Mechanistic PKPD to Overcome Translational Considerations for Antibody Drug Conjugates (ADC) and THIOMABs (TDCS)—Nonclinical to First in Human and Beyond 2013

Antibody-drug conjugates (ADCs) and THIOMABs (TDCs) represent promising therapeutic options in malignancy as these agents combined the antibody targeting potential with a cytotoxic payload (e.g. maytansinoids, calicheamicin, and auristatins) delivered directly to the tumor cells. Mechanistic PK-PD models plays a critical role in characterizing exposure-response relationships in cross reactive non-clinical species, evaluating the impact of the drug-to-antibody (DAR) ratio on PK in non-human primate studies, describing the target mediated drug disposition that can be observed with ADCs. Furthermore, this course will highlight the use of preclinical ADC-specific parameters that can be used to develop mechanistic models. The aim of this short course is to discuss mechanistic model based approaches that can be exercised to improve ADC developability for first in man translation and to improve strategies for secondary indications. Both ADCs and TDCs require the design of appropriate preclinical studies for clinical dose selection and further development to ensure a competitive entrance on the market; during this course specific case examples such as T-Dm1 will be used to illustrate the role of mechanistic models in ADC development.
Upon completion of the short course participants should be able to 1) describe important ADC specific parameters that can be used to develop mechanistic models for characterization of PK and/or PK/PD, 2) identify ADCs currently approved and describe differences in the payloads and linker properties, and 3) describe methods employed for dose selection of ADCs and proposing dose selection for secondary indications as well.