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

• Published in: PloS one Vol. 11; no. 11; p. e0165909
• Main Authors: Chan, Anissa S. H., Jonas, Adria Bykowski, Qiu, Xiaohong, Ottoson, Nadine R., Walsh, Richard M., Gorden, Keith B, Harrison, Ben, Maimonis, Peter J., Leonardo, Steven M., Ertelt, Kathleen E., Danielson, Michael E., Michel, Kyle S., Nelson, Mariana, Graff, Jeremy R., Patchen, Myra L., Bose, Nandita
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 03.11.2016; Public Library of Science (PLoS)
• Subjects: Activation; Angiogenesis; Antibodies; Antigen-Antibody Complex - immunology; Antigen-Antibody Complex - metabolism; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Arthritis; Beta glucan; beta-Glucans - chemistry; beta-Glucans - immunology; beta-Glucans - pharmacology; Biology and Life Sciences; Biomarkers; Cancer; Cancer treatment; Cell activation; Clinical trials; Complement; Complement activation; Complement receptor 3; Complex formation; Effector cells; Glucan; HEK293 Cells; Humans; Immune response; Immune system; Immunity, Innate - drug effects; Immunoglobulins; Immunology; Leukocytes (neutrophilic); Lymphoma; Lymphomas; Macrophage-1 Antigen - metabolism; Medical research; Medicine and Health Sciences; Monocytes; Neutrophils; Opsonization; Oxygen; Phagocytosis; Pharmaceuticals; Pretreatment; Proteins; Reactive oxygen species; Receptors, IgG - metabolism; Research and Analysis Methods; Supplementation; Supplements; Tumor cells; β-Glucan; United States > US; Minnesota
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0165909

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.