45

Ser Arg Thr Pro Val Val Thr Cys Val Val Val Asn Leu Ser Asp Gln

50 55 60

Tyr Pro Asp Val Gln Phe Ser Trp Tyr Val Asp Asn Thr Glu Val His

65 70 75 80

Ser Ala Ile Thr Lys Gln Arg Glu Ala Gln Phe Asn Ser Thr Tyr Arg

85 90 95

Val Val Ser Val Leu Pro Ile Gln His Gln Asp Trp Leu Ser Gly Lys

100 105 110

Glu Phe Lys Cys Ser Val Thr Asn Val Gly Val Pro Gln Pro Ile Ser

115 120 125

Arg Ala Ile Ser Arg Gly Lys Gly Pro Ser Arg Val Pro Gln Val Tyr

130 135 140

Val Leu Pro Pro His Pro Asp Glu Leu Ala Lys Ser Lys Val Ser Val

145 150 155 160

Thr Cys Leu Val Lys Asp Phe Tyr Pro Pro Asp Ile Ser Val Glu Trp

165 170 175

Gln Ser Asn Arg Trp Pro Glu Leu Glu Gly Lys Tyr Ser Thr Thr Pro

180 185 190

Ala Gln Leu Asp Gly Asp Gly Ser Tyr Phe Leu Tyr Ser Lys Leu Ser

195 200 205

Leu Glu Thr Ser Arg Trp Gln Gln Val Glu Ser Phe Thr Cys Ala Val

210 215 220

Met His Glu Ala Leu His Asn His Tyr Thr Lys Thr Asp Ile Ser Glu

225 230 235 240

Ser Leu Gly Lys

<210> 107

<211> 237

<212> PRT

<213> 人工序列

<220>

<223> 合成的: 具有猫类IgG1铰链的示例性变体猫类IgG2 Fc

<400> 107

Arg Lys Thr Asp His Pro Pro Gly Pro Lys Pro Cys Asp Cys Pro Lys

1 5 10 15

Cys Pro Pro Pro Glu Met Leu Gly Gly Pro Ser Val Phe Ile Phe Pro

20 25 30

Pro Lys Pro Lys Asp Thr Leu Ser Ile Ser Arg Thr Pro Glu Val Thr

35 40 45

Cys Leu Val Val Asp Leu Gly Pro Asp Asp Ser Asn Val Gln Ile Thr

50 55 60

Trp Phe Val Asp Asn Thr Glu Met His Thr Ala Lys Thr Arg Pro Arg

65 70 75 80

Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Pro Ile

85 90 95

Leu His Gln Asp Trp Leu Lys Gly Lys Glu Phe Lys Cys Lys Val Asn

100 105 110

Ser Lys Ser Leu Pro Ser Ala Met Glu Arg Thr Ile Ser Lys Ala Lys

115 120 125

Gly Gln Pro His Glu Pro Gln Val Tyr Val Leu Pro Pro Thr Gln Glu

130 135 140

Glu Leu Ser Glu Asn Lys Val Ser Val Thr Cys Leu Ile Lys Gly Phe

145 150 155 160

His Pro Pro Asp Ile Ala Val Glu Trp Glu Ile Thr Gly Gln Pro Glu

165 170 175

Pro Glu Asn Asn Tyr Gln Thr Thr Pro Pro Gln Leu Asp Ser Asp Gly

180 185 190

Thr Tyr Phe Leu Tyr Ser Arg Leu Ser Val Asp Arg Ser His Trp Gln

195 200 205

Arg Gly Asn Thr Tyr Thr Cys Ser Val Ser His Glu Ala Leu His Ser

210 215 220

His His Thr Gln Lys Ser Leu Thr Gln Ser Pro Gly Lys

225 230 235

<210> 108

<211> 228

<212> PRT

<213> 人工序列

<220>

<223> 合成的: 示例性变体马类Fc IgG2 (具有马类IgG1

铰链) 蛋白A - C1q -

<400> 108

Asp Met Ser Lys Cys Pro Lys Cys Pro Ala Pro Glu Leu Leu Gly Gly

1 5 10 15

Pro Ser Val Phe Ile Phe Pro Pro Asn Pro Lys Asp Ala Leu Met Ile

20 25 30

Ser Arg Thr Pro Val Val Thr Cys Val Val Val Asn Leu Ser Asp Gln

35 40 45

Tyr Pro Asp Val Gln Phe Ser Trp Tyr Val Asp Asn Thr Glu Val His

50 55 60

Ser Ala Ile Thr Lys Gln Arg Glu Ala Gln Phe Asn Ser Thr Tyr Arg

65 70 75 80

Val Val Ser Val Leu Pro Ile Gln His Gln Asp Trp Leu Ser Gly Lys

85 90 95

Glu Phe Lys Cys Ser Val Thr Asn Val Gly Val Pro Gln Pro Ile Ser

100 105 110

Arg Ala Ile Ser Arg Gly Lys Gly Pro Ser Arg Val Pro Gln Val Tyr

115 120 125

Val Leu Pro Pro His Pro Asp Glu Leu Ala Lys Ser Lys Val Ser Val

130 135 140

Thr Cys Leu Val Lys Asp Phe Tyr Pro Pro Asp Ile Ser Val Glu Trp

145 150 155 160

Gln Ser Asn Arg Trp Pro Glu Leu Glu Gly Lys Tyr Ser Thr Thr Pro

165 170 175

Ala Gln Leu Asp Gly Asp Gly Ser Tyr Phe Leu Tyr Ser Lys Leu Ser

180 185 190

Leu Glu Thr Ser Arg Trp Gln Gln Val Glu Ser Phe Thr Cys Ala Val

195 200 205

Met His Glu Ala Leu His Asn His Phe Thr Lys Thr Asp Ile Ser Glu

210 215 220

Ser Leu Gly Lys

225

<210> 109

<211> 228

<212> PRT

<213> 人工序列

<220>

<223> 合成的: 示例性变体马类IgG2 Fc (具有马类IgG1

铰链) C1q - 蛋白A + A(29)T F(217)Y

<400> 109

Asp Met Ser Lys Cys Pro Lys Cys Pro Ala Pro Glu Leu Leu Gly Gly

1 5 10 15

Pro Ser Val Phe Ile Phe Pro Pro Asn Pro Lys Asp Thr Leu Met Ile

20 25 30

Ser Arg Thr Pro Val Val Thr Cys Val Val Val Asn Leu Ser Asp Gln

35 40 45

Tyr Pro Asp Val Gln Phe Ser Trp Tyr Val Asp Asn Thr Glu Val His

50 55 60

Ser Ala Ile Thr Lys Gln Arg Glu Ala Gln Phe Asn Ser Thr Tyr Arg

65 70 75 80

Val Val Ser Val Leu Pro Ile Gln His Gln Asp Trp Leu Ser Gly Lys

85 90 95

Glu Phe Lys Cys Ser Val Thr Asn Val Gly Val Pro Gln Pro Ile Ser

100 105 110

Arg Ala Ile Ser Arg Gly Lys Gly Pro Ser Arg Val Pro Gln Val Tyr

115 120 125

Val Leu Pro Pro His Pro Asp Glu Leu Ala Lys Ser Lys Val Ser Val

130 135 140

Thr Cys Leu Val Lys Asp Phe Tyr Pro Pro Asp Ile Ser Val Glu Trp

145 150 155 160

Gln Ser Asn Arg Trp Pro Glu Leu Glu Gly Lys Tyr Ser Thr Thr Pro

165 170 175

Ala Gln Leu Asp Gly Asp Gly Ser Tyr Phe Leu Tyr Ser Lys Leu Ser

180 185 190

Leu Glu Thr Ser Arg Trp Gln Gln Val Glu Ser Phe Thr Cys Ala Val

195 200 205

Met His Glu Ala Leu His Asn His Tyr Thr Lys Thr Asp Ile Ser Glu

210 215 220

Ser Leu Gly Lys

225

<210> 110

<211> 384

<212> PRT

<213> 人工序列

<220>

<223> 合成的: 具有信号序列的示例性犬类TrkA ECD v2 - 变体犬类

IgG-B Fc 蛋白A+ C1q - CD16 -

<400> 110

Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp

1 5 10 15

Leu Arg Gly Ala Arg Cys Val Ser Phe Pro Ala Ser Val Gln Leu His

20 25 30

Glu Ala Val Glu Leu His His Trp Cys Ile Pro Phe Ser Val Asp Gly

35 40 45

Gln Pro Ala Pro Ser Leu Arg Trp Leu Phe Asn Gly Ser Val Leu Asn

50 55 60

Glu Thr Ser Phe Ile Phe Thr Glu Phe Leu Glu Pro Val Ala Asn Glu

65 70 75 80

Thr Val Arg His Gly Cys Leu Arg Leu Asn Gln Pro Thr His Val Asn

85 90 95

Asn Gly Asn Tyr Thr Leu Leu Ala Ala Asn Pro Ser Gly Arg Ala Ala

100 105 110

Ala Phe Val Met Ala Ala Phe Met Asp Asn Pro Phe Glu Phe Asn Pro

115 120 125

Glu Asp Pro Ile Pro Val Ser Phe Ser Pro Val Asp Thr Asn Ser Thr

130 135 140

Ser Gly Asp Ser Gly Gly Gly Ser Gly Gly Gly Ser Arg Pro Pro Asp

145 150 155 160

Cys Pro Lys Cys Pro Ala Pro Glu Pro Leu Gly Gly Pro Ser Val Phe

165 170 175

Ile Phe Pro Pro Lys Pro Lys Asp Thr Leu Leu Ile Ala Arg Thr Pro

180 185 190

Glu Val Thr Cys Val Val Val Asp Leu Asp Arg Glu Asp Pro Glu Val

195 200 205

Gln Ile Ser Trp Phe Val Asp Gly Lys Gln Met Gln Thr Ala Lys Thr

210 215 220

Gln Pro Arg Glu Glu Gln Phe Asn Gly Thr Tyr Arg Val Val Ser Val

225 230 235 240

Leu Pro Ile Gly His Gln Asp Trp Leu Lys Gly Lys Gln Phe Thr Cys

245 250 255

Arg Val Asn Asn Lys Ala Leu Pro Ser Pro Ile Glu Arg Thr Ile Ser

260 265 270

Lys Ala Arg Gly Gln Ala His Gln Pro Ser Val Tyr Val Leu Pro Pro

275 280 285

Ser Arg Glu Glu Leu Ser Lys Asn Thr Val Ser Leu Thr Cys Leu Ile

290 295 300

Lys Asp Phe Phe Pro Pro Asp Ile Asp Val Glu Trp Gln Ser Asn Gly

305 310 315 320

Gln Gln Glu Pro Glu Ser Lys Tyr Arg Thr Thr Pro Pro Gln Leu Asp

325 330 335

Glu Asp Gly Ser Tyr Phe Leu Tyr Ser Lys Leu Ser Val Asp Lys Ser

340 345 350

Arg Trp Gln Arg Gly Asp Thr Phe Ile Cys Ala Val Met His Glu Ala

355 360 365

Leu His Asn His Tyr Thr Gln Glu Ser Leu Ser His Ser Pro Gly Lys

370 375 380

<210> 111

<211> 360

<212> PRT

<213> 人工序列

<220>

<223> 合成的: 具有信号序列的示例性犬类TrkA ECD v3 - 变体犬类

IgG-B Fc 蛋白A+ C1q - CD16 -

<400> 111

Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp

1 5 10 15

Leu Arg Gly Ala Arg Cys Val Ser Phe Pro Ala Ser Val Gln Leu His

20 25 30

Glu Ala Val Glu Leu His His Trp Cys Ile Pro Phe Ser Val Asp Gly

35 40 45

Gln Pro Ala Pro Ser Leu Arg Trp Leu Phe Asn Gly Ser Val Leu Asn

50 55 60

Glu Thr Ser Phe Ile Phe Thr Glu Phe Leu Glu Pro Val Ala Asn Glu

65 70 75 80

Thr Val Arg His Gly Cys Leu Arg Leu Asn Gln Pro Thr His Val Asn

85 90 95

Asn Gly Asn Tyr Thr Leu Leu Ala Ala Asn Pro Ser Gly Arg Ala Ala

100 105 110

Ala Phe Val Met Ala Ala Phe Met Asp Asn Pro Ser Gly Gly Gly Ser

115 120 125

Gly Gly Gly Ser Arg Pro Pro Asp Cys Pro Lys Cys Pro Ala Pro Glu

130 135 140

Pro Leu Gly Gly Pro Ser Val Phe Ile Phe Pro Pro Lys Pro Lys Asp

145 150 155 160

Thr Leu Leu Ile Ala Arg Thr Pro Glu Val Thr Cys Val Val Val Asp

165 170 175

Leu Asp Arg Glu Asp Pro Glu Val Gln Ile Ser Trp Phe Val Asp Gly

180 185 190

Lys Gln Met Gln Thr Ala Lys Thr Gln Pro Arg Glu Glu Gln Phe Asn

195 200 205

Gly Thr Tyr Arg Val Val Ser Val Leu Pro Ile Gly His Gln Asp Trp

210 215 220

Leu Lys Gly Lys Gln Phe Thr Cys Arg Val Asn Asn Lys Ala Leu Pro

225 230 235 240

Ser Pro Ile Glu Arg Thr Ile Ser Lys Ala Arg Gly Gln Ala His Gln

245 250 255

Pro Ser Val Tyr Val Leu Pro Pro Ser Arg Glu Glu Leu Ser Lys Asn

260 265 270

Thr Val Ser Leu Thr Cys Leu Ile Lys Asp Phe Phe Pro Pro Asp Ile

275 280 285

Asp Val Glu Trp Gln Ser Asn Gly Gln Gln Glu Pro Glu Ser Lys Tyr

290 295 300

Arg Thr Thr Pro Pro Gln Leu Asp Glu Asp Gly Ser Tyr Phe Leu Tyr

305 310 315 320

Ser Lys Leu Ser Val Asp Lys Ser Arg Trp Gln Arg Gly Asp Thr Phe

325 330 335

Ile Cys Ala Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Glu

340 345 350

Ser Leu Ser His Ser Pro Gly Lys

355 360

<210> 112

<211> 358

<212> PRT

<213> 人工序列

<220>

<223> 合成的: 具有信号序列的示例性犬类TrkA ECD v4 - 变体犬类

IgG-B Fc 蛋白A+ C1q - CD16 -

<400> 112

Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp

1 5 10 15

Leu Arg Gly Ala Arg Cys Phe Pro Ala Ser Val Gln Leu His Glu Ala

20 25 30

Val Glu Leu His His Trp Cys Ile Pro Phe Ser Val Asp Gly Gln Pro

35 40 45

Ala Pro Ser Leu Arg Trp Leu Phe Asn Gly Ser Val Leu Asn Glu Thr

50 55 60

Ser Phe Ile Phe Thr Glu Phe Leu Glu Pro Val Ala Asn Glu Thr Val

65 70 75 80

Arg His Gly Cys Leu Arg Leu Asn Gln Pro Thr His Val Asn Asn Gly

85 90 95

Asn Tyr Thr Leu Leu Ala Ala Asn Pro Ser Gly Arg Ala Ala Ala Phe

100 105 110

Val Met Ala Ala Phe Met Asp Asn Pro Ser Gly Gly Gly Ser Gly Gly

115 120 125

Gly Ser Arg Pro Pro Asp Cys Pro Lys Cys Pro Ala Pro Glu Pro Leu

130 135 140

Gly Gly Pro Ser Val Phe Ile Phe Pro Pro Lys Pro Lys Asp Thr Leu

145 150 155 160

Leu Ile Ala Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Leu Asp

165 170 175

Arg Glu Asp Pro Glu Val Gln Ile Ser Trp Phe Val Asp Gly Lys Gln

180 185 190

Met Gln Thr Ala Lys Thr Gln Pro Arg Glu Glu Gln Phe Asn Gly Thr

195 200 205

Tyr Arg Val Val Ser Val Leu Pro Ile Gly His Gln Asp Trp Leu Lys

210 215 220

Gly Lys Gln Phe Thr Cys Arg Val Asn Asn Lys Ala Leu Pro Ser Pro

225 230 235 240

Ile Glu Arg Thr Ile Ser Lys Ala Arg Gly Gln Ala His Gln Pro Ser

245 250 255

Val Tyr Val Leu Pro Pro Ser Arg Glu Glu Leu Ser Lys Asn Thr Val

260 265 270

Ser Leu Thr Cys Leu Ile Lys Asp Phe Phe Pro Pro Asp Ile Asp Val

275 280 285

Glu Trp Gln Ser Asn Gly Gln Gln Glu Pro Glu Ser Lys Tyr Arg Thr

290 295 300

Thr Pro Pro Gln Leu Asp Glu Asp Gly Ser Tyr Phe Leu Tyr Ser Lys

305 310 315 320

Leu Ser Val Asp Lys Ser Arg Trp Gln Arg Gly Asp Thr Phe Ile Cys

325 330 335

Ala Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Glu Ser Leu

340 345 350

Ser His Ser Pro Gly Lys

355

<210> 113

<211> 388

<212> PRT

<213> 人工序列

<220>

<223> 合成的: 具有信号序列的示例性犬类TrkA ECD v2 - 变体犬类

IgG-A Fc C1q - 蛋白A +

<400> 113

Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp

1 5 10 15

Leu Arg Gly Ala Arg Cys Val Ser Phe Pro Ala Ser Val Gln Leu His

20 25 30

Glu Ala Val Glu Leu His His Trp Cys Ile Pro Phe Ser Val Asp Gly

35 40 45

Gln Pro Ala Pro Ser Leu Arg Trp Leu Phe Asn Gly Ser Val Leu Asn

50 55 60

Glu Thr Ser Phe Ile Phe Thr Glu Phe Leu Glu Pro Val Ala Asn Glu

65 70 75 80

Thr Val Arg His Gly Cys Leu Arg Leu Asn Gln Pro Thr His Val Asn

85 90 95

Asn Gly Asn Tyr Thr Leu Leu Ala Ala Asn Pro Ser Gly Arg Ala Ala

100 105 110

Ala Phe Val Met Ala Ala Phe Met Asp Asn Pro Phe Glu Phe Asn Pro

115 120 125

Glu Asp Pro Ile Pro Val Ser Phe Ser Pro Val Asp Thr Asn Ser Thr

130 135 140

Ser Gly Asp Ser Gly Gly Gly Ser Gly Gly Gly Ser Phe Asn Glu Cys

145 150 155 160

Arg Cys Thr Asp Thr Pro Cys Pro Val Pro Glu Pro Leu Gly Gly Pro

165 170 175

Ser Val Leu Ile Phe Pro Pro Lys Pro Lys Asp Thr Leu Leu Ile Ala

180 185 190

Arg Thr Pro Glu Val Thr Cys Val Val Leu Asp Leu Gly Arg Glu Asp

195 200 205

Pro Glu Val Gln Ile Ser Trp Phe Val Asp Gly Lys Glu Val His Thr

210 215 220

Ala Lys Thr Gln Ser Arg Glu Gln Gln Phe Asn Gly Thr Tyr Arg Val

225 230 235 240

Val Ser Val Leu Pro Ile Gly His Gln Asp Trp Leu Thr Gly Lys Glu

245 250 255

Phe Lys Cys Arg Val Asn His Ile Asp Leu Pro Ser Pro Ile Glu Arg

260 265 270

Thr Ile Ser Lys Ala Arg Gly Arg Ala His Lys Pro Ser Val Tyr Val

275 280 285

Leu Pro Pro Ser Pro Lys Glu Leu Ser Ser Ser Asp Thr Val Ser Ile

290 295 300

Thr Cys Leu Ile Lys Asp Phe Tyr Pro Pro Asp Ile Asp Val Glu Trp

305 310 315 320

Gln Ser Asn Gly Gln Gln Glu Pro Glu Arg Lys His Arg Met Thr Pro

325 330 335

Pro Gln Leu Asp Glu Asp Gly Ser Tyr Phe Leu Tyr Ser Lys Leu Ser

340 345 350

