Antibody coupling drug, intermediate thereof, preparation method and application
阅读说明：本技术 一种抗体偶联药物、其中间体、制备方法及应用 (Antibody coupling drug, intermediate thereof, preparation method and application ) 是由 鲍彬 郭青松 高贝 张一帆 邱雪飞 杨彤 沈毅珺 张文伯 吕伟 王磊 于 2020-06-05 设计创作，主要内容包括：本发明公开了一种抗体偶联药物、其中间体、制备方法及应用。本发明提供了抗体偶联药物,其结构通式为Ab-(L-(3)-L-(2)-L-(1)-D)-(m)。该抗体偶联药物具有更好的生物学活性、稳定性和均一性,具有降低的毒副作用,且在肿瘤细胞内有更快的酶切释放速率。采用这种新型的抗体偶联药物可以实现细胞毒性药物,特别是喜树碱在ADC领域的广泛应用,治疗对于微管类ADC耐药的肿瘤病人。(The invention discloses an antibody conjugate drug, an intermediate thereof, a preparation method and application. The invention provides an antibody coupling drug with a structural general formula of Ab- (L) 3 ‑L 2 ‑L 1 ‑D) m . The antibody conjugate drug has better biological activity, stability and uniformity, reduced toxic and side effects and faster enzyme digestion release rate in tumor cells. The novel antibody conjugate drug can realize the wide application of cytotoxic drugs, particularly camptothecin in the field of ADC, and treat microtubular ADC-resistant tumor patients.)
An antibody coupling medicine with the structural general formula Ab- (L)3-L 2-L 1-D) m；
Wherein Ab is an antibody;
d is a cytotoxic drug;
m is 2-8;
L 1the structure of (A) is shown in formula I, II, III or IV, the a end of the (A) is connected with the cytotoxic drug, the e end is connected with the L2The end c is connected;
wherein L is independently a phenylalanine residue, an alanine residue, a glycine residue, a glutamic acid residue, an aspartic acid residue, a cysteine residue, a glutamic acid residue, a histidine residue, an isoleucine residue, a leucine residue, a lysine residue, a methionine residue, a proline residue, a serine residue, a threonine residue, a tryptophan residue, a tyrosine residue, or a valine residue; p is 2-4;
R 1is-NR1-1R 1-2Substituted C1～C 6Alkyl radical, R1-3S(O) 2-substituted C1～C 6Alkyl radical, C1～C 6Alkyl radical, C3～C 10Cycloalkyl radical, C6～C 14Aryl or 5-to 14-membered heteroaryl; the heteroatom in the 5-14-membered heteroaryl is selected from one or more of N, O and S, and the number of the heteroatoms is 1,2, 3 or 4;
said R1-1、R 1-2And R1-3Independently is C1～C 6An alkyl group;
L 2is composed of
Wherein n is independently 1-12, c is terminal and L1Is connected to the e terminal, and the f terminal is connected to the L terminal3The d ends of the two are connected;
L 3is composed ofWherein the b terminal is connected to the Ab, and the d terminal is connected to the L2The f ends are connected;
when said L is1The structure of (A) is shown in formula I, and L is3Is composed ofWhen said L is2Is not that
The antibody-conjugated drug of claim 1, wherein,
the antibody is anti-HER 2 antibody Trastuzumab or a variant thereof, anti-B7-H3 antibody P2E5 or a variant thereof, anti-Claudin 18.2 antibody IMAB362 or a variant thereof, or anti-Trop 2 antibody RS7 or a variant thereof, preferably anti-HER 2 antibody Trastuzumab or a variant thereof, anti-B7-H3 antibody P2E5 or a variant thereof, or anti-Claudin 18.2 antibody IMAB362 or a variant thereof; the amino acid sequence of the light chain in the anti-HER 2 antibody Trastuzumab is preferably shown as SEQ ID No.5 in a sequence table, and the amino acid sequence of the heavy chain is preferably shown as SEQ ID No.6 in the sequence table; the amino acid sequence of the light chain in the anti-B7-H3 antibody P2E5 is preferably shown as SEQ ID No.7 in the sequence table, and the amino acid sequence of the heavy chain is preferably shown as SEQ ID No.8 in the sequence table; the amino acid sequence of the light chain in the anti-Claudin18.2 antibody IMAB362 is preferably shown as SEQ ID No.1 in the sequence table, and the amino acid sequence of the heavy chain is preferably shown as SEQ ID No.2 in the sequence table; the amino acid sequence of the light chain in the anti-Trop 2 antibody RS7 is preferably shown as SEQ ID No.3 in a sequence table, and the amino acid sequence of the heavy chain is preferably shown as SEQ ID No.4 in the sequence table; said anti-HER 2 antibody Trastuzumab variant has at least 70%, 75%, 80%, 85%, 90%, 95%, 98% or more than 99% homology to the anti-HER 2 antibody Trastuzumab sequence; the anti-B7-H3 antibody P2E5 variant has at least 70%, 75%, 80%, 85%, 90%, 95%, 98% or 99% or more homology to the anti-B7-H3 antibody P2E 5; the anti-Trop 2 antibody RS7 variant has at least 70%, 75%, 80%, 85%, 90%, 95%, 98% or 99% homology with the anti-Trop 2 antibody RS7 sequence; said anti-claudin 18.2 antibody IMAB362 variant has at least 70%, 75%, 80%, 85%, 90%, 95%, 98% or 99% or more homology to said anti-claudin 18.2 antibody IMAB362 sequence;
