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-11136633-B2
Publication Date
2021-10-05
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 disclosed invention relates to antibody-drug conjugate (ADC) compounds that use site-specific linker-drug conjugation through engineered cysteine residues. In particular, the ADC includes an antibody or an antigen binding fragment having an engineered cysteine at heavy chain position 41 (according to Kabat numbering), and a linker drug conjugated to the antibody or antigen binding fragment through that engineered cysteine.
The antibody binds an antigen target expressed on the cell surface of tumor or malignancy cells. The described approach addresses deficiencies associated with conventional conjugation by selecting conjugation sites that reduce hydrophobicity and protease-mediated cleavage while preserving antigen binding.
The document associates the selection of antibody conjugation sites with different antibody cavities, including Fab and Fc conjugation sites, and with reduced cathepsin B-mediated cleavage for particular engineered-cysteine positions. Additional embodiments specify an engineered cysteine at heavy chain position 375 (Eu numbering) and exemplary linker-drug classes including duocarmycin derivatives and valine-citrulline (vc) linker systems such as vc-seco-DUBA and vc-MMAE.
Claims Coverage
The claim set includes one independent claim and related dependent claims. The core inventive features center on an ADC treatment method using an antibody-drug conjugate with an engineered cysteine at heavy chain position 41 (Kabat numbering) and an antibody that binds a cell-surface antigen, with additional claims refining anti-5T4 targeting, sequence-defined antibodies, formula constraints, an additional engineered-cysteine position, and optional combination therapy.
Engineered cysteine at heavy chain position 41 for linker-drug conjugation
An ADC comprises an antibody or antigen binding fragment having an engineered cysteine at heavy chain position 41 (according to Kabat numbering) and a linker drug conjugated through said engineered cysteine.
Antibody binding a cell-surface antigen on tumor or malignancy cells
The antibody binds an antigen target expressed on the cell surface of tumor or malignancy cells.
Treatment of human solid tumors or haematological malignancies by administering the ADC
A method of treating human solid tumors or haematological malignancies in a patient in need thereof comprises administering an effective amount of an ADC containing the engineered-cysteine conjugation arrangement and antibody binding to a cell-surface antigen.
Engineered cysteine at heavy chain position 375 (Eu numbering)
An ADC includes an engineered cysteine at heavy chain position 375 (according to Eu numbering) with linker drug conjugation through said engineered cysteine.
Solid tumor applications using anti-5T4 monoclonal antibody
The treatment method is applied to a patient with a specified solid tumor type and uses an anti-5T4 monoclonal antibody in the ADC.
Engineered anti-5T4 ADC defined by sequences SEQ ID NO:8 and SEQ ID NO:11
The anti-5T4 monoclonal antibody used in the ADC includes heavy chain and light chain sequences comprising amino acid sequences SEQ ID NO:8 and SEQ ID NO:11, respectively.
ADC formula (I) constraints including engineered-cysteine at heavy chain position 41 and average DAR
An ADC of formula (I) includes an anti-5T4 monoclonal antibody with an engineered cysteine at heavy chain position 41, where n can be 0-3 and the average DAR m is from 1 to 6, with additional constraints for y and selection of R1 and R2 from specified groups.
Optional combination with one or more therapeutic antibodies and/or chemotherapeutic agents
The method further includes administering an effective amount of one or more therapeutic antibodies and/or chemotherapeutic agents to a patient.
The claim coverage centers on ADC-based treatment methods using site-specific linker-drug conjugation through an engineered cysteine at heavy chain position 41 and an antibody that binds a cell-surface antigen. The claims further narrow embodiments with anti-5T4 targeting, sequence-defined antibodies, formula (I) constraints including average DAR, an additional engineered-cysteine position at heavy chain 375, and optional combination administration.
Stated Advantages
Improved hydrophilicity versus wild-type partially reduced conjugates, supported by hydrophobic interaction chromatography (HIC) retention/relative hydrophobicity.
Maintained in vitro binding and cytotoxic potency against antigen-positive cell lines.
Reduced cathepsin B-mediated cleavage for certain conjugation positions, including HC41C/LC41C.
Improved in vivo efficacy in xenograft models, with monitored tumor growth and body weight changes.
Documented Applications
Treating human solid tumors and haematological malignancies in a patient in need thereof.
Solid tumor treatment examples include breast cancer, gastric cancer, colorectal cancer, ovarian cancer, non-small cell lung cancer (NSCLC), small-cell lung cancer (SCLC), and malignant pleural mesothelioma.
Application to a PSMA-targeting antigen context is described as an in vitro/cell-line potency example.
Application to an anti-5T4-targeting antigen context is described as in vitro binding/cytotoxic potency and in vivo xenograft model context.
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