Val Asp Lys Ser Arg Trp Gln Gln Gly Asp Pro Phe Thr Cys Ala Val

355 360 365

Met His Glu Ala Leu His Asn His Tyr Thr Asp Leu Ser Leu Ser His

370 375 380

Ser Pro Gly Lys

385

<210> 114

<211> 364

<212> PRT

<213> 人工序列

<220>

<223> 合成的: 具有信号序列的示例性犬类TrkA ECD v3 - 变体犬类

IgG-A Fc C1q - 蛋白A +

<400> 114

Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp

1 5 10 15

Leu Arg Gly Ala Arg Cys Val Ser Phe Pro Ala Ser Val Gln Leu His

20 25 30

Glu Ala Val Glu Leu His His Trp Cys Ile Pro Phe Ser Val Asp Gly

35 40 45

Gln Pro Ala Pro Ser Leu Arg Trp Leu Phe Asn Gly Ser Val Leu Asn

50 55 60

Glu Thr Ser Phe Ile Phe Thr Glu Phe Leu Glu Pro Val Ala Asn Glu

65 70 75 80

Thr Val Arg His Gly Cys Leu Arg Leu Asn Gln Pro Thr His Val Asn

85 90 95

Asn Gly Asn Tyr Thr Leu Leu Ala Ala Asn Pro Ser Gly Arg Ala Ala

100 105 110

Ala Phe Val Met Ala Ala Phe Met Asp Asn Pro Ser Gly Gly Gly Ser

115 120 125

Gly Gly Gly Ser Phe Asn Glu Cys Arg Cys Thr Asp Thr Pro Cys Pro

130 135 140

Val Pro Glu Pro Leu Gly Gly Pro Ser Val Leu Ile Phe Pro Pro Lys

145 150 155 160

Pro Lys Asp Thr Leu Leu Ile Ala Arg Thr Pro Glu Val Thr Cys Val

165 170 175

Val Leu Asp Leu Gly Arg Glu Asp Pro Glu Val Gln Ile Ser Trp Phe

180 185 190

Val Asp Gly Lys Glu Val His Thr Ala Lys Thr Gln Ser Arg Glu Gln

195 200 205

Gln Phe Asn Gly Thr Tyr Arg Val Val Ser Val Leu Pro Ile Gly His

210 215 220

Gln Asp Trp Leu Thr Gly Lys Glu Phe Lys Cys Arg Val Asn His Ile

225 230 235 240

Asp Leu Pro Ser Pro Ile Glu Arg Thr Ile Ser Lys Ala Arg Gly Arg

245 250 255

Ala His Lys Pro Ser Val Tyr Val Leu Pro Pro Ser Pro Lys Glu Leu

260 265 270

Ser Ser Ser Asp Thr Val Ser Ile Thr Cys Leu Ile Lys Asp Phe Tyr

275 280 285

Pro Pro Asp Ile Asp Val Glu Trp Gln Ser Asn Gly Gln Gln Glu Pro

290 295 300

Glu Arg Lys His Arg Met Thr Pro Pro Gln Leu Asp Glu Asp Gly Ser

305 310 315 320

Tyr Phe Leu Tyr Ser Lys Leu Ser Val Asp Lys Ser Arg Trp Gln Gln

325 330 335

Gly Asp Pro Phe Thr Cys Ala Val Met His Glu Ala Leu His Asn His

340 345 350

Tyr Thr Asp Leu Ser Leu Ser His Ser Pro Gly Lys

355 360

<210> 115

<211> 362

<212> PRT

<213> 人工序列

<220>

<223> 合成的: 具有信号序列的示例性犬类TrkA ECD v4 - 变体犬类

IgG-A Fc C1q - 蛋白A +

<400> 115

Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp

1 5 10 15

Leu Arg Gly Ala Arg Cys Phe Pro Ala Ser Val Gln Leu His Glu Ala

20 25 30

Val Glu Leu His His Trp Cys Ile Pro Phe Ser Val Asp Gly Gln Pro

35 40 45

Ala Pro Ser Leu Arg Trp Leu Phe Asn Gly Ser Val Leu Asn Glu Thr

50 55 60

Ser Phe Ile Phe Thr Glu Phe Leu Glu Pro Val Ala Asn Glu Thr Val

65 70 75 80

Arg His Gly Cys Leu Arg Leu Asn Gln Pro Thr His Val Asn Asn Gly

85 90 95

Asn Tyr Thr Leu Leu Ala Ala Asn Pro Ser Gly Arg Ala Ala Ala Phe

100 105 110

Val Met Ala Ala Phe Met Asp Asn Pro Ser Gly Gly Gly Ser Gly Gly

115 120 125

Gly Ser Phe Asn Glu Cys Arg Cys Thr Asp Thr Pro Cys Pro Val Pro

130 135 140

Glu Pro Leu Gly Gly Pro Ser Val Leu Ile Phe Pro Pro Lys Pro Lys

145 150 155 160

Asp Thr Leu Leu Ile Ala Arg Thr Pro Glu Val Thr Cys Val Val Leu

165 170 175

Asp Leu Gly Arg Glu Asp Pro Glu Val Gln Ile Ser Trp Phe Val Asp

180 185 190

Gly Lys Glu Val His Thr Ala Lys Thr Gln Ser Arg Glu Gln Gln Phe

195 200 205

Asn Gly Thr Tyr Arg Val Val Ser Val Leu Pro Ile Gly His Gln Asp

210 215 220

Trp Leu Thr Gly Lys Glu Phe Lys Cys Arg Val Asn His Ile Asp Leu

225 230 235 240

Pro Ser Pro Ile Glu Arg Thr Ile Ser Lys Ala Arg Gly Arg Ala His

245 250 255

Lys Pro Ser Val Tyr Val Leu Pro Pro Ser Pro Lys Glu Leu Ser Ser

260 265 270

Ser Asp Thr Val Ser Ile Thr Cys Leu Ile Lys Asp Phe Tyr Pro Pro

275 280 285

Asp Ile Asp Val Glu Trp Gln Ser Asn Gly Gln Gln Glu Pro Glu Arg

290 295 300

Lys His Arg Met Thr Pro Pro Gln Leu Asp Glu Asp Gly Ser Tyr Phe

305 310 315 320

Leu Tyr Ser Lys Leu Ser Val Asp Lys Ser Arg Trp Gln Gln Gly Asp

325 330 335

Pro Phe Thr Cys Ala Val Met His Glu Ala Leu His Asn His Tyr Thr

340 345 350

Asp Leu Ser Leu Ser His Ser Pro Gly Lys

355 360

<210> 116

<211> 389

<212> PRT

<213> 人工序列

<220>

<223> 合成的: 具有信号序列的示例性犬类TrkA ECD v2 - 变体犬类

IgG-D Fc C1q - 蛋白A +

<400> 116

Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp

1 5 10 15

Leu Arg Gly Ala Arg Cys Val Ser Phe Pro Ala Ser Val Gln Leu His

20 25 30

Glu Ala Val Glu Leu His His Trp Cys Ile Pro Phe Ser Val Asp Gly

35 40 45

Gln Pro Ala Pro Ser Leu Arg Trp Leu Phe Asn Gly Ser Val Leu Asn

50 55 60

Glu Thr Ser Phe Ile Phe Thr Glu Phe Leu Glu Pro Val Ala Asn Glu

65 70 75 80

Thr Val Arg His Gly Cys Leu Arg Leu Asn Gln Pro Thr His Val Asn

85 90 95

Asn Gly Asn Tyr Thr Leu Leu Ala Ala Asn Pro Ser Gly Arg Ala Ala

100 105 110

Ala Phe Val Met Ala Ala Phe Met Asp Asn Pro Phe Glu Phe Asn Pro

115 120 125

Glu Asp Pro Ile Pro Val Ser Phe Ser Pro Val Asp Thr Asn Ser Thr

130 135 140

Ser Gly Asp Ser Gly Gly Gly Ser Gly Gly Gly Ser Pro Lys Glu Ser

145 150 155 160

Thr Cys Lys Cys Ile Ser Pro Cys Pro Val Pro Glu Ser Leu Gly Gly

165 170 175

Pro Ser Val Phe Ile Phe Pro Pro Lys Pro Lys Asp Thr Leu Leu Ile

180 185 190

Ala Arg Thr Pro Glu Ile Thr Cys Val Val Leu Asp Leu Gly Arg Glu

195 200 205

Asp Pro Glu Val Gln Ile Ser Trp Phe Val Asp Gly Lys Glu Val His

210 215 220

Thr Ala Lys Thr Gln Pro Arg Glu Gln Gln Phe Asn Ser Thr Tyr Arg

225 230 235 240

Val Val Ser Val Leu Pro Ile Gly His Gln Asp Trp Leu Thr Gly Lys

245 250 255

Glu Phe Lys Cys Arg Val Asn His Ile Gly Leu Pro Ser Pro Ile Glu

260 265 270

Arg Thr Ile Ser Lys Ala Arg Gly Gln Ala His Gln Pro Ser Val Tyr

275 280 285

Val Leu Pro Pro Ser Pro Lys Glu Leu Ser Ser Ser Asp Thr Val Thr

290 295 300

Leu Thr Cys Leu Ile Lys Asp Phe Phe Pro Pro Glu Ile Asp Val Glu

305 310 315 320

Trp Gln Ser Asn Gly Gln Pro Glu Pro Glu Ser Lys Tyr His Thr Thr

325 330 335

Ala Pro Gln Leu Asp Glu Asp Gly Ser Tyr Phe Leu Tyr Ser Lys Leu

340 345 350

Ser Val Asp Lys Ser Arg Trp Gln Gln Gly Asp Thr Phe Thr Cys Ala

355 360 365

Val Met His Glu Ala Leu His Asn His Tyr Thr Asp Leu Ser Leu Ser

370 375 380

His Ser Pro Gly Lys

385

<210> 117

<211> 365

<212> PRT

<213> 人工序列

<220>

<223> 合成的: 具有信号序列的示例性犬类TrkA ECD v3 - 变体犬类

IgG-D Fc C1q - 蛋白A +

<400> 117

Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp

1 5 10 15

Leu Arg Gly Ala Arg Cys Val Ser Phe Pro Ala Ser Val Gln Leu His

20 25 30

Glu Ala Val Glu Leu His His Trp Cys Ile Pro Phe Ser Val Asp Gly

35 40 45

Gln Pro Ala Pro Ser Leu Arg Trp Leu Phe Asn Gly Ser Val Leu Asn

50 55 60

Glu Thr Ser Phe Ile Phe Thr Glu Phe Leu Glu Pro Val Ala Asn Glu

65 70 75 80

Thr Val Arg His Gly Cys Leu Arg Leu Asn Gln Pro Thr His Val Asn

85 90 95

Asn Gly Asn Tyr Thr Leu Leu Ala Ala Asn Pro Ser Gly Arg Ala Ala

100 105 110

Ala Phe Val Met Ala Ala Phe Met Asp Asn Pro Ser Gly Gly Gly Ser

115 120 125

Gly Gly Gly Ser Pro Lys Glu Ser Thr Cys Lys Cys Ile Ser Pro Cys

130 135 140

Pro Val Pro Glu Ser Leu Gly Gly Pro Ser Val Phe Ile Phe Pro Pro

145 150 155 160

Lys Pro Lys Asp Thr Leu Leu Ile Ala Arg Thr Pro Glu Ile Thr Cys

165 170 175

Val Val Leu Asp Leu Gly Arg Glu Asp Pro Glu Val Gln Ile Ser Trp

180 185 190

Phe Val Asp Gly Lys Glu Val His Thr Ala Lys Thr Gln Pro Arg Glu

195 200 205

Gln Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Pro Ile Gly

210 215 220

His Gln Asp Trp Leu Thr Gly Lys Glu Phe Lys Cys Arg Val Asn His

225 230 235 240

Ile Gly Leu Pro Ser Pro Ile Glu Arg Thr Ile Ser Lys Ala Arg Gly

245 250 255

Gln Ala His Gln Pro Ser Val Tyr Val Leu Pro Pro Ser Pro Lys Glu

260 265 270

Leu Ser Ser Ser Asp Thr Val Thr Leu Thr Cys Leu Ile Lys Asp Phe

275 280 285

Phe Pro Pro Glu Ile Asp Val Glu Trp Gln Ser Asn Gly Gln Pro Glu

290 295 300

Pro Glu Ser Lys Tyr His Thr Thr Ala Pro Gln Leu Asp Glu Asp Gly

305 310 315 320

Ser Tyr Phe Leu Tyr Ser Lys Leu Ser Val Asp Lys Ser Arg Trp Gln

325 330 335

Gln Gly Asp Thr Phe Thr Cys Ala Val Met His Glu Ala Leu His Asn

340 345 350

His Tyr Thr Asp Leu Ser Leu Ser His Ser Pro Gly Lys

355 360 365

<210> 118

<211> 363

<212> PRT

<213> 人工序列

<220>

<223> 合成的: 具有信号序列的示例性犬类TrkA ECD v4 - 变体犬类

IgG-D Fc C1q - 蛋白A +

<400> 118

Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp

1 5 10 15

Leu Arg Gly Ala Arg Cys Phe Pro Ala Ser Val Gln Leu His Glu Ala

20 25 30

Val Glu Leu His His Trp Cys Ile Pro Phe Ser Val Asp Gly Gln Pro

35 40 45

Ala Pro Ser Leu Arg Trp Leu Phe Asn Gly Ser Val Leu Asn Glu Thr

50 55 60

Ser Phe Ile Phe Thr Glu Phe Leu Glu Pro Val Ala Asn Glu Thr Val

65 70 75 80

Arg His Gly Cys Leu Arg Leu Asn Gln Pro Thr His Val Asn Asn Gly

85 90 95

Asn Tyr Thr Leu Leu Ala Ala Asn Pro Ser Gly Arg Ala Ala Ala Phe

100 105 110

Val Met Ala Ala Phe Met Asp Asn Pro Ser Gly Gly Gly Ser Gly Gly

115 120 125

Gly Ser Pro Lys Glu Ser Thr Cys Lys Cys Ile Ser Pro Cys Pro Val

130 135 140

Pro Glu Ser Leu Gly Gly Pro Ser Val Phe Ile Phe Pro Pro Lys Pro

145 150 155 160

Lys Asp Thr Leu Leu Ile Ala Arg Thr Pro Glu Ile Thr Cys Val Val

165 170 175

Leu Asp Leu Gly Arg Glu Asp Pro Glu Val Gln Ile Ser Trp Phe Val

180 185 190

Asp Gly Lys Glu Val His Thr Ala Lys Thr Gln Pro Arg Glu Gln Gln

195 200 205

Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Pro Ile Gly His Gln

210 215 220

Asp Trp Leu Thr Gly Lys Glu Phe Lys Cys Arg Val Asn His Ile Gly

225 230 235 240

Leu Pro Ser Pro Ile Glu Arg Thr Ile Ser Lys Ala Arg Gly Gln Ala

245 250 255

His Gln Pro Ser Val Tyr Val Leu Pro Pro Ser Pro Lys Glu Leu Ser

260 265 270

Ser Ser Asp Thr Val Thr Leu Thr Cys Leu Ile Lys Asp Phe Phe Pro

275 280 285

Pro Glu Ile Asp Val Glu Trp Gln Ser Asn Gly Gln Pro Glu Pro Glu

290 295 300

Ser Lys Tyr His Thr Thr Ala Pro Gln Leu Asp Glu Asp Gly Ser Tyr

305 310 315 320

Phe Leu Tyr Ser Lys Leu Ser Val Asp Lys Ser Arg Trp Gln Gln Gly

325 330 335

Asp Thr Phe Thr Cys Ala Val Met His Glu Ala Leu His Asn His Tyr

340 345 350

Thr Asp Leu Ser Leu Ser His Ser Pro Gly Lys

355 360

<210> 119

<211> 373

<212> PRT

<213> 人工序列

<220>

<223> 合成的: 具有信号序列的示例性马类TrkA ECD v2 - 具有IgG1

铰链的变体马类IgG2 C1q - 蛋白A +

<400> 119

Met Glu Thr Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro

1 5 10 15

Gly Ser Thr Gly Val Ser Phe Pro Ala Ser Val His Leu Gln Thr Ala

20 25 30

Val Glu Gln His His Trp Cys Ile Pro Phe Ser Val Asp Gly Gln Pro

35 40 45

Ala Pro Thr Leu Arg Trp Leu Phe Asn Gly Ser Val Leu Asn Glu Thr

50 55 60

Ser Phe Ile Phe Thr Glu Phe Leu Glu Ser Ala Ala Asn Glu Thr Met

65 70 75 80

Arg His Gly Cys Leu Arg Leu Asn Gln Pro Thr His Val Asn Asn Gly

85 90 95

Asn Tyr Thr Leu Leu Ala Thr Asn Pro Tyr Gly Gln Asp Ser Ala Ser

100 105 110

Val Met Val Ala Phe Met Asp Asn Pro Phe Glu Phe Asn Pro Glu Asp

115 120 125

Pro Ile Pro Val Ser Phe Ser Pro Val Asp Thr Asn Ser Thr Ser Arg

130 135 140

Asp Asp Met Ser Lys Cys Pro Lys Cys Pro Ala Pro Glu Leu Leu Gly

145 150 155 160

Gly Pro Ser Val Phe Ile Phe Pro Pro Asn Pro Lys Asp Thr Leu Met

165 170 175

Ile Ser Arg Thr Pro Val Val Thr Cys Val Val Val Asn Leu Ser Asp

180 185 190

Gln Tyr Pro Asp Val Gln Phe Ser Trp Tyr Val Asp Asn Thr Glu Val

195 200 205

His Ser Ala Ile Thr Lys Gln Arg Glu Ala Gln Phe Asn Ser Thr Tyr

210 215 220

Arg Val Val Ser Val Leu Pro Ile Gln His Gln Asp Trp Leu Ser Gly

225 230 235 240

Lys Glu Phe Lys Cys Ser Val Thr Asn Val Gly Val Pro Gln Pro Ile

245 250 255

Ser Arg Ala Ile Ser Arg Gly Lys Gly Pro Ser Arg Val Pro Gln Val

260 265 270

Tyr Val Leu Pro Pro His Pro Asp Glu Leu Ala Lys Ser Lys Val Ser

275 280 285

Val Thr Cys Leu Val Lys Asp Phe Tyr Pro Pro Asp Ile Ser Val Glu

290 295 300

Trp Gln Ser Asn Arg Trp Pro Glu Leu Glu Gly Lys Tyr Ser Thr Thr

305 310 315 320

Pro Ala Gln Leu Asp Gly Asp Gly Ser Tyr Phe Leu Tyr Ser Lys Leu

325 330 335

Ser Leu Glu Thr Ser Arg Trp Gln Gln Val Glu Ser Phe Thr Cys Ala

340 345 350

Val Met His Glu Ala Leu His Asn His Tyr Thr Lys Thr Asp Ile Ser

355 360 365

Glu Ser Leu Gly Lys

370

<210> 120

<211> 349

<212> PRT

<213> 人工序列

<220>

<223> 合成的: 具有信号序列的示例性马类TrkA ECD v3 - 具有IgG1

铰链的变体马类IgG2 C1q - 蛋白A +

<400> 120

Met Glu Thr Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro

1 5 10 15

Gly Ser Thr Gly Val Ser Phe Pro Ala Ser Val His Leu Gln Thr Ala

20 25 30

Val Glu Gln His His Trp Cys Ile Pro Phe Ser Val Asp Gly Gln Pro

35 40 45

Ala Pro Thr Leu Arg Trp Leu Phe Asn Gly Ser Val Leu Asn Glu Thr

50 55 60

Ser Phe Ile Phe Thr Glu Phe Leu Glu Ser Ala Ala Asn Glu Thr Met

65 70 75 80

Arg His Gly Cys Leu Arg Leu Asn Gln Pro Thr His Val Asn Asn Gly

