Immune modulation and treatment of solid tumors with antibodies that specifically bind CD38

Patent metadata

Field	Value
Publication number	US-11021543-B2
Application number	US-201816162355-A
Country	US
Kind code	B2
Filing date	Oct 16, 2018
Priority date	Jun 24, 2015
Publication date	Jun 1, 2021
Grant date	Jun 1, 2021

Abstract

The present invention relates to methods of immunomodulation and treating patients having solid tumors with antibodies that specifically bind CD38.

First claim

We claim:

1. A method of treating a patient having a solid tumor, comprising administering to the patient in need thereof a therapeutically effective amount of an antibody that specifically binds CD38 for a time sufficient to treat the solid tumor, wherein the solid tumor lacks detectable CD38 expression, and wherein the antibody comprises a heavy chain complementarity determining region (HCDR) 1, a HCDR2, a HCDR3 amino acid sequences of SEQ ID NOs: 6, 7 and 8, respectively, and a light chain complementarity determining region (LCDR) 1, a LCDR2 and a LCDR3 amino acid sequences of SEQ ID NOs: 9, 10 and 11, respectively.

2. The method of claim 1 , wherein the solid tumor is a melanoma, a lung cancer, a squamous non-small cell lung cancer (NSCLC), a non-squamous NSCLC, a colorectal cancer, a prostate cancer, a castration-resistant prostate cancer, a stomach cancer, an ovarian cancer, a gastric cancer, a liver cancer, a pancreatic cancer, a thyroid cancer, a squamous cell carcinoma of the head and neck, a carcinoma of the esophagus or gastrointestinal tract, a breast cancer, a fallopian tube cancer, a brain cancer, an urethral cancer, a genitourinary cancer, a cervical cancer or a metastatic lesion of the cancer.

3. The method of claim 1 , wherein the antibody that specifically binds CD38 comprises a heavy chain variable region (VH) amino acid sequence of SEQ ID NO: 4 and a light chain variable region (VL) amino acid sequence of SEQ ID NO: 5.

4. The method of claim 1 , wherein the antibody that specifically binds CD38 is administered in combination with a second therapeutic agent.

5. The method of claim 4 , wherein the second therapeutic agent is
a) a chemotherapeutic agent, a targeted anti-cancer therapy, a standard of care drug for treatment of solid tumor, or an immune checkpoint inhibitor;
b) an anti-PD-1 antibody;
c) an anti-PD-1 antibody comprising
i) the heavy chain variable region (VH) of SEQ ID NO: 22 and the light chain variable region (VL) of SEQ ID NO: 23;
ii) the VH of SEQ ID NO: 24 and the VL of SEQ ID NO: 25;
iii) the VH of SEQ ID NO: 32 and the VL of SEQ ID NO: 33; or
iv) the VH of SEQ ID NO: 34 and the VL of SEQ ID NO:35;

d) an anti-PD-L1 antibody;
e) an anti-PD-L1 antibody comprising
i) the VH of SEQ ID NO: 26 and the VL of SEQ ID NO: 27;
ii) the VH of SEQ ID NO: 28 and the VL of SEQ ID NO: 29; or
iii) the VH of SEQ ID NO: 30 and the VL of SEQ ID NO: 31;

f) an anti-PD-L2 antibody;
g) an anti-LAG3 antibody;
h) an anti-TIM-3 antibody;
i) an anti-TIM-3 antibody comprising
i) the VH of SEQ ID NO: 36 and the VL of SEQ ID NO: 37; or
ii) the VH of SEQ ID NO: 38 and the VL of SEQ ID NO: 39;

j) an anti-CTLA-4 antibody;
k) radiation therapy; or
l) surgery.

6. The method of claim 4 , wherein the antibody that specifically binds CD38 and the second therapeutic agent are administered simultaneously.

7. The method of claim 1 , wherein the antibody that specifically binds CD38 is administered subcutaneously in a pharmaceutical composition comprising the antibody that specifically binds CD38 and a hyaluronidase.

8. The method of claim 1 , wherein the antibody that specifically binds CD38 is administered intravenously in a pharmaceutical composition.

9. The method of claim 4 , wherein the antibody that specifically binds CD38 and the second therapeutic agent are administered sequentially or separately.

