Nicola Stagg
Genentech, USA
Title: Peripheral neuropathy with microtubule inhibitor containing antibody drug conjugates: Challenges and perspectives in translatability from nonclinical toxicology studies to the clinic
Biography
Biography: Nicola Stagg
Abstract
Antibody drug conjugates (ADC) consist of potent cytotoxic drugs conjugated to antibodies via chemical linkers, which enables specific targeting of tumor cells while reducing systemic exposure to the cytotoxic drug to improve the therapeutic window of chemotherapy drugs. The valine citrulline monomethyl auristatin E (vcMMAE) ADC platform (conventional linker-drug conjugation) has shown promising clinical activity in a variety of cancers, but peripheral neuropathy (PN) has been observed in the clinic but not in nonclinical toxicology studies. We evaluated four possible hypotheses for the lack of translatability of PN in nonclinical toxicology studies with conventional vcMMAE ADCs: 1) exposure differences; 2) sensitivity of the animal model; 3) differences in how ADC properties manifest; and 4) susceptibility of clinical population. The result of this hypothesis-based approach identified several challenges with trying to model the PN observed in late stage oncology patients in our nonclinical toxicology studies with MTI containing ADCs due to a combination of factors related to all four hypotheses. However, it also enabled us to more systematically determine if a better in vivo animal model could be employed to improve translatability. While many data gaps still remain; increasing duration of exposure and incorporating an expanded neurohistopathology assessment of peripheral nerves in our nonclinical toxicology studies may enable us to reproduce the PN observed with conventional vcMMAE ADCs. The ultimate goal is to be able to have a model to screen the next generation MTI-ADCs for reduced incidence and severity of peripheral neuropathy.