EV20-mediated delivery of cytotoxic auristatin MMAF exhibits potent therapeutic efficacy in cutaneous melanoma

JOURNAL OF CONTROLLED RELEASE

卷:277

Article

Capone, Emily¹  Lamolinara, Alessia²  D'Agostino, Daniela¹  Rossi, Cosmo³  De laurenzi, Vincenzo¹  Iezzi, Manuela²  Iacobelli, Stefano⁴  Sala, Gianluca^1,4 

[1] Univ G dAnnunzio, Dept Med Oral & Biotechnol Sci, Chieti, Italy

[2] Univ G dAnnunzio, CeSi Met, Dept Med & Aging Sci, Chieti, Italy

[3] Aging Res Ctr & Translat Med CeSI Met, Chieti, Italy

[4] MediaPharma Srl, Via Colonnetta 50-A, Chieti, Italy

关键词: Antibody-drug conjugate (ADC);    HER-3;    Melanoma;    BRAF;    Vemurafenib;   

DOI  :  10.1016/j.jconrel.2018.03.016

来源: Elsevier

【 摘 要 】

Cutaneous melanoma is one of the cancers with the fastest rising incidence and in its advanced metastatic form is a highly lethal disease. Despite the recent approval of several new drugs, the 5-year overall survival rate for advanced cutaneous melanoma is still below 20% and therefore, the development of novel treatments remains a primary need. Antibody-Drug Conjugates are an emerging novel class of anticancer agents, whose preclinical and clinical development has recently seen a remarkable increase in different tumors, including melanoma. Here, we have coupled the anti-HER-3 internalizing antibody EV20 to the cytotoxic drug monomethyl auristatin F (MMAF) to form a novel antibody-drug conjugate (EV20/MMAF). In a panel of human melanoma cell lines, this novel ADC shows a powerful, specific and target-dependent cell killing activity, independently of BRAF status. Efficacy studies demonstrated that a single administration of EV20/MMAF leads to a long-lasting tumor growth inhibition. Remarkably, the effect of this novel ADC was superior to the BRAF inhibitor vemurafenib in preventing kidney, liver and lung melanoma metastases. Overall, these results highlight EV20/MMAF as a novel ADC with promising therapeutic efficacy, warranting extensive pre-clinical evaluation in melanoma with high levels of HER-3 expression.

【 授权许可】

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