Guiding the Killer and Bringing in Accomplices: Bispecific Antibody Treatment for Malignant Melanoma

The Journal of Investigative Dermatology
Eva Szegezdi, Martin Leverkus

Abstract

Discovery of oncogene and immune checkpoint targeting has transformed melanoma therapy in the last 5 years. However, treatment of primary or secondary drug-resistant melanoma remains a challenge. Agents designed to activate the cell death machinery directly, for example by activating the death receptors expressed by melanoma cells, could break drug resistance, and they may achieve long-lasting therapeutic success. He et al. report their studies of an MCSPxDR5 bispecific, tetravalent antibody that can simultaneously target death receptor 5 (DR5, TRAIL-R2) and melanoma-associated chondroitin sulfate proteoglycan (MCSP). This antibody can exert strong and selective DR5-dependent cytotoxic activity against MCSP-expressing melanoma cells. Crosslinking of the antibody with Fcγ-receptors increased the cytotoxic potential further, without compromising its selectivity. This approach offers a novel immunotherapeutic tool via coupling of three cooperating processes: delivering the death receptor agonist to the malignant cell population, potent activation of DR5-mediated cell death signaling, and recruitment of Fcγ-receptor-carrying immune cells that can mount an immune response against the tumor cells.

References

Jan 11, 2011·Cancer Letters·Marco de BruynWijnand Helfrich
Mar 8, 2011·Cell·Douglas Hanahan, Robert A Weinberg
May 17, 2013·Current Cancer Drug Targets·Anatoly B UzdenskyMikhail Y Bibov
Mar 13, 2014·Seminars in Immunology·David A KnorrJeffrey S Miller
Nov 2, 2014·Nature Reviews. Drug Discovery·Ken Garber
Apr 23, 2015·Proceedings of the National Academy of Sciences of the United States of America·Pradeep M NairAvi Ashkenazi
Sep 12, 2015·Cell Death & Disease·P GeserickM Leverkus

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Citations

Oct 25, 2017·Antibodies·Agathe Dubuisson, Olivier Micheau
Dec 31, 2017·Biomedicine & Pharmacotherapy = Biomédecine & Pharmacothérapie·Adel NaimiSaeed Solali

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