85 90 95

Asn Tyr Thr Leu Leu Ala Thr Asn Pro Tyr Gly Gln Asp Ser Ala Ser

100 105 110

Val Met Val Ala Phe Met Asp Asn Pro Asp Met Ser Lys Cys Pro Lys

115 120 125

Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Ile Phe Pro

130 135 140

Pro Asn Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Val Val Thr

145 150 155 160

Cys Val Val Val Asn Leu Ser Asp Gln Tyr Pro Asp Val Gln Phe Ser

165 170 175

Trp Tyr Val Asp Asn Thr Glu Val His Ser Ala Ile Thr Lys Gln Arg

180 185 190

Glu Ala Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Pro Ile

195 200 205

Gln His Gln Asp Trp Leu Ser Gly Lys Glu Phe Lys Cys Ser Val Thr

210 215 220

Asn Val Gly Val Pro Gln Pro Ile Ser Arg Ala Ile Ser Arg Gly Lys

225 230 235 240

Gly Pro Ser Arg Val Pro Gln Val Tyr Val Leu Pro Pro His Pro Asp

245 250 255

Glu Leu Ala Lys Ser Lys Val Ser Val Thr Cys Leu Val Lys Asp Phe

260 265 270

Tyr Pro Pro Asp Ile Ser Val Glu Trp Gln Ser Asn Arg Trp Pro Glu

275 280 285

Leu Glu Gly Lys Tyr Ser Thr Thr Pro Ala Gln Leu Asp Gly Asp Gly

290 295 300

Ser Tyr Phe Leu Tyr Ser Lys Leu Ser Leu Glu Thr Ser Arg Trp Gln

305 310 315 320

Gln Val Glu Ser Phe Thr Cys Ala Val Met His Glu Ala Leu His Asn

325 330 335

His Tyr Thr Lys Thr Asp Ile Ser Glu Ser Leu Gly Lys

340 345

<210> 121

<211> 347

<212> PRT

<213> 人工序列

<220>

<223> 合成的: 具有信号序列的示例性马类TrkA ECD v4 - 具有IgG1

铰链的变体马类IgG2 C1q - 蛋白A +

<400> 121

Met Glu Thr Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro

1 5 10 15

Gly Ser Thr Gly Phe Pro Ala Ser Val His Leu Gln Thr Ala Val Glu

20 25 30

Gln His His Trp Cys Ile Pro Phe Ser Val Asp Gly Gln Pro Ala Pro

35 40 45

Thr Leu Arg Trp Leu Phe Asn Gly Ser Val Leu Asn Glu Thr Ser Phe

50 55 60

Ile Phe Thr Glu Phe Leu Glu Ser Ala Ala Asn Glu Thr Met Arg His

65 70 75 80

Gly Cys Leu Arg Leu Asn Gln Pro Thr His Val Asn Asn Gly Asn Tyr

85 90 95

Thr Leu Leu Ala Thr Asn Pro Tyr Gly Gln Asp Ser Ala Ser Val Met

100 105 110

Val Ala Phe Met Asp Asn Pro Asp Met Ser Lys Cys Pro Lys Cys Pro

115 120 125

Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Ile Phe Pro Pro Asn

130 135 140

Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Val Val Thr Cys Val

145 150 155 160

Val Val Asn Leu Ser Asp Gln Tyr Pro Asp Val Gln Phe Ser Trp Tyr

165 170 175

Val Asp Asn Thr Glu Val His Ser Ala Ile Thr Lys Gln Arg Glu Ala

180 185 190

Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Pro Ile Gln His

195 200 205

Gln Asp Trp Leu Ser Gly Lys Glu Phe Lys Cys Ser Val Thr Asn Val

210 215 220

Gly Val Pro Gln Pro Ile Ser Arg Ala Ile Ser Arg Gly Lys Gly Pro

225 230 235 240

Ser Arg Val Pro Gln Val Tyr Val Leu Pro Pro His Pro Asp Glu Leu

245 250 255

Ala Lys Ser Lys Val Ser Val Thr Cys Leu Val Lys Asp Phe Tyr Pro

260 265 270

Pro Asp Ile Ser Val Glu Trp Gln Ser Asn Arg Trp Pro Glu Leu Glu

275 280 285

Gly Lys Tyr Ser Thr Thr Pro Ala Gln Leu Asp Gly Asp Gly Ser Tyr

290 295 300

Phe Leu Tyr Ser Lys Leu Ser Leu Glu Thr Ser Arg Trp Gln Gln Val

305 310 315 320

Glu Ser Phe Thr Cys Ala Val Met His Glu Ala Leu His Asn His Tyr

325 330 335

Thr Lys Thr Asp Ile Ser Glu Ser Leu Gly Lys

340 345

<210> 122

<211> 384

<212> PRT

<213> 人工序列

<220>

<223> 合成的: 具有信号序列的示例性犬类TrkA ECD v2 - 变体犬类

IgG-B Fc 额外的二硫化物 蛋白A+ C1q - CD16 -

<400> 122

Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp

1 5 10 15

Leu Arg Gly Ala Arg Cys Val Ser Phe Pro Ala Ser Cys Gln Leu His

20 25 30

Glu Ala Val Glu Leu His His Trp Cys Ile Pro Phe Ser Val Asp Gly

35 40 45

Gln Pro Ala Pro Ser Leu Arg Trp Leu Phe Asn Gly Ser Val Leu Asn

50 55 60

Glu Thr Ser Phe Ile Phe Thr Glu Phe Leu Glu Pro Val Ala Asn Glu

65 70 75 80

Thr Val Arg His Gly Cys Leu Arg Leu Asn Gln Pro Thr His Val Asn

85 90 95

Asn Gly Asn Tyr Thr Leu Leu Ala Ala Asn Pro Ser Gly Arg Cys Ala

100 105 110

Ala Phe Val Met Ala Ala Phe Met Asp Asn Pro Phe Glu Phe Asn Pro

115 120 125

Glu Asp Pro Ile Pro Val Ser Phe Ser Pro Val Asp Thr Asn Ser Thr

130 135 140

Ser Gly Asp Ser Gly Gly Gly Ser Gly Gly Gly Ser Arg Pro Pro Asp

145 150 155 160

Cys Pro Lys Cys Pro Ala Pro Glu Pro Leu Gly Gly Pro Ser Val Phe

165 170 175

Ile Phe Pro Pro Lys Pro Lys Asp Thr Leu Leu Ile Ala Arg Thr Pro

180 185 190

Glu Val Thr Cys Val Val Val Asp Leu Asp Arg Glu Asp Pro Glu Val

195 200 205

Gln Ile Ser Trp Phe Val Asp Gly Lys Gln Met Gln Thr Ala Lys Thr

210 215 220

Gln Pro Arg Glu Glu Gln Phe Asn Gly Thr Tyr Arg Val Val Ser Val

225 230 235 240

Leu Pro Ile Gly His Gln Asp Trp Leu Lys Gly Lys Gln Phe Thr Cys

245 250 255

Arg Val Asn Asn Lys Ala Leu Pro Ser Pro Ile Glu Arg Thr Ile Ser

260 265 270

Lys Ala Arg Gly Gln Ala His Gln Pro Ser Val Tyr Val Leu Pro Pro

275 280 285

Ser Arg Glu Glu Leu Ser Lys Asn Thr Val Ser Leu Thr Cys Leu Ile

290 295 300

Lys Asp Phe Phe Pro Pro Asp Ile Asp Val Glu Trp Gln Ser Asn Gly

305 310 315 320

Gln Gln Glu Pro Glu Ser Lys Tyr Arg Thr Thr Pro Pro Gln Leu Asp

325 330 335

Glu Asp Gly Ser Tyr Phe Leu Tyr Ser Lys Leu Ser Val Asp Lys Ser

340 345 350

Arg Trp Gln Arg Gly Asp Thr Phe Ile Cys Ala Val Met His Glu Ala

355 360 365

Leu His Asn His Tyr Thr Gln Glu Ser Leu Ser His Ser Pro Gly Lys

370 375 380

<210> 123

<211> 360

<212> PRT

<213> 人工序列

<220>

<223> 合成的: 具有信号序列的示例性犬类TrkA ECD v3 - 变体犬类

IgG-B Fc 额外的二硫化物 蛋白A+ C1q - CD16 -

<400> 123

Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp

1 5 10 15

Leu Arg Gly Ala Arg Cys Val Ser Phe Pro Ala Ser Cys Gln Leu His

20 25 30

Glu Ala Val Glu Leu His His Trp Cys Ile Pro Phe Ser Val Asp Gly

35 40 45

Gln Pro Ala Pro Ser Leu Arg Trp Leu Phe Asn Gly Ser Val Leu Asn

50 55 60

Glu Thr Ser Phe Ile Phe Thr Glu Phe Leu Glu Pro Val Ala Asn Glu

65 70 75 80

Thr Val Arg His Gly Cys Leu Arg Leu Asn Gln Pro Thr His Val Asn

85 90 95

Asn Gly Asn Tyr Thr Leu Leu Ala Ala Asn Pro Ser Gly Arg Cys Ala

100 105 110

Ala Phe Val Met Ala Ala Phe Met Asp Asn Pro Ser Gly Gly Gly Ser

115 120 125

Gly Gly Gly Ser Arg Pro Pro Asp Cys Pro Lys Cys Pro Ala Pro Glu

130 135 140

Pro Leu Gly Gly Pro Ser Val Phe Ile Phe Pro Pro Lys Pro Lys Asp

145 150 155 160

Thr Leu Leu Ile Ala Arg Thr Pro Glu Val Thr Cys Val Val Val Asp

165 170 175

Leu Asp Arg Glu Asp Pro Glu Val Gln Ile Ser Trp Phe Val Asp Gly

180 185 190

Lys Gln Met Gln Thr Ala Lys Thr Gln Pro Arg Glu Glu Gln Phe Asn

195 200 205

Gly Thr Tyr Arg Val Val Ser Val Leu Pro Ile Gly His Gln Asp Trp

210 215 220

Leu Lys Gly Lys Gln Phe Thr Cys Arg Val Asn Asn Lys Ala Leu Pro

225 230 235 240

Ser Pro Ile Glu Arg Thr Ile Ser Lys Ala Arg Gly Gln Ala His Gln

245 250 255

Pro Ser Val Tyr Val Leu Pro Pro Ser Arg Glu Glu Leu Ser Lys Asn

260 265 270

Thr Val Ser Leu Thr Cys Leu Ile Lys Asp Phe Phe Pro Pro Asp Ile

275 280 285

Asp Val Glu Trp Gln Ser Asn Gly Gln Gln Glu Pro Glu Ser Lys Tyr

290 295 300

Arg Thr Thr Pro Pro Gln Leu Asp Glu Asp Gly Ser Tyr Phe Leu Tyr

305 310 315 320

Ser Lys Leu Ser Val Asp Lys Ser Arg Trp Gln Arg Gly Asp Thr Phe

325 330 335

Ile Cys Ala Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Glu

340 345 350

Ser Leu Ser His Ser Pro Gly Lys

355 360

<210> 124

<211> 358

<212> PRT

<213> 人工序列

<220>

<223> 合成的: 具有信号序列的示例性犬类TrkA ECD v4 - 变体犬类

IgG-B Fc 额外的二硫化物 蛋白A+ C1q - CD16 -

<400> 124

Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp

1 5 10 15

Leu Arg Gly Ala Arg Cys Phe Pro Ala Ser Cys Gln Leu His Glu Ala

20 25 30

Val Glu Leu His His Trp Cys Ile Pro Phe Ser Val Asp Gly Gln Pro

35 40 45

Ala Pro Ser Leu Arg Trp Leu Phe Asn Gly Ser Val Leu Asn Glu Thr

50 55 60

Ser Phe Ile Phe Thr Glu Phe Leu Glu Pro Val Ala Asn Glu Thr Val

65 70 75 80

Arg His Gly Cys Leu Arg Leu Asn Gln Pro Thr His Val Asn Asn Gly

85 90 95

Asn Tyr Thr Leu Leu Ala Ala Asn Pro Ser Gly Arg Cys Ala Ala Phe

100 105 110

Val Met Ala Ala Phe Met Asp Asn Pro Ser Gly Gly Gly Ser Gly Gly

115 120 125

Gly Ser Arg Pro Pro Asp Cys Pro Lys Cys Pro Ala Pro Glu Pro Leu

130 135 140

Gly Gly Pro Ser Val Phe Ile Phe Pro Pro Lys Pro Lys Asp Thr Leu

145 150 155 160

Leu Ile Ala Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Leu Asp

165 170 175

Arg Glu Asp Pro Glu Val Gln Ile Ser Trp Phe Val Asp Gly Lys Gln

180 185 190

Met Gln Thr Ala Lys Thr Gln Pro Arg Glu Glu Gln Phe Asn Gly Thr

195 200 205

Tyr Arg Val Val Ser Val Leu Pro Ile Gly His Gln Asp Trp Leu Lys

210 215 220

Gly Lys Gln Phe Thr Cys Arg Val Asn Asn Lys Ala Leu Pro Ser Pro

225 230 235 240

Ile Glu Arg Thr Ile Ser Lys Ala Arg Gly Gln Ala His Gln Pro Ser

245 250 255

Val Tyr Val Leu Pro Pro Ser Arg Glu Glu Leu Ser Lys Asn Thr Val

260 265 270

Ser Leu Thr Cys Leu Ile Lys Asp Phe Phe Pro Pro Asp Ile Asp Val

275 280 285

Glu Trp Gln Ser Asn Gly Gln Gln Glu Pro Glu Ser Lys Tyr Arg Thr

290 295 300

Thr Pro Pro Gln Leu Asp Glu Asp Gly Ser Tyr Phe Leu Tyr Ser Lys

305 310 315 320

Leu Ser Val Asp Lys Ser Arg Trp Gln Arg Gly Asp Thr Phe Ile Cys

325 330 335

Ala Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Glu Ser Leu

340 345 350

Ser His Ser Pro Gly Lys

355

<210> 125

<211> 384

<212> PRT

<213> 人工序列

<220>

<223> 合成的: 具有信号序列的示例性犬类TrkA ECD v2 - 变体犬类

IgG-B Fc 蛋白A + C1q - CD16 -

<400> 125

Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp

1 5 10 15

Leu Arg Gly Ala Arg Cys Val Ser Phe Pro Ala Ser Val Gln Leu His

20 25 30

Glu Ala Val Glu Leu His His Trp Cys Ile Pro Phe Ser Val Asp Gly

35 40 45

Gln Pro Ala Pro Ser Leu Arg Trp Leu Phe Asn Gly Ser Val Leu Asn

50 55 60

Glu Thr Ser Phe Ile Phe Thr Glu Phe Leu Glu Pro Val Ala Asn Glu

65 70 75 80

Thr Val Arg His Gly Cys Leu Arg Leu Asn Gln Pro Thr His Val Asn

85 90 95

Asn Gly Asn Tyr Thr Leu Leu Ala Ala Asn Pro Ser Gly Arg Ala Ala

100 105 110

Ala Phe Val Met Ala Ala Phe Met Asp Asn Pro Phe Glu Phe Asn Pro

115 120 125

Glu Asp Pro Ile Pro Val Ser Phe Ser Pro Val Asp Thr Asn Ser Thr

130 135 140

Ser Gly Asp Ser Gly Gly Gly Ser Gly Gly Gly Ser Arg Pro Pro Asp

145 150 155 160

Cys Pro Lys Cys Pro Ala Pro Glu Met Leu Gly Gly Pro Ser Val Phe

165 170 175

Ile Phe Pro Pro Lys Pro Lys Asp Thr Leu Leu Ile Ala Arg Thr Pro

180 185 190

Glu Val Thr Cys Val Val Val Asp Leu Asp Pro Glu Asp Pro Glu Val

195 200 205

Gln Ile Ser Trp Phe Val Asp Gly Lys Gln Met Gln Thr Ala Lys Thr

210 215 220

Gln Pro Arg Glu Glu Gln Phe Asn Gly Thr Tyr Arg Val Val Ser Val

225 230 235 240

Leu Pro Ile Gly His Gln Asp Trp Leu Lys Gly Lys Gln Phe Thr Cys

245 250 255

Arg Val Asn Asn Ile Gly Leu Pro Ser Pro Ile Glu Arg Thr Ile Ser

260 265 270

Lys Ala Arg Gly Gln Ala His Gln Pro Ser Val Tyr Val Leu Pro Pro

275 280 285

Ser Arg Glu Glu Leu Ser Lys Asn Thr Val Ser Leu Thr Cys Leu Ile

290 295 300

Lys Asp Phe Phe Pro Pro Asp Ile Asp Val Glu Trp Gln Ser Asn Gly

305 310 315 320

Gln Gln Glu Pro Glu Ser Lys Tyr Arg Thr Thr Pro Pro Gln Leu Asp

325 330 335

Glu Asp Gly Ser Tyr Phe Leu Tyr Ser Lys Leu Ser Val Asp Lys Ser

340 345 350

Arg Trp Gln Arg Gly Asp Thr Phe Ile Cys Ala Val Met His Glu Ala

355 360 365

Leu His Asn His Tyr Thr Gln Glu Ser Leu Ser His Ser Pro Gly Lys

370 375 380

<210> 126

<211> 360

<212> PRT

<213> 人工序列

<220>

<223> 合成的: 具有信号序列的示例性犬类TrkA ECD v3 - 变体犬类

IgG-B Fc 蛋白A + C1q - CD16 -

<400> 126

Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp

1 5 10 15

Leu Arg Gly Ala Arg Cys Val Ser Phe Pro Ala Ser Val Gln Leu His

20 25 30

Glu Ala Val Glu Leu His His Trp Cys Ile Pro Phe Ser Val Asp Gly

35 40 45

Gln Pro Ala Pro Ser Leu Arg Trp Leu Phe Asn Gly Ser Val Leu Asn

50 55 60

Glu Thr Ser Phe Ile Phe Thr Glu Phe Leu Glu Pro Val Ala Asn Glu

65 70 75 80

Thr Val Arg His Gly Cys Leu Arg Leu Asn Gln Pro Thr His Val Asn

85 90 95

Asn Gly Asn Tyr Thr Leu Leu Ala Ala Asn Pro Ser Gly Arg Ala Ala

100 105 110

Ala Phe Val Met Ala Ala Phe Met Asp Asn Pro Ser Gly Gly Gly Ser

115 120 125

Gly Gly Gly Ser Arg Pro Pro Asp Cys Pro Lys Cys Pro Ala Pro Glu

130 135 140

Met Leu Gly Gly Pro Ser Val Phe Ile Phe Pro Pro Lys Pro Lys Asp

145 150 155 160

Thr Leu Leu Ile Ala Arg Thr Pro Glu Val Thr Cys Val Val Val Asp

165 170 175

Leu Asp Pro Glu Asp Pro Glu Val Gln Ile Ser Trp Phe Val Asp Gly

180 185 190

Lys Gln Met Gln Thr Ala Lys Thr Gln Pro Arg Glu Glu Gln Phe Asn

195 200 205

Gly Thr Tyr Arg Val Val Ser Val Leu Pro Ile Gly His Gln Asp Trp

210 215 220

Leu Lys Gly Lys Gln Phe Thr Cys Arg Val Asn Asn Ile Gly Leu Pro

225 230 235 240

Ser Pro Ile Glu Arg Thr Ile Ser Lys Ala Arg Gly Gln Ala His Gln

245 250 255

