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-10407743-B2
Publication Date
2019-09-10
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 tumors 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 compound comprising an antibody or an antigen binding fragment thereof and a linker drug. The linker drug is conjugated to the antibody or antigen binding fragment through an engineered cysteine at heavy chain position 41 according to Kabat numbering.
The antibody-drug conjugate is defined to have the formula (I) with structural parameters including n, m, R1, y, and R2. The invention specifies that n is 0, 1, 2, or 3 and that m represents an average DAR of from 1 to 6, with preferred selections and ranges for the defined parameters.
The invention emphasizes engineered-cysteine site-specific conjugation at defined heavy-chain positions to support ADC stability and cleavage-related behavior, including cathepsin B cleavage. Documented results include in vivo xenograft tumor models using anti-PSMA and anti-5T4 and in vitro data addressing binding, cytotoxicity, and cathepsin B cleavage.
Claims Coverage
The independent claim is clm-00001. It contains the core inventive structure centered on an ADC with a linker drug site-specifically conjugated via an engineered cysteine at a defined Kabat heavy-chain position, together with formula (I) constraints and parameter selections.
Engineered-cysteine conjugation at Kabat heavy-chain position 41
An antibody-drug conjugate compound comprising an antibody or antigen binding fragment thereof and a linker drug conjugated to the antibody or antigen binding fragment through an engineered cysteine at heavy chain position 41 according to Kabat numbering.
ADC formula (I) with constrained n and average DAR m
The antibody-drug conjugate has the formula (I), wherein n is 0, 1, 2, or 3 and m represents an average DAR of from 1 to 6, with additional selections for R1, y, and R2 as specified in the claim.
Overall, the claim coverage is anchored by site-specific conjugation through an engineered cysteine at Kabat heavy-chain position 41, combined with an ADC defined by formula (I) and parameter constraints on n, average DAR m, and the selections for R1, y, and R2.
Stated Advantages
Improved ADC stability, including cathepsin B cleavage-related behavior.
Improved in vivo efficacy supported by xenograft tumor models.
Enhanced in vitro binding and cytotoxicity relative to the described ADC embodiments.
Documented Applications
Therapeutic use as a medicament, including use of the antibody-drug conjugate and pharmaceutical compositions in lyophilized powder or frozen solution forms.
Tumor xenograft models using antibodies directed to PSMA and 5T4, including in vivo evaluation in those models.
In vitro evaluation including binding, cytotoxicity, and cathepsin B cleavage.
Combination therapy context described as combination with therapeutic antibodies and/or chemotherapeutic agents.
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