A Multifunctional Pre-Clinical Workstream to Advance ADC’s From Discovery to FIH Dosing

In this presentation I will lay out the interdisciplinary workflow for the pre-clinical development of antibody drug conjugates (ADC’s). Specifically, I’ll cover the activities performed by protein engineering, pharmacology, chemistry, toxicology and Pre-clinical pharmacokinetics to select the appropriate linker-payload and antibody prior to conjugation. Pharmacokinetic/ADME data informs chemistry, protein engineering and pharmacology of potential concerns and/or issues. Optimization occurs in an iterative fashion between DMPK and chemistry to meet the requirements of design features such as stable vs cleavable linker. ADMET properties of payload (e.g. permeability, metabolic stability, hERG, transporter liabilities) need to be determined and potentially optimized in close collaboration with chemistry.
Full characterization of the drug disposition requires an analytical strategy that includes monitoring of ADC, total antibody (TAB), payload and potential metabolites thereof. Stage appropriate assays are required and require good communication between DMPK and the Bioanalytical Team to ensure timely methods development to assess plasma and tissue concentrations of TAB, ADC and payload. Exposure data from efficacy studies is required to establish PKPD relationships. The learnings from PK studies feed into the design of toxicology studies and inform the manufacturing team of material requirements. The strategy for the toxicology program involves assessing cross reactivity in various species, the novelty of the payload and its metabolism across species. Pharmacometricians will perform modeling and simulation to establish the safe starting and efficacious dose and provide guidance for material requirements during early clinical development. In conclusion, an efficient preclinical development program relies on strong interdisciplinary relationships, which start with an appropriate team composition.