Peripheral neuropathy with microtubule inhibitor containing antibody drug conjugates: Challenges and perspectives in translatability from nonclinical toxicology studies to the clinic

• Published in: Regulatory toxicology and pharmacology Vol. 82; pp. 1 - 13
• Main Authors: Stagg, Nicola J., Shen, Ben-Quan, Brunstein, Flavia, Li, Chunze, Kamath, Amrita V., Zhong, Fiona, Schutten, Melissa, Fine, Bernard M.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Inc 01.12.2016
• Subjects: Animals; Antibodies - chemistry; Antibodies - toxicity; Antibody drug conjugate (ADC); Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacokinetics; Antineoplastic Agents - toxicity; Chemotherapy; Clinical; Dose-Response Relationship, Drug; Drug Compounding; Drug Interactions; Humans; Immunoconjugates - chemistry; Immunoconjugates - pharmacokinetics; Immunoconjugates - toxicity; Microtubules; Models, Animal; Monomethyl auristatin E (MMAE); Nonclinical; Oligopeptides - chemistry; Oligopeptides - pharmacokinetics; Oligopeptides - toxicity; Peripheral Nervous System Diseases - chemically induced; Peripheral neuropathy (PN); Pharmacogenetics; Risk Assessment; Species Specificity; Time Factors; Toxicity Tests - methods; Translational Medical Research - methods; Tubulin Modulators - chemistry; Tubulin Modulators - pharmacokinetics; Tubulin Modulators - toxicity; Chemotherapy; Monomethyl auristatin E (MMAE); Microtubules; Clinical; Peripheral neuropathy (PN); Antibody drug conjugate (ADC); Nonclinical
• ISSN: 0273-2300; 1096-0295
• DOI: 10.1016/j.yrtph.2016.10.012

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 and improving the therapeutic window. The valine citrulline monomethyl auristatin E (vcMMAE, conventional linker-drug) ADC platform has shown promising clinical activity in several cancers, but peripheral neuropathy (PN) is a frequent adverse event leading to treatment discontinuation and dose reduction. This was not predicted based on nonclinical toxicology studies in monkeys or rats treated with vcMMAE ADCs. We evaluated four hypotheses for the lack of translatability of PN with vcMMAE ADCs: 1) species differences in exposure; 2) insensitivity of animal models; 3) species differences in target biology and other vcMMAE ADC properties in peripheral nerves and 4) increased susceptibility of patient population. The result of this hypothesis-based approach identified opportunities to improve the predictivity of PN in our animal models by increasing duration of exposure and adding an expanded neurohistopathology assessment of peripheral nerves. The utility of a predictive animal model would be to provide possible mitigation strategies in the clinic with vcMMAE ADCs and help to screen the next generation microtubule inhibitor (MTI) ADCs for reduced PN. •Peripheral neuropathy (PN) in patients with vcMMAE ADCs not observed pre-clinically.•Evaluated four hypotheses for the lack of translatability of PN with vcMMAE ADCs.•Identified opportunities to improve the predictivity of PN in our animal models.•A more predictive PN animal model for ADCs will be invaluable for drug development.