Abstract
Background & Purpose
Peripheral neuropathy (PN) is a common side effect of chemotherapy and antibody-drug conjugates (ADCs), often caused by off-target toxicity and the bystander effect. Traditional models lack the complexity to fully assess PN mechanisms. This study introduces a human co-culture model of iPSC-derived sensory neurons and primary human Schwann cells to evaluate the neurotoxic effects of chemotherapeutics and ADCs. The model aims to improve drug screening and support high-content screening (HCS) for neurotoxicity assessment.
Methods
- Cell Culture:
- Mono-cultures and co-cultures of human sensory neurons and Schwann cells were plated in multi-well plates.
- Drug Treatment:
- Paclitaxel and Oxaliplatin were tested for chemotherapy-induced peripheral neuropathy effects.
- MMAE and MMAF (as small molecules and ADCs) were assessed for bystander effect contributions to neurotoxicity.
- High-Content Imaging & Analysis:
- Key endpoints measured:
- Neurite length
- Number of branches & processes
- Total cell counts
Results
- Chemotherapeutics:
- Paclitaxel showed a lower X50 value for neurite length in co-culture than in mono-culture, indicating higher toxicity in the presence of Schwann cells.
- Oxaliplatin showed a lower X50 value for neuron count in co-culture compared to mono-culture.
- Antibody-Drug Conjugates (ADCs) & Small Molecules:
- MMAE (high bystander effect ADC) showed greater potency in co-culture, suggesting Schwann cell involvement in neurotoxicity.
- MMAF (low bystander effect ADC) did not show the same potency increase in co-culture.
- Neurotoxicity Mechanisms:
- Both chemotherapeutics and ADCs caused dose-dependent Schwann cell toxicity in co-culture, demonstrating the importance of including Schwann cells in neurotoxicity screening.
Conclusion
The human co-culture model successfully characterizes chemotherapy- and ADC-induced peripheral neuropathy, providing a sensitive, high-content screening tool for neurotoxicity testing. The model’s ability to differentiate bystander effect contributions highlights its potential for drug development and safety assessment.