Pro Ser Val Tyr Val Leu Pro Pro Ser Arg Glu Glu Leu Ser Lys Asn

260 265 270

Thr Val Ser Leu Thr Cys Leu Ile Lys Asp Phe Phe Pro Pro Asp Ile

275 280 285

Asp Val Glu Trp Gln Ser Asn Gly Gln Gln Glu Pro Glu Ser Lys Tyr

290 295 300

Arg Thr Thr Pro Pro Gln Leu Asp Glu Asp Gly Ser Tyr Phe Leu Tyr

305 310 315 320

Ser Lys Leu Ser Val Asp Lys Ser Arg Trp Gln Arg Gly Asp Thr Phe

325 330 335

Ile Cys Ala Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Glu

340 345 350

Ser Leu Ser His Ser Pro Gly Lys

355 360

<210> 127

<211> 358

<212> PRT

<213> 人工序列

<220>

<223> 合成的: 具有信号序列的示例性犬类TrkA ECD v4 - 变体犬类

IgG-B Fc 蛋白A + C1q - CD16 -

<400> 127

Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp

1 5 10 15

Leu Arg Gly Ala Arg Cys Phe Pro Ala Ser Val Gln Leu His Glu Ala

20 25 30

Val Glu Leu His His Trp Cys Ile Pro Phe Ser Val Asp Gly Gln Pro

35 40 45

Ala Pro Ser Leu Arg Trp Leu Phe Asn Gly Ser Val Leu Asn Glu Thr

50 55 60

Ser Phe Ile Phe Thr Glu Phe Leu Glu Pro Val Ala Asn Glu Thr Val

65 70 75 80

Arg His Gly Cys Leu Arg Leu Asn Gln Pro Thr His Val Asn Asn Gly

85 90 95

Asn Tyr Thr Leu Leu Ala Ala Asn Pro Ser Gly Arg Ala Ala Ala Phe

100 105 110

Val Met Ala Ala Phe Met Asp Asn Pro Ser Gly Gly Gly Ser Gly Gly

115 120 125

Gly Ser Arg Pro Pro Asp Cys Pro Lys Cys Pro Ala Pro Glu Met Leu

130 135 140

Gly Gly Pro Ser Val Phe Ile Phe Pro Pro Lys Pro Lys Asp Thr Leu

145 150 155 160

Leu Ile Ala Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Leu Asp

165 170 175

Pro Glu Asp Pro Glu Val Gln Ile Ser Trp Phe Val Asp Gly Lys Gln

180 185 190

Met Gln Thr Ala Lys Thr Gln Pro Arg Glu Glu Gln Phe Asn Gly Thr

195 200 205

Tyr Arg Val Val Ser Val Leu Pro Ile Gly His Gln Asp Trp Leu Lys

210 215 220

Gly Lys Gln Phe Thr Cys Arg Val Asn Asn Ile Gly Leu Pro Ser Pro

225 230 235 240

Ile Glu Arg Thr Ile Ser Lys Ala Arg Gly Gln Ala His Gln Pro Ser

245 250 255

Val Tyr Val Leu Pro Pro Ser Arg Glu Glu Leu Ser Lys Asn Thr Val

260 265 270

Ser Leu Thr Cys Leu Ile Lys Asp Phe Phe Pro Pro Asp Ile Asp Val

275 280 285

Glu Trp Gln Ser Asn Gly Gln Gln Glu Pro Glu Ser Lys Tyr Arg Thr

290 295 300

Thr Pro Pro Gln Leu Asp Glu Asp Gly Ser Tyr Phe Leu Tyr Ser Lys

305 310 315 320

Leu Ser Val Asp Lys Ser Arg Trp Gln Arg Gly Asp Thr Phe Ile Cys

325 330 335

Ala Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Glu Ser Leu

340 345 350

Ser His Ser Pro Gly Lys

355

<210> 128

<211> 384

<212> PRT

<213> 人工序列

<220>

<223> 合成的: 具有信号序列的示例性犬类TrkA ECD v2 - 变体犬类

IgG-B Fc 蛋白A + C1q - CD16 -

<400> 128

Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp

1 5 10 15

Leu Arg Gly Ala Arg Cys Val Ser Phe Pro Ala Ser Val Gln Leu His

20 25 30

Glu Ala Val Glu Leu His His Trp Cys Ile Pro Phe Ser Val Asp Gly

35 40 45

Gln Pro Ala Pro Ser Leu Arg Trp Leu Phe Asn Gly Ser Val Leu Asn

50 55 60

Glu Thr Ser Phe Ile Phe Thr Glu Phe Leu Glu Pro Val Ala Asn Glu

65 70 75 80

Thr Val Arg His Gly Cys Leu Arg Leu Asn Gln Pro Thr His Val Asn

85 90 95

Asn Gly Asn Tyr Thr Leu Leu Ala Ala Asn Pro Ser Gly Arg Ala Ala

100 105 110

Ala Phe Val Met Ala Ala Phe Met Asp Asn Pro Phe Glu Phe Asn Pro

115 120 125

Glu Asp Pro Ile Pro Val Ser Phe Ser Pro Val Asp Thr Asn Ser Thr

130 135 140

Ser Gly Asp Ser Gly Gly Gly Ser Gly Gly Gly Ser Arg Pro Pro Asp

145 150 155 160

Cys Pro Lys Cys Pro Ala Pro Glu Pro Leu Gly Gly Pro Ser Val Phe

165 170 175

Ile Phe Pro Pro Lys Pro Lys Asp Thr Leu Leu Ile Ala Arg Thr Pro

180 185 190

Glu Val Thr Cys Val Val Val Asp Leu Gly Arg Glu Asp Pro Glu Val

195 200 205

Gln Ile Ser Trp Phe Val Asp Gly Lys Gln Met Gln Thr Ala Lys Thr

210 215 220

Gln Pro Arg Glu Glu Gln Phe Asn Gly Thr Tyr Arg Val Val Ser Val

225 230 235 240

Leu Pro Ile Gly His Gln Asp Trp Leu Lys Gly Lys Gln Phe Thr Cys

245 250 255

Arg Val Asn Asn Lys Ala Leu Pro Ser Pro Ile Glu Arg Thr Ile Ser

260 265 270

Lys Ala Arg Gly Gln Ala His Gln Pro Ser Val Tyr Val Leu Pro Pro

275 280 285

Ser Arg Glu Glu Leu Ser Lys Asn Thr Val Ser Leu Thr Cys Leu Ile

290 295 300

Lys Asp Phe Phe Pro Pro Asp Ile Asp Val Glu Trp Gln Ser Asn Gly

305 310 315 320

Gln Gln Glu Pro Glu Ser Lys Tyr Arg Thr Thr Pro Pro Gln Leu Asp

325 330 335

Glu Asp Gly Ser Tyr Phe Leu Tyr Ser Lys Leu Ser Val Asp Lys Ser

340 345 350

Arg Trp Gln Arg Gly Asp Thr Phe Ile Cys Ala Val Met His Glu Ala

355 360 365

Leu His Asn His Tyr Thr Gln Glu Ser Leu Ser His Ser Pro Gly Lys

370 375 380

<210> 129

<211> 360

<212> PRT

<213> 人工序列

<220>

<223> 合成的: 具有信号序列的示例性犬类TrkA ECD v3 - 变体犬类

IgG-B Fc 蛋白A + C1q - CD16 -

<400> 129

Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp

1 5 10 15

Leu Arg Gly Ala Arg Cys Val Ser Phe Pro Ala Ser Val Gln Leu His

20 25 30

Glu Ala Val Glu Leu His His Trp Cys Ile Pro Phe Ser Val Asp Gly

35 40 45

Gln Pro Ala Pro Ser Leu Arg Trp Leu Phe Asn Gly Ser Val Leu Asn

50 55 60

Glu Thr Ser Phe Ile Phe Thr Glu Phe Leu Glu Pro Val Ala Asn Glu

65 70 75 80

Thr Val Arg His Gly Cys Leu Arg Leu Asn Gln Pro Thr His Val Asn

85 90 95

Asn Gly Asn Tyr Thr Leu Leu Ala Ala Asn Pro Ser Gly Arg Ala Ala

100 105 110

Ala Phe Val Met Ala Ala Phe Met Asp Asn Pro Ser Gly Gly Gly Ser

115 120 125

Gly Gly Gly Ser Arg Pro Pro Asp Cys Pro Lys Cys Pro Ala Pro Glu

130 135 140

Pro Leu Gly Gly Pro Ser Val Phe Ile Phe Pro Pro Lys Pro Lys Asp

145 150 155 160

Thr Leu Leu Ile Ala Arg Thr Pro Glu Val Thr Cys Val Val Val Asp

165 170 175

Leu Gly Arg Glu Asp Pro Glu Val Gln Ile Ser Trp Phe Val Asp Gly

180 185 190

Lys Gln Met Gln Thr Ala Lys Thr Gln Pro Arg Glu Glu Gln Phe Asn

195 200 205

Gly Thr Tyr Arg Val Val Ser Val Leu Pro Ile Gly His Gln Asp Trp

210 215 220

Leu Lys Gly Lys Gln Phe Thr Cys Arg Val Asn Asn Lys Ala Leu Pro

225 230 235 240

Ser Pro Ile Glu Arg Thr Ile Ser Lys Ala Arg Gly Gln Ala His Gln

245 250 255

Pro Ser Val Tyr Val Leu Pro Pro Ser Arg Glu Glu Leu Ser Lys Asn

260 265 270

Thr Val Ser Leu Thr Cys Leu Ile Lys Asp Phe Phe Pro Pro Asp Ile

275 280 285

Asp Val Glu Trp Gln Ser Asn Gly Gln Gln Glu Pro Glu Ser Lys Tyr

290 295 300

Arg Thr Thr Pro Pro Gln Leu Asp Glu Asp Gly Ser Tyr Phe Leu Tyr

305 310 315 320

Ser Lys Leu Ser Val Asp Lys Ser Arg Trp Gln Arg Gly Asp Thr Phe

325 330 335

Ile Cys Ala Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Glu

340 345 350

Ser Leu Ser His Ser Pro Gly Lys

355 360

<210> 130

<211> 358

<212> PRT

<213> 人工序列

<220>

<223> 合成的: 具有信号序列的示例性犬类TrkA ECD v4 - 变体犬类

IgG-B Fc 蛋白A + C1q - CD16 -

<400> 130

Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp

1 5 10 15

Leu Arg Gly Ala Arg Cys Phe Pro Ala Ser Val Gln Leu His Glu Ala

20 25 30

Val Glu Leu His His Trp Cys Ile Pro Phe Ser Val Asp Gly Gln Pro

35 40 45

Ala Pro Ser Leu Arg Trp Leu Phe Asn Gly Ser Val Leu Asn Glu Thr

50 55 60

Ser Phe Ile Phe Thr Glu Phe Leu Glu Pro Val Ala Asn Glu Thr Val

65 70 75 80

Arg His Gly Cys Leu Arg Leu Asn Gln Pro Thr His Val Asn Asn Gly

85 90 95

Asn Tyr Thr Leu Leu Ala Ala Asn Pro Ser Gly Arg Ala Ala Ala Phe

100 105 110

Val Met Ala Ala Phe Met Asp Asn Pro Ser Gly Gly Gly Ser Gly Gly

115 120 125

Gly Ser Arg Pro Pro Asp Cys Pro Lys Cys Pro Ala Pro Glu Pro Leu

130 135 140

Gly Gly Pro Ser Val Phe Ile Phe Pro Pro Lys Pro Lys Asp Thr Leu

145 150 155 160

Leu Ile Ala Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Leu Gly

165 170 175

Arg Glu Asp Pro Glu Val Gln Ile Ser Trp Phe Val Asp Gly Lys Gln

180 185 190

Met Gln Thr Ala Lys Thr Gln Pro Arg Glu Glu Gln Phe Asn Gly Thr

195 200 205

Tyr Arg Val Val Ser Val Leu Pro Ile Gly His Gln Asp Trp Leu Lys

210 215 220

Gly Lys Gln Phe Thr Cys Arg Val Asn Asn Lys Ala Leu Pro Ser Pro

225 230 235 240

Ile Glu Arg Thr Ile Ser Lys Ala Arg Gly Gln Ala His Gln Pro Ser

245 250 255

Val Tyr Val Leu Pro Pro Ser Arg Glu Glu Leu Ser Lys Asn Thr Val

260 265 270

Ser Leu Thr Cys Leu Ile Lys Asp Phe Phe Pro Pro Asp Ile Asp Val

275 280 285

Glu Trp Gln Ser Asn Gly Gln Gln Glu Pro Glu Ser Lys Tyr Arg Thr

290 295 300

Thr Pro Pro Gln Leu Asp Glu Asp Gly Ser Tyr Phe Leu Tyr Ser Lys

305 310 315 320

Leu Ser Val Asp Lys Ser Arg Trp Gln Arg Gly Asp Thr Phe Ile Cys

325 330 335

Ala Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Glu Ser Leu

340 345 350

Ser His Ser Pro Gly Lys

355

<210> 131

<211> 470

<212> PRT

<213> 人工序列

<220>

<223> 合成的: 具有信号序列的示例性犬类TrkA ECD v3 x2 - 变体犬类

IgG-B Fc 蛋白A + C1q - CD16 -

<400> 131

Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp

1 5 10 15

Leu Arg Gly Ala Arg Cys Val Ser Phe Pro Ala Ser Val Gln Leu His

20 25 30

Glu Ala Val Glu Leu His His Trp Cys Ile Pro Phe Ser Val Asp Gly

35 40 45

Gln Pro Ala Pro Ser Leu Arg Trp Leu Phe Asn Gly Ser Val Leu Asn

50 55 60

Glu Thr Ser Phe Ile Phe Thr Glu Phe Leu Glu Pro Val Ala Asn Glu

65 70 75 80

Thr Val Arg His Gly Cys Leu Arg Leu Asn Gln Pro Thr His Val Asn

85 90 95

Asn Gly Asn Tyr Thr Leu Leu Ala Ala Asn Pro Ser Gly Arg Ala Ala

100 105 110

Ala Phe Val Met Ala Ala Phe Met Asp Asn Pro Ser Gly Gly Gly Ser

115 120 125

Gly Gly Gly Ser Val Ser Phe Pro Ala Ser Val Gln Leu His Glu Ala

130 135 140

Val Glu Leu His His Trp Cys Ile Pro Phe Ser Val Asp Gly Gln Pro

145 150 155 160

Ala Pro Ser Leu Arg Trp Leu Phe Asn Gly Ser Val Leu Asn Glu Thr

165 170 175

Ser Phe Ile Phe Thr Glu Phe Leu Glu Pro Val Ala Asn Glu Thr Val

180 185 190

Arg His Gly Cys Leu Arg Leu Asn Gln Pro Thr His Val Asn Asn Gly

195 200 205

Asn Tyr Thr Leu Leu Ala Ala Asn Pro Ser Gly Arg Ala Ala Ala Phe

210 215 220

Val Met Ala Ala Phe Met Asp Asn Pro Ser Gly Gly Gly Ser Gly Gly

225 230 235 240

Gly Ser Arg Pro Pro Asp Cys Pro Lys Cys Pro Ala Pro Glu Pro Leu

245 250 255

Gly Gly Pro Ser Val Phe Ile Phe Pro Pro Lys Pro Lys Asp Thr Leu

260 265 270

Leu Ile Ala Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Leu Gly

275 280 285

Arg Glu Asp Pro Glu Val Gln Ile Ser Trp Phe Val Asp Gly Lys Gln

290 295 300

Met Gln Thr Ala Lys Thr Gln Pro Arg Glu Glu Gln Phe Asn Gly Thr

305 310 315 320

Tyr Arg Val Val Ser Val Leu Pro Ile Gly His Gln Asp Trp Leu Lys

325 330 335

Gly Lys Gln Phe Thr Cys Arg Val Asn Asn Lys Ala Leu Pro Ser Pro

340 345 350

Ile Glu Arg Thr Ile Ser Lys Ala Arg Gly Gln Ala His Gln Pro Ser

355 360 365

Val Tyr Val Leu Pro Pro Ser Arg Glu Glu Leu Ser Lys Asn Thr Val

370 375 380

Ser Leu Thr Cys Leu Ile Lys Asp Phe Phe Pro Pro Asp Ile Asp Val

385 390 395 400

Glu Trp Gln Ser Asn Gly Gln Gln Glu Pro Glu Ser Lys Tyr Arg Thr

405 410 415

Thr Pro Pro Gln Leu Asp Glu Asp Gly Ser Tyr Phe Leu Tyr Ser Lys

420 425 430

Leu Ser Val Asp Lys Ser Arg Trp Gln Arg Gly Asp Thr Phe Ile Cys

435 440 445

Ala Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Glu Ser Leu

450 455 460

Ser His Ser Pro Gly Lys

465 470

<210> 132

<211> 367

<212> PRT

<213> 人工序列

<220>

<223> 合成的: 具有信号序列的示例性变体犬类IgG-B Fc - 犬类

TrkA ECD v3 蛋白A + C1q - CD16 -

<400> 132

Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp

1 5 10 15

Leu Arg Gly Ala Arg Cys Pro Lys Arg Glu Asn Gly Arg Val Pro Arg

20 25 30

Pro Pro Asp Cys Pro Lys Cys Pro Ala Pro Glu Pro Leu Gly Gly Pro

35 40 45

Ser Val Phe Ile Phe Pro Pro Lys Pro Lys Asp Thr Leu Leu Ile Ala

50 55 60

Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Leu Gly Arg Glu Asp

65 70 75 80

Pro Glu Val Gln Ile Ser Trp Phe Val Asp Gly Lys Gln Met Gln Thr

85 90 95

Ala Lys Thr Gln Pro Arg Glu Glu Gln Phe Asn Gly Thr Tyr Arg Val

100 105 110

Val Ser Val Leu Pro Ile Gly His Gln Asp Trp Leu Lys Gly Lys Gln

115 120 125

Phe Thr Cys Arg Val Asn Asn Lys Ala Leu Pro Ser Pro Ile Glu Arg

130 135 140

Thr Ile Ser Lys Ala Arg Gly Gln Ala His Gln Pro Ser Val Tyr Val

145 150 155 160

Leu Pro Pro Ser Arg Glu Glu Leu Ser Lys Asn Thr Val Ser Leu Thr

165 170 175

Cys Leu Ile Lys Asp Phe Phe Pro Pro Asp Ile Asp Val Glu Trp Gln

180 185 190

Ser Asn Gly Gln Gln Glu Pro Glu Ser Lys Tyr Arg Thr Thr Pro Pro

195 200 205

Gln Leu Asp Glu Asp Gly Ser Tyr Phe Leu Tyr Ser Lys Leu Ser Val

210 215 220

Asp Lys Ser Arg Trp Gln Arg Gly Asp Thr Phe Ile Cys Ala Val Met

225 230 235 240

His Glu Ala Leu His Asn His Tyr Thr Gln Glu Ser Leu Ser His Ser

245 250 255

Pro Gly Lys Ser Gly Gly Gly Ser Gly Gly Val Ser Phe Pro Ala Ser

260 265 270

Val Gln Leu His Glu Ala Val Glu Leu His His Trp Cys Ile Pro Phe

275 280 285

Ser Val Asp Gly Gln Pro Ala Pro Ser Leu Arg Trp Leu Phe Asn Gly

290 295 300

Ser Val Leu Asn Glu Thr Ser Phe Ile Phe Thr Glu Phe Leu Glu Pro