and/or the cytotoxic drug is a hydroxyl-containing topoisomerase inhibitor, preferably a hydroxyl-containing topoisomerase I inhibitor, more preferably a camptothecin compound, and even more preferably a hydroxyl-containing topoisomerase I inhibitor
And/or, when said R is1is-NR1-1R 1-2Substituted C1～C 6When alkyl, said C1～C 6Alkyl is C1～C 4Alkyl radicalPreferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, most preferably ethyl; said R1-1And R1-2Are each independently preferably C1～C 4An alkyl group, more preferably a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group or a tert-butyl group, and most preferably a methyl group;
and/or, when said R is1Is R1-3S(O) 2-substituted C1～C 6When alkyl, said C1～C 6Alkyl is C1～C 4An alkyl group, preferably a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, or a tert-butyl group, and more preferably an ethyl group; said R1-3Preferably C1～C 4An alkyl group, more preferably a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group or a tert-butyl group, and most preferably a methyl group;
and/or, when said R is1Is C1～C 6When alkyl, said C1～C 6Alkyl is C1～C 4Alkyl, more preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, most preferably methyl or ethyl;
and/or m is 4-8, preferably 7-8, such as 7.3, 7.4, 7.5, 7.6, 7.7, 7.8 and 8.0;
and/or n is preferably 8-12.
The antibody-conjugated drug of claim 1 or 2, wherein,
l is valine residue or alanine residue, and p is preferably 2; said (L) p is more preferablyWherein the amino terminus is attached to the carbonyl terminus of formula III;
and/or, said R1is-NR1-1R 1-2Substituted C1～C 6Alkyl radical, R1-3S(O) 2-substituted C1～C 6Alkyl, or C1～C 6Alkyl, preferably-NR1-1R 1-2Substituted C1～C 6Alkyl or R1-3S(O) 2-substituted C1～C 6Alkyl, more preferably R1-3S(O) 2-substituted C1～C 6An alkyl group; r1Is C1～C 6When alkyl, said C1～C 6Alkyl is preferably methyl or ethyl; said R1-3S(O) 2-substituted C1～C 6The alkyl group is preferablysaid-NR1-1R 1-2Substituted C1～C 6The alkyl group is preferablySaidPreferably, it is
And/or, said L3Is composed of
And/or when L1When the structure of (A) is as shown in formula I, L is2Is composed of Preferably, it is Further preferred isSaid L3Preferably, it is
And/or when L1When the structure of (A) is as shown in formula II, L is2Is composed of Said L3Preferably, it is
And/or when L1When the structure of (A) is as shown in formula III, L is2Is composed of Preferably, it is More preferably Further preferred isSaid L3Preferably, it is
And/or when L1When the structure of (A) is as shown in formula IV, L is2Is composed of Said L3Preferably, it is
The antibody-conjugated drug of claim 1, wherein,
the Ab is anti-HER 2 antibody Trastuzumab, anti-B7-H3 antibody P2E5 or a variant thereof, or anti-Claudin 18.2 antibody IMAB362 or a variant thereof; d is a cytotoxic drug; m is 2-8;
said L1The structure of the compound is shown as formula I, II, III or IV,
said L2Is composed of N is independently 8-12;
said L3Is composed of
L is independently valine residue or alanine residue; p is 2-4;
said R1is-NR1-1R 1-2Substituted C1～C 6Alkyl radical, R1-3S(O) 2-substituted C1～C 6Alkyl, or C1～C 6An alkyl group;
said R1-1、R 1-2And R1-3Each independently is C1～C 6An alkyl group;
wherein, the amino acid sequence of the light chain in the anti-HER 2 antibody Trastuzumab is preferably shown as SEQ ID No.5 in a sequence table, and the amino acid sequence of the heavy chain is preferably shown as SEQ ID No.6 in the sequence table; the amino acid sequence of the light chain in the anti-B7-H3 antibody P2E5 is preferably shown as SEQ ID No.7 in the sequence table, and the amino acid sequence of the heavy chain is preferably shown as SEQ ID No.8 in the sequence table; the amino acid sequence of the light chain in the anti-Claudin18.2 antibody IMAB362 is preferably shown as SEQ ID No.1 in the sequence table, and the amino acid sequence of the heavy chain is preferably shown as SEQ ID No.2 in the sequence table.
