阅读说明：本技术 用于治疗眼部疾病的组合物和方法 (Compositions and methods for treating ocular diseases ) 是由 尼兰詹·B·潘迪 于 2020-03-26 设计创作，主要内容包括：在各个方面和实施方案中,本发明提供了用于治疗眼部疾病的方法和药物组合物,所述眼部疾病包括涉及眼部血管通透性或眼部炎症的眼部疾病。在各个方面和实施方案中,本发明包括通过眼内注射向患者施用约1μg至约1mg的Ⅳ型胶原蛋白源性仿生肽或其盐。注射以约每个月一次至约每两年一次的频率提供。在各个实施方案中,所述方法和组合物提供了在不频繁玻璃体内注射小体积下,强效的作用和长久的作用持续时间。(In various aspects and embodiments, the present invention provides methods and pharmaceutical compositions for treating ocular diseases, including ocular diseases involving ocular vascular permeability or ocular inflammation. In various aspects and embodiments, the invention comprises administering to a patient by intraocular injection about 1 μ g to about 1mg of a type IV collagen-derived biomimetic peptide or salt thereof. Injections are provided at a frequency of about once per month to about once per two years. In various embodiments, the methods and compositions provide potent effects and long duration of effect at low volume with infrequent intravitreal injections.)

1. A method for preventing or treating a disorder involving ocular vascular permeability or inflammation in a patient, the method comprising: administering to said patient a unit dose of a type IV collagen-derived biomimetic peptide or salt thereof by intraocular injection at a frequency of up to about once per month.

2. The method of claim 1, wherein the unit dose comprises from about 10 μ g to about 1mg of the peptide.

3. The method of claim 2, wherein the unit dose is formulated as naked peptide in aqueous solution without particle encapsulation.

4. The method of claim 1, wherein the patient has a disorder selected from: diabetic macular edema, retinal vein occlusion, wet age-related macular degeneration (wet AMD), or background diabetic retinopathy.

5. The method of claim 1, wherein the patient has acute or chronic inflammation of the eye.

6. The method of claim 5, wherein the patient has uveitis.

7. The method of claim 5, wherein the inflammation is associated with an autoimmune disorder.

8. The method of claim 7, wherein the unit dose comprises about 700 μ g or less, or about 500 μ g or less of the peptide or salt thereof.

9. The method of claim 8, wherein the unit dose comprises about 250 μ g or less of the peptide or salt thereof.

10. The method of claim 9, wherein the unit dose comprises about 100 μ g or less of the peptide or salt thereof.

11. The method of any one of claims 1 to 10, wherein the unit dose is administered by intraocular injection at a frequency of at most once every three months.

12. The method of claim 11, wherein the unit dose is administered by intraocular injection at a frequency of at most once every four months.

13. The method of claim 11, wherein the unit dose is administered by intraocular injection at a frequency of at most once every six months.

14. The method of claim 11, wherein the unit dose is administered by intraocular injection at a frequency of at most once every eight months.

15. The method of claim 11, wherein the unit dose is administered by intraocular injection at a frequency of at most once per year.

16. The method of claim 11, wherein the unit dose is administered by intraocular injection at a frequency of at most once every 18 months.

17. The method of claim 11, wherein the unit dose is administered by intraocular injection at a frequency of at most once every 2 years.

18. The method of any one of claims 1 to 7, wherein the unit dose comprises about 10 μ g to about 50 μ g of the peptide or salt thereof and is administered at a frequency of at most about once per month.

19. The method of claim 18, wherein the unit dose comprises about 25 μ g of the peptide or salt thereof, and the unit dose is administered by intraocular injection about once per month.

20. The method of any one of claims 1 to 7, wherein the unit dose comprises from about 50 μ g to about 150 μ g of the peptide or salt thereof, and the unit dose is administered by intraocular injection at a frequency of at most once every three months.

21. The method of claim 20, wherein the unit dose is administered at a frequency of at most once every four months.

22. The method of claim 20, wherein the unit dose is administered at a frequency of at most once every six months.

23. The method of claim 20, wherein the unit dose comprises about 50 μ g of the peptide or salt thereof, and the unit dose is administered at a frequency of once every three or four months.

24. The method of claim 20, wherein the unit dose comprises from about 100 μ g to about 150 μ g of the peptide or salt thereof, and the unit dose is administered at a frequency of once every five months to seven months, and optionally once every six months.

25. The method of any one of claims 1 to 7, wherein the unit dose comprises from about 150 μ g to about 250 μ g of the peptide or salt thereof and is administered at a frequency of at most once every six months.

26. The method of claim 25, wherein the unit dose is administered at a frequency of at most once every eight months.

27. The method of claim 25, wherein the unit dose is administered at a frequency of at most once every twelve months.

28. The method of claim 25, wherein the unit dose comprises about 200 μ g to about 250 of the peptide or salt thereof and is administered at a frequency of once every six months to twelve months.

29. The method of any one of claims 1 to 7, wherein the unit dose comprises about 250 μ g to about 700 μ g of the peptide or salt thereof and is administered at a frequency of at most once every six months.

30. The method of claim 29, wherein the unit dose comprises about 300 μ g to about 700 μ g of the peptide or salt thereof.

31. The method of claim 29, wherein the unit dose comprises about 400 μ g to about 700 μ g of the peptide or salt thereof.

32. The method of claim 29, wherein the unit dose comprises about 500 μ g to about 700 μ g of the peptide or salt thereof.

33. The method of claim 29, wherein the unit dose comprises about 600 μ g to about 700 μ g of the peptide or salt thereof.

34. The method of any one of claims 29-33, wherein the unit dose is administered at a frequency of once every six months to eighteen months.

35. The method of claim 34, wherein the unit dose is administered about once every seven months, about once every eight months, about once every nine months, about once every ten months, about once every eleven months, or about once every twelve months, or about once every eighteen months.

36. The method of any one of claims 1 to 7, wherein the unit dose comprises from about 700 μ g to about 1mg of the peptide or salt thereof, and the unit dose is administered at a frequency of at most once every twelve months.

37. The method of claim 36, wherein the unit dose comprises about 800 μ g to about 1mg of the peptide or salt thereof.

38. The method of claim 36, wherein the unit dose comprises about 900 μ g to about 1mg of the peptide or salt thereof.

39. The method of any one of claims 36-38, wherein the unit dose is administered at a frequency of once every twelve months to once every two years.

40. The method of claim 39, wherein the unit dose is administered about once every eighteen months to about once every two years.

