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 monoclonal antibody or antigen-binding fragment thereof that specifically binds CD47 and comprises:
a variable heavy chain CDR1 amino acid sequence (HCDR1) amino acid sequence set forth in SEQ ID NO:3;
a variable heavy chain CDR2 amino acid sequence (HCDR2) amino acid sequence set forth in SEQ ID NO:6;
a variable heavy chain CDR3 amino acid sequence (HCDR3) amino acid sequence set forth in SEQ ID NO:10;
a variable light chain CDR1 amino acid sequence (LCDR1) amino acid sequence set forth in SEQ ID NO:14;
a variable light chain CDR2 amino acid sequence (LCDR2) amino acid sequence set forth in SEQ ID NO:17; and
a variable light chain CDR3 amino acid sequence (LCDR3) amino acid sequence set forth in SEQ ID NO:18.
2. The monoclonal antibody or antigen-binding fragment thereof of claim 1 , wherein the monoclonal antibody, or antigen-binding fragment thereof is chimeric or humanized.
3. The monoclonal antibody or antigen-binding fragment thereof of claim 1 , wherein the monoclonal antibody, or antigen-binding fragment thereof specifically binds human CD47.
4. The monoclonal antibody or antigen-binding fragment thereof of claim 3 , wherein the monoclonal antibody, or antigen-binding fragment thereof specifically binds at least one of cynomolgus monkey, rat, or mouse CD47.
5. The monoclonal antibody or antigen-binding fragment thereof of claim 1 , further comprising a heavy chain variable domain (V H ) and a light chain variable domain (V L ), selected from:
(i) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO:36 and a light chain variable domain comprising the amino acid sequence SEQ ID NO:51;
(ii) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO:36 and a light chain variable domain comprising the amino acid sequence SEQ ID NO:52;
(iii) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO:37 and a light chain variable domain comprising the amino acid sequence SEQ ID NO:51;
(iv) a heavy chain variable domain comprising the amino acid sequence SEQ ID NO:37 and a light chain variable domain comprising the amino acid sequence SEQ ID NO:52;
(v) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO:38 and a light chain variable domain comprising the amino acid sequence SEQ ID NO:51; and
(vi) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO:38 and a light chain variable domain comprising the amino acid sequence SEQ ID NO:52.
6. The monoclonal antibody or antigen-binding fragment thereof of claim 5 , 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.
7. The monoclonal antibody or antigen binding fragment thereof of claim 5 , comprising one heavy chain and one light chain selected from:
(i) 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;
(ii) 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;
(iii) 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;
(iv) 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;
(v) 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:73;
(vi) 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.
8. The monoclonal antibody or antigen binding fragment thereof of claim 7 comprising 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.
9. A pharmaceutical composition, comprising the monoclonal antibody, or antigen-binding fragment thereof, of claim 1 , and a pharmaceutically or physiologically acceptable carrier, diluent, or excipient.
10. A pharmaceutical composition, comprising the monoclonal antibody, or antigen-binding fragment thereof, of claim 5 , and a pharmaceutically or physiologically acceptable carrier, diluent, or excipient.
11. A pharmaceutical composition, comprising the monoclonal antibody, or antigen-binding fragment thereof, of claim 6 , and a pharmaceutically or physiologically acceptable carrier, diluent, or excipient.
12. A pharmaceutical composition, comprising the monoclonal antibody, or antigen-binding fragment thereof, of claim 7 , and a pharmaceutically or physiologically acceptable carrier, diluent, or excipient.
13. A pharmaceutical composition, comprising the monoclonal antibody, or antigen-binding fragment thereof, of claim 8 , and a pharmaceutically or physiologically acceptable carrier, diluent, or excipient.
14. The pharmaceutical composition of claim 13 , wherein the pharmaceutical composition is administered intravenously.