Abstract
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.
Highlights
Imprime, a yeast derived soluble β-1,3/1,6 glucan (BTH1677); is currently in clinical development as an intravenously administered immunotherapy in combination with tumor-targeting, anti-angiogenic and immune checkpoint inhibitor antibodies
Using whole blood (WB) from healthy human subjects, we show that ex vivo Imprime treatment triggers a constellation of innate immune responses, including complement activation, chemokine production, and phenotypic activation of neutrophils and monocytes
Classical complement pathway activation is required for Imprime binding We have previously shown that Imprime binding to isolated neutrophils and monocytes requires complement [9]
Summary
A yeast derived soluble β-1,3/1,6 glucan (BTH1677); is currently in clinical development as an intravenously administered immunotherapy in combination with tumor-targeting, anti-angiogenic and immune checkpoint inhibitor antibodies. In a randomized phase II trial, first-line treatment of advanced non-squamous non-small cell lung cancer (NSCLC) patients. Anti-Cancer Immune Effects of Imprime Immune Complexes preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
