ReachBio Research Labs Offers New Services for ADC Off-target Toxicity and Linker Stability

ReachBio Research Labs (trade name under ReachBio LLC), a CRO specializing in primary cell assay services and products, is now offering off-target toxicity and linker stability assay services for antibody drug conjugates (ADCs).

ReachBio has developed two distinct assay platforms to assess cytotoxicity caused by ADCs. The first platform evaluates off-target toxicity using colony-forming cell (CFC) assays to assess effects on erythroid, myeloid or megakaryocyte progenitors using bone marrow derived from human, NHP, rat and mouse.

The second platform focuses on the stability of various linker constructs. ReachBio adapted the neutrophil differentiation assay described by Zhao et al, whereby neutrophils cause their own demise by releasing enzymes which cleave the payload from the antibody and thus kill developing neutrophils. Using primitive human bone marrow CD34+ cells and specialized cytokine formulations, ReachBio can induce neutrophil development in vitro. By adding client ADCs to this assay platform after the development of the neutrophils, ReachBio scientists can assess the stability of various linker constructs (e.g. single or dual cleavable).

Antibody drug conjugates (ADCs) combine the benefits of both therapeutic monoclonal antibodies (mAb) and potent small molecule cytotoxic drugs. These moieties are connected through linkers that should be stable within systemic circulation, while maintaining the ability to cleave within the mAb-targeted cells to release highly specific payloads. Although ADCs are designed for ‘targeted killing,’ some ADCs appear to have significant ‘off-target’ toxicities causing adverse events that include neutropenia and thrombocytopenia which have necessitated some clinical trials being terminated early.

Dr. Emer Clarke, Chief Scientific Officer at ReachBio, mentions, “As more complex biological drug structures emerge, we see a subsequent rise in new challenges such as off-target toxicity which may be in part be related to the structure. We have clients that are looking for assays that can ‘rank’ a series of such compounds in terms of toxicity. We also have clients that are interested in these new assay platforms to see if they correlate with their in vivo toxicity models, and therefore provide an alternate ‘rapid and less expensive’ way to assess either efficacy or toxicity.”