Treatment of diabetic retinopathy with fully-human post-translationally modified anti-vegf fab

Patent metadata

Field	Value
Publication number	US-2022280608-A1
Application number	US-202017638517-A
Country	US
Kind code	A1
Filing date	Aug 25, 2020
Priority date	Aug 26, 2019
Publication date	Sep 8, 2022
Grant date	—

Abstract

Compositions and methods are described for the delivery of a fully human post-translaionally modified (HuPTM) monoclonal antibody (“mAh”) or the antigen-binding fragment of a mAh against human vascular endothelial growth factor (“hVEGF”)—such as, e.g., a fully human-glycosylated (HuGly) anti-hVEGF antigen-binding fragment—to the retina/vitreal humour in the eye(s) of human subjects diagnosed with diabetic retinopathy.

First claim

What is claimed:

1 . A method of treating a human subject diagnosed with diabetic retinopathy (DR), comprising administering to the subretinal space in the eye of said human subject an expression vector encoding an anti-human vascular endothelial growth factor (hVEGF) antibody, wherein the expression vector is administered via subretinal delivery in a single dose about 1.6×10 11 GC/eye at a concentration of 6.2×10 11 GC/mL or about 2.5×10 11 GC/eye at a concentration of 1.0×10 12 GC/mL, wherein the anti-hVEGF antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO. 2 or SEQ ID NO. 4, and a light chain comprising the amino acid sequence of SEQ ID NO. 1, or SEQ ID NO. 3; and wherein the expression vector is an AAV8 vector.

2 . The method of claim 1 , wherein the administering is by injecting the expression vector into the subretinal space using a subretinal drug delivery device.

3 . The method of any one of claims 1 - 2 , wherein the administering delivers a therapeutically effective amount of the anti-hVEGF antibody to the retina of said human subject.

4 . The method of claim 3 , wherein the therapeutically effective amount of the anti-hVEGF antibody is produced by human retinal cells of said human subject.

5 . The method of claim 4 , wherein the therapeutically effective amount of the anti-hVEGF antibody is produced by human photoreceptor cells, horizontal cells, bipolar cells, amacrine cells, retina ganglion cells, and/or retinal pigment epithelial cells in the external limiting membrane of said human subject.

6 . The method of claim 5 , wherein the human photoreceptor cells are cone cells and/or rod cells.

7 . The method of claim 6 , wherein the retina ganglion cells are midget cells, parasol cells, bistratified cells, giant retina ganglion cells, photosensitive ganglion cells, and/or Müllner glia.

8 . The method of any one of claims 1 - 7 , wherein the expression vector comprises the CB7 promoter.

9 . The method of claim 8 , wherein the expression vector is Construct II.

10 . A single dose composition comprising 1.6×10 11 GC at a concentration of 6.2×10 11 GC/mL or 2.5×10 11 GC at a concentration of 1.0×10 12 GC/mL of an expression vector encoding an anti-human vascular endothelial growth factor (hVEGF) antibody in a formulation buffer (pH=7.4), wherein the formulation buffer comprises Dulbecco's phosphate buffered saline and 0.001% Pluronic F68, wherein the anti-hVEGF antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO. 2 or SEQ ID NO. 4, and a light chain comprising the amino acid sequence of SEQ ID NO. 1, or SEQ ID NO. 3; and wherein the wherein the expression vector is an AAV8 vector.

11 . The composition of claim 10 , wherein the expression vector is Construct II.

12 . The method of any one of claims 1 - 9 , which further comprises, after the administering step, a step of monitoring the post ocular injection thermal profile of the injected material in the eye using an infrared thermal camera.

13 . The method of claim 12 , wherein the infrared thermal camera is a FLIR T530 infrared thermal camera.

14 . A method of treating a human subject diagnosed with DR, comprising administering to the subretinal space in the eye of said human subject an expression vector encoding an anti-human vascular endothelial growth factor (hVEGF) antibody, wherein about 2.5×10 11 genome copies per eye of the expression vector are administered by double suprachoroidal injections, wherein the anti-hVEGF antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO. 2 or SEQ ID NO. 4, and a light chain comprising the amino acid sequence of SEQ ID NO. 1, or SEQ ID NO. 3; and wherein the expression vector is an AAV8 vector.

