Methods of treating an eye disorder
Provided herein are methods of treating eye disorders by administering an anti-VEGF antibody and/or conjugate to a subject having an eye disorder. The anti-VEGF antibody of the present disclosure may be an anti-VEGF antibody conjugate that includes a polymeric moiety that extends the half-life/effectiveness/properties of the antibody when administered to a subject. A method of the present disclosure includes administering one or more doses of an anti-VEGF antibody conjugate to a subject (e.g., human or other mammalian patient) in need of treating an eye disorder, where the anti-VEGF antibody conjugate may be administered less frequently than a standard anti-VEGF therapy to treat the eye disorder.
1. A method of treating an eye disorder, comprising:
administering three loading doses of an anti-VEGF antibody conjugate to a subject in need of treating an eye disorder at a first loading dose, wherein the eye disorder is wet age-related macular degeneration (wAMD),
wherein the anti-VEGF antibody conjugate comprises:
an antibody conjugate comprising a light chain and a heavy chain, wherein the heavy chain comprises CDR H 1: GYDFTHYGMN (SEQ ID NO: 9), CDR H 2: WINTYTGEPTYAADFKR (SEQ ID NO: 10), and CDR H 3: YPYYYGTSHWYFDV (SEQ ID NO: 11), and the light chain comprises CDR L 1: SASQDISNYLN (SEQ ID NO: 12), CDR L 2: FTSSLHS (SEQ ID NO: 13), and CDR L 3: QQYSTVPWT (SEQ ID NO: 14), and wherein the heavy chain comprises an amino acid sequence at least 90% identical to SEQ ID NO: 1 and the light chain comprises an amino acid sequence at least 90% identical to SEQ ID NO: 2; and
a phosphorylcholine containing polymer covalently bonded to the heavy chain, wherein the polymer comprises 2-(methacryloyloxyethyl)-2′-(trimethylammonium)ethyl phosphate (MPC) monomers, and wherein the polymer has a molecular weight of between about 600,000 and about 1,000,000 Da
whereby the subject retains a therapeutic result of the anti-VEGF antibody conjugate therapy for at least 12 weeks after a final loading dose.
2. The method of claim 1 , wherein the therapeutic result of the anti-VEGF antibody conjugate therapy lasts for at least 14 weeks past a final loading dose.
3. The method of claim 2 , no further administration of the anti-VEGF antibody conjugate is provided to the subject within 14 weeks of a final loading dose.
4. The method of claim 1 , wherein the therapeutic result of the anti-VEGF antibody conjugate therapy lasts for at least 20 weeks past a final loading dose.
5. The method of claim 4 , no further administration of the anti-VEGF antibody conjugate is provided to the subject within twenty weeks of a final loading dose.
6. The method of claim 1 , no further administration of the anti-VEGF antibody conjugate is provided to the subject within four weeks of a final loading dose.
7. The method of claim 1 , no further administration of the anti-VEGF antibody conjugate is provided to the subject within ten weeks of a final loading dose.
8. The method of claim 1 , wherein the heavy chain comprises an Fc region comprising a non-native cysteine, and wherein the polymer is covalently bonded at the cysteine.
9. The method of claim 1 , wherein the therapeutic result of the anti-VEGF antibody conjugate therapy lasts for at least 12 weeks past a final loading dose.
10. The method of claim 1 , wherein the therapeutic result of the anti-VEGF antibody conjugate therapy lasts for at least 16 weeks past a final loading dose.
11. The method of claim 1 , wherein the therapeutic result of the anti-VEGF antibody conjugate therapy lasts for at least 20 weeks past a final loading dose.
12. The method of claim 1 , wherein the loading doses are administered with about one to two months between each loading dose.
13. The method of claim 12 , further comprising administering one or more subsequent doses of the anti-VEGF antibody conjugate to the subject after the final loading dose.
14. The method of claim 13 , wherein the one or more subsequent doses of the anti-VEGF antibody conjugate is administered on average no more frequently than once every 24 weeks.
15. The method of claim 13 , comprising:
administering a first subsequent dose of the anti-VEGF antibody conjugate at a first time period after the final loading dose; and
administering a second subsequent dose at a second time period after the first subsequent dose, wherein the anti-VEGF antibody conjugate is not administered between the first subsequent dose and the second subsequent dose,
wherein the first time period is shorter than the second time period.
16. The method of claim 13 , wherein any subsequent dose of the anti-VEGF antibody conjugate is administered no more frequently than once every 16 weeks.
17. The method of claim 13 , wherein any subsequent dose of the anti-VEGF antibody conjugate is administered no more frequently than once every 12 weeks.
18. The method of claim 13 , wherein any subsequent dose of the anti-VEGF antibody conjugate is administered no more frequently than once every 20 weeks.
19. The method of claim 17 , wherein at least about 1.25 mg of antibody per loading dose is administered to the subject in the form of the anti-VEGF antibody conjugate.
20. The method of claim 19 , wherein about 5 mg of antibody per loading dose is administered to the subject in the form of the anti-VEGF antibody conjugate.