305 310 315 320

Val Ala Asn Glu Thr Val Arg His Gly Cys Leu Arg Leu Asn Gln Pro

325 330 335

Thr His Val Asn Asn Gly Asn Tyr Thr Leu Leu Ala Ala Asn Pro Ser

340 345 350

Gly Arg Ala Ala Ala Phe Val Met Ala Ala Phe Met Asp Asn Pro

355 360 365

<210> 133

<211> 468

<212> PRT

<213> 人工序列

<220>

<223> 合成的: 具有信号序列的示例性犬类TrkA ECD v3 - 变体犬类

IgG-B Fc - 犬类TrkA ECD v3 蛋白A + C1q - CD16 -

<400> 133

Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp

1 5 10 15

Leu Arg Gly Ala Arg Cys Val Ser Phe Pro Ala Ser Val Gln Leu His

20 25 30

Glu Ala Val Glu Leu His His Trp Cys Ile Pro Phe Ser Val Asp Gly

35 40 45

Gln Pro Ala Pro Ser Leu Arg Trp Leu Phe Asn Gly Ser Val Leu Asn

50 55 60

Glu Thr Ser Phe Ile Phe Thr Glu Phe Leu Glu Pro Val Ala Asn Glu

65 70 75 80

Thr Val Arg His Gly Cys Leu Arg Leu Asn Gln Pro Thr His Val Asn

85 90 95

Asn Gly Asn Tyr Thr Leu Leu Ala Ala Asn Pro Ser Gly Arg Ala Ala

100 105 110

Ala Phe Val Met Ala Ala Phe Met Asp Asn Pro Ser Gly Gly Gly Ser

115 120 125

Gly Gly Gly Ser Arg Pro Pro Asp Cys Pro Lys Cys Pro Ala Pro Glu

130 135 140

Pro Leu Gly Gly Pro Ser Val Phe Ile Phe Pro Pro Lys Pro Lys Asp

145 150 155 160

Thr Leu Leu Ile Ala Arg Thr Pro Glu Val Thr Cys Val Val Val Asp

165 170 175

Leu Gly Arg Glu Asp Pro Glu Val Gln Ile Ser Trp Phe Val Asp Gly

180 185 190

Lys Gln Met Gln Thr Ala Lys Thr Gln Pro Arg Glu Glu Gln Phe Asn

195 200 205

Gly Thr Tyr Arg Val Val Ser Val Leu Pro Ile Gly His Gln Asp Trp

210 215 220

Leu Lys Gly Lys Gln Phe Thr Cys Arg Val Asn Asn Lys Ala Leu Pro

225 230 235 240

Ser Pro Ile Glu Arg Thr Ile Ser Lys Ala Arg Gly Gln Ala His Gln

245 250 255

Pro Ser Val Tyr Val Leu Pro Pro Ser Arg Glu Glu Leu Ser Lys Asn

260 265 270

Thr Val Ser Leu Thr Cys Leu Ile Lys Asp Phe Phe Pro Pro Asp Ile

275 280 285

Asp Val Glu Trp Gln Ser Asn Gly Gln Gln Glu Pro Glu Ser Lys Tyr

290 295 300

Arg Thr Thr Pro Pro Gln Leu Asp Glu Asp Gly Ser Tyr Phe Leu Tyr

305 310 315 320

Ser Lys Leu Ser Val Asp Lys Ser Arg Trp Gln Arg Gly Asp Thr Phe

325 330 335

Ile Cys Ala Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Glu

340 345 350

Ser Leu Ser His Ser Pro Gly Lys Ser Gly Gly Gly Ser Gly Gly Val

355 360 365

Ser Phe Pro Ala Ser Val Gln Leu His Glu Ala Val Glu Leu His His

370 375 380

Trp Cys Ile Pro Phe Ser Val Asp Gly Gln Pro Ala Pro Ser Leu Arg

385 390 395 400

Trp Leu Phe Asn Gly Ser Val Leu Asn Glu Thr Ser Phe Ile Phe Thr

405 410 415

Glu Phe Leu Glu Pro Val Ala Asn Glu Thr Val Arg His Gly Cys Leu

420 425 430

Arg Leu Asn Gln Pro Thr His Val Asn Asn Gly Asn Tyr Thr Leu Leu

435 440 445

Ala Ala Asn Pro Ser Gly Arg Ala Ala Ala Phe Val Met Ala Ala Phe

450 455 460

Met Asp Asn Pro

465

<210> 134

<211> 541

<212> PRT

<213> 家犬

<220>

<221> 尚未归类的特征

<223> 犬类NGFR

<400> 134

Met Ala Ile Ala Gly Asp Asn Arg Val Ala Val Thr Val Ala Met Gly

1 5 10 15

Arg Ile Val Gly Val Val Ala Met Ala Val Val Ala Val Val Val Leu

20 25 30

Val Val Met Pro Val Ser Trp Leu Arg Gly Gly Arg Ala Arg Phe Arg

35 40 45

Gly Trp Ala Gly Trp Ala Gly Arg Arg Arg Gly Arg Arg Thr Gly Phe

50 55 60

Ser Gln Pro Leu Pro Pro Ser Ala Arg Ala Ser Gly Ala Ser Ala Ser

65 70 75 80

Ser Gly Gly Arg Ala Leu Glu Arg Ser Ala Ala Gln Pro Tyr Pro Ser

85 90 95

Ala Glu Arg Thr Pro Leu Glu Ala Glu Arg Cys His Arg Arg Arg Ala

100 105 110

Val Gly Ala Gly Ala Ala Gly Cys Ala Met Asp Gly Pro Arg Leu Leu

115 120 125

Leu Leu Leu Leu Leu Leu Leu Gly Val Ser Leu Gly Gly Ala Lys Glu

130 135 140

Ala Cys Pro Thr Gly Leu Tyr Thr His Ser Gly Glu Cys Cys Lys Ala

145 150 155 160

Cys Asn Leu Gly Glu Gly Val Ala Gln Pro Cys Gly Ala Asn Gln Thr

165 170 175

Val Cys Glu Pro Cys Leu Asp Ser Val Thr Phe Ser Asp Val Val Ser

180 185 190

Ala Thr Glu Pro Cys Lys Pro Cys Thr Glu Cys Val Gly Leu Gln Ser

195 200 205

Met Ser Ala Pro Cys Val Glu Ala Asp Asp Ala Val Cys Arg Cys Ala

210 215 220

Tyr Gly Tyr Tyr Gln Asp Glu Thr Thr Gly Arg Cys Glu Ala Cys Arg

225 230 235 240

Val Cys Glu Ala Gly Ser Gly Leu Val Phe Ser Cys Gln Asp Arg Gln

245 250 255

Asn Thr Val Cys Glu Glu Cys Pro Asp Gly Thr Tyr Ser Asp Glu Ala

260 265 270

Asn His Val Asp Pro Cys Leu Pro Cys Thr Val Cys Glu Asp Thr Glu

275 280 285

Arg Gln Leu Arg Glu Cys Thr Arg Trp Ala Asp Ala Glu Cys Glu Glu

290 295 300

Ile Pro Gly Arg Trp Ile Thr Arg Ser Thr Pro Ser Glu Asp Ser Asp

305 310 315 320

Ser Thr Ala Pro Ser Thr Glu Glu Pro Glu Leu Pro Pro Asp Gln Glu

325 330 335

Ile Ile Ala Ser Thr Met Ala Asp Val Val Thr Thr Val Met Gly Ser

340 345 350

Ser Gln Pro Val Val Thr Arg Gly Thr Ala Asp Asn Leu Ile Pro Val

355 360 365

Tyr Cys Ser Ile Leu Ala Ala Val Val Val Gly Leu Val Ala Tyr Ile

370 375 380

Ala Phe Lys Arg Trp Asn Ser Cys Lys Gln Asn Lys Gln Gly Ala Asn

385 390 395 400

Ser Arg Pro Val Asn Gln Thr Pro Pro Pro Glu Gly Glu Lys Leu His

405 410 415

Ser Asp Ser Gly Ile Ser Val Asp Ser Gln Ser Leu His Asp Gln Gln

420 425 430

Pro His Thr Gln Thr Ala Ala Gly Gln Ala Leu Lys Gly Asp Gly Gly

435 440 445

Leu Tyr Ser Ser Leu Pro Pro Ala Lys Arg Glu Glu Val Glu Lys Leu

450 455 460

Leu Asn Gly Ser Ala Gly Asp Thr Trp Arg His Leu Ala Gly Glu Leu

465 470 475 480

Gly Tyr Gln Pro Glu His Ile Asp Ser Phe Thr His Glu Ala Cys Pro

485 490 495

Ala Arg Ala Leu Leu Ala Ser Trp Ala Ala Gln Asp Ser Ala Thr Leu

500 505 510

Asp Ala Leu Leu Ala Ala Leu Arg Arg Ile Gln Arg Ala Asp Ile Val

515 520 525

Glu Ser Leu Cys Ser Glu Ser Thr Ala Thr Ser Pro Val

530 535 540

<210> 135

<211> 163

<212> PRT

<213> 人工序列

<220>

<223> 合成的: 示例性犬类NGFR ECD

<400> 135

Ala Lys Glu Ala Cys Pro Thr Gly Leu Tyr Thr His Ser Gly Glu Cys

1 5 10 15

Cys Lys Ala Cys Asn Leu Gly Glu Gly Val Ala Gln Pro Cys Gly Ala

20 25 30

Asn Gln Thr Val Cys Glu Pro Cys Leu Asp Ser Val Thr Phe Ser Asp

35 40 45

Val Val Ser Ala Thr Glu Pro Cys Lys Pro Cys Thr Glu Cys Val Gly

50 55 60

Leu Gln Ser Met Ser Ala Pro Cys Val Glu Ala Asp Asp Ala Val Cys

65 70 75 80

Arg Cys Ala Tyr Gly Tyr Tyr Gln Asp Glu Thr Thr Gly Arg Cys Glu

85 90 95

Ala Cys Arg Val Cys Glu Ala Gly Ser Gly Leu Val Phe Ser Cys Gln

100 105 110

Asp Arg Gln Asn Thr Val Cys Glu Glu Cys Pro Asp Gly Thr Tyr Ser

115 120 125

Asp Glu Ala Asn His Val Asp Pro Cys Leu Pro Cys Thr Val Cys Glu

130 135 140

Asp Thr Glu Arg Gln Leu Arg Glu Cys Thr Arg Trp Ala Asp Ala Glu

145 150 155 160

Cys Glu Glu

<210> 136

<211> 430

<212> PRT

<213> 家猫

<220>

<221> 尚未归类的特征

<223> 猫类NGFR

<400> 136

Met Gly Ala Gly Ala Ala Gly Arg Ala Met Asp Gly Pro Arg Pro Leu

1 5 10 15

Leu Leu Leu Leu Pro Leu Leu Leu Gly Val Ser Leu Gly Gly Ala Lys

20 25 30

Glu Ala Cys Pro Thr Gly Leu Phe Thr His Ser Gly Glu Cys Cys Lys

35 40 45

Ala Cys Asn Leu Gly Glu Gly Val Ala Gln Pro Cys Gly Ala Asn Gln

50 55 60

Thr Val Cys Glu Pro Cys Leu Asp Ser Val Thr Phe Ser Asp Val Val

65 70 75 80

Ser Ala Thr Glu Pro Cys Lys Pro Cys Thr Glu Cys Val Gly Leu Gln

85 90 95

Ser Met Ser Ala Pro Cys Val Glu Ala Asp Asp Ala Val Cys Arg Cys

100 105 110

Ala Tyr Gly Tyr Tyr Gln Asp Glu Thr Thr Gly Arg Cys Glu Ala Cys

115 120 125

Arg Val Cys Glu Ala Gly Ser Gly Leu Val Phe Ser Cys Gln Asp Arg

130 135 140

Gln Asn Thr Val Cys Glu Glu Cys Pro Asp Gly Thr Tyr Ser Asp Glu

145 150 155 160

Ala Asn His Val Asp Pro Cys Leu Pro Cys Thr Val Cys Glu Asp Thr

165 170 175

Glu Arg Gln Leu Arg Glu Cys Thr Arg Trp Ala Asp Ala Glu Cys Glu

180 185 190

Glu Ile Pro Gly Arg Trp Ile Thr Arg Ser Thr Pro Ser Glu Gly Ser

195 200 205

Asp Ser Thr Ala Pro Ser Thr Glu Glu Pro Glu Val Pro Pro Glu Gln

210 215 220

Asp Leu Ile Ala Ser Thr Val Ala Asp Val Val Thr Thr Val Met Gly

225 230 235 240

Ser Ser Gln Pro Val Val Thr Arg Gly Thr Ala Asp Asn Leu Ile Pro

245 250 255

Val Tyr Cys Ser Ile Leu Ala Ala Val Val Val Gly Leu Val Ala Tyr

260 265 270

Ile Ala Phe Lys Arg Trp Asn Ser Cys Lys Gln Asp Lys Gln Gly Ala

275 280 285

Asn Ser Arg Pro Val Asn Gln Thr Pro Pro Pro Glu Gly Glu Lys Leu

290 295 300

His Ser Asp Ser Gly Ile Ser Val Asp Ser Gln Ser Leu His Asp Gln

305 310 315 320

Gln Ser His Thr Gln Thr Ala Ala Gly Gln Ala Leu Lys Gly Asp Gly

325 330 335

Gly Leu Tyr Ser Ser Leu Pro Ser Ala Lys Arg Glu Glu Val Glu Lys

340 345 350

Leu Leu Asn Gly Ser Ala Gly Asp Thr Trp Arg His Leu Ala Gly Glu

355 360 365

Leu Gly Tyr Gln Pro Glu His Ile Asp Ser Phe Thr Arg Glu Ala Cys

370 375 380

Pro Ala Arg Ala Leu Leu Ala Ser Trp Ala Ala Gln Asp Ser Ala Thr

385 390 395 400

Leu Asp Ala Leu Leu Ala Ala Leu Arg Arg Ile Gln Arg Ala Asp Ile

405 410 415

Val Glu Ser Leu Cys Ser Glu Ser Thr Ala Thr Ser Pro Val

420 425 430

<210> 137

<211> 163

<212> PRT

<213> 人工序列

<220>

<223> 合成的: 示例性猫类NGFR ECD

<400> 137

Ala Lys Glu Ala Cys Pro Thr Gly Leu Phe Thr His Ser Gly Glu Cys

1 5 10 15

Cys Lys Ala Cys Asn Leu Gly Glu Gly Val Ala Gln Pro Cys Gly Ala

20 25 30

Asn Gln Thr Val Cys Glu Pro Cys Leu Asp Ser Val Thr Phe Ser Asp

35 40 45

Val Val Ser Ala Thr Glu Pro Cys Lys Pro Cys Thr Glu Cys Val Gly

50 55 60

Leu Gln Ser Met Ser Ala Pro Cys Val Glu Ala Asp Asp Ala Val Cys

65 70 75 80

Arg Cys Ala Tyr Gly Tyr Tyr Gln Asp Glu Thr Thr Gly Arg Cys Glu

85 90 95

Ala Cys Arg Val Cys Glu Ala Gly Ser Gly Leu Val Phe Ser Cys Gln

100 105 110

Asp Arg Gln Asn Thr Val Cys Glu Glu Cys Pro Asp Gly Thr Tyr Ser

115 120 125

Asp Glu Ala Asn His Val Asp Pro Cys Leu Pro Cys Thr Val Cys Glu

130 135 140

Asp Thr Glu Arg Gln Leu Arg Glu Cys Thr Arg Trp Ala Asp Ala Glu

145 150 155 160

Cys Glu Glu

<210> 138

<211> 429

<212> PRT

<213> 家马

<220>

<221> 尚未归类的特征

<223> 马类NGFR

<400> 138

Met Arg Ala Gly Ala Ala Asp Cys Ala Met Asp Gly Pro Arg Leu Leu

1 5 10 15

Leu Leu Leu Leu Leu Leu Gly Val Cys Leu Leu Gly Gly Ala Lys Glu

20 25 30

Val Cys Pro Thr Asp Leu Tyr Thr His Ser Gly Glu Cys Cys Lys Ala

35 40 45

Cys Asn Leu Gly Glu Gly Val Ala Gln Pro Cys Gly Ala Asn Gln Thr

50 55 60

Val Cys Glu Pro Cys Leu Asp Ser Val Thr Phe Ser Asp Val Val Ser

65 70 75 80

Ala Thr Glu Pro Cys Lys Pro Cys Thr Glu Cys Val Gly Leu Gln Ser

85 90 95

Met Ser Ala Pro Cys Val Glu Ala Asp Asp Ala Val Cys Arg Cys Ala

100 105 110

Tyr Gly Tyr Tyr Gln Asp Glu Thr Thr Gly Arg Cys Glu Ala Cys Gln

115 120 125

Val Cys Glu Ala Gly Ser Gly Leu Val Phe Ser Cys Gln Asp Lys Gln

130 135 140

Asn Thr Val Cys Glu Glu Cys Pro Asp Gly Thr Tyr Ser Asp Glu Ala

145 150 155 160

Asn His Val Asp Pro Cys Leu Pro Cys Thr Val Cys Glu Asp Thr Glu

165 170 175

Arg Gln Leu Arg Glu Cys Thr Arg Trp Ala Asp Ala Glu Cys Glu Glu

180 185 190

Ile Pro Ser Arg Trp Ile Thr Arg Ala Thr Pro Pro Glu Gly Ser Asp

195 200 205

Ser Thr Ala Pro Ser Thr Gln Glu Pro Glu Gly Pro Pro Glu Lys Asp

210 215 220

Leu Val Ala Ser Thr Val Ala Asp Val Val Thr Thr Val Met Gly Ser

225 230 235 240

Ser Gln Pro Val Val Thr Arg Gly Thr Thr Asp Asn Leu Ile Pro Val

245 250 255

Tyr Cys Ser Ile Leu Ala Ala Val Val Val Gly Leu Val Ala Tyr Ile

260 265 270

Ala Phe Lys Arg Trp Asn Ser Cys Lys Gln Asn Lys Gln Gly Ala Asn

275 280 285

Ser Arg Pro Val Asn Gln Thr Pro Pro Pro Glu Gly Glu Lys Leu His

290 295 300

Ser Asp Ser Gly Ile Ser Val Asp Ser Gln Ser Leu His Asp Gln Gln

305 310 315 320

Pro His Thr Gln Thr Ala Ala Gly Gln Ala Leu Lys Gly Asp Gly Gly

325 330 335

Leu Tyr Ser Ser Leu Pro Leu Ala Lys Arg Glu Glu Val Glu Lys Leu

340 345 350

Leu Asn Gly Ser Ala Gly Asp Thr Trp Arg His Leu Ala Gly Glu Leu

355 360 365

Gly Tyr Gln Pro Glu His Ile Asp Ser Phe Thr His Glu Ala Cys Pro

370 375 380

Val Arg Ala Leu Leu Ala Ser Trp Ala Ala Gln Asp Ser Ala Thr Phe

385 390 395 400

Asp Ala Leu Leu Thr Ala Leu Arg Arg Ile Gln Arg Ala Asp Ile Val

405 410 415

Glu Ser Leu Cys Ser Glu Ser Thr Ala Thr Ser Pro Val

420 425

<210> 139

<211> 163

<212> PRT

<213> 人工序列

<220>

<223> 合成的: 示例性马类NGFR ECD

<400> 139

Ala Lys Glu Val Cys Pro Thr Asp Leu Tyr Thr His Ser Gly Glu Cys

1 5 10 15

Cys Lys Ala Cys Asn Leu Gly Glu Gly Val Ala Gln Pro Cys Gly Ala

20 25 30

Asn Gln Thr Val Cys Glu Pro Cys Leu Asp Ser Val Thr Phe Ser Asp

35 40 45

Val Val Ser Ala Thr Glu Pro Cys Lys Pro Cys Thr Glu Cys Val Gly

50 55 60

Leu Gln Ser Met Ser Ala Pro Cys Val Glu Ala Asp Asp Ala Val Cys

65 70 75 80

Arg Cys Ala Tyr Gly Tyr Tyr Gln Asp Glu Thr Thr Gly Arg Cys Glu

85 90 95

Ala Cys Gln Val Cys Glu Ala Gly Ser Gly Leu Val Phe Ser Cys Gln

100 105 110

Asp Lys Gln Asn Thr Val Cys Glu Glu Cys Pro Asp Gly Thr Tyr Ser

115 120 125

Asp Glu Ala Asn His Val Asp Pro Cys Leu Pro Cys Thr Val Cys Glu

