Compositions for treatment of wet age-related macular degeneration

Patent metadata

Field	Value
Publication number	US-12558434-B2
Application number	US-201916971215-A
Country	US
Kind code	B2
Filing date	Feb 18, 2019
Priority date	Feb 20, 2018
Publication date	Feb 24, 2026
Grant date	Feb 24, 2026

Abstract

A liquid suspension product comprising a recombinant adeno-associated virus (rAAV) having an AAV8 capsid which is suitable for intra-retinal injection is provided herein. Also provided herein are liquid suspensions containing these rAAV8.aVEGF and methods of using same for treatment of wet AMD and other ocular conditions.

First claim

The invention claimed is:

1 . A method for administering an anti-human vascular endothelial growth factor (anti-hVEGF) antigen binding fragment (Fab) to a human patient having neovascular age-related macular degeneration (nAMD), the method comprising subretinally injecting a liquid suspension suitable for subretinal injection into an eye of the human patient, said liquid suspension comprising an aqueous liquid and a recombinant adeno-associated virus (rAAV) having an AAV8 capsid, wherein the rAAV comprises a vector genome in the capsid, said vector genome comprising:
(a) a first AAV inverted terminal repeat (ITR); (b) a nucleic acid sequence encoding a first interleukin 2 (IL-2) leader sequence fused in frame to a coding sequence for the anti-h VEGF Fab heavy immunoglobulin chain, a linker, and a nucleic acid sequence encoding a second IL-2 leader sequence fused in frame to a coding sequence for the ant-VEGF Fab light immunoglobulin chain, wherein the coding sequences are operably linked to regulatory elements which direct expression of the anti-h VEGF Fab in the eye, and wherein the encoded anti-hVEGF Fab comprises a heavy chain variable region having amino acid 1 to amino acid 123 of SEQ ID NO: 1 and further comprises a light chain variable region having amino acid 1 to amino acid 107 of SEQ ID NO: 2; (c) the regulatory elements of (b) which direct expression of the heavy and light immunoglobulin chains of the anti-hVEGF Fab and which comprise a chicken beta-actin promoter; and (d) a second AAV ITR, wherein said liquid suspension is injected as a dose per eye at a dose of greater than 6.0×10 10 Genome Copies (GC) of the rAAV per eye and less than 1.0×10 12 GC of the rAAV per eye.

2 . The method of claim 1 , wherein the heavy chain of the anti-hVEGF Fab consists of the amino acid sequence of SEQ ID NO: 1 and the light chain of the anti-hVEGF Fab consists of the amino acid sequence of SEQ ID NO: 2.

3 . The method of claim 1 , wherein the human patient is free of adverse ocular events for at least 12 months post administration of the liquid suspension.

4 . The method of claim 1 , wherein the liquid suspension is injected subretinally avoiding the macula.

5 . The method of claim 4 , wherein the dose does not result in sustained T-cell response to the anti-hVEGF Fab.

6 . The method of claim 1 , wherein:
(a) the first AAV ITR is a 5′ AAV ITR; (b) the regulatory elements comprise:
(i) a cytomegalovirus immediate early (CMV IE) enhancer and the chicken beta actin promoter; and
(ii) a chicken beta actin intron;
(c) the linker comprises a self-cleaving furin (F)/F2A linker; (d) the second AAV ITR is a 3′ AAV ITR; and (e) the vector genome further comprises a rabbit beta globin polyadenylation (polyA) signal.

7 . The method of claim 1 , wherein the heavy chain of the anti-hVEGF Fab comprises the amino acid sequence of SEQ ID NO: 1 and the light chain of the anti-hVEGF Fab comprises the amino acid sequence of SEQ ID NO: 2.

8 . The method of claim 1 , wherein the vector genome further comprises a UTR sequence.

9 . The method of claim 1 , wherein the first and the second ITRs are from AAV2.

10 . The method of claim 1 , wherein the liquid suspension further comprises a poloxamer.

11 . The method of claim 10 , wherein the liquid suspension has a pH of 7.2 to 7.6.

12 . The method of claim 10 , wherein the heavy chain of the anti-hVEGF Fab comprises the amino acid sequence of SEQ ID NO: 1 and the light chain of the anti-hVEGF Fab comprises the amino acid sequence of SEQ ID NO: 2.

13 . The method of claim 6 , wherein the heavy chain of the anti-hVEGF Fab comprises the amino acid sequence of SEQ ID NO: 1 and the light chain of the anti-hVEGF Fab comprises the amino acid sequence of SEQ ID NO: 2.