21. The method of claim 20 , wherein no dose is administered until at least 24 weeks following the last loading dose.
22. The method of claim 20 , wherein no dose is administered until at least 20 weeks following the last loading dose.
23. The method of claim 22 , wherein the therapeutic result comprises one or more of improved visual acuity, reduced retinal thickness, improved perfusion in at least one eye, improved diabetic retinopathy severity score (DRSS), or reduced disease activity of the eye disorder, compared to a pre-treatment level.
24. The method of claim 23 , wherein the anti-VEGF antibody conjugate is administered via intravitreal injection.
25. The method of claim 24 , wherein the anti-VEGF antibody conjugate comprises: an antibody conjugate comprising an anti-VEGF-A immunoglobulin G (IgG) bonded to the polymer, wherein the sequence of the anti-VEGF-A antibody heavy chain is SEQ ID NO: 1, and the sequence of the anti-VEGF-A antibody light chain is SEQ ID NO: 2, and wherein the antibody is bonded at C449 in SEQ ID NO: 1 to the polymer.
26. The method of claim 25 , wherein the antibody conjugate has the following structure:
wherein:
each heavy chain of the anti-VEGF-A antibody is denoted by the letter H, and each light chain of the anti-VEGF-A antibody is denoted by the letter L;
the polymer is bonded to the anti-VEGF-A antibody through the sulfhydryl of C443 (EU numbering), which bond is depicted on one of the heavy chains;
PC is where the curvy line indicates the point of attachment to the rest of the polymer, where X is a) —OR where R is —H, methyl, ethyl, propyl, isopropyl, b) —H, c) any halogen, including —Br, —Cl, or —I, d) —SCN, or e) —NCS; and
n1, n2, n3, n4, n5, n6, n7, n8 and n9 are the same or different such that the sum of n1, n2, n3, n4, n5, n6, n7, n8 and n9 is 2500 plus or minus 15%.
27. A method of treating an eye disorder, comprising:
administering three loading doses of an anti-VEGF antibody conjugate to a subject in need of treating an eye disorder, wherein the eye disorder is wet age-related macular degeneration (wAMD);
wherein the anti-VEGF antibody conjugate comprises:
an antibody conjugate comprising a light chain and a heavy chain, wherein the heavy chain comprises CDR H 1: GYDFTHYGMN (SEQ ID NO: 9), CDR H 2: WINTYTGEPTYAADFKR (SEQ ID NO: 10), and CDR H 3: YPYYYGTSHWYFDV (SEQ ID NO: 11), and the light chain comprises CDR L 1: SASQDISNYLN (SEQ ID NO: 12), CDR L 2: FTSSLHS (SEQ ID NO: 13), and CDR L 3: QQYSTVPWT (SEQ ID NO: 14), and wherein the heavy chain comprises an amino acid sequence at least 90% identical to SEQ ID NO: 1 and the light chain comprises an amino acid sequence at least 90% identical to SEQ ID NO: 2; and
a phosphorylcholine containing polymer covalently bonded to the heavy chain, wherein the polymer comprises 2-(methacryloyloxyethyl)-2′-(trimethylammonium)ethyl phosphate (MPC) monomers, and wherein the polymer has a molecular weight of between about 600,000 and about 1,000,000 Da; and
administering at least one subsequent dose of the anti-VEGF antibody conjugate after the final loading dose, thereby treating the eye disorder,
wherein the loading doses and the at least one subsequent dose are administered no more frequently than once a month.
28. The method of claim 27 , wherein the heavy chain comprises an Fc region comprising a non-native cysteine, and wherein the polymer is covalently bonded at the cysteine.
29. The method of claim 27 , wherein the one or more subsequent doses of the anti-VEGF antibody conjugate is administered at a dosing schedule of Q12W, Q16W, or Q20W.
30. The method of claim 27 , wherein the one or more subsequent doses of the anti-VEGF antibody conjugate is administered at a dosing schedule of between Q12W and Q20W.
31. The method of claim 27 , wherein the anti-VEGF antibody conjugate is administered at a dosing schedule of Q4W.
32. The method of claim 27 , wherein the one or more subsequent doses of the anti-VEGF antibody conjugate is administered at a dosing schedule of Q4W, Q8W, Q12W, Q16W, Q20W, Q24W, or longer.
33. The method of claim 32 , wherein about 5 mg of antibody per loading dose and/or subsequent dose is administered to the subject in the form of the anti-VEGF antibody conjugate.
34. The method of claim 33 , wherein the anti-VEGF antibody conjugate is administered via intravitreal injection.
35. The method of claim 34 , wherein the heavy chain comprises an amino acid sequence of at least residues 1-449 of SEQ ID NO:1, and the light chain comprises an amino acid sequence of SEQ ID NO:2.
