HIGH-AFFINITY, ISOFORM-SELECTIVE TGFß1 INHIBITORS AND USE THEREOF

Patent metadata

Field	Value
Publication number	US-2021122814-A1
Application number	US-201917258771-A
Country	US
Kind code	A1
Filing date	Jul 11, 2019
Priority date	Jul 11, 2018
Publication date	Apr 29, 2021
Grant date	—

Abstract

Disclosed herein are monoclonal antibodies and antigen-binding fragments thereof capable of selectively inhibiting TGFβ1 with high potency. Related compositions, methods and therapeutic use are also disclosed.

First claim

1 . An antibody or an antigen-binding fragment thereof that binds each of the following antigen complexes with a KD of ≥10 nM, as measured by a solution equilibrium titration-based assay:
i) human LTBP1-proTGFβ1;
ii) human LTBP3-proTGFβ1;
iii) human GARP-proTGFβ1; and,
iv) human LRRC33-proTGFβ1;
wherein the antibody or the fragment thereof is a fully human or humanized antibody or fragment thereof, wherein optionally, the antibody or the fragment binds with a KD ≤1 nM.

2 . The antibody or the antigen-binding fragment thereof of claim 1 , which binds the Latency Lasso of the complexes, wherein optionally, the antibody or the antigen-binding fragment thereof further binds a portion of the growth factor domain.

3 . The antibody or the antigen-binding fragment thereof of claim 1 or 2 , which is of human IgG4 or IgG1 subtype.

4 . A composition comprising the antibody, or the antigen-binding fragment thereof, of any one of the preceding claims, and an excipient.

5 . The antibody or the antigen-binding fragment thereof according to claims 1 - 3 , or the composition according to claim 4 , for use in the treatment of a TGFβ1 indication in a subject.

6 . The antibody or the antigen-binding fragment thereof, or composition for use according to claim 5 , wherein the TGFβ1 indication is cancer.

7 . The antibody or the antigen-binding fragment thereof, or composition for use according to claim 5 , wherein the TGFβ1 indication is myelofibrosis.

8 . The antibody or the antigen-binding fragment thereof, or composition for use according to claim 6 , wherein the subject is poorly responsive to a cancer therapy, wherein optionally the cancer therapy is checkpoint inhibition therapy, chemotherapy and/or radiation therapy.

9 . The antibody or the antigen-binding fragment thereof, or composition for use according to claim 8 , wherein the treatment comprises administration of the composition of claim 4 , in conjunction with additional cancer therapy, selected from the group consisting of checkpoint inhibitor, chemotherapy and radiation therapy and/or cancer vaccine.

10 . A method for screening an isoform-selective TGFβ1 inhibitor suitable for therapeutic use, the method comprising:
i) providing an antibody that specifically binds each of: human LTBP1-proTGFβ1, human LTBP3-proTGFβ1, human GARP-proTGFβ1 and human LRRC33-proTGFβ1 complexes with a KD ≤1 nM,
ii) carrying out an in vivo efficacy study to determine an amount of the antibody effective to achieve efficacy in a preclinical model comprising TGFβ1-biased expression;
iii) carrying out a toxicology study in a preclinical model known to be sensitive to TGFβ inhibition, to determine a maximally tolerated and/or minimum toxic amount of the antibody; and,
iv) based on steps (ii) and (iii), selecting the antibody as a therapeutic candidate if a sufficient therapeutic window is obtained.

11 . The method according to claim 10 , wherein the amount effective to achieve efficacy of step (ii) is between about 1 and 30 mg/kg.

12 . The method according to claim 10 , wherein the maximally tolerated amount or minimum toxic amount of step (iii) is at least 100 mg/kg.

13 . The method of any one of claims 10 - 12 , wherein the therapeutic window is at least six-fold.

14 . A method for manufacturing a pharmaceutical composition comprising:
i) providing an antibody selected by the method according to any one of claims 10 - 13 ; ii) formulating the antibody into a pharmaceutical composition comprising an isoform-selective TGFβ1 inhibitor.

Assignees

• Scholar Rock Inc

Inventors

• Datta Abhishek
• Capili Allan
• Schurpf Thomas
• Martin Constance
• Dagbay Kevin B
• Chapron Christopher
• Wawersik Stefan
• Littlefield Christopher
• Carven Gregory J
• Buckler Alan
• Lin Susan
• Jackson Justin W
• Stein Caitlin
• Avery Andrew
• Cooper Anthony
• Salotto Matthew

Classifications

• A61K2039/505

  comprising antibodies · CPC title

• G01N33/53

  Immunoassay; Biospecific binding assay; Materials therefor · CPC title

• A61K2039/70

  Multivalent vaccine · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• G01N2500/00

  Screening for compounds of potential therapeutic value · CPC title