Anti-DR4 agonist antibodies
View Patent ↗The present invention provides antibodies and antibody fragments that specifically recognize and agonize the death receptor 4 (DR4). Also provided in the invention are polynucleotides and vectors that encode such molecules and host cells that harbor the polynucleotides or vectors.
1. An antibody that binds to and is an agonist of DR4, wherein the antibody comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region and the light chain variable region each comprise the following three complementary determining regions (CDRs): CDR1, CDR2 and CDR3; wherein:
i) the CDR1 of the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:8;
ii) the CDR2 of the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:9;
iii) the CDR3 of the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:10;
iv) the CDR1 of the light chain variable region comprises the amino acid sequence of SEQ ID NO:5;
v) the CDR2 of the light chain variable region comprises the amino acid sequence of SEQ ID NO:6;
vi) the CDR3 of the light chain variable region comprises the amino acid sequence of SEQ ID NO:7.
2. The antibody of claim 1 , wherein the antibody comprises the light chain variable segment (FR1-CDR1-FR2-CDR2-FR3) of SEQ ID NO:1 and the heavy chain variable segment (FR1-CDR1-FR2-CDR2-FR3) of SEQ ID NO:2.
3. The antibody of claim 1 , wherein the antibody comprises a light chain variable region having at least 50% sequence identity to SEQ ID NO:1 and a heavy chain variable region having at least 50% sequence identity to SEQ ID NO:2.
4. The antibody of claim 3 , wherein the antibody comprises a light chain variable region having at least 80% sequence identity to SEQ ID NO:1 and a heavy chain variable region having at least 80% sequence identity to SEQ ID NO:2.
5. The antibody of claim 1 , wherein the antibody is a human antibody.
6. The antibody of claim 1 , wherein the antibody is a multivalent antibody.
7. The antibody of claim 6 , wherein the antibody is a multispecific antibody.
8. The antibody of claim 7 , wherein the antibody is a bispecific antibody.
9. The antibody of claim 1 , wherein the antibody is cross-linked.
10. A composition comprising an antibody of claim 1 , and a pharmaceutically acceptable carrier.
11. A polynucleotide encoding an antibody of claim 1 .
12. An expression cassette comprising the polynucleotide of claim 11 .
13. A host cell comprising the expression cassette of claim 12 .
14. A method of inducing apoptosis in a target cancer cell expressing DR4 comprising contacting the target cancer cell with an antibody of claim 1 .
15. The method of claim 14 , wherein the cell is in vivo.
16. The method of claim 14 , wherein the cell is in vitro.
17. The method of claim 14 , wherein the cell is a cancer cell.
18. A method of reducing or inhibiting the growth of a cancer expressing DR4 in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of an antibody of claim 1 .
19. The method of claim 18 , further comprising administering to the subject an anticancer chemotherapeutic drug and/or irradiation.
20. A kit containing an antibody of claim 1 and a pharmaceutically acceptable carrier.
21. The kit of claim 20 , further comprising a second agent for co-administration with the antibody.