10. The method of claim 1 , wherein the antibody that specifically binds CD38 elicits an immune response in the patient that is an effector T cell (Teff) response mediated by CD8 + T cells.

11. The method of claim 1 , wherein the antibody that specifically binds CD38 increases the number of CD8 + T cells, increases CD8 + T cell proliferation, increases T cell clonal expansion, increases CD8 + memory cell formation, increases antigen-dependent antibody production, increases cytokine production, increases chemokine production or increases interleukin production.

12. The method of claim 1 , wherein the antibody that specifically binds CD38
a) inhibits function of a regulatory T cell (Treg);
b) inhibits function of a CD3 + CD4 + CD25 + CD127 dim Treg;
c) inhibits function of a CD38 + Treg; or
d) kills the Treg by antibody-dependent cell cytotoxicity (ADCC).

13. The method of claim 1 , wherein the antibody that specifically binds CD38
a) inhibits function of a myeloid-derived suppressor cell (MDSC);
b) inhibits function of a CD11b + HLADR − CD14 − CD33 + CD15 + MDSC;
c) inhibits function of a CD38 + MDSC; or
d) kills the MDSC by ADCC.

14. The method of claim 1 , wherein the antibody that specifically binds CD38
a) inhibits function of a regulatory B cell (Breg);
b) inhibits function of a CD19 + CD24 + CD38 + Breg; or
c) kills the Breg by ADCC.

15. A method of suppressing activity of an immune suppressor cell in a patient having a solid tumor that lacks detectable CD38 expression, comprising administering to the patient a therapeutically effective amount of an antibody that specifically binds CD38, wherein the antibody comprises a heavy chain complementarity determining region (HCDR) 1, a HCDR2, a HCDR3 amino acid sequences of SEQ ID NOs: 6, 7 and 8, respectively, and a light chain complementarity determining region (LCDR) 1, a LCDR2 and a LCDR3 amino acid sequences of SEQ ID NOs: 9, 10 and 11, respectively.

16. The method of claim 15 , wherein
a) the immune suppressor cell is a regulatory T cell (Treg);
b) the immune suppressor cell is a CD3 + CD4 + CD25 + CD127 dim Treg;
c) the immune suppressor cell is a myeloid-derived suppressor cell (MDSC);
d) the immune suppressor cell is a CD11b + HLADR − CD14 − CD33 + CD15 + MDSC;
e) the immune suppressor cell is a regulatory B cell (Breg); or
f) the immune suppressor cell is a CD19 + CD24 + CD38 + Breg.

17. The method of claim 16 , wherein the antibody that specifically binds CD38 comprises a heavy chain variable region (VH) amino acid sequence of SEQ ID NO: 4 and a light chain variable region (VL) amino acid sequence of SEQ ID NO: 5.

18. A method of enhancing an immune response in a patient having a solid tumor that lacks detectable CD38 expression, comprising administering to the patient an antibody that specifically binds CD38, wherein the antibody comprises a heavy chain complementarity determining region (HCDR) 1, a HCDR2, a HCDR3 amino acid sequences of SEQ ID NOs: 6, 7 and 8, respectively, and a light chain complementarity determining region (LCDR) 1, a LCDR2 and a LCDR3 amino acid sequences of SEQ ID NOs: 9, 10 and 11, respectively.

19. The method of claim 18 , wherein the antibody that specifically binds CD38 comprises a heavy chain variable region (VH) amino acid sequence of SEQ ID NO: 4 and a light chain variable region (VL) amino acid sequence of SEQ ID NO: 5.

Assignees

• Janssen Biotech Inc

Inventors

• Ahmadi Tahamtan
• Casneuf Tineke
• Lokhorst Henk
• Mutis Tuna
• Sasser Amy
• Van De Donk Niels

Classifications

• A61K31/573

  substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone · CPC title

• A61K2039/505

  comprising antibodies · CPC title

• A61K38/47

  acting on glycosyl compounds (3.2), e.g. cellulases, lactases · CPC title

• C07K16/2896 Primary

  against molecules with a "CD"-designation, not provided for elsewhere · CPC title

• A61K31/454

  containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone · CPC title