41. The method of any one of claims 1 to 40, wherein the peptide or salt thereof is administered after an unsuccessful VEGF blocking or inhibitor therapy.

42. The method of any one of claims 1 to 40, wherein the patient's condition is refractory to, or only partially responsive to, VEGF blocking or inhibitor therapy.

43. The method of any one of claims 1 to 40, wherein the peptide or salt thereof is administered as a replacement therapy for VEGF blocking or inhibitor therapy.

44. The method of any one of claims 1 to 40, wherein the peptide or salt thereof is administered in combination with VEGF blocking therapy.

45. The method of any one of claims 1 to 44, wherein the peptide comprises the amino acid sequence of any one of SEQ ID NOs 1 to 36.

46. The method of any one of claims 1 to 44 wherein the peptide is derived from α 5 fibrils of type IV collagen or mimetics thereof.

47. The method of claim 45 or 46, wherein the peptide is:

LRRFSTMPFMF(Abu)NINNV(Abu)NF(SEQ ID NO:5)，

LRRFSTMPAMF(Abu)NINNV(Abu)NF(SEQ ID NO:6)，

LRRFSTMPFAF(Abu)NINNV(Abu)NF(SEQ ID NO:7)，

LRRFSTMPFMA(Abu)NINNV(Abu)NF(SEQ ID NO:8)，

LRRFSTMPF(Nle)F(Abu)NINNV(Abu)NF(SEQ ID NO:9)，

LRRFSTMPFM(4-ClPhe)(Abu)NINNV(Abu)NF(SEQ ID NO:10)，

LRRFSTMPFMFSNINNVSNF(SEQ ID NO:11)，

LRRFSTMPFMFANINNVANF(SEQ ID NO:12)，

LRRFSTMPFMFININNVINF(SEQ ID NO:13)，

LRRFSTMPFMFTNINNVTNF(SEQ ID NO:14)，

LRRFSTMPFMF (allyl Gly) NINNV (allyl Gly) NF (SEQ ID NO:15),

LRRFSTMPFMFVNINNVVNF(SEQ ID NO:16)，

LRRFSTMPFdAFININNVINF(SEQ ID NO:17)，

LRRFSTMPFAFININNVINF(SEQ ID NO:18)，

LRRFSTAPFAFININNVINF(SEQ ID NO:19)，

LRRFSTAPFdAFIDINDVINF(SEQ ID NO:20)，

LRRFSTAPFAFIDINDVINW(SEQ ID NO:21)，

dLRRdLRRFSTAPFAFIDINDVINF(SEQ ID NO:22)，

LRRFSTAPFAFIDINDVINDF (SEQ ID NO:23), or

dLRRFSTAPFAFIDINDVINdF(SEQ ID NO:24)。

48. The method of claim 45 or 46, wherein the peptide is:

F(Abu)NINNV(Abu)N(SEQ ID NO:25)，

FTNINNVTN(SEQ ID NO:26)，

FININNVINF(SEQ ID NO:27)，

FSNINNVSNF(SEQ ID NO:28)，

FANINNVANF(SEQ ID NO:29)，

f (allyl Gly) NINNV (allyl Gly) NF (SEQ ID NO:30),

FVNINNVVNF(SEQ ID NO:31)，

FIDINDVINF(SEQ ID NO:32)，

FIDINDVINW(SEQ ID NO:33)，

FTDINDVTN(SEQ ID NO:34)，

a (Abu) NINNV (Abu) NF (SEQ ID NO:35), or

(4-ClPhe)(Abu)NINNV(Abu)NF(SEQ ID NO:36)。

49. The method of claim 46, wherein the peptide has the amino acid sequence LRRFSTAPFAFIDINDVINGF (SEQ ID NO: 1).

50. The method of any one of claims 1 to 49, wherein the unit dose has a volume in the range of about 1 μ L to about 1mL, or a volume in the range of about 10 μ L to about 0.5mL, or a volume in the range of about 10 μ L to about 250 μ L, or a volume in the range of about 10 μ L to about 50 μ L.

51. The method of claim 50, wherein the unit dose has a volume in the range of about 25 μ L to about 0.5mL, or a volume in the range of about 25 μ L to about 200 μ L, or a volume in the range of about 25 μ L to about 100 μ L.

52. The method of claim 50, wherein the unit volume is less than about 100 μ L, or less than about 50 μ L, or less than about 25 μ L.

53. A pharmaceutical composition suitable for intravitreal injection comprising as a unit dose in a pre-filled syringe from about 1 μ g to about 1mg of a type iv collagen-derived biomimetic peptide or salt thereof, formulated in aqueous solution without particle encapsulation.

54. The pharmaceutical composition of claim 53, wherein the unit dose comprises about 1mg of the peptide or salt thereof.

55. The pharmaceutical composition of claim 53, wherein the unit dose comprises about 700 μ g of the peptide or salt thereof.

56. The pharmaceutical composition of claim 53, wherein the unit dose comprises about 500 μ g or less of the peptide or salt thereof.

57. The pharmaceutical composition of claim 53, wherein the unit dose comprises about 250 μ g or less of the peptide or salt thereof.

58. The pharmaceutical composition of claim 53, wherein the unit dose comprises about 100 μ g or less of the peptide or salt thereof.

59. The pharmaceutical composition of claim 53, wherein the unit dose comprises about 10 μ g to about 50 μ g of the peptide or salt thereof.

60. The pharmaceutical composition of claim 53, wherein the unit dose comprises about 50 μ g to about 150 μ g of the peptide or salt thereof.

61. The pharmaceutical composition of claim 53, wherein the unit dose comprises about 150 μ g to about 250 μ g of the peptide or salt thereof.

62. The pharmaceutical composition of claim 53, wherein the unit dose comprises about 250 μ g to about 700 μ g of the peptide or salt thereof.

63. The pharmaceutical composition of claim 53, wherein the unit dose comprises about 300 μ g to about 700 μ g of the peptide or salt thereof.

64. The pharmaceutical composition of claim 53, wherein the unit dose comprises about 400 μ g to about 700 μ g of the peptide or salt thereof.

65. The pharmaceutical composition of claim 53, wherein the unit dose comprises about 500 μ g to about 700 μ g of the peptide or salt thereof.

66. The pharmaceutical composition of claim 53, wherein the unit dose comprises about 600 μ g to about 700 μ g of the peptide or salt thereof.