36. The method of claim 35 , wherein the antibody conjugate has the following structure:
wherein:
each heavy chain of the anti-VEGF-A antibody is denoted by the letter H, and each light chain of the anti-VEGF-A antibody is denoted by the letter L;
the polymer is bonded to the anti-VEGF-A antibody through the sulfhydryl of C443 (EU numbering), which bond is depicted on one of the heavy chains;
PC is where the curvy line indicates the point of attachment to the rest of the polymer, where X is a) —OR where R is —H, methyl, ethyl, propyl, isopropyl, b) —H, c) any halogen, including —Br, —Cl, or —I, d) —SCN, or e) —NCS; and
n1, n2, n3, n4, n5, n6, n7, n8 and n9 are the same or different such that the sum of n1, n2, n3, n4, n5, n6, n7, n8 and n9 is 2500 plus or minus 15%.
37. A method of treating an eye disorder, comprising:
administering three doses of an anti-VEGF antibody conjugate to a subject in need of treating an eye disorder, wherein the eye disorder is wet age-related macular degeneration (wAMD), wherein the anti-VEGF antibody conjugate comprises:
an antibody conjugate comprising a light chain and a heavy chain, wherein the heavy chain comprises CDR H 1: GYDFTHYGMN (SEQ ID NO: 9), CDR H 2: WINTYTGEPTYAADFKR (SEQ ID NO: 10), and CDR H 3: YPYYYGTSHWYFDV (SEQ ID NO: 11), and the light chain comprises CDR L 1: SASQDISNYLN (SEQ ID NO: 12), CDR L 2: FTSSLHS (SEQ ID NO: 13), and CDR L 3: QQYSTVPWT (SEQ ID NO: 14), and wherein the heavy chain comprises an amino acid sequence at least 90% identical to SEQ ID NO: 1 and the light chain comprises an amino acid sequence at least 90% identical to SEQ ID NO: 2; and
a phosphorylcholine containing polymer covalently bonded to the heavy chain, wherein the polymer comprises 2-(methacryloyloxyethyl)-2′-(trimethylammonium)ethyl phosphate (MPC) monomers, and wherein the polymer has a molecular weight of between about 600,000 and about 1,000,000 Da; and
administering one or more additional doses after the third dose at a dosing schedule based on an outcome of one or more assessment tests for ocular health and/or function carried out on the subject,
thereby treating the eye disorder, wherein the doses are administered no more frequently than once a month.
38. The method of claim 37 , wherein the dosing schedule comprises Q4W, Q8W, Q12W, Q16W, Q20W, Q24W, or longer.
39. The method of claim 37 , wherein about 5 mg of antibody per dose is administered to the subject in the form of the anti-VEGF antibody conjugate.
40. The method of claim 39 , wherein the anti-VEGF antibody conjugate is administered via intravitreal injection.
41. The method of claim 40 , wherein the heavy chain comprises an amino acid sequence of at least residues 1-449 of SEQ ID NO:1, and the light chain comprises an amino acid sequence of SEQ ID NO:2.
42. The method of claim 41 , wherein the antibody conjugate has the following structure:
wherein:
each heavy chain of the anti-VEGF-A antibody is denoted by the letter H, and each light chain of the anti-VEGF-A antibody is denoted by the letter L;
the polymer is bonded to the anti-VEGF-A antibody through the sulfhydryl of C443 (EU numbering), which bond is depicted on one of the heavy chains;
PC is where the curvy line indicates the point of attachment to the rest of the polymer, where X is a) —OR where R is —H, methyl, ethyl, propyl, isopropyl, b) —H, c) any halogen, including —Br, —Cl, or —I, d) —SCN, or e) —NCS; and
n1, n2, n3, n4, n5, n6, n7, n8 and n9 are the same or different such that the sum of n1, n2, n3, n4, n5, n6, n7, n8 and n9 is 2500 plus or minus 15%.
43. A method of disease modification of an eye disorder, wherein the method comprises:
administering an anti-VEGF antibody conjugate to a subject having an eye disorder at a first loading dose, wherein the eye disorder is wet age-related macular degeneration (wAMD),
wherein the anti-VEGF antibody conjugate comprises:
an antibody conjugate comprising a light chain and a heavy chain, wherein the heavy chain comprises CDR H 1: GYDFTHYGMN (SEQ ID NO: 9), CDR H 2: WINTYTGEPTYAADFKR (SEQ ID NO: 10), and CDR H 3: YPYYYGTSHWYFDV (SEQ ID NO: 11), and the light chain comprises CDR L 1: SASQDISNYLN (SEQ ID NO: 12), CDR L 2: FTSSLHS (SEQ ID NO: 13), and CDR L 3: QQYSTVPWT (SEQ ID NO: 14), and wherein the heavy chain comprises an amino acid sequence at least 90% identical to SEQ ID NO: 1 and the light chain comprises an amino acid sequence at least 90% identical to SEQ ID NO: 2; and
a phosphorylcholine containing polymer covalently bonded to the heavy chain, wherein the polymer comprises 2-(methacryloyloxyethyl)-2′-(trimethylammonium)ethyl phosphate (MPC) monomers, and wherein the polymer has a molecular weight of between about 600,000 and about 1,000,000 Da,
whereby the eye disorder is modified in a beneficial manner to the subject.