130 135 140

Asp Thr Glu Arg Gln Leu Arg Glu Cys Thr Arg Trp Ala Asp Ala Glu

145 150 155 160

Cys Glu Glu

<210> 140

<211> 631

<212> PRT

<213> 人工序列

<220>

<223> 合成的: 具有信号序列的示例性犬类TrkA ECD v3 - 犬类NGFR ECD -

变体犬类IgG-B Fc - 犬类TrkA ECD v3

蛋白A + C1q - CD16 -

<400> 140

Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp

1 5 10 15

Leu Arg Gly Ala Arg Cys Val Ser Phe Pro Ala Ser Val Gln Leu His

20 25 30

Glu Ala Val Glu Leu His His Trp Cys Ile Pro Phe Ser Val Asp Gly

35 40 45

Gln Pro Ala Pro Ser Leu Arg Trp Leu Phe Asn Gly Ser Val Leu Asn

50 55 60

Glu Thr Ser Phe Ile Phe Thr Glu Phe Leu Glu Pro Val Ala Asn Glu

65 70 75 80

Thr Val Arg His Gly Cys Leu Arg Leu Asn Gln Pro Thr His Val Asn

85 90 95

Asn Gly Asn Tyr Thr Leu Leu Ala Ala Asn Pro Ser Gly Arg Ala Ala

100 105 110

Ala Phe Val Met Ala Ala Phe Met Asp Asn Pro Ser Gly Gly Gly Ser

115 120 125

Gly Gly Gly Ser Ala Lys Glu Ala Cys Pro Thr Gly Leu Tyr Thr His

130 135 140

Ser Gly Glu Cys Cys Lys Ala Cys Asn Leu Gly Glu Gly Val Ala Gln

145 150 155 160

Pro Cys Gly Ala Asn Gln Thr Val Cys Glu Pro Cys Leu Asp Ser Val

165 170 175

Thr Phe Ser Asp Val Val Ser Ala Thr Glu Pro Cys Lys Pro Cys Thr

180 185 190

Glu Cys Val Gly Leu Gln Ser Met Ser Ala Pro Cys Val Glu Ala Asp

195 200 205

Asp Ala Val Cys Arg Cys Ala Tyr Gly Tyr Tyr Gln Asp Glu Thr Thr

210 215 220

Gly Arg Cys Glu Ala Cys Arg Val Cys Glu Ala Gly Ser Gly Leu Val

225 230 235 240

Phe Ser Cys Gln Asp Arg Gln Asn Thr Val Cys Glu Glu Cys Pro Asp

245 250 255

Gly Thr Tyr Ser Asp Glu Ala Asn His Val Asp Pro Cys Leu Pro Cys

260 265 270

Thr Val Cys Glu Asp Thr Glu Arg Gln Leu Arg Glu Cys Thr Arg Trp

275 280 285

Ala Asp Ala Glu Cys Glu Glu Arg Pro Pro Asp Cys Pro Lys Cys Pro

290 295 300

Ala Pro Glu Pro Leu Gly Gly Pro Ser Val Phe Ile Phe Pro Pro Lys

305 310 315 320

Pro Lys Asp Thr Leu Leu Ile Ala Arg Thr Pro Glu Val Thr Cys Val

325 330 335

Val Val Asp Leu Gly Arg Glu Asp Pro Glu Val Gln Ile Ser Trp Phe

340 345 350

Val Asp Gly Lys Gln Met Gln Thr Ala Lys Thr Gln Pro Arg Glu Glu

355 360 365

Gln Phe Asn Gly Thr Tyr Arg Val Val Ser Val Leu Pro Ile Gly His

370 375 380

Gln Asp Trp Leu Lys Gly Lys Gln Phe Thr Cys Arg Val Asn Asn Lys

385 390 395 400

Ala Leu Pro Ser Pro Ile Glu Arg Thr Ile Ser Lys Ala Arg Gly Gln

405 410 415

Ala His Gln Pro Ser Val Tyr Val Leu Pro Pro Ser Arg Glu Glu Leu

420 425 430

Ser Lys Asn Thr Val Ser Leu Thr Cys Leu Ile Lys Asp Phe Phe Pro

435 440 445

Pro Asp Ile Asp Val Glu Trp Gln Ser Asn Gly Gln Gln Glu Pro Glu

450 455 460

Ser Lys Tyr Arg Thr Thr Pro Pro Gln Leu Asp Glu Asp Gly Ser Tyr

465 470 475 480

Phe Leu Tyr Ser Lys Leu Ser Val Asp Lys Ser Arg Trp Gln Arg Gly

485 490 495

Asp Thr Phe Ile Cys Ala Val Met His Glu Ala Leu His Asn His Tyr

500 505 510

Thr Gln Glu Ser Leu Ser His Ser Pro Gly Lys Ser Gly Gly Gly Ser

515 520 525

Gly Gly Val Ser Phe Pro Ala Ser Val Gln Leu His Glu Ala Val Glu

530 535 540

Leu His His Trp Cys Ile Pro Phe Ser Val Asp Gly Gln Pro Ala Pro

545 550 555 560

Ser Leu Arg Trp Leu Phe Asn Gly Ser Val Leu Asn Glu Thr Ser Phe

565 570 575

Ile Phe Thr Glu Phe Leu Glu Pro Val Ala Asn Glu Thr Val Arg His

580 585 590

Gly Cys Leu Arg Leu Asn Gln Pro Thr His Val Asn Asn Gly Asn Tyr

595 600 605

Thr Leu Leu Ala Ala Asn Pro Ser Gly Arg Ala Ala Ala Phe Val Met

610 615 620

Ala Ala Phe Met Asp Asn Pro

625 630

<210> 141

<211> 631

<212> PRT

<213> 人工序列

<220>

<223> 合成的: 具有信号序列的示例性犬类NGFR ECD - 犬类

TrkA ECD v3 - 变体犬类IgG-B Fc - 犬类TrkA ECD v3

蛋白A + C1q - CD16 -

<400> 141

Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp

1 5 10 15

Leu Arg Gly Ala Arg Cys Ala Lys Glu Ala Cys Pro Thr Gly Leu Tyr

20 25 30

Thr His Ser Gly Glu Cys Cys Lys Ala Cys Asn Leu Gly Glu Gly Val

35 40 45

Ala Gln Pro Cys Gly Ala Asn Gln Thr Val Cys Glu Pro Cys Leu Asp

50 55 60

Ser Val Thr Phe Ser Asp Val Val Ser Ala Thr Glu Pro Cys Lys Pro

65 70 75 80

Cys Thr Glu Cys Val Gly Leu Gln Ser Met Ser Ala Pro Cys Val Glu

85 90 95

Ala Asp Asp Ala Val Cys Arg Cys Ala Tyr Gly Tyr Tyr Gln Asp Glu

100 105 110

Thr Thr Gly Arg Cys Glu Ala Cys Arg Val Cys Glu Ala Gly Ser Gly

115 120 125

Leu Val Phe Ser Cys Gln Asp Arg Gln Asn Thr Val Cys Glu Glu Cys

130 135 140

Pro Asp Gly Thr Tyr Ser Asp Glu Ala Asn His Val Asp Pro Cys Leu

145 150 155 160

Pro Cys Thr Val Cys Glu Asp Thr Glu Arg Gln Leu Arg Glu Cys Thr

165 170 175

Arg Trp Ala Asp Ala Glu Cys Glu Glu Ser Gly Gly Gly Ser Gly Gly

180 185 190

Gly Ser Val Ser Phe Pro Ala Ser Val Gln Leu His Glu Ala Val Glu

195 200 205

Leu His His Trp Cys Ile Pro Phe Ser Val Asp Gly Gln Pro Ala Pro

210 215 220

Ser Leu Arg Trp Leu Phe Asn Gly Ser Val Leu Asn Glu Thr Ser Phe

225 230 235 240

Ile Phe Thr Glu Phe Leu Glu Pro Val Ala Asn Glu Thr Val Arg His

245 250 255

Gly Cys Leu Arg Leu Asn Gln Pro Thr His Val Asn Asn Gly Asn Tyr

260 265 270

Thr Leu Leu Ala Ala Asn Pro Ser Gly Arg Ala Ala Ala Phe Val Met

275 280 285

Ala Ala Phe Met Asp Asn Pro Arg Pro Pro Asp Cys Pro Lys Cys Pro

290 295 300

Ala Pro Glu Pro Leu Gly Gly Pro Ser Val Phe Ile Phe Pro Pro Lys

305 310 315 320

Pro Lys Asp Thr Leu Leu Ile Ala Arg Thr Pro Glu Val Thr Cys Val

325 330 335

Val Val Asp Leu Gly Arg Glu Asp Pro Glu Val Gln Ile Ser Trp Phe

340 345 350

Val Asp Gly Lys Gln Met Gln Thr Ala Lys Thr Gln Pro Arg Glu Glu

355 360 365

Gln Phe Asn Gly Thr Tyr Arg Val Val Ser Val Leu Pro Ile Gly His

370 375 380

Gln Asp Trp Leu Lys Gly Lys Gln Phe Thr Cys Arg Val Asn Asn Lys

385 390 395 400

Ala Leu Pro Ser Pro Ile Glu Arg Thr Ile Ser Lys Ala Arg Gly Gln

405 410 415

Ala His Gln Pro Ser Val Tyr Val Leu Pro Pro Ser Arg Glu Glu Leu

420 425 430

Ser Lys Asn Thr Val Ser Leu Thr Cys Leu Ile Lys Asp Phe Phe Pro

435 440 445

Pro Asp Ile Asp Val Glu Trp Gln Ser Asn Gly Gln Gln Glu Pro Glu

450 455 460

Ser Lys Tyr Arg Thr Thr Pro Pro Gln Leu Asp Glu Asp Gly Ser Tyr

465 470 475 480

Phe Leu Tyr Ser Lys Leu Ser Val Asp Lys Ser Arg Trp Gln Arg Gly

485 490 495

Asp Thr Phe Ile Cys Ala Val Met His Glu Ala Leu His Asn His Tyr

500 505 510

Thr Gln Glu Ser Leu Ser His Ser Pro Gly Lys Ser Gly Gly Gly Ser

515 520 525

Gly Gly Val Ser Phe Pro Ala Ser Val Gln Leu His Glu Ala Val Glu

530 535 540

Leu His His Trp Cys Ile Pro Phe Ser Val Asp Gly Gln Pro Ala Pro

545 550 555 560

Ser Leu Arg Trp Leu Phe Asn Gly Ser Val Leu Asn Glu Thr Ser Phe

565 570 575

Ile Phe Thr Glu Phe Leu Glu Pro Val Ala Asn Glu Thr Val Arg His

580 585 590

Gly Cys Leu Arg Leu Asn Gln Pro Thr His Val Asn Asn Gly Asn Tyr

595 600 605

Thr Leu Leu Ala Ala Asn Pro Ser Gly Arg Ala Ala Ala Phe Val Met

610 615 620

Ala Ala Phe Met Asp Asn Pro

625 630

<210> 142

<211> 530

<212> PRT

<213> 人工序列

<220>

<223> 合成的: 具有信号序列的示例性犬类TrkA ECD v3 -变体犬类

IgG-B Fc - 犬类NGFR ECD 蛋白A + C1q - CD16 -

<400> 142

Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp

1 5 10 15

Leu Arg Gly Ala Arg Cys Val Ser Phe Pro Ala Ser Val Gln Leu His

20 25 30

Glu Ala Val Glu Leu His His Trp Cys Ile Pro Phe Ser Val Asp Gly

35 40 45

Gln Pro Ala Pro Ser Leu Arg Trp Leu Phe Asn Gly Ser Val Leu Asn

50 55 60

Glu Thr Ser Phe Ile Phe Thr Glu Phe Leu Glu Pro Val Ala Asn Glu

65 70 75 80

Thr Val Arg His Gly Cys Leu Arg Leu Asn Gln Pro Thr His Val Asn

85 90 95

Asn Gly Asn Tyr Thr Leu Leu Ala Ala Asn Pro Ser Gly Arg Ala Ala

100 105 110

Ala Phe Val Met Ala Ala Phe Met Asp Asn Pro Ser Gly Gly Gly Ser

115 120 125

Gly Gly Gly Ser Arg Pro Pro Asp Cys Pro Lys Cys Pro Ala Pro Glu

130 135 140

Pro Leu Gly Gly Pro Ser Val Phe Ile Phe Pro Pro Lys Pro Lys Asp

145 150 155 160

Thr Leu Leu Ile Ala Arg Thr Pro Glu Val Thr Cys Val Val Val Asp

165 170 175

Leu Gly Arg Glu Asp Pro Glu Val Gln Ile Ser Trp Phe Val Asp Gly

180 185 190

Lys Gln Met Gln Thr Ala Lys Thr Gln Pro Arg Glu Glu Gln Phe Asn

195 200 205

Gly Thr Tyr Arg Val Val Ser Val Leu Pro Ile Gly His Gln Asp Trp

210 215 220

Leu Lys Gly Lys Gln Phe Thr Cys Arg Val Asn Asn Lys Ala Leu Pro

225 230 235 240

Ser Pro Ile Glu Arg Thr Ile Ser Lys Ala Arg Gly Gln Ala His Gln

245 250 255

Pro Ser Val Tyr Val Leu Pro Pro Ser Arg Glu Glu Leu Ser Lys Asn

260 265 270

Thr Val Ser Leu Thr Cys Leu Ile Lys Asp Phe Phe Pro Pro Asp Ile

275 280 285

Asp Val Glu Trp Gln Ser Asn Gly Gln Gln Glu Pro Glu Ser Lys Tyr

290 295 300

Arg Thr Thr Pro Pro Gln Leu Asp Glu Asp Gly Ser Tyr Phe Leu Tyr

305 310 315 320

Ser Lys Leu Ser Val Asp Lys Ser Arg Trp Gln Arg Gly Asp Thr Phe

325 330 335

Ile Cys Ala Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Glu

340 345 350

Ser Leu Ser His Ser Pro Gly Lys Ser Gly Gly Gly Ser Gly Gly Ala

355 360 365

Lys Glu Ala Cys Pro Thr Gly Leu Tyr Thr His Ser Gly Glu Cys Cys

370 375 380

Lys Ala Cys Asn Leu Gly Glu Gly Val Ala Gln Pro Cys Gly Ala Asn

385 390 395 400

Gln Thr Val Cys Glu Pro Cys Leu Asp Ser Val Thr Phe Ser Asp Val

405 410 415

Val Ser Ala Thr Glu Pro Cys Lys Pro Cys Thr Glu Cys Val Gly Leu

420 425 430

Gln Ser Met Ser Ala Pro Cys Val Glu Ala Asp Asp Ala Val Cys Arg

435 440 445

Cys Ala Tyr Gly Tyr Tyr Gln Asp Glu Thr Thr Gly Arg Cys Glu Ala

450 455 460

Cys Arg Val Cys Glu Ala Gly Ser Gly Leu Val Phe Ser Cys Gln Asp

465 470 475 480

Arg Gln Asn Thr Val Cys Glu Glu Cys Pro Asp Gly Thr Tyr Ser Asp

485 490 495

Glu Ala Asn His Val Asp Pro Cys Leu Pro Cys Thr Val Cys Glu Asp

500 505 510

Thr Glu Arg Gln Leu Arg Glu Cys Thr Arg Trp Ala Asp Ala Glu Cys

515 520 525

Glu Glu

530

<210> 143

<211> 4

<212> PRT

<213> 人工序列

<220>

<223> 合成的: 示例性接头

<400> 143

Gly Ser Gly Ser

1

<210> 144

<211> 6

<212> PRT

<213> 人工序列

<220>

<223> 合成的: 示例性接头

<400> 144

Gly Ser Gly Ser Gly Ser

1 5

<210> 145

<211> 6

<212> PRT

<213> 人工序列

<220>

<223> 合成的: 示例性接头

<400> 145

Gly Gly Ser Gly Gly Ser

1 5

<210> 146

<211> 9

<212> PRT

<213> 人工序列

<220>

<223> 合成的: 示例性接头

<400> 146

Gly Gly Ser Gly Gly Ser Gly Gly Ser

1 5

<210> 147

<211> 4

<212> PRT

<213> 人工序列

<220>

<223> 合成的: 示例性接头

<400> 147

Gly Gly Gly Ser

1

<210> 148

<211> 8

<212> PRT

<213> 人工序列

<220>

<223> 合成的: 示例性接头

<400> 148

Gly Gly Gly Ser Gly Gly Gly Ser

1 5

<210> 149

<211> 12

<212> PRT

<213> 人工序列

<220>

<223> 合成的: 示例性接头

<400> 149

Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly Gly Ser

1 5 10

<210> 150

<211> 6

<212> PRT

<213> 人工序列

<220>

<223> 合成的: 示例性接头

<400> 150

Gly Ser Ser Gly Ser Ser

1 5

<210> 151

<211> 9

<212> PRT

<213> 人工序列

<220>

<223> 合成的: 示例性接头

<400> 151

Gly Ser Ser Gly Ser Ser Gly Ser Ser

1 5

<210> 152

<211> 4

<212> PRT

<213> 人工序列

<220>

<223> 合成的: 示例性接头

<400> 152

Gly Gly Ser Ser

1

<210> 153

<211> 8

<212> PRT

<213> 人工序列

<220>

<223> 合成的: 示例性接头

<400> 153

Gly Gly Ser Ser Gly Gly Ser Ser

1 5

<210> 154

<211> 11

<212> PRT

<213> 人工序列

<220>

<223> 合成的: 示例性接头

<400> 154

Gly Gly Ser Ser Gly Gly Ser Ser Gly Gly Ser

1 5 10

<210> 155

<211> 7

<212> PRT

<213> 人工序列

<220>

<223> 合成的: 示例性接头

<400> 155

Ser Gly Gly Ser Gly Gly Ser

1 5

<210> 156

<211> 9

<212> PRT

<213> 人工序列

<220>

<223> 合成的: 示例性接头

<400> 156

Ser Gly Gly Gly Ser Gly Gly Gly Ser

1 5

<210> 157

<211> 12

<212> PRT

<213> 人工序列

<220>

<223> 合成的: 示例性接头

<400> 157

Gly Gly Ser Ser Gly Gly Ser Ser Gly Gly Ser Ser

1 5 10

<210> 158

<211> 4

<212> PRT

<213> 人工序列

<220>

<223> 合成的: 示例性接头

<400> 158

Ser Gly Gly Gly

1

<210> 159

<211> 362

<212> PRT

<213> 人工序列

<220>

<223> 合成的: 示例性犬类TrkA ECD v2 - 野生型犬类IgG-B

Fc 蛋白A+ C1q + CD16 +

<400> 159

Val Ser Phe Pro Ala Ser Val Gln Leu His Glu Ala Val Glu Leu His

1 5 10 15

His Trp Cys Ile Pro Phe Ser Val Asp Gly Gln Pro Ala Pro Ser Leu

20 25 30

Arg Trp Leu Phe Asn Gly Ser Val Leu Asn Glu Thr Ser Phe Ile Phe

35 40 45

Thr Glu Phe Leu Glu Pro Val Ala Asn Glu Thr Val Arg His Gly Cys

50 55 60

Leu Arg Leu Asn Gln Pro Thr His Val Asn Asn Gly Asn Tyr Thr Leu

65 70 75 80

Leu Ala Ala Asn Pro Ser Gly Arg Ala Ala Ala Phe Val Met Ala Ala

85 90 95

Phe Met Asp Asn Pro Phe Glu Phe Asn Pro Glu Asp Pro Ile Pro Val

100 105 110

Ser Phe Ser Pro Val Asp Thr Asn Ser Thr Ser Gly Asp Ser Gly Gly

115 120 125

Gly Ser Gly Gly Gly Ser Arg Pro Pro Asp Cys Pro Lys Cys Pro Ala

130 135 140

Pro Glu Met Leu Gly Gly Pro Ser Val Phe Ile Phe Pro Pro Lys Pro

145 150 155 160

Lys Asp Thr Leu Leu Ile Ala Arg Thr Pro Glu Val Thr Cys Val Val

165 170 175

Val Asp Leu Asp Pro Glu Asp Pro Glu Val Gln Ile Ser Trp Phe Val

180 185 190

