ANTI-MET ANTIBODIES, BISPECIFIC ANTIGEN BINDING MOLECULES THAT BIND MET, AND METHODS OF USE THEREOF
Provided herein are antibodies and bispecific antigen-binding molecules that bind MET and methods of use thereof. The bispecific antigen-binding molecules comprise a first and a second antigen-binding domain, wherein the first and second antigen-binding domains bind to two different (preferably non-overlapping) epitopes of the extracellular domain of human MET. The bispecific antigen-binding molecules are capable of blocking the interaction between human MET and its ligand HGF. The bispecific antigen-binding molecules can exhibit minimal or no MET agonist activity, e.g., as compared to monovalent antigen-binding molecules that comprise only one of the antigen-binding domains of the bispecific molecule, which tend to exert unwanted MET agonist activity. Also included are antibody-drug conjugates (ADCs) comprising the antibodies or bispecific antigen-binding molecules provided herein linked to a cytotoxic agent, radionuclide, or other moiety, as well as methods of treating cancer in a subject by administering to the subject a bispecific antigen-binding molecule or an ADC thereof.
1 . A compound or a pharmaceutically acceptable salt thereof, having the following formula
wherein R 1 is H, an acyl, aryloxycarbonyl, heteroarylcarbonyl, or alkyloxycarbonyl, each of which is optionally substituted.
2 . The compound or a pharmaceutically acceptable salt thereof according to claim 1 , wherein said compound has the following formula
wherein R 2 is H, an acyl, aryloxycarbonyl, heteroarylcarbonyl, or alkyloxycarbonyl, each of which is optionally substituted.
3 . The compound or a pharmaceutically acceptable salt thereof according to claim 2 , wherein said compound has the following formula
wherein R 3 is H, an acyl, aryloxycarbonyl, heteroarylcarbonyl, or alkyloxycarbonyl, each of which is optionally substituted.
4 . The compound or a pharmaceutically acceptable salt thereof according to claim 3 , wherein said compound has the following formula
wherein n=0, 1, 2, 3, 4, or 5; R 4 is OH, an acyloxy, alkyloxy, aryloxy, heteroaryloxy, or succinimidyloxy, each of which is optionally substituted.
5 . The compound or a pharmaceutically acceptable salt thereof according to claim 4 , wherein said compound has the following formula
wherein R 4 is OH, an acyloxy, alkyloxy, aryloxy, heteroaryloxy, aminooxy, or succinimidyloxy, each of which is optionally substituted.
6 . The compound or a pharmaceutically acceptable salt thereof according to claim 5 , wherein said compound has the following formula
7 . A process to manufacture a compound or a pharmaceutically acceptable salt thereof having the following formula
comprising the steps of
a) exposing
to Fmoc-N-Me-beta-alanine in the presence of an activating agent and a base to afford
b) removing Fmoc protection from (3) using piperidine and then coupling to an activated ester
to afford
c) removing Fmoc protection from (Fmoc-7) using piperidine (to afford compound 7) and then coupling (compound 7) to adipic acid in the presence of an activating agent and a base to afford
and
d) exposing compound 8 to N-Hydroxysuccinimide (NHS) in the presence of an activating agent and a base to afford said compound (1).
8 . A process to manufacture a compound or a pharmaceutically acceptable salt thereof having the following formula
comprising the steps of
a) exposing
to an activated ester Fmoc-Val-Cit-PAB-PNPC to afford
b) removing Fmoc protection from
using piperidine to afford
c) exposing compound (10) to compound (6) in the presence of an activating agent and a base to afford
d) removing Fmoc protection from (Fmoc-7) using piperidine (to afford compound 7) and then coupling (compound 7) to adipic acid in the presence of an activating agent and a base to afford compound (8)
and
e) exposing compound 8 to N-Hydroxysuccinimide (NHS) in the presence of an activating agent and a base to afford said compound (1).
9 . A process to manufacture a compound or a pharmaceutically acceptable salt thereof having the following formula
comprising the steps of
a) exposing
to an activated ester Fmoc-Val-Cit-PAB-PNPC to afford
b) removing Fmoc protection from
using piperidine to afford
c) exposing compound (10) to compound (6) in the presence of an activating agent and a base to afford
d) removing Fmoc protection from (Fmoc-7) using piperidine to afford (7)
and
e) coupling (7) to an activated adipic acid ester
to afford said product (1).
10 . A product manufactured according to the process of claims 7 - 9 .