Therapeutic CD47 antibodies
Provided are anti-CD47 monoclonal antibodies (anti-CD47 mAbs) with distinct functional profiles as described herein, methods to generate anti-CD47 mAbs, and to methods of using these anti-CD47 mAbs as therapeutics for the prevention and treatment of solid and hematological cancers, ischemia-reperfusion injury, cardiovascular diseases, autoimmune diseases, inflammatory diseases or as diagnostics for determining the level of CD47 in tissue samples.
1. A method of treating multiple myeloma, ovarian cancer, endometrial cancer, prostate cancer, non-small cell lung cancer, thyroid cancer, gastric cancer, and head and neck cancer in a subject in need thereof, comprising administering to the subject an effective amount of a monoclonal antibody or antigen-binding fragment thereof that specifically binds CD47 and comprises a heavy chain variable domain (V H ) and a light chain variable domain (V L ) chosen from:
i. a heavy chain variable domain (V H ) comprising the amino acid sequence of SEQ ID NO:38 and a light chain variable domain (V L ) comprising the amino acid sequence SEQ ID NO:51;
ii. a heavy chain variable domain (V H ) comprising the amino acid sequence of SEQ ID NO:39 and a light chain variable domain (V L ) comprising the amino acid sequence SEQ ID NO:51;
iii. a heavy chain variable domain (V H ) comprising the amino acid sequence of SEQ ID NO:36 and a light chain variable domain (V L ) comprising the amino acid sequence SEQ ID NO:52;
iv. a heavy chain variable domain (V H ) comprising the amino acid sequence of SEQ ID NO:38 and a light chain variable domain (V L ) comprising the amino acid sequence SEQ ID NO:52;
v. a heavy chain variable domain (V H ) comprising the amino acid sequence of SEQ ID NO:39 and a light chain variable domain (V L ) comprising the amino acid sequence SEQ ID NO:52;
vi. a heavy chain variable domain (V H ) comprising the amino acid sequence of SEQ ID NO:40 and a light chain variable domain (V L ) comprising the amino acid sequence SEQ ID NO:52; wherein
said multiple myeloma, ovarian cancer, endometrial cancer, prostate cancer, non-small cell lung cancer, thyroid cancer, gastric cancer, and head and neck cancer express CD47.
2. The method of claim 1 , wherein the monoclonal antibody or antigen-binding fragment thereof further comprises an IgG isotype selected from IgG1, IgG1-N297Q, IgG2, IgG4, IgG4 S228P, and IgG4 PE (S228P/L235E).
3. The method of claim 1 , wherein the monoclonal antibody or antigen fragment thereof further comprises one heavy chain and one light chain chosen from:
i. a heavy chain comprising the amino acid sequence of SEQ ID NO:80 and a light chain comprising the amino acid sequence SEQ ID NO:73;
ii. a heavy chain comprising the amino acid sequence of SEQ ID NO:81 and a light chain comprising the amino acid sequence SEQ ID NO:73;
iii. a heavy chain comprising the amino acid sequence of SEQ ID NO:79 and a light chain comprising the amino acid sequence SEQ ID NO:70;
iv. a heavy chain comprising the amino acid sequence of SEQ ID NO:80 and a light chain comprising the amino acid sequence SEQ ID NO:70;
v. a heavy chain comprising the amino acid sequence of SEQ ID NO:81 and a light chain comprising the amino acid sequence SEQ ID NO:70; and
vi. a heavy chain comprising the amino acid sequence of SEQ ID NO:87 and a light chain comprising the amino acid sequence SEQ ID NO:70.
4. The method of claim 3 , wherein the monoclonal antibody or antigen-fragment thereof is administered in combination with a pharmaceutically or physiologically acceptable carrier, diluent, or excipient.
5. The method of claim 3 , wherein the monoclonal antibody or antigen-binding fragment thereof is administered intravenously.
6. The method of claim 3 , wherein the monoclonal antibody or antigen-binding fragment thereof is administered subcutaneously.
7. The method of claim 3 , wherein the method is treating multiple myeloma.
8. The method of claim 3 , wherein the method is treating ovarian cancer.
9. The method of claim 3 , wherein the method is treating endometrial cancer.
10. The method of claim 3 , wherein the method is treating prostate cancer.
11. The method of claim 3 , wherein the method is treating non-small cell lung cancer.
12. The method of claim 3 , wherein the method is treating gastric cancer.
13. The method of claim 3 , wherein the monoclonal antibody or antigen-binding fragment thereof, is administered in combination with a chemotherapeutic agent or a therapeutic antibody.