Buildable linkers: Site-Specific Antibody-Drug Conjugates with Well-Defined Payloads 2308812
TL;DR
The benefits of creating a buildable drug scaffold that’s accommodating for achieving exact payload conjugated at a specific site on Trastuzumab are shown, which will enable all therapeutic antibodies to be conjugated in a uniform manner, accelerating the advancing field of ADC therapeutics.
Abstract
Immunotherapy is experiencing rapid growth by increasingly its use of antibody drug conjugates (ADC). Antibodies are a desired vehicle for immunotherapy because they can deliver a drug to a precise cellular location. Heterogenous conjugates have been shown to affect stability, efficacy and binding to intended target. Successful cellular internalization of an ADC with the controlled release of the cytotoxic drug is required for an effective ADC. The creation of a site-specific, tailor-made ADC with a buildable scaffold is expected to increase an ADC’s functional efficacy and its sensitivity in immunoassays. The well-established Trastuzumab is conjugated to various linker structures and using NHS chemistry with 4 molar excesses to generate conjugates that range in degree of labeling (DOL) from 3-14. Trastuzumab site specific conjugates have a buildable scaffold that corresponds to the NHS DOLs. The performance of the antibody conjugates is compared by immunoassay results, including immunofluorescence (IF) and cell viability assay. Antibody drug conjugates that are generated using NHS and site-specific chemistry methods show that lower degrees of labeling for NHS and site specific are comparable in binding results. However, as the DOL increases with high labeling and size of the scaffold grows, there’s a distinction between the effectiveness of NHS and site-specific conjugates with expanding drug scaffolds. Antibody drug conjugates (ADC) provide the specificity of the monoclonal antibody with the precise delivery of a covalently labeled cytotoxic drug. Therefor generating an ADC that is homogenous will mitigate the undesirable effects of a heterogenous conjugate. Here we show the benefits of creating a buildable drug scaffold that’s accommodating for achieving exact payload conjugated at a specific site on Trastuzumab. This approach will enable all therapeutic antibodies to be conjugated in a uniform manner, accelerating the advancing field of ADC therapeutics. National Science Foundation EPSCoR Award #2119237 Technological Innovations in Immunology (TECH)