67. The pharmaceutical composition of claim 53, wherein the unit dose comprises about 700 μ g to about 1mg of the peptide or salt thereof.

68. The pharmaceutical composition of claim 53, wherein the unit dose comprises from about 800 μ g to about 1mg of the peptide or salt thereof.

69. The pharmaceutical composition of any one of claims 53 to 68, wherein the unit dose has a volume in the range of about 1 μ L to about 1mL, or a volume in the range of about 10 μ L to about 0.5mL, or a volume in the range of about 10 μ L to about 250 μ L, or a volume in the range of about 10 μ L to about 50 μ L.

70. The pharmaceutical composition of claim 69, wherein the unit dose has a volume in the range of about 25 μ L to about 0.5mL, or a volume in the range of about 25 μ L to about 200 μ L, or a volume in the range of about 25 μ L to about 100 μ L.

71. The pharmaceutical composition of claim 70, wherein the unit dose has a volume of less than about 100 μ L, or less than about 50 μ L, or less than about 25 μ L.

72. The pharmaceutical composition of any one of claims 53-71, wherein the peptide comprises the amino acid sequence of any one of SEQ ID NOs 1-36 or a derivative thereof.

73. The pharmaceutical composition of claim 72, wherein the peptide has the amino acid sequence of SEQ ID NO 1.

74. The pharmaceutical composition of claim 72, wherein the peptide has an amino acid sequence selected from the group consisting of SEQ ID NOs:

LRRFSTMPFMF(Abu)NINNV(Abu)NF(SEQ ID NO:5)，

LRRFSTMPAMF(Abu)NINNV(Abu)NF(SEQ ID NO:6)，

LRRFSTMPFAF(Abu)NINNV(Abu)NF(SEQ ID NO:7)，

LRRFSTMPFMA(Abu)NINNV(Abu)NF(SEQ ID NO:8)，

LRRFSTMPF(Nle)F(Abu)NINNV(Abu)NF(SEQ ID NO:9)，

LRRFSTMPFM(4-ClPhe)(Abu)NINNV(Abu)NF(SEQ ID NO:10)，

LRRFSTMPFMFSNINNVSNF(SEQ ID NO:11)，

LRRFSTMPFMFANINNVANF(SEQ ID NO:12)，

LRRFSTMPFMFININNVINF(SEQ ID NO:13)，

LRRFSTMPFMFTNINNVTNF(SEQ ID NO:14)，

LRRFSTMPFMF (allyl Gly) NINNV (allyl Gly) NF (SEQ ID NO:15),

LRRFSTMPFMFVNINNVVNF(SEQ ID NO:16)，

LRRFSTMPFdAFININNVINF(SEQ ID NO:17)，

LRRFSTMPFAFININNVINF(SEQ ID NO:18)，

LRRFSTAPFAFININNVINF(SEQ ID NO:19)，

LRRFSTAPFdAFIDINDVINF(SEQ ID NO:20)，

LRRFSTAPFAFIDINDVINW(SEQ ID NO:21)，

dLRRdLRRFSTAPFAFIDINDVINF(SEQ ID NO:22)，

LRRFSTAPFAFIDINDVINDF (SEQ ID NO:23), or

dLRRFSTAPFAFIDINDVINdF(SEQ ID NO:24)。

75. The pharmaceutical composition of claim 72, wherein the amino acid sequence of the peptide is selected from the group consisting of:

F(Abu)NINNV(Abu)N(SEQ ID NO:25)，

FTNINNVTN(SEQ ID NO:26)，

FININNVINF(SEQ ID NO:27)，

FSNINNVSNF(SEQ ID NO:28)，

FANINNVANF(SEQ ID NO:29)，

f (allyl Gly) NINNV (allyl Gly) NF (SEQ ID NO:30),

FVNINNVVNF(SEQ ID NO:31)，

FIDINDVINF(SEQ ID NO:32)，

FIDINDVINW(SEQ ID NO:33)，

FTDINDVTN(SEQ ID NO:34)，

a (Abu) NINNV (Abu) NF (SEQ ID NO:35), or

(4-ClPhe)(Abu)NINNV(Abu)NF(SEQ ID NO:36)。

Background

Diabetic Macular Edema (DME) and wet age-related macular degeneration (AMD) are the leading causes of blindness in adults. Progression of AMD can cause erosion of central vision, which is essential for everyday activities such as reading, driving, and identifying the face. While dry AMD causes progressive loss of vision, wet AMD causes more rapid loss of vision and is the latest form of the disease.

The introduction of injectable vascular endothelial growth factor (anti-VEGF) inhibitors (anti-VEGF drugs) greatly reduced the incidence of AMD-related blindness and allowed many patients to maintain vision. These anti-VEGF drugs include ranibizumab (LUCENTIS) and aflibercept (EYLEA). During treatment, the ophthalmologist places anesthetic and anti-bacterial drops on the eye, followed by administration of the anti-VEGF drug by injection into the vitreous (e.g., near the retina behind the eye). The recommended frequency of these injections varies from every few weeks to every few months. Patients often require multiple doses over the course of several months, and continued benefit requires repeated treatments. The cost per treatment can be high, in the united states, approximately $ 2000 per injection. In addition, possible complications of intravitreal injection include infection (e.g., infection caused by streptococcal endophthalmitis), retinal detachment, ocular hypertension, cataracts, inflammation, and the like.

Thus, there is a need for a potent, safe and patient-friendly therapy for eye diseases, including retinal diseases such as wet AMD and diabetic macular edema.

Disclosure of Invention

In various aspects and embodiments, the present invention provides methods and pharmaceutical compositions for treating ocular diseases, including retinal diseases involving vascular permeability and/or inflammation. In various aspects and embodiments, the invention comprises administering to a patient by intraocular injection about 1 μ g to about 1mg of a type IV collagen-derived biomimetic peptide or salt thereof. Injections are provided at a frequency of about once per month to at most about once every two years. As disclosed herein, the peptides form clear gels upon intraocular injection and provide sustained release at surprisingly small amounts of active agent over a long period of time. Thus, the peptides can provide a potent effect and a long duration of effect at low volume of infrequent intravitreal injections.

