Compositions and methods for preventing or reversing t-cell exhaustion through ectonucleotidase inhibition and antibody-mediated target cytosis

Patent metadata

Field	Value
Publication number	US-12559564-B2
Application number	US-201917251507-A
Country	US
Kind code	B2
Filing date	Jun 14, 2019
Priority date	Jun 14, 2018
Publication date	Feb 24, 2026
Grant date	Feb 24, 2026

Abstract

In combination with conventional therapies (e.g., targeted therapy, chemotherapy, and angiogenesis inhibitors etc.), immunotherapies targeting checkpoint molecules have shown promise in the treatment of solid or liquid tumors. However, apoptotic regulatory T cells (Treg) induced by such therapies often become more suppressive in the tumor microenvironment (TME), through increased generation of adenosine tightly controlled by ectonucleotidases, viz. CD39 and CD73. CD39/ENTPD1, a novel checkpoint molecule, is highly expressed and activated on the tumor vasculature and infiltrating immune cells, promoting tumor growth. Deletion or blockade of CD39 enhances anti-tumor activity by augmenting anti-tumor immune responses and inhibiting tumor angiogenesis. The present invention is based at least in part on the development of anti-CD39 antibodies which mediate CD39 downregulation on immune cells, such as T-cells with markers of T-cell exhaustion, and the demonstrated utility of these antibodies in blocking tumor growth with minimal side effects in pre-clinical models.

First claim

The invention claimed is:

1 . A method for promoting an anti-tumor immune response in a human patient having a tumor with vascular endothelia and/or immune cells that overexpress cluster of differentiation 39 (CD39), the method comprising administering to the human patient with a tumor a hypofucosylated or afucosylated humanized anti-CD39 antibody or antigen-binding fragment thereof wherein the antibody or antigen-binding fragment thereof comprises an Fc domain that binds FcγRIIIa, wherein the antibody or antigen-binding fragment thereof retains antibody-dependent cellular cytotoxicity (ADCC), and wherein administration of the antibody to the human patient results in a reduction of CD39 expression on the immune cells and/or in the vascular endothelia in the tumor;
wherein the anti-CD39 antibody or antigen-binding fragment thereof comprises:
(a) a heavy chain variable region comprising the complementarity determining regions (CDRs) of SEQ ID NO: 2 and a light chain variable region comprising the CDRs of SEQ ID NO: 1;
(b) a heavy chain variable region comprising the CDRs of SEQ ID NO: 3 and a light chain variable region comprising the CDRs of SEQ ID NO: 4;
(c) a heavy chain variable region comprising the CDRs of SEQ ID NO: 5 and a light chain variable region comprising the CDRs of SEQ ID NO: 6;
(d) a heavy chain variable region comprising the CDRs of SEQ ID NO: 7 and a light chain variable region comprising the CDRs of SEQ ID NO: 8;
(e) a heavy chain variable region comprising the CDRs of SEQ ID NO: 9 and a light chain variable region comprising the CDRs of SEQ ID NO: 10; or
(f) a heavy chain variable region comprising the CDRs of SEQ ID NO: 11 and a light chain variable region comprising the CDRs of SEQ ID NO: 12; wherein the CDRs are determined according to the Kabat numbering scheme.

2 . The method of claim 1 , wherein:
(a) the anti-CD39 antibody or antigen-binding fragment thereof (i) causes antibody-mediated target depletion cytosis of CD39 on CD45+ the immune cells, wherein the immune cells are CD45+ immune cells, (ii) causes antibody-mediated target depletion cytosis of CD39 from tumor the vascular endothelia of the tumor endothelium disruption; or (iii) or collapses the vasculature network in the tumor; or (b) the anti-CD39 antibody or antigen-binding fragment thereof is an IgG1 or IgG3 isotype.

3 . The method of claim 1 , wherein the tumor is a solid tumor.

4 . The method of claim 3 , wherein the solid tumor is pancreatic cancer, liver cancer, lung cancer, stomach cancer, esophageal cancer, head and neck squamous cell carcinoma, prostate cancer, colon cancer, breast cancer, lymphoma, gallbladder cancer, renal cancer, multiple myeloma, ovarian cancer, cervical cancer or glioma.

5 . The method of claim 1 wherein the tumor is a liquid tumor.

6 . The method of claim 5 , wherein the liquid tumor is leukemia.

Assignees

• Beth Israel Deaconess Medical Ct Inc
• Antagen Institute For Biomedical Res

Inventors

• Robson Simon C
• Shang Yan Wu
• Gao Wenda
• Zhang Haohai
• De Andrade Mello Paola

Classifications

• C07K2317/732

  Antibody-dependent cellular cytotoxicity [ADCC] · CPC title

• C07K2317/565

  Complementarity determining region [CDR] · CPC title

• C07K2317/41

  Glycosylation, sialylation, or fucosylation · CPC title

• C07K2317/31

  multispecific · CPC title

• C07K2317/24

  containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered · CPC title