Site-specific conjugation of linker drugs to antibodies and resulting ADCs
Inventors
Ariaans, Gerardus Joseph Andreas • Coumans, Rudy Gerardus Elisabeth
Assignees
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Publication Number
US-12180552-B2
Publication Date
2024-12-31
Expiration Date
Abstract
The present invention relates to antibody-drug conjugates (ADCs) wherein a linker drug is site-specifically conjugated to an antibody through an engineered cysteine, and their use as a medicament, notably for the treatment of human solid tumours and haematological malignancies, in particular breast cancer, gastric cancer, colorectal cancer, urothelial cancer, ovarian cancer, uterine cancer, lung cancer, mesothelioma, liver cancer, pancreatic cancer, prostate cancer, and leukaemia.
Core Innovation
The invention relates to an antibody-drug conjugate (ADC) comprising an antibody or antigen binding fragment that contains an engineered cysteine at light chain position 41 according to Kabat numbering. A linker drug is conjugated to the antibody or antigen binding fragment through the engineered cysteine at light chain position 41, and the disclosed ADC framework centers on site-specific conjugation at a specified Kabat light-chain cysteine position.
The document describes ADC design considerations for selecting engineered cysteine locations by comparing Fab cavity and Fc cavity fitting and associated hydrophobicity and protease accessibility. These considerations are used to justify selecting particular engineered cysteine sites and associated conjugation architectures, including engineered-cysteine variants at light chain positions and heavy-chain positions reported with numbering schemes such as Kabat and Eu.
Comparative outcomes are reported for ADCs that use the described engineered-cysteine conjugation sites versus native disulfide or other prior engineered-cysteine sites. The reported comparisons include maintaining similar antigen binding and comparable in vitro cytotoxicity, while reducing hydrophobicity/aggregates and reducing cathepsin B cleavage. The document further reports improved in vivo tumor xenograft efficacy for the disclosed site-specific ADCs.
Claims Coverage
The independent claim covers an ADC defined by an antibody or antigen binding fragment with an engineered cysteine at light chain position 41 (Kabat numbering) and a linker drug conjugated through that engineered cysteine. The claim set further refines the ADC with additional positional cysteine options, linker payload selections, and structural formula constraints including DAR-related variables.
Kabat light-chain position 41 engineered cysteine conjugation
An ADC comprising an antibody or antigen binding fragment thereof having an engineered cysteine at light chain position 41 (Kabat numbering), wherein a linker drug is conjugated to said antibody or antigen binding fragment through said engineered cysteine.
Cytotoxic drug payload selection for linker-drug
The linker drug comprises a cytotoxic drug selected from anthracyclines, duocarmycins, pyrrolobenzodiazepine (PBD) dimers, calicheamicins, maytansinoids, and auristatins.
Linker-drug with MMAE or DM1 payloads
The cytotoxic drug is monomethyl auristatin E (MMAE) or emtansine (DM1).
Eu heavy-chain position 375 engineered cysteine conjugation
The antibody or antigen binding fragment includes an engineered cysteine at heavy-chain position 375 (Eu numbering), wherein the linker-drug is conjugated through that engineered cysteine.
Cleavable linker selection as vc or va
The linker-drug has a cleavable linker selected from valine-citrulline (vc) or valine-alanine (va).
Formula-defined ADC constraints with defined DAR range
An ADC defined by formula (I) wherein the antibody or antigen-binding fragment contains an engineered cysteine at light chain position 41, with n=0, 1, or 2, an average DAR of 1 to 6 (m), and structural variables including R1 selected from an indicated group, y=1-16, and R2 selected from an indicated group.
Across the independent claim and its dependents, the core coverage is an ADC with site-specific conjugation via an engineered cysteine at light chain position 41 (Kabat numbering), optionally with additional engineered cysteine positioning at a heavy-chain Eu site, and with selected linker/drug payload types and structural constraints including DAR-related ranges and formula-based variable definitions.
Stated Advantages
Similar antigen binding.
Comparable in vitro cytotoxicity.
Reduced hydrophobicity/aggregates.
Reduced cathepsin B cleavage.
Improved in vivo tumor xenograft efficacy.
Documented Applications
Treatment of solid tumours.
Treatment of haematological malignancies.
Therapeutic emphasis on particularly preferred anti-PSMA ADCs.
Therapeutic emphasis on particularly preferred anti-5T4 ADCs.
Examples of solid-tumour indications listed include breast cancer, gastric cancer, colorectal cancer, urothelial cancer, ovarian cancer, uterine cancer, lung cancer, mesothelioma, liver cancer, pancreatic cancer, and prostate cancer.
Leukaemia is listed as a haematological malignancy indication.
Tumor xenograft model use is described, including LNCaP-C4.2 and PA-1 ovarian cancer model.
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