An exemplary type IV collagen-derived biomimetic peptide comprises, consists of, or consists essentially of the amino acid sequence LRRFSTAPFAFIDINDVINNF (SEQ ID NO: 1). The collagen type iv-derived biomimetic peptide promotes the Tie2 agonistic activity of angiopoietin 2(Ang2), thereby stabilizing the vasculature. The peptides target and disrupt α 5 β 1 and α V β 3 integrins and inhibit signaling through a variety of receptors, including Vascular Endothelial Growth Factor Receptor (VEGFR), Hepatocyte Growth Factor Receptor (HGFR), insulin-like growth factor receptor (IGFR), and Epidermal Growth Factor Receptor (EGFR). The peptide of SEQ ID NO 1 is herein designated AXT 107.

In some embodiments, the peptide or salt thereof is administered to a patient having a disorder selected from diabetic macular edema, retinal vein occlusion, AMD (e.g., wet AMD), or background diabetic retinopathy. In some embodiments, the patient suffers from acute or chronic inflammation of the eye. In some embodiments, the patient has uveitis or an autoimmune or inflammatory condition that manifests in the eye.

In various embodiments of the invention, about 1mg or less of the type IV collagen-derived biomimetic peptide or salt thereof is administered by intraocular injection. For example, the type IV collagen-derived biomimetic peptide or salt thereof is administered at a dose of about 800 μ g or less, or about 500 μ g or less, or about 250 μ g or less (e.g., 50 to 150 μ g). Small amounts of active agent provide unexpectedly long duration of action, which greatly reduces the frequency of injections required. For example, the peptide or salt thereof may be administered by intraocular injection at a frequency of up to about once every three months, or at a frequency of up to about once every four months, or at a frequency of up to about once every six months, or at a frequency of up to about once every eight months, or at a frequency of up to about once every year, or at a frequency of up to about once every 1.5 years, or at a frequency of up to about once every two years, or at a frequency of up to about once every three years.

Furthermore, according to the present invention, the peptides are delivered without using advanced formulation techniques (e.g., particle encapsulation) such as nanoparticle or microparticle encapsulation or liposome encapsulation. That is, the peptide is delivered without any encapsulation technique (e.g., the peptide is delivered as a "naked peptide" in an aqueous solution). The physical properties of the peptides that form transparent gels in the vitreous were observed to be sufficient to achieve a potent effect and a long duration of effect.

In various embodiments, the peptides may be delivered against conditions that are refractory to, or only partially responsive to, Vascular Endothelial Growth Factor (VEGF) blocking or inhibitor therapy, including macular edema, wet AMD.

In other aspects, the invention provides pharmaceutical compositions suitable for intravitreal injection. The pharmaceutical composition comprises from about 1 μ g to about 1mg of a type iv collagen-derived biomimetic peptide or salt thereof (as disclosed herein) as a unit dose in a pre-filled syringe. For example, the unit dose may be about 700 μ g or less of the peptide or salt thereof, or about 500 μ g or less of the peptide or salt thereof, or about 250 μ g or less of the peptide or salt thereof, or about 100 μ g or less of the peptide or salt thereof. One exemplary composition comprises a 50 to 150 μ g dose of peptide (e.g., about 100 μ g).

Other aspects and embodiments of the invention will be apparent from the detailed description below.

Drawings

FIGS. 1A and 1B are graphs showing the inhibitory effect of AXT107 on VEGF-induced vascular leakage by administering 100 μ g AXT107 (FIG. 1A) and 500 μ g AXT107 (FIG. 1B) over 12 months in Dutch-Belted Rabbit (Dutch-Belted Rabbit). The "VEGF" bar indicates no AXT107 control and is used to indicate leakage that occurred in the absence of treatment with AXT 107.

Figure 2 is a graph showing the amount of AXT107 expressed in nanograms per gram (ng/g) present in the retina of a dutch banded rabbit at various time points after intravitreal administration. Significant levels of AXT107 were found in the retina at day 225, 271 and 315 after a single injection.

Figure 3 is an image showing AXT107 gel formation after injection in rabbit eyes. The gel remains below the visual axis and does not block the visual axis or optic nerve.

Figure 4 shows images of gels over 301 days at AXT107 doses of 100, 250, 500 and 1000 μ g after a single injection.

Figure 5 is a graph showing the release of AXT107 from the gel over time at 100 μ g, 250 μ g, 500 μ g, and 1000 μ g. The dashed line shows an estimate of AXT107 levels by day 361.

Figure 6 is an image showing AXT107 gel formation in human vitreous at different ages.

Figure 7 is an image showing the formation of a gel by AXT107 in rabbit eyes from necropsies of dutch stricken rabbits in different doses of AXT107 PK toxicology studies 6 months after administration. Arrows point to the isolated AXT107 gel.

Detailed Description

In various aspects and embodiments, the present invention provides methods and pharmaceutical compositions for treating ocular diseases, including retinal diseases involving vascular permeability and/or inflammation. In various aspects and embodiments, the invention comprises administering to a patient by intraocular injection about 1 μ g to about 1mg of a type IV collagen-derived biomimetic peptide or salt thereof. Injections are provided at a frequency of about once per month to at most about once every two years. As disclosed herein, the peptides form gels upon intraocular injection and provide sustained release at surprisingly small amounts of active agent over a long period of time. Thus, the peptides can provide a potent effect and a long duration of effect at low volume of infrequent intravitreal injections.

According to an aspect of the invention, the active agent is a type iv collagen-derived biomimetic peptide that promotes the Tie2 agonistic activity of angiopoietin 2(Ang2), thereby stabilizing the vasculature and providing an anti-inflammatory effect. See WO 2018/067646, which is incorporated herein by reference in its entirety.

The type IV collagen-derived biomimetic peptide is derived from the type IV collagen alpha 5 fibrils. Exemplary peptides comprise, consist of or consist essentially of the amino acid sequence LRRFSTAPFAFIDINDVINF (SEQ ID NO:1) or a derivative thereof. The peptides target and disrupt α 5 β 1 and α V β 3 integrins and inhibit signaling through a variety of receptors, including Vascular Endothelial Growth Factor Receptor (VEGFR), Hepatocyte Growth Factor Receptor (HGFR), insulin-like growth factor receptor (IGFR), and Epidermal Growth Factor Receptor (EGFR). The peptide of SEQ ID NO 1 is herein designated AXT 107.

