Anti SEZ6 antibodies and methods of use
Provided are novel seizure related 6 (SEZ6) modulators, including antibodies and derivatives thereof, and methods of using such modulators to treat proliferative disorders.
1. A monoclonal antibody that specifically binds a human seizure related 6 homolog (SEZ6) protein, comprising three complementarity determining regions of a light chain variable region (CDR-L1, CDR-L2, and CDR-L3) comprising an amino acid sequence set forth as SEQ ID NO: 190 and three complementarity determining regions of a heavy chain variable region (CDR-H1, CDR-H2, and CDR-H3) comprising an amino acid sequence set forth as SEQ ID NO: 191.
2. The monoclonal antibody of claim 1 , wherein the monoclonal antibody is selected from the group consisting of a chimeric antibody, a CDR-grafted antibody, and a humanized antibody.
3. The monoclonal antibody of claim 2 , comprising:
(a) residues 24-34 of SEQ ID NO: 190 for CDR-L1, residues 50-56 of SEQ ID NO: 190 for CDR-L2, residues 89-97 of SEQ ID NO: 190 for CDR-L3, residues 31-35 of SEQ ID NO: 191 for CDR-H1, residues 50-65 of SEQ ID NO: 191 for CDR-H2 and residues 95-102 of SEQ ID NO: 191 for CDR-H3, wherein the residues are numbered according to Kabat;
(b) residues 23-34 of SEQ ID NO: 190 for CDR-L1, residues 50-56 of SEQ ID NO: 190 for CDR-L2, residues 89-97 of SEQ ID NO: 190 for CDR-L3, residues 26-32 of SEQ ID NO: 191 for CDR-H1, residues 50-58 of SEQ ID NO: 191 for CDR-H2 and residues 95-102 of SEQ ID NO: 191 for CDR-H3, wherein the residues are numbered according to Chothia; or
(c) residues 30-36 of SEQ ID NO: 190 for CDR-L1, residues 46-55 of SEQ ID NO: 190 for CDR-L2, residues 89-96 of SEQ ID NO: 190 for CDR-L3, residues 30-35 of SEQ ID NO: 191 for CDR-H1, residues 47-58 of SEQ ID NO: 191 for CDR-H2 and residues 93-101 of SEQ ID NO: 191 for CDR-H3, wherein the residues are numbered according to MacCallum.
4. The monoclonal antibody of claim 1 , wherein the monoclonal antibody is conjugated to a cytotoxic agent.
5. The monoclonal antibody of claim 4 , wherein the cytotoxic agent is a pyrrolobenzodiazepine, a duocarmycin, an amanitin, an auristatin, a maytansinoid, a calicheamicin, or a radioisotope.
6. The monoclonal antibody of claim 1 , wherein the antibody comprises
a light chain variable region comprising an amino acid sequence set forth as SEQ ID NO: 190 and a heavy chain variable region comprising an amino acid sequence set forth as SEQ ID NO: 191.
7. An antibody drug conjugate comprising a monoclonal antibody conjugated, linked or otherwise associated with a cytotoxic agent, wherein the monoclonal antibody specifically binds a human seizure related 6 homolog (SEZ6) protein and comprises
three complementarity determining regions of a light chain variable region (CDR-L1, CDR-L2, and CDR-L3) comprising an amino acid sequence set forth as SEQ ID NO: 190 and three complementarity determining regions of a heavy chain variable region (CDR-H1, CDR-H2, and CDR-H3) comprising an amino acid sequence set forth as SEQ ID NO: 191.
8. The antibody drug conjugate of claim 7 , wherein the antibody drug conjugate has the formula: Ab-[L-D]n wherein:
(a) Ab comprises the monoclonal antibody;
(b) L comprises an optional linker;
(c) D comprises a drug, which is the cytotoxic agent; and
(d) n is an integer from 1 to 20.
9. The antibody drug conjugate of claim 7 , wherein the cytotoxic agent is a pyrrolobenzodiazepine, a duocarmycin, an amanitin, an auristatin, a maytansinoid, a calicheamicin, or a radioisotope.
10. The antibody drug conjugate of claim 7 , wherein the antibody drug conjugate comprises a linker.
11. The antibody drug conjugate of claim 10 , wherein the linker comprises a non-cleavable linker.
12. An antibody drug conjugate comprising a monoclonal antibody conjugated to a cytotoxic agent,
wherein the monoclonal antibody specifically binds a human seizure related 6 homolog (SEZ6) protein and comprises three complementarity determining regions of a light chain variable region (CDR-L1, CDR-L2, and CDR-L3) comprising an amino acid sequence set forth as SEQ ID NO: 190 and three complementarity determining regions of a heavy chain variable region (CDR-H1, CDR-H2, and CDR-H3) comprising an amino acid sequence set forth as SEQ ID NO: 191; and
wherein the cytotoxic agent is a calicheamicin.
13. The antibody drug conjugate of claim 12 ,
wherein the monoclonal antibody comprises residues 24-34 of SEQ ID NO: 190 for CDR-L1, residues 50-56 of SEQ ID NO: 190 for CDR-L2, residues 89-97 of SEQ ID NO: 190 for CDR-L3, residues 31-35 of SEQ ID NO: 191 for CDR-H1, residues 50-65 of SEQ ID NO: 191 for CDR-H2 and residues 95-102 of SEQ ID NO: 191 for CDR-H3, wherein the residues are numbered according to Kabat.
14. The antibody drug conjugate of claim 12 ,
wherein the monoclonal antibody comprises residues 23-34 of SEQ ID NO: 190 for CDR-L1, residues 50-56 of SEQ ID NO: 190 for CDR-L2, residues 89-97 of SEQ ID NO: 190 for CDR-L3, residues 26-32 of SEQ ID NO: 191 for CDR-H1, residues 50-58 of SEQ ID NO: 191 for CDR-H2 and residues 95-102 of SEQ ID NO: 191 for CDR-H3, wherein the residues are numbered according to Chothia.
15. The antibody drug conjugate of claim 12 ,
wherein the monoclonal antibody comprises residues 30-36 of SEQ ID NO: 190 for CDR-L1, residues 46-55 of SEQ ID NO: 190 for CDR-L2, residues 89-96 of SEQ ID NO: 190 for CDR-L3, residues 30-35 of SEQ ID NO: 191 for CDR-H1, residues 47-58 of SEQ ID NO: 191 for CDR-H2 and residues 93-101 of SEQ ID NO: 191 for CDR-H3, wherein the residues are numbered according to MacCallum.
16. The antibody drug conjugate of claim 12 , wherein the antibody drug conjugate comprises a linker.
17. The antibody drug conjugate of claim 16 , wherein the linker comprises a non-cleavable linker.