Imprime PGG-Mediated Anti-Cancer Immune Activation Requires Immune Complex Formation.

Autor: Chan AS; Biothera Pharmaceuticals Inc., Eagan, Minnesota, United States of America., Jonas AB; Biothera Pharmaceuticals Inc., Eagan, Minnesota, United States of America., Qiu X; Biothera Pharmaceuticals Inc., Eagan, Minnesota, United States of America., Ottoson NR; Biothera Pharmaceuticals Inc., Eagan, Minnesota, United States of America., Walsh RM; Biothera Pharmaceuticals Inc., Eagan, Minnesota, United States of America., Gorden KB; Biothera Pharmaceuticals Inc., Eagan, Minnesota, United States of America., Harrison B; Biothera Pharmaceuticals Inc., Eagan, Minnesota, United States of America., Maimonis PJ; Biothera Pharmaceuticals Inc., Eagan, Minnesota, United States of America., Leonardo SM; Biothera Pharmaceuticals Inc., Eagan, Minnesota, United States of America., Ertelt KE; Biothera Pharmaceuticals Inc., Eagan, Minnesota, United States of America., Danielson ME; Biothera Pharmaceuticals Inc., Eagan, Minnesota, United States of America., Michel KS; Biothera Pharmaceuticals Inc., Eagan, Minnesota, United States of America., Nelson M; Biothera Pharmaceuticals Inc., Eagan, Minnesota, United States of America., Graff JR; Biothera Pharmaceuticals Inc., Eagan, Minnesota, United States of America., Patchen ML; Biothera Pharmaceuticals Inc., Eagan, Minnesota, United States of America., Bose N; Biothera Pharmaceuticals Inc., Eagan, Minnesota, United States of America.
Jazyk: angličtina
Zdroj: PloS one [PLoS One] 2016 Nov 03; Vol. 11 (11), pp. e0165909. Date of Electronic Publication: 2016 Nov 03 (Print Publication: 2016).
DOI: 10.1371/journal.pone.0165909
Abstrakt: Imprime PGG (Imprime), an intravenously-administered, soluble β-glucan, has shown compelling efficacy in multiple phase 2 clinical trials with tumor targeting or anti-angiogenic antibodies. Mechanistically, Imprime acts as pathogen-associated molecular pattern (PAMP) directly activating innate immune effector cells, triggering a coordinated anti-cancer immune response. Herein, using whole blood from healthy human subjects, we show that Imprime-induced anti-cancer functionality is dependent on immune complex formation with naturally-occurring, anti-β glucan antibodies (ABA). The formation of Imprime-ABA complexes activates complement, primarily via the classical complement pathway, and is opsonized by iC3b. Immune complex binding depends upon Complement Receptor 3 and Fcg Receptor IIa, eliciting phenotypic activation of, and enhanced chemokine production by, neutrophils and monocytes, enabling these effector cells to kill antibody-opsonized tumor cells via the generation of reactive oxygen species and antibody-dependent cellular phagocytosis. Importantly, these innate immune cell changes were not evident in subjects with low ABA levels but could be rescued with exogenous ABA supplementation. Together, these data indicate that pre-existing ABA are essential for Imprime-mediated anti-cancer immune activation and suggest that pre-treatment ABA levels may provide a plausible patient selection biomarker to delineate patients most likely to benefit from Imprime-based therapy.
Competing Interests: Anissa S.H. Chan, Adria Bykowski Jonas, Xiaohong Qiu, Nadine R. Ottoson, Richard M. Walsh, Keith B. Gorden, Ben Harrison, Peter J. Maimonis, Steven Leonardo, Kathleen E. Ertelt, Michael E. Danielson, Kyle S. Michel, Mariana Nelson, Jeremy R. Graff, Myra L. Patchen and Nandita Bose are employed by Biothera Pharmaceuticals Inc. All of the authors, with the exception of P.M. and M.N., own stock in Biothera Pharmaceuticals Inc. Imprime is a product in clinical development and has all the associated patents [WO2007146416, WO2015084732, WO2015510271, WO2015510272]. This does not alter our adherence to all the PLOS ONE policies on sharing data and materials, as detailed online in the guide for authors.
Databáze: MEDLINE
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