Anti-CD40 antibodies
The present invention provides high affinity anti-CD40 monoclonal antibodies and related compositions, which may be used in any of a variety of therapeutic methods for the treatment of cancer and other diseases.
1. An isolated antibody, or an antigen-binding fragment thereof, that binds to CD40, comprising (i) a heavy chain variable region comprising the VHCDR1, VHCDR2, and VHCDR3 set forth in SEQ ID NOs:3-5; and (ii) a light chain variable region comprising the VLCDR1, the VLCDR2, and the VLCDR3 set forth in SEQ ID NOs:6-8;
or a variant of said antibody, or an antigen-binding fragment thereof, comprising heavy and light chain variable regions identical to the heavy and light chain variable regions of (i) and (ii) except for up to 8 amino acid substitutions in said CDR regions.
2. The isolated antibody, or antigen-binding fragment thereof, of claim 1 wherein the heavy chain variable region comprises the amino acid sequence set forth in SEQ ID NO:9.
3. The isolated antibody, or antigen-binding fragment thereof, of claim 1 wherein the light chain variable region comprises the amino acid sequence set forth in SEQ ID NO:10.
4. An isolated antibody, or an antigen-binding fragment thereof, that binds to CD40, comprising a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO:9 and a light chain variable region which comprises an amino acid sequence having at least 90% identity to the amino acid sequence set forth in SEQ ID NO:10.
5. The isolated antibody, or an antigen-binding fragment thereof, of claim 4 comprising a light chain variable region which comprises the amino acid sequence set forth in SEQ ID NO:10.
6. An isolated antibody, or an antigen-binding fragment thereof, that binds to CD40, comprising a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO:10 and a heavy chain variable region which comprises an amino acid sequence having at least 90% identity to the amino acid sequence set forth in SEQ ID NO:9.
7. The isolated antibody of claim 1 , wherein the antibody is humanized.
8. The isolated antibody, or antigen-binding fragment thereof, of claim 1 that binds CD40 with a KD of 0.96 nM or lower.
9. The isolated antibody, or antigen-binding fragment thereof of claim 8 , wherein the isolated antibody, or antigen-binding fragment thereof:
a) blocks binding of CD40 to CD40L;
b) is a CD40 agonist;
c) activates antigen presenting cells;
d) stimulates cytokine release from antigen presenting cells;
e) induces tumor cell apoptosis;
f) inhibits tumor cell proliferation;
g) kills tumor cells via induction of effector functions selected from the group consisting of antibody dependent cellular cytotoxicity, complement dependent cytotoxicty, and antibody dependent cellular phagocytosis;
h) stimulates anti-tumor T cell responses;
i) reduces established tumors;
j) inhibits rituximab-resistant tumors and other CD40 expressing tumors; or
k) a combination of any one or more of a)-j).
10. A composition comprising a physiologically acceptable carrier and a therapeutically effective amount of the isolated antibody or antigen-binding fragment thereof according to claim 1 .
11. A composition comprising a physiologically acceptable carrier and a therapeutically effective amount of the isolated antibody or antigen-binding fragment thereof according to claim 5 .
12. The isolated antibody of claim 1 wherein the antibody is selected from the group consisting of a single chain antibody, a ScFv, a univalent antibody lacking a hinge region, and a minibody.
13. The isolated antibody of claim 1 wherein the antibody is a Fab or a Fab′ fragment.
14. The isolated antibody of claim 1 wherein the antibody is a whole antibody.
15. The isolated antibody of claim 1 wherein the isolated antibody comprises an IgG1 Fc region.