EV20-Sap, a novel anti-HER-3 antibody-drug conjugate, displays promising antitumor activity in melanoma

Abstract

Melanoma is the most biologically aggressive skin cancer of well established constitutive and induced resistance to pharmacological treatment. Despite the recent progresses in immunotherapies, many advanced metastatic melanoma patients still face a significant mortality risk. The aggressive nature of this disease sustains an urgent need for more successful, effective drugs. HER-3 - one of the four member of the tyrosin kinase epidermal growth factor receptors (EGFRs) family- is frequently overexpressed in solid tumors, including melanoma. Moreover, up-regulation of HER-3 and its ligand NRGβ-1 are associated with poor prognosis, thus suggesting this receptor as a suitable target for cancer therapy. Several monoclonal antibodies targeting HER-3 are currently available, but preliminary results from clinical testing of these agents reveal a modest efficacy. Thus, a substantial improvement over this immunotherapeutic approach could be offered by an anti-HER-3 based Antibody-Drug Conjugate (ADC). In the present paper, we describe the generation of an ADC obtained by coupling the HER-3 targeting antibody EV20 linked to the plant toxin Saporin (Sap). In vitro, this ADC displays a powerful, specific and target-dependent cytotoxic activity which correlates with the degree of expression and internalization of HER-3 on tumor cells. Furthermore, in a murine melanoma model, EV20-Sap treatment leads to a significant reduction of the number of pulmonary metastasis.

HER3 signaling and targeted therapy in cancer

“…EV20-Sap treatment results in significant reduction of pulmonary metastasis in murine melanoma model. 158 …”

Mechanisms of Receptor Tyrosine-Protein Kinase ErbB-3 (ERBB3) Action in Human Neoplasia

“…Small-molecule inhibitors that bind to the ATPbinding pocket of ERBB3 (TX1-85-1, TX-121-1) also effectively promote ERBB3 degradation, interfere with ERBB3 heterodimerization, and inhibit ERBB3-dependent pathways. 92 Anti-ERBB3 antibodies conjugated to cytotoxic drugs, such as saponin, 93 monomethyl auristatin F, 94 and the topoisomerase I inhibitor DXd (exatecan derivative for ADC), 95 have shown promise in mouse cancer models and human cancer cell lines. Finally, vaccines using peptides derived from ERBB3 exert antitumor effects against breast and pancreatic cancers.…”

An auristatin‐based antibody‐drug conjugate targeting HER3 enhances the radiation response in pancreatic cancer

“…41 To date, uncleavable saporin-or MMAF-conjugated HER3-specific ADCs have been preclinically proposed as monotherapy for melanoma. 42,43 The anti-HER3 antibody patritumab conjugated to a topoisomerase I inhibitor via a cleavable linker is currently tested in phase I/II trials for patients with metastatic breast cancer 44 and has been preclinically demonstrated to be an effective treatment for EGFR-mutant NSCLC with acquired resistance to EGFR TKIs. 45 However, no HER3-specific ADC linked to a cleavable MMAE has been proposed for the radiosensitization of pancreatic tumors.…”