Anti-MUC1 antibody-drug conjugate
Inventors
GELLERT, Johanna • FLECHNER, ANKE • Weigelt, Doreen • Danielczyk, Antje • NAGASE, AKIKO
Assignees
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Publication Number
US-12479926-B2
Publication Date
2025-11-25
Expiration Date
Abstract
The present disclosure relates to antibody drug conjugates directed against the cancer antigen MUC1. In particular, an antibody with improved antigen binding was obtained by deleting a glycosylation site in the CDR-H2 of a known anti-MUC1 antibody. The conjugates consist of exatecan derivatives coupled to the anti MUC1 antibodies.
Core Innovation
The invention relates to treating cancer by administering a therapeutically effective amount of an antibody-drug conjugate in which an antibody is conjugated to a drug-linker by a thioether bond. The conjugate is represented by a formula in which AB represents the antibody and y represents an average number of units of the drug-linker structure conjugated to the antibody. The linker comprises glycine-glycine-phenylalanine-glycine (SEQ ID NO: 24).
The conjugate specifies an antibody whose heavy chain variable region and light chain variable region are defined by amino acid sequences of SEQ ID NO: 10 and SEQ ID NO: 12 in one embodiment, or by a heavy chain having the amino acid sequence of SEQ ID NO: 22 or a variant thereof in which one amino acid has been removed from the C-terminus and a light chain having the amino acid sequence of SEQ ID NO: 16 in another embodiment. The disclosure further includes an anti-MUC1 antibody derived from PankoMab with deletion of the CDR-H2 glycosylation site Asn57 and discusses glycosylation-dependent antigen-binding epitopes of TA-MUC1, including PDTR and PESR.
The disclosure further characterizes the antibody-drug conjugates by determining drug-to-antibody ratio using UV and HPLC analyses and by defining antibody glycosylation/Fc activity considerations in relation to antigen-binding behavior. Payloads discussed include exatecan derivatives, including DX-8951/exatecan and DXd, coupled through the specified drug-linker structures. The disclosed conjugates are described as providing significant anti-tumor efficacy for MUC1-positive cancers.
Claims Coverage
Two independent claims are identified, each directed to cancer treatment by administering a thioether-bond antibody-drug conjugate with a linker containing the glycine-glycine-phenylalanine-glycine motif and an average drug-linker loading parameter y. The independent claims differ in the specified antibody sequences, while dependent features refine y, antibody modifications, cancer selection, and additional therapeutic agent use.
Thioether-bond antibody-drug conjugate with GGFG linker motif and defined variable regions
A method for treating cancer by administering a therapeutically effective amount of a conjugate comprising an antibody conjugated to a drug-linker by a thioether bond, where the conjugate is represented by a formula and AB represents the antibody comprising a heavy chain variable region with the amino acid sequence of SEQ ID NO: 10 and a light chain variable region with the amino acid sequence of SEQ ID NO: 12; y represents an average number of units of the drug-linker structure conjugated to the antibody per itself; and the linker comprises glycine-glycine-phenylalanine-glycine (SEQ ID NO: 24).
Thioether-bond antibody-drug conjugate with GGFG linker motif using SEQ ID NO: 22 heavy-chain and SEQ ID NO: 16 light-chain
A method for treating cancer by administering a therapeutically effective amount of a conjugate comprising an antibody conjugated to a drug-linker by a thioether bond, where the conjugate is represented by a formula and AB represents the antibody comprising a heavy chain having the amino acid sequence of SEQ ID NO: 22 or a variant thereof in which one amino acid has been removed from the C-terminus and a light chain having the amino acid sequence of SEQ ID NO: 16; y represents an average number of units of the drug-linker structure conjugated to the antibody per itself; and the linker comprises glycine-glycine-phenylalanine-glycine (SEQ ID NO: 24).
Average drug-linker loading constraint on y
Conjugating the antibody-drug conjugate such that y, the average number of units of the drug-linker structure conjugated to the antibody per itself, is within specified values or ranges, including ranges such as 2 to 8 and other specified y ranges.
Antibody modification and processing constraints for the antibody
Employing an antibody having specified antibody modifications, including defucosylation or reduced fucose, glycosylation and processing changes, LALA substitutions, amidation, and C-terminal deletion or lack, along with additional specified chemical modifications such as deamidation, aspartic acid isomerization, methionine oxidation, and proline amidation.
Cancer selection based on TA-MUC1 expression and specified cancer types including metastases
Treating cancer characterized by expression of TA-MUC1 and/or treating cancers limited to specified cancer types, including metastases thereof.
Additional therapeutic agent in the cancer treatment method
Administering an additional therapeutic agent as part of the cancer treatment method.
The claim coverage is centered on cancer treatment by administering a therapeutically effective amount of a thioether-linked antibody-drug conjugate defined by an antibody with specified sequences or variants and a drug-linker comprising the glycine-glycine-phenylalanine-glycine motif, with y as the average conjugation stoichiometry. Dependent embodiments narrow performance by specifying y values or ranges, antibody modification and glycosylation or processing characteristics, selecting TA-MUC1 expressing cancers and specified cancer types including metastases, and optionally including an additional therapeutic agent.
Stated Advantages
Provides significant anti-tumor efficacy for MUC1-positive cancers.
Documented Applications
Treating cancer in a subject in need thereof by administering a therapeutically effective amount of an antibody-drug conjugate or a pharmaceutical composition.
Treating TA-MUC1-expressing cancer by administering the conjugate or pharmaceutical composition.
Treating cancers limited to specified cancer types, including metastases thereof, by administering the conjugate or pharmaceutical composition.
Using the cancer treatment method that includes administering an additional therapeutic agent as part of the treatment regimen.
Using the methods for cancers including ovarian, breast, pancreatic, lung, colon, stomach, liver, kidney, blood cancer, endometrial cancer, thyroid cancer, leukemia, seminomas, melanomas, carcinomas, teratomas, lymphomas, sarcomas, mesotheliomas, neuroblastomas, gliomas, rectal cancer, adrenal cancer, skin cancer, cancer of the brain, cervical cancer, intestinal cancer, intestine-related cancer, head and neck cancer, gastrointestinal cancer, lymph node cancer, esophagus cancer, colorectal cancer, ear, nose and throat (ENT) cancer, and prostate cancer, as well as metastases thereof.
Combination therapy by administering an additional therapeutic agent as part of the treatment method.
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