Collagen type iv-derived biomimetic peptides include those described in US 9,056,923 and US 9,802,984, which are incorporated herein by reference in their entirety. For example, peptides according to the following disclosure include peptides comprising the amino acid sequence LRRFSTXPXXXNNVXNF (SEQ ID NO:2), wherein X is a standard amino acid or a nongenomically encoded amino acid. In some embodiments, X at position 7 is M, A or G; x at position 9 is F, A, Y or G; x at position 10 is M, A, G, D-alanine (dA) or norleucine (Nle); x at position 11 is F, A, Y, G or 4-chlorophenylalanine (4-ClPhe); x at positions 12 and 18 is independently selected from 2-aminobutyric acid (Abu), G, S, A, V, T, I, L or allylglycine (allylGly). In various embodiments, the peptide contains about 30 amino acids or less, or about 25 amino acids or less, or about 24 amino acids, or about 23 amino acids, or about 22 amino acids, or about 21 amino acids, or about 20 amino acids. In other embodiments, one, two, three, four, or five amino acids of SEQ ID NO 2 are deleted. In some embodiments, the peptide comprises or consists of amino acid sequence LRRFSTAPFAFININNVINF (SEQ ID NO: 3).

In some embodiments, the peptide comprises the amino acid sequence LRRFSTAPFAFIDINDVINFF (SEQ ID NO:1) or a derivative thereof. Derivatives of the peptide of SEQ ID NO:1 include peptides having 1 to 5 amino acid substitutions, insertions or deletions (e.g. 1, 2, 3, 4 or 5 amino acid substitutions, insertions or deletions collectively) relative to SEQ ID NO:1, although in some embodiments the Asp at positions 13 and 16 is maintained. In some embodiments, the sequence DINDV is maintained in the derivative. The peptide may have the amino acid sequence LRRFSTXPXXXXXDINDVXNF, where X is a standard amino acid or a nongenetic encoded amino acid (SEQ ID NO: 4). In some embodiments, X at position 7 is M, A or G; x at position 9 is F, A, Y or G; x at position 10 is M, A, G, D-alanine (dA) or norleucine (Nle); x at position 11 is F, A, Y, G or 4-chlorophenylalanine (4-ClPhe); x at positions 12 and 18 is independently selected from 2-aminobutyric acid (Abu), G, S, A, V, T, I, L or allylglycine (allylGly). In various embodiments, the peptide contains about 30 amino acids or less, or about 25 amino acids or less, or about 24 amino acids, or about 23 amino acids, or about 22 amino acids, or about 21 amino acids, or about 20 amino acids. In other embodiments, one, two, three, four or five amino acids of SEQ ID NO 4 or SEQ ID NO 1 are deleted.

In some embodiments, amino acid substitutions are made at any position of the peptide of SEQ ID No. 1 or 3, which substitutions may be independently selected from conservative or non-conservative substitutions. In these or other embodiments, the peptide includes 1 to 10 amino acids added to one or both termini (collectively). The N-terminus and/or C-terminus may optionally be occupied by another chemical group (other than an amine or carboxyl group, e.g., an amide or thiol).

Conservative substitutions may be made, for example, based on the polarity, charge, size, solubility, hydrophobicity, hydrophilicity, and/or the amphipathic nature of the amino acid residues involved. The amino acids encoded by the 20 genes can be divided into the following six standard amino acid groups:

(1) hydrophobicity: met, Ala, Val, Leu, Ile;

(2) neutral hydrophilicity: cys, Ser, Thr; asn, Gln;

(3) acidity: asp and Glu;

(4) alkalinity: his, Lys, Arg;

(5) residues that influence chain orientation: gly, Pro; and

(6) aromatic: trp, Tyr, Phe.

As used herein, a "conservative substitution" is defined as the exchange of one amino acid for another amino acid listed within the same one of the six standard amino acid groups shown above. For example, the exchange of Asp for Glu retains a negative charge in the modified polypeptide. In addition, glycine and proline may be substituted for each other based on their ability to disrupt alpha-helices. Some preferred conservative substitutions within the above six groups are interchanged within the following subgroups: (i) ala, Val, Leu and Ile; (ii) ser and Thr; (iii) asn and Gln; (iv) lys and Arg; and (v) Tyr and Phe.

As used herein, a "non-conservative substitution" is defined as the exchange of one amino acid for another amino acid listed in a different one of the six standard amino acid groups (1) to (6) shown above.

In various embodiments, the biomimetic peptide or peptide agent is a peptide of about 8 to about 30 amino acids or about 10 to about 20 amino acids and has at least 4, at least 5, or at least 6 contiguous amino acids of SEQ ID NO:1 or 3. In some embodiments, the peptide contains at least one, at least two, or at least three d-amino acids. In some embodiments, the peptide contains one to about five (e.g., 1, 2, or 3) non-gene encoded amino acids, optionally selected from 2-aminobutyric acid (Abu), norleucine (Nle), 4-chlorophenylalanine (4-ClPhe), and allylglycine (allylgly).

Exemplary biomimetic peptides according to the present disclosure include:

LRRFSTMPFMF(Abu)NINNV(Abu)NF(SEQ ID NO:5)，

LRRFSTMPAMF(Abu)NINNV(Abu)NF(SEQ ID NO:6)，

LRRFSTMPFAF(Abu)NINNV(Abu)NF(SEQ ID NO:7)，

LRRFSTMPFMA(Abu)NINNV(Abu)NF(SEQ ID NO:8)，

LRRFSTMPF(Nle)F(Abu)NINNV(Abu)NF(SEQ ID NO:9)，

LRRFSTMPFM(4-ClPhe)(Abu)NINNV(Abu)NF(SEQ ID NO:10)，

LRRFSTMPFMFSNINNVSNF(SEQ ID NO:11)，

LRRFSTMPFMFANINNVANF(SEQ ID NO:12)，

LRRFSTMPFMFININNVINF(SEQ ID NO:13)，

LRRFSTMPFMFTNINNVTNF(SEQ ID NO:14)，

LRRFSTMPFMF (allyl Gly) NINNV (allyl Gly) NF (SEQ ID NO:15),

LRRFSTMPFMFVNINNVVNF(SEQ ID NO:16)，

LRRFSTMPFdAFININNVINF(SEQ ID NO:17)，

LRRFSTMPFAFININNVINF(SEQ ID NO:18)，

LRRFSTAPFAFININNVINF(SEQ ID NO:19)，

LRRFSTAPFdAFIDINDVINF(SEQ ID NO:20)，

LRRFSTAPFAFIDINDVINW(SEQ ID NO:21)，

dLRRdLRRFSTAPFAFIDINDVINF(SEQ ID NO:22)，

LRRFSTAPFAFIDINDVINdF(SEQ ID NO:23)，

dLRRFSTAPFAFIDINDVINdF(SEQ ID NO:24)，

F(Abu)NINNV(Abu)N(SEQ ID NO:25)，

FTNINNVTN(SEQ ID NO:26)，

FININNVINF(SEQ ID NO:27)，

FSNINNVSNF(SEQ ID NO:28)，

FANINNVANF(SEQ ID NO:29)，

f (allyl Gly) NINNV (allyl Gly) NF (SEQ ID NO:30),

FVNINNVVNF(SEQ ID NO:31)，

FIDINDVINF(SEQ ID NO:32)，

FIDINDVINW(SEQ ID NO:33)，

FTDINDVTN(SEQ ID NO:34)，

a (Abu) NINNV (Abu) NF (SEQ ID NO:35), or

(4-ClPhe)(Abu)NINNV(Abu)NF(SEQ ID NO:36)。

In various embodiments, the biomimetic peptide forms a gel in the human vitreous.

