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

ABSTRACT: Imprime PGG (Imprime), an intravenously-administered, soluble ?-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-? 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.

SUBMITTER: Chan AS

PROVIDER: S-EPMC5094785 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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

Chan Anissa S H AS Jonas Adria Bykowski AB Qiu Xiaohong X Ottoson Nadine R NR Walsh Richard M RM Gorden Keith B KB Harrison Ben B Maimonis Peter J PJ Leonardo Steven M SM Ertelt Kathleen E KE Danielson Michael E ME Michel Kyle S KS Nelson Mariana M Graff Jeremy R JR Patchen Myra L ML Bose Nandita N

PloS one 20161103 11

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 im ...[more]

PMID: 27812183

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Project description:BackgroundPeptidyl arginine deiminase 4 (PAD4) is an enzyme that converts arginine into citrulline. PAD4 is expressed in neutrophils that, when activated, can drive the formation of neutrophil extracellular traps (NETs). Uncontrolled activation of PAD4 and subsequent citrullination of proteins is increasingly recognized as a driver of (auto)immune diseases. Currently, our understanding of PAD4 structure-function relationships and activity control in vivo is incomplete.AimsTo provide the current state-of-the-art on PAD4 structure-activity relationships and involvement of PAD4 in autoimmune disorders as well as in thrombo-inflammatory disease.Materials & methodsLiterature review and molecular modelling Results: In this review, we used molecular modelling to generate a three-dimensional structure of the complete PAD4 molecule. Using our model, we discuss the catalytic conversion of the arginine substrate to citrulline. Besides mechanistic insight into PAD4 function, we give an overview of biological functions of PAD4 and mechanisms that influence its activation. In addition, we discuss the crucial role of PAD4-mediated citrullination of histones during the formation of NETs. Subsequently, we focus on the role of PAD4-mediated NET formation and its role in pathogenesis of rheumatoid arthritis, sepsis and (immune-)thrombosis. Finally, we summarize current efforts to design different classes of PAD4 inhibitors that are being developed for improved treatment of autoimmune disorders as well as thrombo-inflammatory disease.DiscussionAdvances in PAD4 structure-function are still necessary to gain a complete insight in mechanisms that control PAD4 activity in vivo. The involvement of PAD4 in several diseases signifies the need for a PAD4 inhibitor. Although progress has been made to produce an isotype specific and potent PAD4 inhibitor, currently no PAD4 inhibitor is ready for clinical use.ConclusionMore research into PAD4 structure and function and into the regulation of its activity is required for the development of PAD4 specific inhibitors that may prove vital to combat and prevent autoimmune disorders and (thrombo)inflammatory disease.

Dataset Information

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

Publications

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

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