14 . The method of claim 13 , wherein the vector genome further comprises a UTR sequence.

15 . The method of claim 14 , wherein the first and the second ITRs are from AAV2.

16 . The method of claim 10 , wherein:
(a) the first AAV ITR is a 5′ AAV ITR; (b) the regulatory elements comprise:
(i) a cytomegalovirus immediate early (CMV IE) enhancer and the chicken beta actin promoter; and
(ii) a chicken beta actin intron;
(c) the linker comprises a self-cleaving furin (F)/F2A linker; (d) the second AAV ITR is a 3′ AAV ITR; and (e) the vector genome further comprises a rabbit beta globin polyadenylation (polyA) signal.

17 . The method of claim 16 , wherein the heavy chain of the anti-hVEGF Fab comprises the amino acid sequence of SEQ ID NO: 1 and the light chain of the anti-hVEGF Fab comprises the amino acid sequence of SEQ ID NO: 2.

18 . The method of claim 17 , wherein the vector genome further comprises a UTR sequence.

19 . The method of claim 18 , wherein the first and the second ITRs are from AAV2.

20 . The method of claim 19 , wherein the liquid suspension has a pH of 7.2 to 7.6.

21 . A method for delivering an anti-human vascular endothelial growth factor (anti-hVEGF) antigen binding fragment (Fab) to a human patient, the method comprising injecting a single dose into an eye of the human patient a liquid suspension comprising an aqueous liquid and a recombinant adeno-associated virus (rAAV) having an AAV8 capsid, wherein the rAAV comprises a vector genome in the AAV8 capsid, said vector genome comprising:
(a) a first AAV inverted terminal repeat (ITR); (b) a nucleic acid sequence encoding a first interleukin 2 (IL-2) leader sequence fused in frame to a coding sequence for an anti-hVEGF Fab heavy immunoglobulin chain, a linker, and a nucleic acid sequence encoding a second IL-2 leader sequence fused in frame to a coding sequence for an anti-VEGF Fab light immunoglobulin chain, wherein the coding sequences are operably linked to regulatory elements which direct expression of the anti-h VEGF Fab in the eye, and wherein the encoded anti-hVEGF Fab comprises a heavy chain variable region having amino acid 1 to amino acid 123 of SEQ ID NO: 1 and further comprises a light chain variable region having amino acid 1 to amino acid 107 of SEQ ID NO: 2; (c) regulatory elements operably linked to the heavy and light immunoglobulin chains of the anti-hVEGF Fab which comprise a chicken beta-actin promoter; and (d) a second AAV ITR, wherein said single dose comprises greater than 6.0×10 10 Genome Copies (GC) of the rAAV per eye.

22 . The method of claim 21 , wherein the patient is injected subretinally.

23 . The method of claim 21 , wherein the patient has neovascular age-related macular degeneration (nAMD), diabetic retinopathy (DR), or diabetic macular edema (DME).

24 . A method for treating neovascular age-related macular degeneration (nAMD) for at least a 12-month period in the absence of adverse drug-related ocular events with a single dose per eye, the method comprising injecting a single dose per treated eye of a human patient, said single dose being a liquid suspension comprising an aqueous liquid and a recombinant adeno-associated virus (rAAV) having an AAV8 capsid, wherein the rAAV comprises a vector genome in the capsid, said vector genome comprising:
(a) a first AAV inverted terminal repeat (ITR); (b) a nucleic acid sequence comprising regulatory elements operably linked to a nucleic acid sequence encoding a heavy immunoglobulin chain of an anti-hVEGF antigen binding fragment (Fab) having an interleukin 2 (IL-2) leader sequence, a self-cleaving furin (F)/F2A linker, and a light immunoglobu

Assignees

• Univ Pennsylvania
• Regenxbio Inc
• Regenx Bio Inc

Inventors

• Wilson James M
• Yoo Stephen
• Van Everen Sherri
• Bennett Jean
• Maguire Albert M
• Aleman Tomas Santiago
• Marshall Tristan James
• Tretiakova Anna

Classifications

• A61K48/0075 Primary

  characterised by an aspect of the delivery route, e.g. oral, subcutaneous · CPC title

• C12N2750/14145

  Special targeting system for viral vectors · CPC title

• C12N2750/14143

  viral genome or elements thereof as genetic vector · CPC title

• C12N15/86

  Viral vectors · CPC title

• C07K2317/55

  Fab or Fab' · CPC title