In some embodiments, the peptide or salt thereof is administered to a patient having a disorder selected from diabetic macular edema, retinal vein occlusion, AMD (e.g., wet AMD), or background diabetic retinopathy. In some embodiments, the patient suffers from acute or chronic inflammation of the eye. In some embodiments, the patient has uveitis or an autoimmune or inflammatory condition that manifests in the eye.

In some embodiments, the patient has macular edema. Macular edema occurs when fluid and protein deposits concentrate on or under the macula (the yellow central region of the retina) of the eye and cause the macula to thicken and swell. Causes of macular edema include chronic or uncontrolled type 2 diabetes (e.g., diabetic retinopathy), in which peripheral blood vessels, including those of the retina, leak fluid into the retina. Other causes and/or related disorders include age-related macular degeneration (AMD), chronic uveitis, atherosclerosis, hypertension, and glaucoma. In some embodiments, the patient has or is at risk of retinal vein occlusion, which can cause severe damage to the retina and blindness due to ischemia and edema.

In some embodiments, the patient has AMD, which is optionally wet AMD or in some embodiments dry AMD.

In various embodiments, the invention provides for the treatment of retinal diseases with intravitreal injections of type IV collagen-derived biomimetic peptides that require only small amounts of active agent to be administered with infrequent injections. Typically, intravitreal injection is into the eye, and particularly into the vitreous, which is a gelatinous fluid that fills the eye. During this procedure, for example, as commonly used for administration of anti-VEGF drugs, health care providers inject the drug into the vitreous, behind the eye, near the retina. The procedure often takes about 15 to 30 minutes. For example, the procedure generally involves placing drops in the eye to dilate the pupil, placing drops of anesthesia in the eye, and injecting the drug into the eye with a small needle. Antibiotic drops may also be used to prevent infections. While the procedure is routine, it is not without risk and possible complications. In addition to systemic side effects, these complications include endophthalmitis, retinal detachment, elevated intraocular pressure, ocular hemorrhage. See Falavarjani KG and Nguyen QDs,Adverse events and complications associated with intravitreal injection ofanti-VEGF agents: a review of literature.eye 2013, month 7; 27(7):787-794. Furthermore, the procedures for administering conventional anti-VEGF drugs are costly and inconvenient, as frequent injections are typically required.

In various embodiments of the invention, about 1mg or less of the type IV collagen-derived biomimetic peptide or salt thereof is administered by intraocular injection. In various embodiments, a unit dose of peptide is administered at the base of the eye, e.g., between 5:00 and 7:00, so that a gel is formed at the base. For example, the type IV collagen-derived biomimetic peptide or salt thereof is administered in a dose of about 25 μ g to about 1000 μ g. For example, about 800 μ g or less, or about 700 μ g or less, or about 500 μ g or less, or about 250 μ g or less, or about 100 μ g or less of the peptide or salt thereof is administered per intraocular injection. In such embodiments, at least about 25 μ g or at least about 50 μ g is administered per intraocular injection. In some embodiments, the unit dose is greater than 1mg, e.g., 1mg to about 2 mg. Small amounts of active agent provide unexpectedly long duration of action, which greatly reduces the frequency of injections required. For example, the peptide or salt thereof may be administered by intraocular injection at a frequency of up to about once every three months, or at a frequency of up to about once every four months, or at a frequency of up to about once every six months, or at a frequency of up to about once every eight months, or at a frequency of up to about once every year, or at a frequency of up to about once every 1.5 years, or at a frequency of up to about once every two years, or at a frequency of up to about once every three years.

Furthermore, according to the present invention, the peptides are delivered without using advanced formulation techniques (e.g., particle encapsulation) such as nanoparticle or microparticle encapsulation or liposome encapsulation. That is, the peptide is delivered without any encapsulation technique (e.g., the peptide is delivered as a "naked peptide" in an aqueous solution). The physical properties of the peptide that forms a gel in the vitreous were observed to be sufficient to achieve a potent effect and a long duration of effect.

Unless specifically stated otherwise or apparent from the context, as used herein, the term "about" includes values within plus or minus 10% of the stated value.

In various embodiments, about 10 μ g to about 50 μ g of the type IV collagen-derived biomimetic peptide or salt thereof is administered per intraocular injection and at a frequency of about once per month or about once every other month. For example, about 25 μ g of the peptide or salt thereof can be administered by intraocular injection about once per month. Alternatively, about 50 μ g to about 150 μ g per intraocular injection is administered at a frequency of at most about once every three months or at most about once every four months or at most about once every six months. For example, the peptide or salt thereof is administered at a frequency of about 50 μ g and about once every three or four months. In some embodiments, the peptide or salt thereof is administered at about 100 μ g to about 150 μ g per injection and at a frequency of about once every five months to seven months, and optionally about once every six months. In some embodiments, a dose of 100 to 150 μ g is administered about once every eight months or about once every nine months.

In other embodiments, the amount of active agent delivered per injection is increased, which provides an unexpected duration of action. For example, the type IV collagen-derived biomimetic peptide or salt thereof is administered at a frequency of about 150 μ g to about 250 μ g per intraocular injection and at most about once every six months. For example, in these embodiments, the peptide or salt thereof is administered at a frequency of up to about once every eight months. In some embodiments, the peptide or salt thereof is administered at a frequency of up to about once every ten months or about once every twelve months. In some embodiments, the peptide or salt thereof is administered at a frequency of about 200 μ g and about once every six months to eight months. In some embodiments, the peptide or salt thereof is administered at a frequency of about 250 μ g and about once every six months to twelve months.

