Prodruggable antibodies, prodrugs thereof, and methods of use and making

Patent metadata

Field	Value
Publication number	US-11623965-B2
Application number	US-201816103654-A
Country	US
Kind code	B2
Filing date	Aug 14, 2018
Priority date	Aug 16, 2017
Publication date	Apr 11, 2023
Grant date	Apr 11, 2023

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.

First claim

What is claimed is:

1. 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, 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; and
wherein blocking moiety BM is a poly(ethylene glycol).

2. The prodrugged antibody of claim 1 , wherein the at least one replaced amino acid in antibody Ab is at Kabat position 1, 3, 5, 19, 23, 25, 43, 46, 68, 72, 74, 75, 76, 82a, 82b, 83, 84, 85, or 105 of the heavy chain variable region or at Kabat position 1, 3, 5, 7, 8, 18, 20, 45, 57, 60, 63, 65, 66, 67, 69, 77, or 100 of the light chain variable region.

3. The prodrugged antibody of claim 1 , wherein the at least one replaced amino acid in antibody Ab is at Kabat position 23 of the heavy chain or Kabat position 67 of the light chain.

4. The prodrugged antibody of claim 1 , wherein the at least one replaced amino acid in antibody Ab is at Kabat position 23 of the heavy chain.

5. The prodrugged antibody of claim 1 , wherein the at least one replaced amino acid in antibody Ab is Kabat position 67 of the light chain.

6. The prodrugged antibody of claim 1 , wherein the poly(ethylene glycol) has a molecular weight of at least about 2 kDa.

7. The prodrugged antibody of claim 1 , wherein cleavable moiety in L is an enzymatically cleavable peptide.

8. The prodrugged antibody of claim 7 , wherein the enzymatically cleavable peptide is cleavable by at least one enzyme selected from the group consisting of fibroblast activation protein (FAP), urokinase-type plasminogen activator (uPA, urokinase), MT-SP1/matriptase, legumain, and a matrix metalloprotease.

9. The prodrugged antibody of claim 8 , wherein the enzyme is matriptase.

10. The prodrugged antibody of claim 7 , wherein the enzymatically cleavable peptide is LSGRSDNH (SEQ ID NO:5), LSGX (SEQ ID NO:16) or LSGK (SEQ ID NO:16).

11. The prodrugged antibody of claim 1 , having a structure according to formula (IIa) to (IIh):

Assignees

• Bristol Myers Squibb Co

Inventors

• Krystek Jr Stanley R
• Zhang Yong
• Vite Gregory D
• Rajpal Arvind
• Rao-Naik Chetana
• Morin Paul E
• Srinivasan Mohan
• Lin Zheng
• Lafont Virginie
• Pritsker Alla

Classifications

• A61K47/65

  Peptidic linkers, binders or spacers, e.g. peptidic enzyme-labile linkers · CPC title

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title

• C07K2317/24

  containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• C07K16/464 Primary

  Igs containing CDR-residues from one specie grafted between FR-residues from another · CPC title