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-11104968-B2
Publication Date
2021-08-31
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 disclosure relates to antibody-drug conjugate (ADC) compounds formed by site-specific conjugation of a linker drug to an antibody or antigen binding fragment through an engineered cysteine. The engineered cysteine is positioned at a heavy chain site corresponding to heavy chain position 41 according to Kabat numbering, and the linker drug is conjugated through this engineered cysteine.
The described approach emphasizes conjugation using engineered cysteines located in specified structural cavities of the antibody, including Fab cavity and Fc cavity considerations, with reference to Kabat numbering and Eu numbering. The disclosure contrasts this engineered-cysteine site-specific conjugation with alternative conjugation approaches such as lysine or native-disulfide conjugation, and the engineered placement is used to address reduced hydrophobicity, reduced susceptibility to cathepsin B cleavage, and preserved antigen binding.
A linker drug including a cytotoxic payload is conjugated via the engineered cysteine, and the disclosure describes linker drug classes and cleavable linker options including valine-citrulline (vc) and valine-alanine (va). The disclosure reports improved in vivo efficacy and provides example ADC compound formats including duocarmycin derivatives with cleavable vc or va linkers and conjugates with defined drug-to-antibody ratio (DAR), with examples associated with PSMA and 5T4 contexts.
Claims Coverage
The independent claim covers an antibody-drug conjugate compound defined by conjugation through a specific engineered heavy-chain cysteine site at heavy chain position 41, Kabat numbering. The dependent claims refine the ADC by restricting antibody format and target specificity, specifying cytotoxic payload options, selecting cleavable linker types, and further constraining linker/payload and engineered cysteine-related features.
Engineered heavy chain cysteine at position 41 for ADC conjugation
An antibody-drug conjugate compound comprising an antibody or antigen binding fragment thereof having an engineered cysteine at heavy chain position 41, according to Kabat numbering, with a linker drug conjugated through the engineered cysteine.
Cytotoxic payload class defined for the linker drug
The ADC includes a linker drug comprising a cytotoxic drug selected from anthracyclines, duocarmycins, pyrrolobenzodiazepine (PBD) dimers, calicheamicins, maytansinoids, and auristatins.
Named cytotoxic payload options
The cytotoxic drug in the ADC is monomethyl auristatin E (MMAE) or emtansine (DM1).
Human or humanized IgG monoclonal antibody format restriction
The antibody or antigen binding fragment is a human or humanized IgG monoclonal antibody or antigen binding fragment thereof.
Enumerated target-antibody options
The ADC comprises an antibody selected from anti-annexin A1, anti-CD115, anti-CD123, anti-CLL-1, anti-c-MET, anti-MUC1, anti-PSMA, anti-5T4, and anti-TF antibodies.
Cleavable linker selection
The linker drug comprises a cleavable linker selected from valine-citrulline (vc) and valine-alanine (va).
Overall, the claim set defines ADC compounds by a site-specific engineered cysteine at antibody heavy chain position 41 as the conjugation anchor, and further covers selected cytotoxic payload classes and named examples, cleavable linker types, and constrained antibody format and target specificities.
Stated Advantages
Reduced hydrophobicity.
Reduced susceptibility to cathepsin B cleavage.
Preserved antigen binding.
Improved in vivo efficacy.
Documented Applications
Antibody-drug conjugate use for tumor indications including PSMA and 5T4 contexts, supported by example ADC comparisons and xenograft efficacy results.
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