Compositions for treatment of wet age-related macular degeneration
AssigneesThe Trustees of the University of Pennsylvania, Regenx Bio Inc
InventorsJames M. Wilson, Stephen Yoo, Sherri Van Everen, Jean Bennett, Albert M. Maguire, Tomas Santiago Aleman, Tristan James Marshall, Anna Tretiakova
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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.
Claims38
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 6.0×1010 Genome Copies (GC) of the rAAV per eye and less than 1.0×1012 GC of the rAAV per eye.
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 6.0×1010 Genome Copies (GC) of the rAAV per eye.
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 immunoglobulin chain of the anti-hVEGF Fab having an IL-2 leader sequence, wherein the heavy immunoglobulin chain comprises a variable region having amino acids 1 to amino acid 123 of SEQ ID NO:
- 1, and the light immunoglobulin chain comprises a light chain variable region comprising amino acid 1 to amino acid 107 of SEQ ID NO:
- 2, and wherein the regulatory elements comprise a chicken beta actin promoter and a rabbit beta globin polyadenylation (polyA) signal;
- and
- (c) a second AAV ITR.
A method for inhibiting human vascular endothelial growth factor (hVEGF) in an eye of a human patient, comprising administering a single dose of a recombinant adeno-associated virus (rAAV) to the eye, wherein the rAAV comprises a vector genome in an AAV8 capsid, and the vector genome comprises:
- (a) a 5′ AAV2 inverted terminal repeat (ITR);
- (b) an expression cassette comprising regulatory elements operably linked to a nucleic acid sequence which encodes a first interleukin 2 (IL-2) leader sequence, a heavy immunoglobulin chain of an anti-hVEGF antigen binding fragment (Fab), a self-cleaving furin (F)/F2A linker, a second IL-2 leader sequence and a light immunoglobulin chain of the anti-hVEGF Fab, wherein the regulatory elements comprises a cytomegalovirus immediate early (CMV IE) enhancer, a chicken beta actin promoter and a chicken beta actin intron, wherein the heavy immunoglobulin chain comprises SEQ ID NO:
- 1 and the light immunoglobulin chain comprises SEQ ID NO:
- 2, and wherein the expression cassette further comprises a rabbit beta globin polyadenylation (polyA) signal;
- and
- (c) a 3′ AAV2 ITR,
- wherein said single dose maintains effective expression of the anti-h VEGF Fab in the eye at 6-month, and is safe during 12 months, after said administration without additional dosing of the rAAV, and said single dose is effective in treating a retinal disease associated with hVEGF in said patient.
Dependencies are inferred from the claim text.