Asp Gly Lys Gln Met Gln Thr Ala Lys Thr Gln Pro Arg Glu Glu Gln

195 200 205

Phe Asn Gly Thr Tyr Arg Val Val Ser Val Leu Pro Ile Gly His Gln

210 215 220

Asp Trp Leu Lys Gly Lys Gln Phe Thr Cys Lys Val Asn Asn Lys Ala

225 230 235 240

Leu Pro Ser Pro Ile Glu Arg Thr Ile Ser Lys Ala Arg Gly Gln Ala

245 250 255

His Gln Pro Ser Val Tyr Val Leu Pro Pro Ser Arg Glu Glu Leu Ser

260 265 270

Lys Asn Thr Val Ser Leu Thr Cys Leu Ile Lys Asp Phe Phe Pro Pro

275 280 285

Asp Ile Asp Val Glu Trp Gln Ser Asn Gly Gln Gln Glu Pro Glu Ser

290 295 300

Lys Tyr Arg Thr Thr Pro Pro Gln Leu Asp Glu Asp Gly Ser Tyr Phe

305 310 315 320

Leu Tyr Ser Lys Leu Ser Val Asp Lys Ser Arg Trp Gln Arg Gly Asp

325 330 335

Thr Phe Ile Cys Ala Val Met His Glu Ala Leu His Asn His Tyr Thr

340 345 350

Gln Glu Ser Leu Ser His Ser Pro Gly Lys

355 360

<210> 160

<211> 338

<212> PRT

<213> 人工序列

<220>

<223> 合成的: 示例性犬类TrkA ECD v3 - 野生型犬类IgG-B

Fc 蛋白A+ C1q + CD16 +

<400> 160

Val Ser Phe Pro Ala Ser Val Gln Leu His Glu Ala Val Glu Leu His

1 5 10 15

His Trp Cys Ile Pro Phe Ser Val Asp Gly Gln Pro Ala Pro Ser Leu

20 25 30

Arg Trp Leu Phe Asn Gly Ser Val Leu Asn Glu Thr Ser Phe Ile Phe

35 40 45

Thr Glu Phe Leu Glu Pro Val Ala Asn Glu Thr Val Arg His Gly Cys

50 55 60

Leu Arg Leu Asn Gln Pro Thr His Val Asn Asn Gly Asn Tyr Thr Leu

65 70 75 80

Leu Ala Ala Asn Pro Ser Gly Arg Ala Ala Ala Phe Val Met Ala Ala

85 90 95

Phe Met Asp Asn Pro Ser Gly Gly Gly Ser Gly Gly Gly Ser Arg Pro

100 105 110

Pro Asp Cys Pro Lys Cys Pro Ala Pro Glu Met Leu Gly Gly Pro Ser

115 120 125

Val Phe Ile Phe Pro Pro Lys Pro Lys Asp Thr Leu Leu Ile Ala Arg

130 135 140

Thr Pro Glu Val Thr Cys Val Val Val Asp Leu Asp Pro Glu Asp Pro

145 150 155 160

Glu Val Gln Ile Ser Trp Phe Val Asp Gly Lys Gln Met Gln Thr Ala

165 170 175

Lys Thr Gln Pro Arg Glu Glu Gln Phe Asn Gly Thr Tyr Arg Val Val

180 185 190

Ser Val Leu Pro Ile Gly His Gln Asp Trp Leu Lys Gly Lys Gln Phe

195 200 205

Thr Cys Lys Val Asn Asn Lys Ala Leu Pro Ser Pro Ile Glu Arg Thr

210 215 220

Ile Ser Lys Ala Arg Gly Gln Ala His Gln Pro Ser Val Tyr Val Leu

225 230 235 240

Pro Pro Ser Arg Glu Glu Leu Ser Lys Asn Thr Val Ser Leu Thr Cys

245 250 255

Leu Ile Lys Asp Phe Phe Pro Pro Asp Ile Asp Val Glu Trp Gln Ser

260 265 270

Asn Gly Gln Gln Glu Pro Glu Ser Lys Tyr Arg Thr Thr Pro Pro Gln

275 280 285

Leu Asp Glu Asp Gly Ser Tyr Phe Leu Tyr Ser Lys Leu Ser Val Asp

290 295 300

Lys Ser Arg Trp Gln Arg Gly Asp Thr Phe Ile Cys Ala Val Met His

305 310 315 320

Glu Ala Leu His Asn His Tyr Thr Gln Glu Ser Leu Ser His Ser Pro

325 330 335

Gly Lys

<210> 161

<211> 336

<212> PRT

<213> 人工序列

<220>

<223> 合成的: 示例性犬类TrkA ECD v4 - 野生型犬类IgG-B

Fc 蛋白A+ C1q + CD16 +

<400> 161

Phe Pro Ala Ser Val Gln Leu His Glu Ala Val Glu Leu His His Trp

1 5 10 15

Cys Ile Pro Phe Ser Val Asp Gly Gln Pro Ala Pro Ser Leu Arg Trp

20 25 30

Leu Phe Asn Gly Ser Val Leu Asn Glu Thr Ser Phe Ile Phe Thr Glu

35 40 45

Phe Leu Glu Pro Val Ala Asn Glu Thr Val Arg His Gly Cys Leu Arg

50 55 60

Leu Asn Gln Pro Thr His Val Asn Asn Gly Asn Tyr Thr Leu Leu Ala

65 70 75 80

Ala Asn Pro Ser Gly Arg Ala Ala Ala Phe Val Met Ala Ala Phe Met

85 90 95

Asp Asn Pro Ser Gly Gly Gly Ser Gly Gly Gly Ser Arg Pro Pro Asp

100 105 110

Cys Pro Lys Cys Pro Ala Pro Glu Met Leu Gly Gly Pro Ser Val Phe

115 120 125

Ile Phe Pro Pro Lys Pro Lys Asp Thr Leu Leu Ile Ala Arg Thr Pro

130 135 140

Glu Val Thr Cys Val Val Val Asp Leu Asp Pro Glu Asp Pro Glu Val

145 150 155 160

Gln Ile Ser Trp Phe Val Asp Gly Lys Gln Met Gln Thr Ala Lys Thr

165 170 175

Gln Pro Arg Glu Glu Gln Phe Asn Gly Thr Tyr Arg Val Val Ser Val

180 185 190

Leu Pro Ile Gly His Gln Asp Trp Leu Lys Gly Lys Gln Phe Thr Cys

195 200 205

Lys Val Asn Asn Lys Ala Leu Pro Ser Pro Ile Glu Arg Thr Ile Ser

210 215 220

Lys Ala Arg Gly Gln Ala His Gln Pro Ser Val Tyr Val Leu Pro Pro

225 230 235 240

Ser Arg Glu Glu Leu Ser Lys Asn Thr Val Ser Leu Thr Cys Leu Ile

245 250 255

Lys Asp Phe Phe Pro Pro Asp Ile Asp Val Glu Trp Gln Ser Asn Gly

260 265 270

Gln Gln Glu Pro Glu Ser Lys Tyr Arg Thr Thr Pro Pro Gln Leu Asp

275 280 285

Glu Asp Gly Ser Tyr Phe Leu Tyr Ser Lys Leu Ser Val Asp Lys Ser

290 295 300

Arg Trp Gln Arg Gly Asp Thr Phe Ile Cys Ala Val Met His Glu Ala

305 310 315 320

Leu His Asn His Tyr Thr Gln Glu Ser Leu Ser His Ser Pro Gly Lys

325 330 335

<210> 162

<211> 371

<212> PRT

<213> 人工序列

<220>

<223> 合成的: 示例性猫类TrkA ECD v2 - 野生型猫类IgG2 Fc

蛋白A + C1q - CD16 -

<400> 162

Val Ser Phe Pro Ala Ser Val Gln Leu His Ala Ala Val Glu Leu His

1 5 10 15

His Trp Cys Ile Pro Phe Ser Val Asp Gly Gln Pro Ala Pro Ser Leu

20 25 30

Arg Trp Leu Phe Asn Gly Ser Val Leu Asn Glu Thr Ser Phe Ile Phe

35 40 45

Thr Glu Phe Leu Glu Pro Ala Ala Asn Glu Thr Val Arg His Gly Cys

50 55 60

Leu Arg Leu Asn Gln Pro Thr His Val Asn Asn Gly Asn Tyr Thr Leu

65 70 75 80

Leu Ala Ala Asn Pro Ser Gly Arg Ala Ala Ala Ser Val Leu Ala Ala

85 90 95

Phe Met Asp Asn Pro Phe Glu Phe Asn Pro Glu Asp Pro Ile Pro Val

100 105 110

Ser Phe Ser Pro Val Asp Ser Asn Ser Thr Ser Gly Asp Ser Gly Gly

115 120 125

Gly Ser Gly Gly Gly Ser Pro Lys Thr Ala Ser Thr Ile Glu Ser Lys

130 135 140

Thr Gly Glu Gly Pro Lys Cys Pro Val Pro Glu Ile Pro Gly Ala Pro

145 150 155 160

Ser Val Phe Ile Phe Pro Pro Lys Pro Lys Asp Thr Leu Ser Ile Ser

165 170 175

Arg Thr Pro Glu Val Thr Cys Leu Val Val Asp Leu Gly Pro Asp Asp

180 185 190

Ser Asn Val Gln Ile Thr Trp Phe Val Asp Asn Thr Glu Met His Thr

195 200 205

Ala Lys Thr Arg Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val

210 215 220

Val Ser Val Leu Pro Ile Leu His Gln Asp Trp Leu Lys Gly Lys Glu

225 230 235 240

Phe Lys Cys Lys Val Asn Ser Lys Ser Leu Pro Ser Ala Met Glu Arg

245 250 255

Thr Ile Ser Lys Ala Lys Gly Gln Pro His Glu Pro Gln Val Tyr Val

260 265 270

Leu Pro Pro Thr Gln Glu Glu Leu Ser Glu Asn Lys Val Ser Val Thr

275 280 285

Cys Leu Ile Lys Gly Phe His Pro Pro Asp Ile Ala Val Glu Trp Glu

290 295 300

Ile Thr Gly Gln Pro Glu Pro Glu Asn Asn Tyr Gln Thr Thr Pro Pro

305 310 315 320

Gln Leu Asp Ser Asp Gly Thr Tyr Phe Leu Tyr Ser Arg Leu Ser Val

325 330 335

Asp Arg Ser His Trp Gln Arg Gly Asn Thr Tyr Thr Cys Ser Val Ser

340 345 350

His Glu Ala Leu His Ser His His Thr Gln Lys Ser Leu Thr Gln Ser

355 360 365

Pro Gly Lys

370

<210> 163

<211> 347

<212> PRT

<213> 人工序列

<220>

<223> 合成的: 示例性猫类TrkA ECD v3 - 野生型猫类IgG2 Fc

蛋白A + C1q - CD16 -

<400> 163

Val Ser Phe Pro Ala Ser Val Gln Leu His Ala Ala Val Glu Leu His

1 5 10 15

His Trp Cys Ile Pro Phe Ser Val Asp Gly Gln Pro Ala Pro Ser Leu

20 25 30

Arg Trp Leu Phe Asn Gly Ser Val Leu Asn Glu Thr Ser Phe Ile Phe

35 40 45

Thr Glu Phe Leu Glu Pro Ala Ala Asn Glu Thr Val Arg His Gly Cys

50 55 60

Leu Arg Leu Asn Gln Pro Thr His Val Asn Asn Gly Asn Tyr Thr Leu

65 70 75 80

Leu Ala Ala Asn Pro Ser Gly Arg Ala Ala Ala Ser Val Leu Ala Ala

85 90 95

Phe Met Asp Asn Pro Ser Gly Gly Gly Ser Gly Gly Gly Ser Pro Lys

100 105 110

Thr Ala Ser Thr Ile Glu Ser Lys Thr Gly Glu Gly Pro Lys Cys Pro

115 120 125

Val Pro Glu Ile Pro Gly Ala Pro Ser Val Phe Ile Phe Pro Pro Lys

130 135 140

Pro Lys Asp Thr Leu Ser Ile Ser Arg Thr Pro Glu Val Thr Cys Leu

145 150 155 160

Val Val Asp Leu Gly Pro Asp Asp Ser Asn Val Gln Ile Thr Trp Phe

165 170 175

Val Asp Asn Thr Glu Met His Thr Ala Lys Thr Arg Pro Arg Glu Glu

180 185 190

Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Pro Ile Leu His

195 200 205

Gln Asp Trp Leu Lys Gly Lys Glu Phe Lys Cys Lys Val Asn Ser Lys

210 215 220

Ser Leu Pro Ser Ala Met Glu Arg Thr Ile Ser Lys Ala Lys Gly Gln

225 230 235 240

Pro His Glu Pro Gln Val Tyr Val Leu Pro Pro Thr Gln Glu Glu Leu

245 250 255

Ser Glu Asn Lys Val Ser Val Thr Cys Leu Ile Lys Gly Phe His Pro

260 265 270

Pro Asp Ile Ala Val Glu Trp Glu Ile Thr Gly Gln Pro Glu Pro Glu

275 280 285

Asn Asn Tyr Gln Thr Thr Pro Pro Gln Leu Asp Ser Asp Gly Thr Tyr

290 295 300

Phe Leu Tyr Ser Arg Leu Ser Val Asp Arg Ser His Trp Gln Arg Gly

305 310 315 320

Asn Thr Tyr Thr Cys Ser Val Ser His Glu Ala Leu His Ser His His

325 330 335

Thr Gln Lys Ser Leu Thr Gln Ser Pro Gly Lys

340 345

<210> 164

<211> 345

<212> PRT

<213> 人工序列

<220>

<223> 合成的: 示例性猫类TrkA ECD v4 - 野生型猫类IgG2 Fc

蛋白A + C1q - CD16 -

<400> 164

Phe Pro Ala Ser Val Gln Leu His Ala Ala Val Glu Leu His His Trp

1 5 10 15

Cys Ile Pro Phe Ser Val Asp Gly Gln Pro Ala Pro Ser Leu Arg Trp

20 25 30

Leu Phe Asn Gly Ser Val Leu Asn Glu Thr Ser Phe Ile Phe Thr Glu

35 40 45

Phe Leu Glu Pro Ala Ala Asn Glu Thr Val Arg His Gly Cys Leu Arg

50 55 60

Leu Asn Gln Pro Thr His Val Asn Asn Gly Asn Tyr Thr Leu Leu Ala

65 70 75 80

Ala Asn Pro Ser Gly Arg Ala Ala Ala Ser Val Leu Ala Ala Phe Met

85 90 95

Asp Asn Pro Ser Gly Gly Gly Ser Gly Gly Gly Ser Pro Lys Thr Ala

100 105 110

Ser Thr Ile Glu Ser Lys Thr Gly Glu Gly Pro Lys Cys Pro Val Pro

115 120 125

Glu Ile Pro Gly Ala Pro Ser Val Phe Ile Phe Pro Pro Lys Pro Lys

130 135 140

Asp Thr Leu Ser Ile Ser Arg Thr Pro Glu Val Thr Cys Leu Val Val

145 150 155 160

Asp Leu Gly Pro Asp Asp Ser Asn Val Gln Ile Thr Trp Phe Val Asp

165 170 175

Asn Thr Glu Met His Thr Ala Lys Thr Arg Pro Arg Glu Glu Gln Phe

180 185 190

Asn Ser Thr Tyr Arg Val Val Ser Val Leu Pro Ile Leu His Gln Asp

195 200 205

Trp Leu Lys Gly Lys Glu Phe Lys Cys Lys Val Asn Ser Lys Ser Leu

210 215 220

Pro Ser Ala Met Glu Arg Thr Ile Ser Lys Ala Lys Gly Gln Pro His

225 230 235 240

Glu Pro Gln Val Tyr Val Leu Pro Pro Thr Gln Glu Glu Leu Ser Glu

245 250 255

Asn Lys Val Ser Val Thr Cys Leu Ile Lys Gly Phe His Pro Pro Asp

260 265 270

Ile Ala Val Glu Trp Glu Ile Thr Gly Gln Pro Glu Pro Glu Asn Asn

275 280 285

Tyr Gln Thr Thr Pro Pro Gln Leu Asp Ser Asp Gly Thr Tyr Phe Leu

290 295 300

Tyr Ser Arg Leu Ser Val Asp Arg Ser His Trp Gln Arg Gly Asn Thr

305 310 315 320

Tyr Thr Cys Ser Val Ser His Glu Ala Leu His Ser His His Thr Gln

325 330 335

Lys Ser Leu Thr Gln Ser Pro Gly Lys

340 345

<210> 165

<211> 369

<212> PRT

<213> 人工序列

<220>

<223> 合成的: 示例性马类TrkA ECD v2 - 变体马类IgG2 Fc

蛋白A + C1q - CD16 -

<400> 165

Val Ser Phe Pro Ala Ser Val His Leu Gln Thr Ala Val Glu Gln His

1 5 10 15

His Trp Cys Ile Pro Phe Ser Val Asp Gly Gln Pro Ala Pro Thr Leu

20 25 30

Arg Trp Leu Phe Asn Gly Ser Val Leu Asn Glu Thr Ser Phe Ile Phe

35 40 45

Thr Glu Phe Leu Glu Ser Ala Ala Asn Glu Thr Met Arg His Gly Cys

50 55 60

Leu Arg Leu Asn Gln Pro Thr His Val Asn Asn Gly Asn Tyr Thr Leu

65 70 75 80

Leu Ala Thr Asn Pro Tyr Gly Gln Asp Ser Ala Ser Val Met Val Ala

85 90 95

Phe Met Asp Asn Pro Phe Glu Phe Asn Pro Glu Asp Pro Ile Pro Val

100 105 110

Ser Phe Ser Pro Val Asp Thr Asn Ser Thr Ser Arg Asp Pro Pro Cys

115 120 125

Val Leu Ser Ala Glu Gly Val Ile Pro Ile Pro Ser Val Pro Lys Pro

130 135 140

Gln Cys Pro Pro Tyr Thr His Ser Lys Phe Leu Gly Gly Pro Ser Val

145 150 155 160

Phe Ile Phe Pro Pro Asn Pro Lys Asp Thr Leu Met Ile Ser Arg Thr

165 170 175

Pro Val Val Thr Cys Val Val Val Asn Leu Ser Asp Gln Tyr Pro Asp

180 185 190

Val Gln Phe Ser Trp Tyr Val Asp Asn Thr Glu Val His Ser Ala Ile

195 200 205

Thr Lys Gln Arg Glu Ala Gln Phe Asn Ser Thr Tyr Arg Val Val Ser

210 215 220

Val Leu Pro Ile Gln His Gln Asp Trp Leu Ser Gly Lys Glu Phe Lys

225 230 235 240

Cys Ser Val Thr Asn Val Gly Val Pro Gln Pro Ile Ser Arg Ala Ile

245 250 255

Ser Arg Gly Lys Gly Pro Ser Arg Val Pro Gln Val Tyr Val Leu Pro

260 265 270

Pro His Pro Asp Glu Leu Ala Lys Ser Lys Val Ser Val Thr Cys Leu

275 280 285

Val Lys Asp Phe Tyr Pro Pro Asp Ile Ser Val Glu Trp Gln Ser Asn

290 295 300

Arg Trp Pro Glu Leu Glu Gly Lys Tyr Ser Thr Thr Pro Ala Gln Leu

305 310 315 320

Asp Gly Asp Gly Ser Tyr Phe Leu Tyr Ser Lys Leu Ser Leu Glu Thr

325 330 335

Ser Arg Trp Gln Gln Val Glu Ser Phe Thr Cys Ala Val Met His Glu

340 345 350

Ala Leu His Asn His Tyr Thr Lys Thr Asp Ile Ser Glu Ser Leu Gly

355 360 365

Lys

<210> 166

<211> 345

<212> PRT

<213> 人工序列

<220>

<223> 合成的: 示例性马类TrkA ECD v3 - 变体马类IgG2 Fc

蛋白A + C1q - CD16 -

<400> 166

Val Ser Phe Pro Ala Ser Val His Leu Gln Thr Ala Val Glu Gln His

1 5 10 15

His Trp Cys Ile Pro Phe Ser Val Asp Gly Gln Pro Ala Pro Thr Leu

20 25 30

Arg Trp Leu Phe Asn Gly Ser Val Leu Asn Glu Thr Ser Phe Ile Phe

35 40 45

Thr Glu Phe Leu Glu Ser Ala Ala Asn Glu Thr Met Arg His Gly Cys

