Antibody-drug conjucates and their uses for the treatment of cancer
The present invention relates to antibody-drug conjugates, wherein the antibody specifically binds to TfR, the transferrin receptor, and wherein the drug is preferably chosen among a cytotoxic drug. Such antibody-drug conjugates are useful in particular in treating proliferative diseases including cancers, such as lymphoma or leukaemia.
1 . An antibody-drug conjugate of the formula (I): Ab-L-Z—X-D, wherein:
Ab is an anti-TfR antibody chosen among a full-length antibody or a bivalent fragment, which comprises:
(a) a variable heavy chain polypeptide comprising HCDR1 of SEQ ID NO:1, HCDR2 of SEQ ID NO:2, HCDR3 of SEQ ID NO:3 and a variable light chain polypeptide comprising LCDR1 of SEQ ID NO:4, LCDR2 of SEQ ID NO:5 and LCDR3 of SEQ ID NO:6,
(b) a variable heavy chain polypeptide comprising HCDR1 of SEQ ID NO:1, HCDR2 of SEQ ID NO:2, HCDR3 of SEQ ID NO:3 and a variable light chain polypeptide comprising LCDR1 of SEQ ID NO:4, LCDR2 of SEQ ID NO:8 and LCDR3 of SEQ ID NO:6,
(c) a variable heavy chain polypeptide comprising VH of SEQ ID NO:11 and a variable light chain polypeptide comprising VL of SEQ ID NO:13,
(d) a variable heavy chain polypeptide comprising VH of SEQ ID NO:11 and a variable light chain polypeptide comprising VL of SEQ ID NO:14,
(e) a variable heavy chain polypeptide comprising VH of SEQ ID NO:12 and a variable light chain polypeptide comprising VL of SEQ ID NO:13, or
(f) a variable heavy chain polypeptide comprising VH of SEQ ID NO:12 and a variable light chain polypeptide comprising VL of SEQ ID NO:14,
L is a linker molecule bonded to said anti-TfR antibody, said linker molecule being of formula (II):
wherein n is an integer comprised from 2 and 20 inclusive,
Z is a dipeptide of valine-citrulline bonded to L,
X is an aminobenzyl ester self-immolative group bonded to Z,
D is a drug monomethyl auristatin E bonded to X.
2 . The antibody-drug conjugate according to claim 1 , wherein X is a para-aminobenzyl ester group covalently bonded to Z, said X being of the following formula (III):
J being an optional substituent chosen among F, Cl, Br, NO 2 , NHCOCH 3 , N(CH 3 ) 2 , NHCOCF 3 , alkyl, and haloalkyl, and m being an integer of 0, 1, 2, 3 and 4.
3 . The antibody-drug conjugate according to claim 1 , wherein Lis covalently bonded to one or more thiol residues of said antibody.
4 . The antibody-drug conjugate according to claim 1 , wherein said anti-TfR antibody specifically binds to the transferrin receptor of SEQ ID NO:16.
5 . The antibody-drug conjugate according to claim 1 , wherein said anti-TfR antibody binds to the transferrin receptor with a KD of 10 nM or less, preferably with a KD of 1 nM or less.
6 . The antibody-drug conjugate according to claim 1 , wherein said anti-TfR antibody is a monoclonal antibody and/or a humanized antibody.
7 . The antibody-drug conjugate according to claim 1 , wherein:
said anti-TfR antibody comprises a human IgG4 isotype constant region, or a mutant or chemically modified constant region, wherein said mutant or chemically modified constant region confers no or decreased ADCC activity to said anti-TfR antibody when compared to a corresponding antibody with wild type IgG1 isotype constant region, or
said anti-TfR antibody comprises a human IgG1 isotype constant region, or a mutant or chemically modified constant region, wherein said mutant or chemically modified constant region confers increased ADCC activity to said anti-TfR antibody when compared to a corresponding antibody with wild type IgG1 isotype constant region.
8 . A method of treating a tumor in a subject in need thereof, comprising
administering to the subject a therapeutically effective amount of the antibody-drug conjugate according to claim 1 , wherein the therapeutically effective amount is sufficient to treat the tumor.
9 . A pharmaceutical composition comprising an antibody-drug conjugate according to claim 1 , in combination with one or more pharmaceutically acceptable excipients, diluents or carriers.
10 . A composition comprising an antibody-drug conjugate according to claim 1 , said composition having a pH of 6.5 and further comprising histidine, and optionally sucrose and polysorbate 80.
11 . A lyophilisate formulation, a pre-filled syringe or a vial comprising an antibody-drug conjugate according to claim 1 .
12 . A process for obtaining an antibody-drug conjugate according to claim 1 , wherein the method comprises:
culturing a host cell under conditions suitable for expression of a nucleic acid encoding the antibody as defined in claim 1 ,
isolating the antibody,
synthesizing monomethyl auristatin E bonded to the linker L-Z—X of formula (V):
conjugating said antibody to the monomethyl auristatin E bonded to the linker L-Z—X of formula (V).
13 . The antibody-drug conjugate according to claim 2 , wherein m is 0.
14 . The antibody-drug conjugate according to claim 1 , wherein L is a linker molecule of formula (IV):
15 . The antibody-drug conjugate according to claim 1 , wherein said antibody is mAb1 comprising a heavy chain of SEQ ID NO:18 and a light chain of SEQ ID NO: 17.
16 . A method for treating a tumor according to claim 8 , wherein said tumor is a solid tumor or a hematologic tumor.
17 . A method for treating a tumor according to claim 8 , wherein said tumor is a lymphoma or leukaemia.
18 . The antibody-drug conjugate according to claim 1 , wherein
Ab is an anti-TfR antibody comprising a heavy chain of SEQ ID NO:18 and a light chain of SEQ ID NO:17,
L is a linker molecule bonded to said anti-TfR antibody, said linker molecule being of formula (IV):
Z is a dipeptide of valine-citrulline bonded to L,
X is an aminobenzyl ester self-immolative group bonded to Z, said X being of the following formula (III):
J being an optional substituent chosen among F, Cl, Br, NO 2 , NHCOCH 3 , N(CH 3 ) 2 , NHCOCF 3 , alkyl, and haloalkyl, and m being an integer of 0,
D is a drug monomethyl auristatin E bonded to X.