In other embodiments, the peptide or salt thereof is administered at a frequency of about 250 μ g to about 1mg per intraocular injection and up to about once every six months. In these embodiments, the peptide or salt thereof is administered at about 300 μ g to about 700 μ g per injection, or about 400 μ g to about 700 μ g per injection, or about 500 μ g to about 700 μ g per injection, or about 600 μ g to about 700 μ g per injection. In some embodiments, the peptide or salt thereof is administered at a frequency of about once every six months to twelve months. For example, the peptide or salt thereof is administered about once every seven months, about once every eight months, about once every nine months, about once every ten months, about once every eleven months, or about once every twelve months, or about once every 18 months.

In other embodiments, the peptide or salt thereof is administered at a frequency of about 700 μ g to about 1mg per intraocular injection and at most about once every twelve months or at most once every 15 months. In some embodiments, the peptide or salt thereof is administered at a frequency of about 800 μ g to about 1mg per injection, or about 900 μ g to about 1mg per injection, or once every twelve to eighteen months. In some embodiments, the peptide or salt thereof is administered about once every two years or about once every three years.

In some embodiments, the peptide administered as described above is a peptide consisting of SEQ ID NO:1 (AXT 107).

In various embodiments, the patient will receive multiple doses, and in some embodiments, the therapy may be continued at the recommended injection frequency to control or manage the disease. In some embodiments, where the symptoms or disease have been substantially alleviated, the therapy need not be continued. In various embodiments, the patient receives at least two injections, or at least four injections, or at least six injections, or at least eight injections, or at least ten injections. In some embodiments, the injections are provided in a regimen of four to ten injections.

The collagen type iv-derived biomimetic peptide promotes the Tie2 agonistic activity of angiopoietin 2(Ang2), thereby stabilizing the vasculature. The peptides target and disrupt α 5 β 1 and α V β 3 integrins and inhibit signaling through a variety of receptors, including Vascular Endothelial Growth Factor Receptor (VEGFR), Hepatocyte Growth Factor Receptor (HGFR), insulin-like growth factor receptor (IGFR), and Epidermal Growth Factor Receptor (EGFR). Thus, the peptides disclosed herein provide a potent replacement therapy or potent combination therapy for VEGF blocking or inhibitor therapy.

In various embodiments, the peptides may be delivered against conditions that are refractory to, or only partially responsive to, Vascular Endothelial Growth Factor (VEGF) blocking or inhibitor therapy, including macular edema, wet AMD. Agents that block VEGF include aflibercept, bevacizumab, ranibizumab and ramucirumab (ramucirumab) and similar agents administered to slow or block angiogenesis. Other agents that target VEGF-mediated biological activity include kinase inhibitors such as pazopanib (pazopanib), sorafenib (sorafenib), sunitinib (sunitinib), axitinib (axitinib), panatinib (ponatinib), lenvatinib (lenvatinib), vandetanib (vandetanib), regorafenib (regorafenib), and cabozantinib (cabozantinib).

Aflibercept is a biopharmaceutical drug for the treatment of wet macular degeneration (EYLEA). Aflibercept is a VEGF inhibitor and is a recombinant fusion protein consisting of a Vascular Endothelial Growth Factor (VEGF) binding moiety from the extracellular domains of human VEGF receptors 1 and 2 fused to the Fc portion of a human IgG1 immunoglobulin. Aflibercept binds to VEGF and acts like a "VEGF trap", inhibiting the activity of vascular endothelial growth factor subtypes VEGF-a and VEGF-B, and Placental Growth Factor (PGF).

Bevacizumab (AVASTIN) is an angiogenesis inhibitor, a drug that slows the growth of new blood vessels. Bevacizumab is a recombinant humanized monoclonal antibody that blocks angiogenesis by inhibiting VEGF-a. Bevacizumab is administered to treat certain metastatic cancers, including colon cancer, lung cancer (e.g., NSCLC), renal cancer, ovarian cancer, breast cancer, and glioblastoma. Bevacizumab may also be used to treat eye diseases, including AMD and diabetic retinopathy.

Ranibizumab (LUCENTIS) is a monoclonal antibody fragment (Fab) and is administered for the treatment of wet AMD. The drug is injected intravitreally (into the vitreous humor of the eye) approximately once a month. Ranibizumab is a monoclonal antibody that inhibits angiogenesis by inhibiting VEGF a, similar to bevacizumab.

The biomimetic peptide may be administered after an unsuccessful VEGF blocking therapy, that is, without observing a reduction in angiogenesis, lymphangiogenesis and/or edema. In some embodiments, the peptide is administered as an alternative therapy to VEGF blocking therapy. In other embodiments, the peptide is administered concurrently with, before, or after a VEGF blocking regimen in combination with a VEGF blocking therapy. By activating Tie2 signaling, the biomimetic peptide or peptide agent provides a therapeutic benefit that may not be observed under VEGF blocking therapy or VEGF blocking therapy alone.

Thus, in some embodiments, the peptide or salt thereof is administered after an unsuccessful VEGF blocking or inhibitor therapy. In some embodiments, the patient has a condition that is refractory to, or only partially responsive to, VEGF blocking or inhibitor therapy.

In other aspects, the invention provides pharmaceutical compositions suitable for intravitreal injection. The pharmaceutical composition comprises from about 1 μ g to about 1mg or from about 25 μ g to about 800 μ g of the type iv collagen-derived biomimetic peptide or salt thereof (as disclosed herein) as a unit dose in a pre-filled syringe. For example, the unit dose may be about 700 μ g or less of the peptide or salt thereof, or about 500 μ g or less of the peptide or salt thereof, or about 250 μ g or less of the peptide or salt thereof, or about 100 μ g or less of the peptide or salt thereof. Exemplary unit doses include about 100 μ g, about 250 μ g, about 500 μ g, and about 750 μ g.

In some embodiments, the composition has a unit dose of about 10 μ g to about 50 μ g of the peptide or salt thereof. In other embodiments, the composition has a unit dose of about 50 μ g to about 150 μ g (e.g., about 100 μ g) of the peptide or salt thereof. In some embodiments, the composition has a unit dose of about 150 μ g to about 250 μ g of the peptide or salt thereof. In some embodiments, the composition has a unit dose of peptide or salt thereof of about 250 μ g to about 700 μ g, or about 300 μ g to about 700 μ g, or about 400 μ g to about 700 μ g, or about 500 μ g to about 700 μ g, or about 600 μ g to about 700 μ g.