50 55 60

Leu Arg Leu Asn Gln Pro Thr His Val Asn Asn Gly Asn Tyr Thr Leu

65 70 75 80

Leu Ala Thr Asn Pro Tyr Gly Gln Asp Ser Ala Ser Val Met Val Ala

85 90 95

Phe Met Asp Asn Pro Pro Pro Cys Val Leu Ser Ala Glu Gly Val Ile

100 105 110

Pro Ile Pro Ser Val Pro Lys Pro Gln Cys Pro Pro Tyr Thr His Ser

115 120 125

Lys Phe Leu Gly Gly Pro Ser Val Phe Ile Phe Pro Pro Asn Pro Lys

130 135 140

Asp Thr Leu Met Ile Ser Arg Thr Pro Val Val Thr Cys Val Val Val

145 150 155 160

Asn Leu Ser Asp Gln Tyr Pro Asp Val Gln Phe Ser Trp Tyr Val Asp

165 170 175

Asn Thr Glu Val His Ser Ala Ile Thr Lys Gln Arg Glu Ala Gln Phe

180 185 190

Asn Ser Thr Tyr Arg Val Val Ser Val Leu Pro Ile Gln His Gln Asp

195 200 205

Trp Leu Ser Gly Lys Glu Phe Lys Cys Ser Val Thr Asn Val Gly Val

210 215 220

Pro Gln Pro Ile Ser Arg Ala Ile Ser Arg Gly Lys Gly Pro Ser Arg

225 230 235 240

Val Pro Gln Val Tyr Val Leu Pro Pro His Pro Asp Glu Leu Ala Lys

245 250 255

Ser Lys Val Ser Val Thr Cys Leu Val Lys Asp Phe Tyr Pro Pro Asp

260 265 270

Ile Ser Val Glu Trp Gln Ser Asn Arg Trp Pro Glu Leu Glu Gly Lys

275 280 285

Tyr Ser Thr Thr Pro Ala Gln Leu Asp Gly Asp Gly Ser Tyr Phe Leu

290 295 300

Tyr Ser Lys Leu Ser Leu Glu Thr Ser Arg Trp Gln Gln Val Glu Ser

305 310 315 320

Phe Thr Cys Ala Val Met His Glu Ala Leu His Asn His Tyr Thr Lys

325 330 335

Thr Asp Ile Ser Glu Ser Leu Gly Lys

340 345

<210> 167

<211> 343

<212> PRT

<213> 人工序列

<220>

<223> 合成的: 示例性马类TrkA ECD v4 - 变体马类IgG2 Fc

蛋白A + C1q - CD16 -

<400> 167

Phe Pro Ala Ser Val His Leu Gln Thr Ala Val Glu Gln His His Trp

1 5 10 15

Cys Ile Pro Phe Ser Val Asp Gly Gln Pro Ala Pro Thr Leu Arg Trp

20 25 30

Leu Phe Asn Gly Ser Val Leu Asn Glu Thr Ser Phe Ile Phe Thr Glu

35 40 45

Phe Leu Glu Ser Ala Ala Asn Glu Thr Met Arg His Gly Cys Leu Arg

50 55 60

Leu Asn Gln Pro Thr His Val Asn Asn Gly Asn Tyr Thr Leu Leu Ala

65 70 75 80

Thr Asn Pro Tyr Gly Gln Asp Ser Ala Ser Val Met Val Ala Phe Met

85 90 95

Asp Asn Pro Pro Pro Cys Val Leu Ser Ala Glu Gly Val Ile Pro Ile

100 105 110

Pro Ser Val Pro Lys Pro Gln Cys Pro Pro Tyr Thr His Ser Lys Phe

115 120 125

Leu Gly Gly Pro Ser Val Phe Ile Phe Pro Pro Asn Pro Lys Asp Thr

130 135 140

Leu Met Ile Ser Arg Thr Pro Val Val Thr Cys Val Val Val Asn Leu

145 150 155 160

Ser Asp Gln Tyr Pro Asp Val Gln Phe Ser Trp Tyr Val Asp Asn Thr

165 170 175

Glu Val His Ser Ala Ile Thr Lys Gln Arg Glu Ala Gln Phe Asn Ser

180 185 190

Thr Tyr Arg Val Val Ser Val Leu Pro Ile Gln His Gln Asp Trp Leu

195 200 205

Ser Gly Lys Glu Phe Lys Cys Ser Val Thr Asn Val Gly Val Pro Gln

210 215 220

Pro Ile Ser Arg Ala Ile Ser Arg Gly Lys Gly Pro Ser Arg Val Pro

225 230 235 240

Gln Val Tyr Val Leu Pro Pro His Pro Asp Glu Leu Ala Lys Ser Lys

245 250 255

Val Ser Val Thr Cys Leu Val Lys Asp Phe Tyr Pro Pro Asp Ile Ser

260 265 270

Val Glu Trp Gln Ser Asn Arg Trp Pro Glu Leu Glu Gly Lys Tyr Ser

275 280 285

Thr Thr Pro Ala Gln Leu Asp Gly Asp Gly Ser Tyr Phe Leu Tyr Ser

290 295 300

Lys Leu Ser Leu Glu Thr Ser Arg Trp Gln Gln Val Glu Ser Phe Thr

305 310 315 320

Cys Ala Val Met His Glu Ala Leu His Asn His Tyr Thr Lys Thr Asp

325 330 335

Ile Ser Glu Ser Leu Gly Lys

340

<210> 168

<211> 362

<212> PRT

<213> 人工序列

<220>

<223> 合成的: 示例性犬类TrkA ECD v2 - 变体犬类IgG-B Fc

蛋白A+ C1q - CD16 -

<400> 168

Val Ser Phe Pro Ala Ser Val Gln Leu His Glu Ala Val Glu Leu His

1 5 10 15

His Trp Cys Ile Pro Phe Ser Val Asp Gly Gln Pro Ala Pro Ser Leu

20 25 30

Arg Trp Leu Phe Asn Gly Ser Val Leu Asn Glu Thr Ser Phe Ile Phe

35 40 45

Thr Glu Phe Leu Glu Pro Val Ala Asn Glu Thr Val Arg His Gly Cys

50 55 60

Leu Arg Leu Asn Gln Pro Thr His Val Asn Asn Gly Asn Tyr Thr Leu

65 70 75 80

Leu Ala Ala Asn Pro Ser Gly Arg Ala Ala Ala Phe Val Met Ala Ala

85 90 95

Phe Met Asp Asn Pro Phe Glu Phe Asn Pro Glu Asp Pro Ile Pro Val

100 105 110

Ser Phe Ser Pro Val Asp Thr Asn Ser Thr Ser Gly Asp Ser Gly Gly

115 120 125

Gly Ser Gly Gly Gly Ser Arg Pro Pro Asp Cys Pro Lys Cys Pro Ala

130 135 140

Pro Glu Pro Leu Gly Gly Pro Ser Val Phe Ile Phe Pro Pro Lys Pro

145 150 155 160

Lys Asp Thr Leu Leu Ile Ala Arg Thr Pro Glu Val Thr Cys Val Val

165 170 175

Val Asp Leu Asp Arg Glu Asp Pro Glu Val Gln Ile Ser Trp Phe Val

180 185 190

Asp Gly Lys Gln Met Gln Thr Ala Lys Thr Gln Pro Arg Glu Glu Gln

195 200 205

Phe Asn Gly Thr Tyr Arg Val Val Ser Val Leu Pro Ile Gly His Gln

210 215 220

Asp Trp Leu Lys Gly Lys Gln Phe Thr Cys Arg Val Asn Asn Lys Ala

225 230 235 240

Leu Pro Ser Pro Ile Glu Arg Thr Ile Ser Lys Ala Arg Gly Gln Ala

245 250 255

His Gln Pro Ser Val Tyr Val Leu Pro Pro Ser Arg Glu Glu Leu Ser

260 265 270

Lys Asn Thr Val Ser Leu Thr Cys Leu Ile Lys Asp Phe Phe Pro Pro

275 280 285

Asp Ile Asp Val Glu Trp Gln Ser Asn Gly Gln Gln Glu Pro Glu Ser

290 295 300

Lys Tyr Arg Thr Thr Pro Pro Gln Leu Asp Glu Asp Gly Ser Tyr Phe

305 310 315 320

Leu Tyr Ser Lys Leu Ser Val Asp Lys Ser Arg Trp Gln Arg Gly Asp

325 330 335

Thr Phe Ile Cys Ala Val Met His Glu Ala Leu His Asn His Tyr Thr

340 345 350

Gln Glu Ser Leu Ser His Ser Pro Gly Lys

355 360

<210> 169

<211> 338

<212> PRT

<213> 人工序列

<220>

<223> 合成的: 示例性犬类TrkA ECD v3 - 变体犬类IgG-B Fc

蛋白A+ C1q - CD16 -

<400> 169

Val Ser Phe Pro Ala Ser Val Gln Leu His Glu Ala Val Glu Leu His

1 5 10 15

His Trp Cys Ile Pro Phe Ser Val Asp Gly Gln Pro Ala Pro Ser Leu

20 25 30

Arg Trp Leu Phe Asn Gly Ser Val Leu Asn Glu Thr Ser Phe Ile Phe

35 40 45

Thr Glu Phe Leu Glu Pro Val Ala Asn Glu Thr Val Arg His Gly Cys

50 55 60

Leu Arg Leu Asn Gln Pro Thr His Val Asn Asn Gly Asn Tyr Thr Leu

65 70 75 80

Leu Ala Ala Asn Pro Ser Gly Arg Ala Ala Ala Phe Val Met Ala Ala

85 90 95

Phe Met Asp Asn Pro Ser Gly Gly Gly Ser Gly Gly Gly Ser Arg Pro

100 105 110

Pro Asp Cys Pro Lys Cys Pro Ala Pro Glu Pro Leu Gly Gly Pro Ser

115 120 125

Val Phe Ile Phe Pro Pro Lys Pro Lys Asp Thr Leu Leu Ile Ala Arg

130 135 140

Thr Pro Glu Val Thr Cys Val Val Val Asp Leu Asp Arg Glu Asp Pro

145 150 155 160

Glu Val Gln Ile Ser Trp Phe Val Asp Gly Lys Gln Met Gln Thr Ala

165 170 175

Lys Thr Gln Pro Arg Glu Glu Gln Phe Asn Gly Thr Tyr Arg Val Val

180 185 190

Ser Val Leu Pro Ile Gly His Gln Asp Trp Leu Lys Gly Lys Gln Phe

195 200 205

Thr Cys Arg Val Asn Asn Lys Ala Leu Pro Ser Pro Ile Glu Arg Thr

210 215 220

Ile Ser Lys Ala Arg Gly Gln Ala His Gln Pro Ser Val Tyr Val Leu

225 230 235 240

Pro Pro Ser Arg Glu Glu Leu Ser Lys Asn Thr Val Ser Leu Thr Cys

245 250 255

Leu Ile Lys Asp Phe Phe Pro Pro Asp Ile Asp Val Glu Trp Gln Ser

260 265 270

Asn Gly Gln Gln Glu Pro Glu Ser Lys Tyr Arg Thr Thr Pro Pro Gln

275 280 285

Leu Asp Glu Asp Gly Ser Tyr Phe Leu Tyr Ser Lys Leu Ser Val Asp

290 295 300

Lys Ser Arg Trp Gln Arg Gly Asp Thr Phe Ile Cys Ala Val Met His

305 310 315 320

Glu Ala Leu His Asn His Tyr Thr Gln Glu Ser Leu Ser His Ser Pro

325 330 335

Gly Lys

<210> 170

<211> 336

<212> PRT

<213> 人工序列

<220>

<223> 合成的: 示例性犬类TrkA ECD v4 - 变体犬类IgG-B Fc

蛋白A+ C1q - CD16 -

<400> 170

Phe Pro Ala Ser Val Gln Leu His Glu Ala Val Glu Leu His His Trp

1 5 10 15

Cys Ile Pro Phe Ser Val Asp Gly Gln Pro Ala Pro Ser Leu Arg Trp

20 25 30

Leu Phe Asn Gly Ser Val Leu Asn Glu Thr Ser Phe Ile Phe Thr Glu

35 40 45

Phe Leu Glu Pro Val Ala Asn Glu Thr Val Arg His Gly Cys Leu Arg

50 55 60

Leu Asn Gln Pro Thr His Val Asn Asn Gly Asn Tyr Thr Leu Leu Ala

65 70 75 80

Ala Asn Pro Ser Gly Arg Ala Ala Ala Phe Val Met Ala Ala Phe Met

85 90 95

Asp Asn Pro Ser Gly Gly Gly Ser Gly Gly Gly Ser Arg Pro Pro Asp

100 105 110

Cys Pro Lys Cys Pro Ala Pro Glu Pro Leu Gly Gly Pro Ser Val Phe

115 120 125

Ile Phe Pro Pro Lys Pro Lys Asp Thr Leu Leu Ile Ala Arg Thr Pro

130 135 140

Glu Val Thr Cys Val Val Val Asp Leu Asp Arg Glu Asp Pro Glu Val

145 150 155 160

Gln Ile Ser Trp Phe Val Asp Gly Lys Gln Met Gln Thr Ala Lys Thr

165 170 175

Gln Pro Arg Glu Glu Gln Phe Asn Gly Thr Tyr Arg Val Val Ser Val

180 185 190

Leu Pro Ile Gly His Gln Asp Trp Leu Lys Gly Lys Gln Phe Thr Cys

195 200 205

Arg Val Asn Asn Lys Ala Leu Pro Ser Pro Ile Glu Arg Thr Ile Ser

210 215 220

Lys Ala Arg Gly Gln Ala His Gln Pro Ser Val Tyr Val Leu Pro Pro

225 230 235 240

Ser Arg Glu Glu Leu Ser Lys Asn Thr Val Ser Leu Thr Cys Leu Ile

245 250 255

Lys Asp Phe Phe Pro Pro Asp Ile Asp Val Glu Trp Gln Ser Asn Gly

260 265 270

Gln Gln Glu Pro Glu Ser Lys Tyr Arg Thr Thr Pro Pro Gln Leu Asp

275 280 285

Glu Asp Gly Ser Tyr Phe Leu Tyr Ser Lys Leu Ser Val Asp Lys Ser

290 295 300

Arg Trp Gln Arg Gly Asp Thr Phe Ile Cys Ala Val Met His Glu Ala

305 310 315 320

Leu His Asn His Tyr Thr Gln Glu Ser Leu Ser His Ser Pro Gly Lys

325 330 335

<210> 171

<211> 366

<212> PRT

<213> 人工序列

<220>

<223> 合成的: 示例性犬类TrkA ECD v2 - 变体犬类IgG-A Fc

C1q - 蛋白A +

<400> 171

Val Ser Phe Pro Ala Ser Val Gln Leu His Glu Ala Val Glu Leu His

1 5 10 15

His Trp Cys Ile Pro Phe Ser Val Asp Gly Gln Pro Ala Pro Ser Leu

20 25 30

Arg Trp Leu Phe Asn Gly Ser Val Leu Asn Glu Thr Ser Phe Ile Phe

35 40 45

Thr Glu Phe Leu Glu Pro Val Ala Asn Glu Thr Val Arg His Gly Cys

50 55 60

Leu Arg Leu Asn Gln Pro Thr His Val Asn Asn Gly Asn Tyr Thr Leu

65 70 75 80

Leu Ala Ala Asn Pro Ser Gly Arg Ala Ala Ala Phe Val Met Ala Ala

85 90 95

Phe Met Asp Asn Pro Phe Glu Phe Asn Pro Glu Asp Pro Ile Pro Val

100 105 110

Ser Phe Ser Pro Val Asp Thr Asn Ser Thr Ser Gly Asp Ser Gly Gly

115 120 125

Gly Ser Gly Gly Gly Ser Phe Asn Glu Cys Arg Cys Thr Asp Thr Pro

130 135 140

Cys Pro Val Pro Glu Pro Leu Gly Gly Pro Ser Val Leu Ile Phe Pro

145 150 155 160

Pro Lys Pro Lys Asp Thr Leu Leu Ile Ala Arg Thr Pro Glu Val Thr

165 170 175

Cys Val Val Leu Asp Leu Gly Arg Glu Asp Pro Glu Val Gln Ile Ser

180 185 190

Trp Phe Val Asp Gly Lys Glu Val His Thr Ala Lys Thr Gln Ser Arg

195 200 205

Glu Gln Gln Phe Asn Gly Thr Tyr Arg Val Val Ser Val Leu Pro Ile

210 215 220

Gly His Gln Asp Trp Leu Thr Gly Lys Glu Phe Lys Cys Arg Val Asn

225 230 235 240

His Ile Asp Leu Pro Ser Pro Ile Glu Arg Thr Ile Ser Lys Ala Arg

245 250 255

Gly Arg Ala His Lys Pro Ser Val Tyr Val Leu Pro Pro Ser Pro Lys

260 265 270

Glu Leu Ser Ser Ser Asp Thr Val Ser Ile Thr Cys Leu Ile Lys Asp

275 280 285

Phe Tyr Pro Pro Asp Ile Asp Val Glu Trp Gln Ser Asn Gly Gln Gln

290 295 300

Glu Pro Glu Arg Lys His Arg Met Thr Pro Pro Gln Leu Asp Glu Asp

305 310 315 320

Gly Ser Tyr Phe Leu Tyr Ser Lys Leu Ser Val Asp Lys Ser Arg Trp

325 330 335

Gln Gln Gly Asp Pro Phe Thr Cys Ala Val Met His Glu Ala Leu His

340 345 350

Asn His Tyr Thr Asp Leu Ser Leu Ser His Ser Pro Gly Lys

355 360 365

<210> 172

<211> 342

<212> PRT

<213> 人工序列

<220>

<223> 合成的: 示例性犬类TrkA ECD v3 - 变体犬类IgG-A Fc

C1q - 蛋白A +

<400> 172

Val Ser Phe Pro Ala Ser Val Gln Leu His Glu Ala Val Glu Leu His

1 5 10 15

His Trp Cys Ile Pro Phe Ser Val Asp Gly Gln Pro Ala Pro Ser Leu

20 25 30

Arg Trp Leu Phe Asn Gly Ser Val Leu Asn Glu Thr Ser Phe Ile Phe

35 40 45

Thr Glu Phe Leu Glu Pro Val Ala Asn Glu Thr Val Arg His Gly Cys

50 55 60

Leu Arg Leu Asn Gln Pro Thr His Val Asn Asn Gly Asn Tyr Thr Leu

65 70 75 80

Leu Ala Ala Asn Pro Ser Gly Arg Ala Ala Ala Phe Val Met Ala Ala

85 90 95

Phe Met Asp Asn Pro Ser Gly Gly Gly Ser Gly Gly Gly Ser Phe Asn

100 105 110

Glu Cys Arg Cys Thr Asp Thr Pro Cys Pro Val Pro Glu Pro Leu Gly

115 120 125

Gly Pro Ser Val Leu Ile Phe Pro Pro Lys Pro Lys Asp Thr Leu Leu

130 135 140

Ile Ala Arg Thr Pro Glu Val Thr Cys Val Val Leu Asp Leu Gly Arg

145 150 155 160

Glu Asp Pro Glu Val Gln Ile Ser Trp Phe Val Asp Gly Lys Glu Val

165 170 175

His Thr Ala Lys Thr Gln Ser Arg Glu Gln Gln Phe Asn Gly Thr Tyr

180 185 190

Arg Val Val Ser Val Leu Pro Ile Gly His Gln Asp Trp Leu Thr Gly

195 200 205

Lys Glu Phe Lys Cys Arg Val Asn His Ile Asp Leu Pro Ser Pro Ile

210 215 220

Glu Arg Thr Ile Ser Lys Ala Arg Gly Arg Ala His Lys Pro Ser Val

225 230 235 240

Tyr Val Leu Pro Pro Ser Pro Lys Glu Leu Ser Ser Ser Asp Thr Val

245 250 255

Ser Ile Thr Cys Leu Ile Lys Asp Phe Tyr Pro Pro Asp Ile Asp Val

260 265 270

Glu Trp Gln Ser Asn Gly Gln Gln Glu Pro Glu Arg Lys His Arg Met

275 280 285

Thr Pro Pro Gln Leu Asp Glu Asp Gly Ser Tyr Phe Leu Tyr Ser Lys

290 295 300

Leu Ser Val Asp Lys Ser Arg Trp Gln Gln Gly Asp Pro Phe Thr Cys

305 310 315 320

Ala Val Met His Glu Ala Leu His Asn His Tyr Thr Asp Leu Ser Leu