Prodruggable antibodies, prodrugs thereof, and methods of use and making
AssigneeBristol-Myers Squibb Company
InventorsStanley R. Krystek, JR., Yong Zhang, Gregory D. Vite, Arvind Rajpal, Chetana Rao-Naik, Paul E. Morin, Mohan Srinivasan, Zheng Lin, Virginie Lafont, Alla Pritsker
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Abstract
A prodrugged antibody has a blocking moiety attached to a Cys on its heavy or light chain via a linker having a cleavable moiety. The blocking moiety inhibits binding of the antibody to its antigen. Cleavage of the cleavable moiety releases the blocking moiety and restores ability of the antibody to bind to its antigen.
Claims20
A prodrugged antibody according to formula (I)
- (BM-L)m-Ab (I)
- wherein
- Ab is an antibody having at least one amino acid in its heavy or light chain variable region replaced by a Cys, wherein the replaced amino acid (a) is in a framework region;
- (b) has a side chain exposure of at least 30% and (c) is within 10 Å, preferably 5 Å, of a CDR amino acid;
- BM is a blocking moiety that inhibits binding of Ab to its antigen;
- each L is, independently, a linker moiety bonded to BM and Ab, L comprising a cleavable moiety and being bonded to Ab at aforesaid Cys;
- and
- m is 1, 2, 3, or 4.
An antibody having a Cys at Kabat position 67 of the light chain.
An antibody having a Cys at Kabat position 23 of the heavy chain.
Dependencies are inferred from the claim text.