Anti-CD16 binding molecules
The present invention relates to binding molecules that specifically bind to the human Fc gamma receptor expressed on the surface of natural killer (NK) cells and macrophages (i.e. FcγRIIIA), and in particular binding molecules that specifically bind the A form FcγRIII but do not bind to the B form of FcγRIII, as well as to the use of such binding molecules in the diagnosis and treatment of disease. The invention further extends to polynucleotides encoding such binding molecules, host cells comprising such polynucleotides and methods of producing binding molecules of the invention using such host cells.
1. An isolated antibody or antigen-binding fragment thereof having specificity for FcγRIIIA but does not bind to FcγRIIIB, comprising:
(a) a heavy chain CDR1 having the amino acid sequence set forth in SEQ ID NO:17; a heavy chain CDR2 having the amino acid sequence set forth in SEQ ID NO:18; a heavy chain CDR3 having the amino acid sequence set forth in SEQ ID NO:19; a light chain CDR1 having an amino acid sequence selected from the group consisting of SEQ ID NOs:20, 23, 26, 29, 33, and 34; a light chain CDR2 having an amino acid sequence selected from the group consisting of SEQ ID NOs:21, 24, 27, 30, 31, and 35; and a light chain CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NOs:22, 25, 28, and 32; or
(b) a light chain variable region having an amino acid sequence selected from the group consisting of SEQ ID NOs:10-16 and a heavy chain variable region; or
(c) a heavy chain variable region having the amino acid sequence set forth in SEQ ID NO:9 and a light chain variable region, wherein the antigen-binding fragment is selected from the group consisting of Fv, Fab, di-Fab, Fab′, F(ab′) 2 , scFv, and single chain antibody.
2. An isolated antibody or antigen-binding fragment thereof according to claim 1 , wherein the antibody or antigen-binding fragment is fully human.
3. An isolated antibody or antigen-binding fragment thereof according to claim 1 , which is capable of activating human cells expressing FcγRIIIA.
4. An isolated antibody or antigen-binding fragment thereof according to claim 3 , which is capable of inducing NK-cell mediated cell killing.
5. An isolated antibody or antigen-binding fragment thereof according to claim 2 , which inhibits activation of human cells expressing FcγRIIIA.
6. An isolated antibody or antigen-binding fragment thereof according to claim 1 , wherein said antibody or antigen-binding fragment thereof comprises at least one additional antigen-binding fragment having specificity for at least one additional antigen.
7. An isolated antibody or antigen-binding fragment thereof according to claim 6 , wherein the at least one additional antigen is a cell-surface antigen.
8. An isolated antibody or antigen-binding fragment thereof according to claim 7 , wherein the cell-surface antigen is selected from the group consisting of CD19, CD20, CD30, the Laminin Receptor Precursor, EGFR1, EGFR2, EGFR3, Ep-CAM, PLAP, Thomsen-Friedenreich antigen, MUC-1, IL4-R alpha, IL13-R, IGFR, FcεRI and CD5.
9. An isolated antibody or antigen-binding fragment thereof according to claim 7 , wherein the cell-surface antigen is CD19 or CD30.
10. An isolated antibody or antigen-binding fragment thereof according to claim 6 , wherein the at least one additional antigen is from an infectious agent.
11. An isolated antibody or antigen-binding fragment thereof according to claim 10 wherein the infectious agent is a virus, a bacterium, a fungus, a mycoplasma, a parasite or a prion.
12. An isolated antibody or antigen-binding fragment thereof according to claim 1 , wherein the antibody is selected from the group consisting of a chimeric antibody, a CDR-grafted antibody, a humanized antibody, and a fully human antibody.
13. An isolated antibody or antigen-binding fragment thereof according to claim 1 , wherein the antibody or antigen-binding fragment thereof is a diabody or a TandAb.
14. An isolated antibody or antigen-binding fragment thereof according to claim 1 , wherein said antibody or antigen-binding fragment thereof further comprises a functional domain.
15. An isolated antibody or antigen-binding fragment thereof according to claim 14 , wherein the functional domain is an antibody Fc domain, an enzyme suitable for antibody-dependent enzyme prodrug therapy, a peptide capable of binding to Fc receptors, or a protein or peptide for increasing the serum half-life of the antibody or antigen-binding fragment thereof.
16. An isolated antibody or antigen-binding fragment thereof according to claim 1 , wherein said antibody or antigen-binding fragment thereof is capable of binding to the FcγRIIIA 158F allelic variant with approximately the same affinity with which it binds to the FcγRIIIA 158V allelic variant.
17. An isolated antibody or antigen-binding fragment thereof according to claim 1 , wherein the antibody or antigen-binding fragment thereof is conjugated to a labeling molecule or a toxin.
18. An isolated antibody or antigen-binding fragment thereof according to claim 17 , wherein the labeling molecule is a radiolabel, a fluorescent label or a luminescent label.
19. A composition comprising an isolated antibody or antigen-binding fragment thereof according to claim 1 and at least one additional component.
20. A composition according to claim 19 , wherein at least one additional component is a suitable pharmaceutical carrier, excipient, diluent stabilizer.
21. A kit comprising an isolated antibody or antigen-binding fragment thereof according to claim 1 and means for detecting the isolated antibody or antigen-binding fragment thereof when bound to FcγRIIIA.