Targeting the Activated Allosteric Conformation of the Endothelin Receptor B in Melanoma with an Antibody-drug Conjugate: Mechanisms and Therapeutic Efficacy

Overview

Journal BJC Rep

Publisher Nature Portfolio

Date 2025 Jan 20

PMID 39833448

Authors

Amaury Herbet

Marie Hautiere

Frederic Jean-Alphonse

Delphine Vivier

Christophe Leboeuf

Narciso Costa

Aloise Mabondzo

Guilhem Bousquet

Franck Denat

Eric Reiter

Didier Boquet

Affiliations

Soon will be listed here.

Abstract

Background: Endothelin 1 receptors are one of the drivers of tumor progression in many cancers. Inhibition of their signaling pathways with antagonist drugs has been the subject of numerous clinical trials, but the results have not met expectations probably due to the high endothelin concentrations in the tumor microenvironment and their unusually high affinity for their receptors.

Methods: We previously reported the rendomab B49 antibody (RB49) exhibiting a preferential affinity for the activated conformation of human endothelin B receptor (ET), not displaced by high endothelin levels, and without any pharmacological properties that could inhibit the division of melanoma cells. In this context, we have developed xiRB49-MMAE, a chimeric antibody-drug conjugated (ADC) to monomethyl auristatin E. We have characterized its physicochemical properties, studied its binding mechanisms, and evaluated its therapeutic potential in a preclinical model. Immunohistochemical analysis of metastatic melanoma lymph nodes evaluated RB49 as a diagnostic tool for patient stratification.

Results: xiRB49-MMAE showed high efficacy against melanoma cells and ET xenograft tumor models. IHC studies indicated that 100% of melanoma patient lymph node biopsies were RB49-positive.

Conclusions: xiRB49-MMAE is a promising drug candidate for clinical trials in ET tumors. RB49 could be used as a diagnostic tool for patient stratification.

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