TGFβ1-binding immunoglobulins and use thereof

Patent metadata

Field	Value
Publication number	US-11643459-B2
Application number	US-201716083637-A
Country	US
Kind code	B2
Filing date	Mar 10, 2017
Priority date	Mar 11, 2016
Publication date	May 9, 2023
Grant date	May 9, 2023

Abstract

Disclosed herein are immunoglobulins, such as antibodies, and antigen binding portions thereof, that specifically bind complexes of GARP-TGFβ1, LTBP1-TGFβ1, LTBP3-TGFβ1, and/or LRRC33-TGFβ1. The application also provides methods of use of these immunoglobulins for, for example, inhibiting TGFβ1 activity, and treating subjects suffering from TGFβ1-related disorders, such as cancer and fibrosis.

First claim

What is claimed is:

1. A method for identifying a transforming growth factor beta 1 (TGFβ1)-specific inhibitor, wherein the TGFβ1-specific inhibitor is an antibody or antigen-binding fragment thereof, comprising:
(i) providing an antibody or antigen-binding fragment thereof and performing a binding assay to detect isoform-specific binding to TGFβ1 and not to TGFβ2 or TGFβ3;
(ii) contacting the antibody or antigen-binding fragment thereof with a TGFβ1 protein or a complex comprising TGFβ1 and determining relative changes in TGFβ1 activation in the presence and absence of the antibody or antigen-binding fragment thereof;
(iii) carrying out an in vivo efficacy study to assess therapeutic effectiveness of the antibody or antigen-binding fragment thereof in an animal model, wherein the inhibitor antibody or antigen-binding fragment thereof shows efficacy when administered at a dose of about 0.1 pg/kg to about 30 mg/kg:
(iv) carrying out an in vivo safety study to assess cardiovascular toxicity of the antibody or antigen-binding fragment thereof in an animal model, wherein the antibody or antigen-binding fragment thereof shows minimal or no cardiovascular toxicity when dosed at 100 mg/kg/week for four weeks, and wherein the cardiovascular toxicity comprises valvulopathy and/or hemorrhage in the heart;
thereby identifying the TGFβ1-specific inhibitor.

2. The method of claim 1 , wherein the animal model of step (iv) is a rat model.

3. The method of claim 1 , wherein the TGFβ1-specific inhibitor shows reduced toxicity as compared to a pan TGFβ inhibitor in the in vivo safety study.

4. The method of claim 1 , wherein the TGFβ1-specific inhibitor achieves reduced expression of at least one gene selected from the group consisting of: plasminogen activator inhibitor-1 (PAI-1), connective tissue growth factor (CTGF), monocyte chemotactic protein 1 (MCP-1), TGFB1, alpha-smooth muscle actin (α-SMA), Fibronectin-1, collagen type I alpha 1 (Col1a1) and collagen type III alpha 1 (Col3a1).

5. The method of claim 1 , wherein the animal model of step (iii) comprises a fibrotic model.

6. The method of claim 1 , wherein the animal model of step (ii) (iii) comprises a tumor model.

7. The method of claim 6 , wherein the in vivo efficacy study in the tumor model further comprises administration of a checkpoint inhibitor.

8. The method of claim 7 , wherein the checkpoint inhibitor is a PD-1 antagonist or a PD-L1 antagonist.

9. The method of claim 6 , wherein the tumor model is a desmoplastic tumor model.

10. The method of claim 1 , wherein the TGFβ1-specific inhibitor specifically binds a pro/latent complex of TGFβ1 but does not bind free mature TGFβ1 which is not associated with the pro/latent complex of TGFβ1.

11. The method of claim 10 , wherein the pro/latent complex comprises glycoprotein-A repetitions predominant protein (GARP), Leucine-Rich Repeat-Containing Protein 33 (LRRC33), latent TGF-beta binding protein 1 (LTBP1), or latent TGF-beta binding protein 3 (LTBP3).

12. The method of claim 1 , wherein the TGFβ1-specific inhibitor is a neutralizing antibody, or antigen-binding fragment thereof.

13. A pharmaceutical composition produced by the method of claim 1 .

14. The method of claim 1 , wherein the TGFβ1-specific inhibitor cross-competes with an antibody, or antigen-binding fragment thereof, comprising six complementarity determining regions (CDRs): CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3,
wherein CDRH1 comprises an amino acid sequence as set forth in SEQ ID NO: 1 or SEQ ID NO: 2,
wherein CDRH2 comprises an amino acid sequence as set forth in SEQ ID NO :3 or SEQ ID NO:4,
wherein CDRH3 comprises an amino acid sequence as set forth in SEQ ID NO: 5 or SEQ ID NO: 6,
wherein CDRL1 comprises an amino acid sequence as set forth in SEQ ID NO: 7 or SEQ ID NO: 8,
wherein CDRL2 comprises an amino acid sequence as set forth in SEQ ID NO: 9 or SEQ ID NO: 10,
wherein CDRL3 comprises an amino acid sequence as set forth in SEQ ID NO: 11 or SEQ ID NO: 12.

15. The method of claim 1 , further comprising a step of:
selecting an antibody, or antigen-binding fragment thereof, that cross-competes with an antibody, or antigen-binding fragment thereof, comprising six complementarity determining regions (CDRs): CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3,
wherein CDRH1 comprises an amino acid sequence as set forth in SEQ ID NO: 2,
wherein CDRH2 comprises an amino acid sequence as set forth in SEQ ID NO: 4,
wherein CDRH3 comprises an amino acid sequence as set forth in SEQ ID NO: 6,
wherein CDRL1 comprises an amino acid sequence as set forth in SEQ ID NO: 8,
wherein CDRL2 comprises an amino acid sequence as set forth in SEQ ID NO: 10,
wherein CDRL3 comprises an amino acid sequence as set forth in SEQ ID NO: 12.

Assignees

• Scholar Rock Inc

Inventors

• Schurpf Thomas
• Carven Gregory J
• Datta Abhishek
• Long Kimberly

Classifications

• A61P21/00

  Drugs for disorders of the muscular or neuromuscular system · CPC title

• C07K16/22 Primary

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

• A61K2039/505

  comprising antibodies · CPC title

• A61P13/12

  of the kidneys · CPC title

• C07K2317/92

  Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value · CPC title