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US 6,759,509 B1Granted
Branched peptide linkers
AssigneeBristol-Myers Squibb Company
InventorsDalton King, Raymond A. Firestone, Gene M. Dubowchik
Life of this patent
Estimating the term…
Abstract
Conjugates containing a targeting ligand, such as an antibody, a therapeutically active drug and a branched peptide linker. The branched peptide linker contains two or more amino acid moieties that provide an enzyme cleavage site. The number of drugs capable of being bonded to the branched linkers varies by a factor of two for each generation of branching.
Claims35
A compound of the following formula II:
- wherein
- A is a thiol acceptor;
- W is a bridging moiety;
- c is an integer of 0 to 1;
- a is an integer of 2 to 12;
- Q is O, NH, or N-lower alkyl;
- p is an integer of 0 or 1;
- d is an integer of 0 or 1;
- E is a polyvalent atom;
- each b is an integer of 1 to 10;
- each X is of the formula
- —CO—Y—Zm—GnD
- wherein
- Y is two amino acid residues in the L form;
- Z is one or two amino acid residues;
- m is an integer of 0 or 1;
- G is a self-immolative spacer;
- n is a integer of 0 or 1;
- provided that when n is 0 then —Y—Zm— an amino acid sequence of SEQ ID NO:1 or SEQ ID NO:2;
- and
- D is a Drug moiety having a backbone and at least one chemically reactive functional group pendant thereto chemically reacted to the self-immolative spacer or terminal amino acid residue to form a covalent bond, said functional group selected from the group consisting of a primary amine or secondary amine, hydroxyl, sulfhydryl, carboxyl, aldehyde therefore ketone;
- or each X is of the formula
- wherein each X1 is of the formula
- —CO—Y—Zm—Gn—D;
- wherein Y, Z, G, D, Q, E, m, d, p and n are as defined above;
- or each X1 is of the formula
- wherein each X2 is of the formula
- —CO—Y—Zm—Gn—D;
- and wherein Y, Z, G, D, Q, E, m, d, p, a, b and n are as defined above;
- or each X2 is of the formula
- wherein each X3 is of the formula
- —CO—Y—Zm—Gn—D;
- and whereinr Z, G, D, Q, E, m, d, p, a, b and n are as defined above;
- or each X3 is of the formula
- and wherein each X4 is of the formula
- —CO—Y—Zm—Gn—D;
- and wherein Y, Z, G, D, Q, E, m, d, p, a, b and n are as defined above.
34 more elements
The compound of claimn 1 wherein the —Ym—Zm group is valine-citrulline.
A compound of the following formula III:
- wherein
- L is a ligand;
- q is an integer of 1 to 10;
- A is a thiol acceptor;
- W is a bridging moiety;
- c is an integer from 0 to 1;
- a is an integer of 2 to 12;
- Q is O, NH, or N-lower alkyl;
- p is an integer of 0 or 1;
- d is an integer of 1 or 2;
- E is a polyvalent atom;
- each b is an integer of 1 to 10;
- each X is of the formula
- —CO—Y—Zm—Gn—D
- wherein
- Y is two amino acid residues in the L form;
- Z is one or two amino acid residues;
- m is an integer of 0 or 1;
- G is a self-immolative spacer;
- and
- n is a integer of 0 or 1;
- provided that when n is 0 then —Y—Zm— is an amino acid sequence of SEQ ID NO:1 or SEQ ID NO:2;
- D is a drug moiety having a backbone and at least one chemically reactive functional group pendant thereto reacted to the self-immolative spacer to form a covalent bond, said funtional group selected from the group consisting of a primary amine secondary amine, hydroxyl, carboxyl, sulfhydryl, aldehyde, therefore ketone;
- or X is of the formula
- wherein each X1 is of the formula
- —CO—Y—Zm—Gn—D;
- and wherein Y, Z, G, D, Q, E, m, d, p, a, b and n are as defined above;
- or each X1 is of the formula
- wherein each X2 is of the formula
- —CO—Y—Zm—Gn—D;
- and wherein Y, Z, G, D, Q, E, m, d, p, a, b and n are as defined above;
- or each X2 is of the formula
- wherein each X3 is of the formula
- —CO—Y—Zm—Gn—D;
- wherein Y, Z, G, D, Q, E, m, d, p, a, b and n are as defined above;
- or each X3 is of the formula
- wherein end X4 is of the formula
- —CO—Ym—Zm—Gn—D;
- wherein Y, Z, G, D, Q, E, m, d, p, a, b and n are as defined above.
36 more elements
Dependencies are inferred from the claim text.