DDR1-binding agents and methods of use thereof
Disclosed are DDR1 binding agents and methods of using the agents for treating diseases such as cancer. The disclosure provides antibodies that specifically bind to an extracellular domain of DDR1 and modulate DDR1 activity. The disclosure further provides methods of using agents that modulate the activity of DDRI, such as antibodies that specifically bind DDR1, to reduce the tumorigenicity of tumors comprising cancer stem cells by reducing the frequency or number of cancer stem cells in the tumor. Also described are methods of treating cancer comprising administering a therapeutically effect amount of an agent or antibody of the present invention to a patient having a tumor or cancer.
1. An isolated antibody that specifically binds an extracellular domain of human DDR1,
wherein the antibody, comprises:
(a) a heavy chain CDR1 comprising GYTFTDYFMK (SEQ ID NO:22), a heavy chain CDR2 comprising DINPNNGDTFYIQKFKG (SEQ ID NO:23), and a heavy chain CDR3 comprising SRDLAY (SEQ ID NO:24) and
(b) a light chain CDR1 comprising KSSQSLLYSNGKTYLN (SEQ ID NO:27), a light chain CDR2 comprising QVSKLDS (SEQ ID NO:28), and a light chain CDR3 comprising VQGTDFPQT (SEQ ID NO:29).
2. The antibody of claim 1 , which comprises: (a) a heavy chain variable region having at least 90% sequence identity to SEQ ID NO:33; and (b) a light chain variable region having at least 90% sequence identity to SEQ ID NO:35.
3. The antibody of claim 1 , which comprises:
(a) a heavy chain variable region comprising SEQ ID NO:33; and
(b) a light chain variable region comprising SEQ ID NO:35.
4. The antibody of claim 1 , which is a recombinant antibody, a monoclonal antibody, a chimeric antibody, a humanized antibody, a human antibody, an antibody fragment, a bispecific antibody, a monospecific antibody, a monovalent antibody, an IgG1 antibody, or an IgG2 antibody.
5. The antibody of claim 1 , which:
(i) modulates the activity of DDR1;
(ii) inhibits binding of a ligand to DDR1;
(iii) is an antagonist of DDR1;
(iv) inhibits activation of DDR1; and/or
(v) blocks collagen-induced tyrosine phosphorylation of DDR1.
6. The antibody of claim 1 , which
(a) inhibits growth of a DDR-expressing tumor; and/or
(b) reduces the frequency of cancer, stem cells in a DDR-expressing tumor.
7. The antibody of claim 6 , wherein the tumor is selected from the group consisting of a breast tumor, colorectal tumor, hepatic tumor, renal tumor, lung tumor, pancreatic tumor, ovarian tumor, melanoma, prostate tumor, and head and neck tumor.
8. An isolated antibody that specifically binds human DDR1, wherein the antibody binds the same DDR1 epitope as the epitope to which antibody 20M102 binds, wherein the antibody 20M102 is produced by the hybridoma deposited as ATCC deposit number PTA-10051.
9. An isolated antibody that competes for specific binding to human DDR1 with the antibody of claim 1 .
10. An antibody produced by the hybridoma 20M102 deposited as ATCC deposit number PTA-10051.
11. An isolated antibody that competes for specific binding to human DDR1 with the antibody of claim 10 .
12. A pharmaceutical composition comprising the antibody of claim 1 and a pharmaceutically acceptable carrier.
13. A cell line producing the antibody of claim 1 .