title: Peripheral neuropathy with microtubule inhibitor containing antibody drug conjugates: Challenges and perspectives in translatability from nonclinical toxicology studies to the clinic.
abstract: 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.
authors: Safety Assessment, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA. Electronic address: Staggn@gene.com.
authors: Nicola J
authors: NJ
authors: Stagg
authors: Department of Preclinical & Translational Pharmacokinetics & Pharmacodynamics, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors: Ben-Quan
authors: BQ
authors: Shen
authors: Drug Safety, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors: Flavia
authors: F
authors: Brunstein
authors: Clinical Pharmacology, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors: Chunze
authors: C
authors: Li
authors: Department of Preclinical & Translational Pharmacokinetics & Pharmacodynamics, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors: Amrita V
authors: AV
authors: Kamath
authors: Safety Assessment, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors: Fiona
authors: F
authors: Zhong
authors: Safety Assessment, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors: Melissa
authors: M
authors: Schutten
authors: Clinical Sciences, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors: Bernard M
authors: BM
authors: Fine
mesh_terms: D000818:Animals; D000906:Antibodies / Q000737:chemistry / Q000633:toxicity*; D000970:Antineoplastic Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D004339:Drug Compounding; D004347:Drug Interactions; D006801:Humans; D018796:Immunoconjugates / Q000737:chemistry / Q000493:pharmacokinetics / Q000633:toxicity*; D023421:Models, Animal; D009842:Oligopeptides / Q000737:chemistry / Q000493:pharmacokinetics / Q000633:toxicity*; D010523:Peripheral Nervous System Diseases / Q000139:chemically induced*; D010597:Pharmacogenetics; D018570:Risk Assessment; D013045:Species Specificity; D013997:Time Factors; D018675:Toxicity Tests / Q000379:methods*; D057170:Translational Research, Biomedical / Q000379:methods*; D050257:Tubulin Modulators / Q000737:chemistry / Q000493:pharmacokinetics / Q000633:toxicity*
chemical_list: D000906:Antibodies; D000970:Antineoplastic Agents; D018796:Immunoconjugates; D009842:Oligopeptides; D050257:Tubulin Modulators; C495575:monomethyl auristatin E
keywords: Antibody drug conjugate (ADC); Chemotherapy; Clinical; Microtubules; Monomethyl auristatin E (MMAE); Nonclinical; Peripheral neuropathy (PN)