The antibody-conjugated drug of any one of claims 1 to 4, wherein,
the Ab is anti-HER 2 antibody Trastuzumab, anti-B7-H3 antibody P2E5 or variant thereof, or anti-Claudin 18.2 antibodyThe body IMAB362 or a variant thereof; d isM is 7-8;
said L1The structure of (A) is shown as formula I or III,
when said L is1When the structure of (A) is as shown in formula I, L is2Is composed of N is independently 8-12;
when said L is1When the structure of (A) is as shown in formula III, L is2Is composed of
N is independently 8-12;
said L3Is composed of
L is independently valine residue or alanine residue; p is 2-4;
said R1is-NR1-1R 1-2Substituted C1～C 4Alkyl radical, R1-3S(O) 2-substituted C1～C 4Alkyl, or C1～C 4An alkyl group; said R1-1、R 1-2And R1-3Independently is C1～C 4An alkyl group;
the amino acid sequence of the light chain in the anti-HER 2 antibody Trastuzumab is preferably shown as SEQ ID No.5 in a sequence table, and the amino acid sequence of the heavy chain is preferably shown as SEQ ID No.6 in the sequence table; the amino acid sequence of the light chain in the anti-B7-H3 antibody P2E5 is preferably shown as SEQ ID No.7 in the sequence table, and the amino acid sequence of the heavy chain is preferably shown as SEQ ID No.8 in the sequence table; the amino acid sequence of the light chain in the anti-Claudin18.2 antibody IMAB362 is preferably shown as SEQ ID No.1 in the sequence table, and the amino acid sequence of the heavy chain is preferably shown as SEQ ID No.2 in the sequence table.
The antibody-conjugated drug of claim 1, wherein,
ab is an antibody; d is
L 1Is composed ofWherein L is a valine residue or an alanine residue, p is 2, and (L) p is preferablyR 1is-NR1-1R 1-2Substituted C1～C 6Alkyl radical, R 1-3S(O) 2-substituted C1～C 6Alkyl or C1～C 6Alkyl, preferably-NR1-1R 1-2Substituted C1～C 6Alkyl or R1-3S(O) 2-substituted C1～C 6Alkyl, more preferably R1-3S(O) 2-substituted C1～C 6An alkyl group; said R1-1、R 1-2And R1-3Independently is C1～C 4Alkyl, preferably methyl; said-NR1-1R 1-2Substituted C1～C 6The alkyl group is preferablySaid R1-3S(O) 2-substituted C1～C 6The alkyl group is preferably
L 2Is composed of Wherein n is preferably 8; l is2Preferably, it isL 3Is composed of
The antibody conjugate drug of claim 1, wherein the antibody conjugate drug is any one of the following compounds:
wherein m is 2 to 8, preferably 7 to 8, such as 7.3, 7.4, 7.5, 7.6, 7.7, 7.8 or 8.0;
ab is anti-HER 2 antibody Trastuzumab, anti-B7-H3 antibody P2E5 or anti-Claudin 18.2 antibody IMAB 362; the amino acid sequence of the light chain in the Ab is shown as SEQ ID No.5 in the sequence table, and the amino acid sequence of the heavy chain is shown as SEQ ID No.6 in the sequence table; the amino acid sequence of the light chain in the anti-B7-H3 antibody P2E5 is shown as SEQ ID No.7 in the sequence table, and the amino acid sequence of the heavy chain is shown as SEQ ID No.8 in the sequence table; the amino acid sequence of the light chain in the anti-Claudin18.2 antibody IMAB362 is shown as SEQ ID No.1 in the sequence table, and the amino acid sequence of the heavy chain is shown as SEQ ID No.2 in the sequence table.
