Functional ADC Safety Profiling with iPSC-Derived Human Tissues

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Part 3: Functional ADC Safety Profiling with iPSC-Derived Human Tissues

Antibody–drug conjugates (ADCs) are a rapidly expanding class of targeted therapeutics, yet clinical development is frequently limited by dose-limiting and off-target toxicities. Traditional preclinical models often lack human relevance and fail to predict tissue-specific safety liabilities. There is increasing regulatory and scientific interest in New Approach Methodologies (NAMs) that leverage human-based systems to improve translational predictivity. Here, we describe a fully human, induced pluripotent stem cell (iPSC)-derived multi-tissue platform for functional safety profiling of biologics. A panel of seven physiologically relevant human iPSC-derived tissues was selected based on in silico analysis of epidermal growth factor receptor (EGFR) expression across human organs. Cytotoxicity was assessed using real-time, label-free impedance measurements, enabling dynamic evaluation of tissue-specific responses. 

The platform was evaluated using cetuximab–monomethyl auristatin E (MMAE) as a model ADC. At supratherapeutic exposure (100 µg/mL), cetuximab-MMAE induced pronounced cytotoxicity in melanocytes, with moderate effects in lung and liver models and minimal effects in cardiac, central nervous system, vascular, and intestinal tissues. At clinically relevant exposure (1 µg/mL), toxicity was largely attenuated, with only low residual sensitivity in melanocytes. These dose-dependent responses align with EGFR expression patterns and recapitulate the known clinical safety profile of cetuximab. This iPSC-derived multi-tissue platform represents a NAM-aligned approach for mechanistically relevant safety assessment of ADCs. It enables early identification of on-target/off-tumor liabilities and supports improved translational confidence in preclinical decision-making.

Presenter: Sanne Holt, Ph.D. (Associate Director Immuno-Oncology, Ncardia Services B.V.)

With over 10 years of experience in immuno-oncology and translational research, Sanne specializes in advancing large molecules and cell therapies from early discovery to IND-enabling studies. At Ncardia, she manages a scientific team and drives innovation in efficacy and safety testing of novel drug therapies on human iPSC-derived cell models.

Previously, she held leadership roles at Merus N.V. and Charles River Laboratories, where she managed cross-functional teams and delivered impactful research solutions. She holds a PhD from King’s College London and is passionate about supporting the translation of cutting-edge science into real-world therapies.