15 . A method of treating a human subject diagnosed with DR, comprising administering to the subretinal space in the eye of said human subject an expression vector encoding an anti-human vascular endothelial growth factor (hVEGF) antibody, wherein about 5.0×10 11 genome copies per eye of the expression vector are administered by double suprachoroidal injections, wherein the anti-hVEGF antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO. 2 or SEQ ID NO. 4, and a light chain comprising the amino acid sequence of SEQ ID NO. 1, or SEQ ID NO. 3; and wherein the expression vector is an AAV8 vector.

16 . The method of any one of claims 14 - 15 , wherein the administering delivers a therapeutically effective amount of the anti-hVEGF antibody to the retina of said human subject.

17 . The method of claim 16 , wherein the therapeutically effective amount of the anti-hVEGF antibody is produced by human retinal cells of said human subject.

18 . The method of claim 17 , wherein the therapeutically effective amount of the anti-hVEGF antibody is produced by human photoreceptor cells, horizontal cells, bipolar cells, amacrine cells, retina ganglion cells, and/or retinal pigment epithelial cells in the external limiting membrane of said human subject.

19 . The method of claim 18 , wherein the human photoreceptor cells are cone cells and/or rod cells.

20 . The method of claim 19 , wherein the retina ganglion cells are midget cells, parasol cells, bistratified cells, giant retina ganglion cells, photosensitive ganglion cells, and/or Múller glia.

21 . The method of any one of claims 14 - 20 , wherein the expression vector comprises the CB7 promoter.

22 . The method of claim 21 , wherein the expression vector is Construct II.

23 . The method of any one of claims 14 - 22 , which further comprises, after the administering step, a step of monitoring the post ocular injection thermal profile of the injected material in the eye using an infrared thermal camera.

24 . The method of claim 23 , wherein the infrared thermal camera is a FLIR T530 infrared thermal camera.

25 . A single dose composition comprising about 6.0×10 10 genome copies per eye, 1.6×10 11 genome copies per eye, 2.5×10 11 genome copies per eye, 5.0×10 11 genome copies per eye, or 3.0×10 12 genome copies per eye of an expression vector encoding an anti-human vascular endothelial growth factor (hVEGF) antibody in a formulation buffer (pH=7.4), wherein the formulation buffer comprises Dulbecco's phosphate buffered saline and 0.0001% Pluronic F68, wherein the anti-hVEGF antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO. 2 or SEQ ID NO. 4, and a light chain comprising the amino acid sequence of SEQ ID NO. 1, or SEQ ID NO. 3; and wherein the wherein the expression vector is an AAV8 vector.

26 . The composition of claim 25 , wherein the expression vector is Construct II.

27 . The method of any one of claims 1 - 9 and 12 - 24 , wherein the method does not result in shedding of the expression vector.

28 . The method of any one of claims 1 - 9 and 12 - 24 , wherein less than 1000, less than 500, less than 100, less than 50 or less than 10 expression vector gene copies/5 μL are detectable by quantitative polymerase chain reaction in a biological fluid at any point after administration.

29 . The method of any one of claims 1 - 9 and 12 - 24 , wherein 210 expression vector gene copies/5 μL or less are detectable by quantitative polymerase chain reaction in a biological fluid at any point after administration.

Assignees

• Regenxbio Inc

Inventors

• Pakola Stephen Joseph
• Van Everen Sherri
• Yoo Jesse I
• Patel Samir Maganbhai
• Ghanekar Avanti Arvind
• O'Berry Anthony Ray
• Irwin-Pack Kim Rees
• Curtiss Darin Thomas

Classifications

• C07K2317/55

  Fab or Fab' · CPC title

• A61P27/02 Primary

  Ophthalmic agents · CPC title

• C07K16/22 Primary

  against growth factors {; against growth regulators} · CPC title

• C12N2750/14143

  viral genome or elements thereof as genetic vector · CPC title

• A61B5/01

  Measuring temperature of body parts {; Diagnostic temperature sensing, e.g. for malignant or inflamed tissue} (clinical contact thermometers G01K13/20) · CPC title