The anti-tumor activity of a neutralizing nanobody targeting leptin receptor in a mouse model of melanoma

• Published in: PloS one Vol. 9; no. 2; p. e89895
• Main Authors: McMurphy, Travis, Xiao, Run, Magee, Daniel, Slater, Andrew, Zabeau, Lennart, Tavernier, Jan, Cao, Lei
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 28.02.2014; Public Library of Science (PLoS)
• Subjects: Adipose tissue; Adiposity - drug effects; Analysis; Animals; Antagonists; Anticancer properties; Antitumor agents; Biology; Blood-brain barrier; Body weight; Body Weight - drug effects; Body weight gain; Brain; Brain research; Brain-derived neurotrophic factor; Cancer; Cancer treatment; Cell Line, Tumor; Colorectal cancer; Cytokines; Diabetes; Drug dosages; Endocrinology; Food intake; Gene therapy; Genetics; Health sciences; Hyperinsulinemia; Hyperinsulinism - chemically induced; Hyperphagia; Hyperphagia - chemically induced; Immunology; Leptin; Leptin - antagonists & inhibitors; Leptin - metabolism; Male; Medicine; Melanoma; Melanoma - drug therapy; Melanoma - therapy; Mice; Mice, Inbred C57BL; Mimicry; Nanobodies; Neutralizing; Obesity; Receptors, Leptin - antagonists & inhibitors; Rodents; Single-Domain Antibodies - pharmacology; Studies; Virology; Weight control; United States > US; Ohio
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0089895

Environmental and genetic activation of a brain-adipocyte axis inhibits cancer progression. Leptin is the primary peripheral mediator of this anticancer effect in a mouse model of melanoma. In this study we assessed the effect of a leptin receptor antagonist on melanoma progression. Local administration of a neutralizing nanobody targeting the leptin receptor at low dose adjacent to tumor decreased tumor mass with no effects on body weight or food intake. In contrast, systemic administration of the nanobody failed to suppress tumor growth. Daily intraperitoneal injection of high-dose nanobody led to weight gain, hyperphagia, increased adiposity, hyperleptinemia, and hyperinsulinemia, and central effects mimicking leptin deficiency. The blockade of central actions of leptin by systemic delivery of nanobody may compromise its anticancer effect, underscoring the need to develop peripherally acting leptin antagonists coupled with efficient cancer-targeting delivery.