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  3. A mouse model of sensory neuropathy induced by a long course of monomethyl-auristatin E treatment

A mouse model of sensory neuropathy induced by a long course of monomethyl-auristatin E treatment

  • Toxicol Appl Pharmacol. 2023 Jul 5;116624. doi: 10.1016/j.taap.2023.116624.
Simon Frachet 1,  Aurore Danigo 2,  Mathilde Duchesne 3,  Laurence Richard 4,  Franck Sturtz 5,  Laurent Magy 6,  Claire Demiot 7
Affiliations

Affiliations

  • 1 NeurIT (Neuropathies et Innovations Thérapeutiques) UR 20218, Faculty of Medicine and Pharmacy, University of Limoges, Limoges 87025, France; Department of Neurology, Reference Center for Rare Peripheral Neuropathies, University Hospital of Limoges, Limoges 87042, France. Electronic address: simon.frachet@unilim.fr.
  • 2 NeurIT (Neuropathies et Innovations Thérapeutiques) UR 20218, Faculty of Medicine and Pharmacy, University of Limoges, Limoges 87025, France. Electronic address: aurore.danigo@unilim.fr.
  • 3 NeurIT (Neuropathies et Innovations Thérapeutiques) UR 20218, Faculty of Medicine and Pharmacy, University of Limoges, Limoges 87025, France; Department of Neurology, Reference Center for Rare Peripheral Neuropathies, University Hospital of Limoges, Limoges 87042, France; Department of Pathology, University Hospital of Limoges, Limoges 87042, France. Electronic address: mathilde.duchesne@unilim.fr.
  • 4 NeurIT (Neuropathies et Innovations Thérapeutiques) UR 20218, Faculty of Medicine and Pharmacy, University of Limoges, Limoges 87025, France; Department of Neurology, Reference Center for Rare Peripheral Neuropathies, University Hospital of Limoges, Limoges 87042, France; Department of Pathology, University Hospital of Limoges, Limoges 87042, France. Electronic address: laurence.richard@unilim.fr.
  • 5 NeurIT (Neuropathies et Innovations Thérapeutiques) UR 20218, Faculty of Medicine and Pharmacy, University of Limoges, Limoges 87025, France. Electronic address: franck.sturtz@unilim.fr.
  • 6 NeurIT (Neuropathies et Innovations Thérapeutiques) UR 20218, Faculty of Medicine and Pharmacy, University of Limoges, Limoges 87025, France; Department of Neurology, Reference Center for Rare Peripheral Neuropathies, University Hospital of Limoges, Limoges 87042, France. Electronic address: laurent.magy@unilim.fr.
  • 7 NeurIT (Neuropathies et Innovations Thérapeutiques) UR 20218, Faculty of Medicine and Pharmacy, University of Limoges, Limoges 87025, France. Electronic address: claire.demiot@unilim.fr.
PMID: 37419214 DOI: 10.1016/j.taap.2023.116624
Abstract

Antibody-drug conjugates (ADCs) are Anticancer drugs consisting of a monoclonal antibody, targeting selective tumor antigens, to which has been frequently associated a highly potent cytotoxic agent, the monomethyl Auristatin E (MMAE) using a chemical linker. MMAE is a tubulin polymerization inhibitor derived from dolastin-10. These MMAE-ADCs are responsible for peripheral nerve toxicities. Our objective was to develop and characterize a mouse model of MMAE-induced peripheral neuropathy induced by free MMAE injections. MMAE was injected in Swiss mice at 50 μg/kg i.p. every other day for 7 weeks. Assessments of motor and sensory nerve functions were performed once a week on MMAE and Vehicle-treated mice. Sciatic nerve and paw skin were removed at the end of experiment for subsequent immunofluorescence and morphological analysis. MMAE did not affect motor coordination, muscular strength and heat nociception, but significantly induced tactile allodynia in MMAE-treated mice compared with Vehicle-treated mice from day 35 to day 49. MMAE significantly reduced myelinated and unmyelinated axon densities in sciatic nerves and led to a loss of intraepidermal nerve fiber in paw skin. In summary, long course of low dose of MMAE induced a peripheral sensory neuropathy associated with nerve degeneration, without general state alteration. This model may represent a ready accessible tool to screen neuroprotective strategies in the context of peripheral neuropathies induced by MMAE-ADCs.

Keywords

Antibody-drug conjugate; Chemotherapy; Monomethyl auristatin E; Mouse model; Neuropathic pain; Peripheral neuropathy.

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