1. Academic Validation
  2. Efficacy of the Antibody-Drug Conjugate W0101 in Preclinical Models of IGF-1 Receptor Overexpressing Solid Tumors

Efficacy of the Antibody-Drug Conjugate W0101 in Preclinical Models of IGF-1 Receptor Overexpressing Solid Tumors

  • Mol Cancer Ther. 2020 Jan;19(1):168-177. doi: 10.1158/1535-7163.MCT-19-0219.
Barbara Akla 1 Matthieu Broussas 1 Noureddine Loukili 1 Alain Robert 1 Charlotte Beau-Larvor 1 Martine Malissard 1 Nicolas Boute 1 Thierry Champion 1 Jean-Francois Haeuw 2 Alain Beck 1 Michel Perez 3 Cyrille Dreyfus 1 Mariya Pavlyuk 3 Eric Chetaille 3 Nathalie Corvaia 1
Affiliations

Affiliations

  • 1 Institut de Recherche Pierre Fabre, Centre d'Immunologie, Saint-Julien-en-Genevois, France.
  • 2 Institut de Recherche Pierre Fabre, Centre d'Immunologie, Saint-Julien-en-Genevois, France. jean.francois.haeuw@pierre-fabre.com.
  • 3 Institut de Recherche Pierre Fabre, Oncology Innovation Unit, Toulouse, France.
Abstract

The insulin-like growth factor type 1 receptor (IGF-1R) is important in tumorigenesis, and its overexpression occurs in numerous tumor tissues. To date, therapeutic approaches based on mAbs and tyrosine kinase inhibitors targeting IGF-1R have only shown clinical benefit in specific patient populations. We report a unique IGF-1R-targeted antibody-drug conjugate (ADC), W0101, designed to deliver a highly potent cytotoxic Auristatin derivative selectively to IGF-1R overexpressing tumor cells. The mAb (hz208F2-4) used to prepare the ADC was selected for its specific binding properties to IGF-1R compared with the Insulin Receptor, and for its internalization properties. Conjugation of a novel Auristatin derivative drug linker to hz208F2-4 did not alter its binding and internalization properties. W0101 induced receptor-dependent cell cytotoxicity in vitro when applied to various cell lines overexpressing IGF-1R, but it did not affect normal cells. Efficacy studies were conducted in several mouse models expressing different levels of IGF-1R to determine the sensitivity of the tumors to W0101. W0101 induced potent tumor regression in certain mouse models. Interestingly, the potency of W0101 correlated with the expression level of IGF-1R evaluated by IHC. In an MCF-7 breast Cancer model with high-level IGF-1R expression, a single injection of W0101 3 mg/kg led to strong inhibition of tumor growth. W0101 provides a potential new therapeutic option for patients overexpressing IGF-1R. A first-in-human trial of W0101 is currently ongoing to address clinical safety.

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