SELF-STABILIZING LINKER CONJUGATES
The present invention provides Ligand-Drug Conjugates, Drug-Linkers, Linkers, and Ligand-Linker Conjugates comprising a self-stabilizing linker assembly component.
1 . A method of treating cancer, an autoimmune disease or an infectious disease that expresses a target antigen comprising administering a Ligand-Functional Agent Conjugate having the formula:
or a salt thereof, wherein
L is a Ligand unit directly attached to the succinimide ring of the Functional Agent Conjugate via a thioether linkage, wherein the Ligand is a monoclonal antibody that specifically binds to the target antigen;
D′ is a Drug unit;
the subscript p ranges from 1 to 20;
—W— is an optional Cleavable unit,
the subscript w′ is 0 or 1;
—Y— is an optional Spacer unit,
the subscript y′ is 0 or 1;
A′ is an optional Stretcher unit; and
the subscript a′ is 0 or 1.
2 . The method of claim 1 wherein p is 1 to 12.
3 . The method of claim 1 wherein p is 1 to 8.
4 . The method of claim 1 wherein p is 1 to 8.
5 . The method of claim 1 wherein D′ is a cytotoxic agent.
6 . The method of claim 1 wherein D′ is an auristatin selected from the group consisting of AE, AFP, AEB, AEVB, MMAF and MMAE.
7 . The method of claim 1 wherein W w′ is selected from the group consisting of Val-Cit, Phe-Lys and Val-Ala.
8 . The method of claim 1 wherein Y y′ is a PAB unit.
9 . The method of claim 8 wherein the PAB unit has a structure of:
wherein the wavy line adjacent to the nitrogen atom indicates covalent binding of that nitrogen atom to W and the # adjacent to the carbonyl indicates covalent binding of its carbon atom to D′.
10 . The method of claim 1 wherein the subscript a′ is 0; W w′ is Val-Cit; and Y y′ is PAB.
11 . The method of claim 1 wherein the subscript a′ is 0; W w′ is Val-Cit; Y y′ is PAB; and D′ is a cytotoxic agent.
12 . The method of claim 1 wherein the subscript a′ is 0; W w′ is Val-Cit; Y y′ is PAB; D′ is a cytotoxic agent; and p is 1 to 8.
13 . The method of claim 1 wherein D′ is MMAE.
14 . The method of claim 1 wherein the subscript a′ is 0; W w , is Val-Cit; Y y′ is PAB; and D′ is MMAE.
15 . The method of claim 1 wherein the Ligand-Functional Agent Conjugate has the structure of:
or the structure wherein the succinimide ring is hydrolyzed, or a salt thereof, wherein
mAb is a monoclonal antibody and S is a sulfur atom from the monoclonal antibody.
16 . The method of claim 15 , wherein the subscript p is about 4.