The antibody conjugate according to claims 1 to 7, wherein the antibody conjugate is any one of the following compounds:
wherein Ab, m and R1As described in any one of claims 1 to 7.
The antibody conjugate drug of claim 1, wherein the antibody conjugate drug is any one of the following compounds:
wherein Ab is anti-HER 2 antibody Trastuzumab; or the amino acid sequence of the light chain in Ab is shown as SEQ ID No.5 in the sequence table, and the amino acid sequence of the heavy chain is shown as SEQ ID No.6 in the sequence table; wherein m is 2 to 8, preferably 7 to 8, such as 7.3, 7.4, 7.5, 7.6, 7.7, 7.8 or 8.0;
or, the antibody conjugate drug is any one of the following compounds:
wherein Ab is anti-HER 2 antibody Trastuzumab; or the amino acid sequence of the light chain in Ab is shown as SEQ ID No.5 in the sequence table, and the amino acid sequence of the heavy chain is shown as SEQ ID No.6 in the sequence table;
or, the antibody conjugate drug is any one of the following compounds:
wherein Ab is anti-B7-H3 antibody P2E 5; or the amino acid sequence of the light chain in Ab is shown as SEQ ID No.7 in the sequence table, and the amino acid sequence of the heavy chain is shown as SEQ ID No.8 in the sequence table; wherein m is 2 to 8, preferably 7 to 8, such as 7.3, 7.4, 7.5, 7.6, 7.7, 7.8 or 8.0;
or, the antibody conjugate drug is any one of the following compounds:
wherein Ab is anti-B7-H3 antibody P2E 5; or the amino acid sequence of the light chain in Ab is shown as SEQ ID No.7 in the sequence table, and the amino acid sequence of the heavy chain is shown as SEQ ID No.8 in the sequence table;
or, the antibody conjugate drug is any one of the following compounds:
wherein Ab is anti-Claudin18.2 antibody IMAB 362; or the amino acid sequence of the light chain in Ab is shown as SEQ ID No.1 in the sequence table, and the amino acid sequence of the heavy chain is shown as SEQ ID No.2 in the sequence table; wherein m is 2 to 8, preferably 7 to 8, such as 7.3, 7.4, 7.5, 7.6, 7.7, 7.8 or 8.0;
or, the antibody conjugate drug is any one of the following compounds:
wherein Ab is anti-Claudin18.2 antibody IMAB 362; or the amino acid sequence of the light chain in Ab is shown as SEQ ID No.1 in the sequence table, and the amino acid sequence of the heavy chain is shown as SEQ ID No.2 in the sequence table.
A connecting group-drug conjugate with a general structural formula of L4-L 2-L 1-D; wherein L is4Is composed of L 2、L 1And D is as defined in any one of claims 1 to 9Yi, L2And the f terminal of (2) and the L4The d ends of the two are connected; when said L is4Is composed ofSaid L1Is composed ofWhen said L is2Is not that
The linker-drug conjugate according to claim 10, which is a compound represented by the following formula,
wherein R is1As defined in any one of claims 1 to 9.
The linker-drug conjugate according to claim 10, wherein the linker-drug conjugate is any one of the compounds:
a method for preparing an antibody-conjugated drug according to any one of claims 1 to 9, comprising the step of conjugating a linker-drug conjugate according to any one of claims 10 to 12 to an antibody according to any one of claims 1 to 9.
A pharmaceutical composition comprising the antibody conjugate drug of any one of claims 1-9 and a pharmaceutically acceptable carrier.
Use of an antibody-conjugated drug according to any one of claims 1 to 9 or a pharmaceutical composition according to claim 14 for the manufacture of a medicament for the prevention and/or treatment of cancer; preferably, the cancer is gastric cancer, breast cancer, non-small cell lung cancer, urothelial cancer or pancreatic cancer.
The compounds shown below are used as the active ingredient,
wherein R is1As defined in any one of claims 1 to 9;
R 2is-N3、-NH 2、
The compound of claim 16, which is a compound of any one of:
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