In other embodiments, the pharmaceutical composition has a unit dose of the peptide or salt thereof from about 700 μ g to about 1mg or from about 800 μ g to about 1 mg. In some embodiments, the unit dose is about 1 mg. In some embodiments, the unit dose is greater than 1mg, e.g., from about 1mg to about 2 mg.

The unit dose volume (according to the compositions and methods described herein) can range from about 1 μ Ι to about 1mL, or from about 10 μ Ι to about 0.5mL, or from about 10 μ Ι to about 250 μ Ι, or from about 10 μ Ι to about 50 μ Ι. In some embodiments, the pharmaceutical composition comprises a unit volume of about 25 μ L to about 0.5mL, or a unit volume of about 25 μ L to about 200 μ L, or a unit volume of about 25 μ L to about 100 μ L. In some embodiments, the unit volume is less than about 100 μ L, or less than about 50 μ L, or less than about 25 μ L. In various embodiments, the volume is about 50 μ L.

The biomimetic peptide or peptide agent can be synthesized chemically and purified using well-known techniques, such as solid phase synthesis. See US 9,051,349, which is incorporated herein by reference in its entirety.

In some embodiments, the peptide may be provided in the form of a pharmaceutically acceptable salt. Pharmaceutically acceptable peptide salts are generally well known to those of ordinary skill in the art.

The biomimetic peptide or peptide agent can be formulated for intraocular injection (i.e., intravitreal injection) using a variety of pharmaceutically acceptable carriers, including, but not limited to, water, physiological saline, dextrose solution, and the like. The biomimetic peptides can be formulated and diluted in aqueous solution, for example in a physiologically compatible buffer.

In certain aspects, the invention provides a method for preventing or treating an eye disease or disorder involving Tie-2 associated vascular permeability in a patient. The method comprises administering to a patient a pharmaceutical composition as described herein over a dosing schedule (i.e., frequency) as described herein. According to embodiments of the present invention, both potent and long-lasting recovery of Tie2 activation can be achieved with only small amounts of active agent and infrequent unit dose injections. In various embodiments, the methods provide therapeutic benefits in disorders associated with edema or vascular permeability, including macular edema, Diabetic Macular Edema (DME), and other disorders, including disorders characterized by acute or chronic ocular inflammation. Tie 2-related disorders include diabetic macular edema, retinal vein occlusion, wet AMD, background diabetic retinopathy.

As used herein, the term "about" includes the relevant numerical values ± 10%.

As used in the specification and the appended claims, the singular forms "a", "an", and "the" include plural referents unless the context clearly dictates otherwise.

As used herein, the term "or" is understood to be inclusive and to cover "or" and "unless specifically stated or apparent from the context.

The invention will be further described in terms of the following non-limiting examples.

Examples

The following examples demonstrate that AXT107 and its derivative peptides are safe, potent and have unexpectedly long duration of action with infrequent intravitreal injections in small volumes. The present invention thus provides a patient-friendly therapy for ocular diseases, including retinal diseases such as wet AMD and diabetic macular edema.

In these experiments, Dutch banded rabbits were anesthetized by intramuscular injection of ketamine (25 mg/kg) and xylazine (2.5 mg/kg) and the pupils were dilated with 2.5% phenylephrine. The conjunctiva was cleaned with 5% povidone-iodine and 100 μ g or 500 μ g AXT107 was injected intravitreally in one eye. Twenty-three days after the injection of AXT107, 10 μ g VEGF was injected into the vitreous and after 7 days, i.e. 30 days after the initial AXT107 injection, a Fluorotron Master fitted with an animal adaptor was used^TMVitrophotometry (VFP) was performed by an ocular fluorometer (OcuMetrics, Mountain View, Calif.). For VFP, 15mg of fluorescein sodium (AK-Fluor 10%, Akorn, Lake Forest, IL) was injected into the ear vein, and after one hour, fluorescence was measured along the visual axis from the retina to the cornea. The area under the fluorescein concentration curve between 5mm and 7mm in front of the retina was calculated to determine the extent of leakage. This VEGF injection and VFP measurement protocol was performed on subsequent days 23 and 30 of each month for 12 months. Leakage per month in eyes administered AXT107 was normalized to animals injected with VEGF alone at the same time. See fig. 1A and 1B.

The results of these experiments show that AXT107 potently inhibits VEGF-induced vascular leakage in rabbit eyes, which due to their size are better human eye substitutes than mouse eyes. In addition, AXT107 potently inhibits VEGF-induced vascular leakage in rabbit eyes for at least 12 months.

In fig. 2, AXT107 was injected into the vitreous of a dutch banded rabbit. Rabbits were then sacrificed at various time points and individual ocular tissues were isolated. Drug levels in the retina were measured by liquid chromatography-mass spectrometry (LC/MS). Drug levels are plotted as ng/g. The Kd for binding of AXT107 to its integrin target is 1-2 nM. AXT107 is present at 100ng/g or greater, such that the concentration in the retina significantly exceeds Kd at time points day 225, day 271 and day 315.

In fig. 3, AXT107 was injected into the vitreous of dutch banded rabbits. After one day, the gel was visible at the injection site. The gel is marked by arrows in fig. 3. The retina with the optic nerve is seen behind the eye. The gel was tight and did not block the visual axis.

In fig. 4, AXT107 forms a gel in the vitreous at the injection site. The gel remains in place and releases the peptide in a sustained manner. Figure 4 shows that the gel becomes smaller in situ over time. At all time points, the back of the eye was transparent, indicating that the peptide did not block the visual axis and therefore did not interfere with vision. The data from this experiment demonstrate that the peptide remains in place in rabbit eyes and does not divide or migrate for 15 months. Figure 4 shows images of gels over 301 days at AXT107 doses of 100 μ g, 250 μ g, 500 μ g and 1000 μ g. Figure 5 is a graph showing AXT107 release from a gel over time. The dashed line shows an estimate of AXT107 levels by day 361.

In the tube in fig. 6, AXT107 is placed into the vitreous of a 5 year old person and a 89 year old person. These pictures show that the peptide forms a gel in the human vitreous similar to that seen in the rabbit vitreous.

In fig. 7, AXT107 was injected into the vitreous of dutch banded rabbits in a PK toxicology study. When the animals were necropsied and the eyes were examined, the gel formed by the peptide was visible in the vitreous at all doses. The size of the gel is dose dependent as seen with a ruler at the bottom of fig. 7 (marked by arrows).