Methods of treating gastrointestinal immune-related adverse events in immune oncology treatments

Patent metadata

Field	Value
Publication number	US-12590157-B2
Application number	US-202318355975-A
Country	US
Kind code	B2
Filing date	Jul 20, 2023
Priority date	Mar 24, 2016
Publication date	Mar 31, 2026
Grant date	Mar 31, 2026

Abstract

The invention provides, inter alia, methods of reducing gastrointestinal immune-related adverse events, such as colitis and diarrhea, in subjects undergoing an immune treatment, such as an immune oncology treatment, such as anti-CTLA4 antibody and anti-PD-1 antibody combination treatment for melanoma. In certain aspects, the methods encompass administering a therapeutically effective amount of a polypeptide that inhibits MAdCAM-integrin binding, such as an anti-α4β7 integrin antibody, such vedolizumab or a related antibody.

First claim

The invention claimed is:

1 . A method of treating a gastrointestinal immune-related adverse event (gi-irAE) in a human subject undergoing an immune oncology treatment comprising treatment with an anti-CTLA4 antibody and an anti-PD-1 antibody, said method comprising administering a therapeutically effective amount of a humanized anti-α4β7 integrin antibody to the human subject, such that the gi-irAE is treated,
wherein the human subject has non-small cell lung cancer and is undergoing concurrent immune oncology treatment comprising treatment with an anti-CTLA4 antibody and an anti-PD-1 antibody,
wherein the humanized anti-α4β7 integrin antibody is administered in response to symptoms of a gi-riAE comprising Grade 3 or 4 diarrhea,
wherein the anti-α4β7 integrin antibody is an IgG1 antibody and comprises the complementarity determining regions (CDRs):
Light chain: CDR1 SEQ ID NO:7
CDR2 SEQ ID NO:8 and
CDR3 SEQ ID NO:9; and

Heavy chain: CDR1 SEQ ID NO:4
CDR2 SEQ ID NO:5 and
CDR3 SEQ ID NO:6, and

wherein the subject exhibits no significant reduction of efficacy of the immune oncology treatment after administration of the anti-α4β7 integrin antibody.

2 . The method of claim 1 , wherein the anti-α4β7 integrin antibody comprises the heavy chain variable region of SEQ ID NO:1 and the light chain variable region of SEQ ID NO:2 or SEQ ID NO:3.

3 . The method of claim 1 , wherein the anti-PD-1 antibody is nivolumab.

4 . The method of claim 1 , wherein the anti-CTLA4 antibody is ipilimumab.

5 . The method of claim 1 , wherein the anti-α4β7 integrin antibody is administered to achieve a serum concentration of about: 10 μg/ml, or more.

6 . The method of claim 1 , wherein the anti-α4β7 integrin antibody is administered at a unit dose of about: 108, 150, 165, 200, 216, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750 mg, or more.

7 . The method of claim 1 , wherein, following at least one administration of the anti-α4β7 integrin:
the anti-PD-1 antibody is administered every two weeks; or
the anti-CTLA4 antibody is administered every three weeks concurrently with the anti-PD-1 antibody; or
the anti-CTLA4 antibody is administered every three weeks concurrently with the anti-PD-1 antibody, wherein following four administrations of the anti-CTLA4 antibody, no further anti-CTLA4 antibody is administered and the anti-PD-1 antibody is administered every two weeks.

8 . The method of claim 1 , wherein, relative to a suitable control undergoing an immune oncology treatment, but does not receive the anti-α4β7 integrin antibody, the subject exhibits one or more of: increased compliance, increased efficacy of the immune oncology treatment, reduced grade of gi-irAE, reduced duration of gi-irAE, reducing or eliminating the use of: corticosteroids, antibiotics, non-corticosteroid immunosuppressive medication, lower endoscopy, hospitalizations, or a combination thereof.

9 . The method of claim 1 , wherein the anti-α4β7 integrin antibody is vedolizumab.

10 . The method of claim 5 , wherein the serum concentration of the anti-α4β7 integrin antibody is about 11 μg/ml, 12 μg/ml, 13 μg/ml, 14 μg/ml, 15 μg/ml, 16 μg/ml, 17 μg/ml, 18 μg/ml, 19 μg/ml, 20 μg/ml, 25 μg/ml, 30 μg/ml, 35 μg/ml, 40 μg/ml, 45 μg/ml, 50 μg/ml, or more.

11 . The method of claim 8 , wherein increased compliance comprises reduced incidence of discontinuation or dose reduction, higher rate of treatment completion, and/or longer treatment duration.

12 . The method of claim 1 , wherein the gi-irAE further comprises colitis.

13 . The method of claim 1 , wherein the anti-PD1 antibody is pembrolizumab.

Assignees

• Takeda Pharmaceuticals Co

Inventors

• Brake Rachael L
• Westin Eric H

Classifications

• C07K2317/565

  Complementarity determining region [CDR] · CPC title

• C07K16/2878

  against the NGF-receptor/TNF-receptor superfamily, e.g. CD27, CD30, CD40, CD95 · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P37/06

  Immunosuppressants, e.g. drugs for graft rejection · CPC title

• C07K16/2803 Primary

  against the immunoglobulin superfamily · CPC title