Imprime PGG-Mediated Anti-Cancer Immune Activation Requires Immune Complex Formation.
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.
Biothera Pharmaceuticals Inc., Eagan, Minnesota, United States of America.
Anissa S H
AS
Chan
Biothera Pharmaceuticals Inc., Eagan, Minnesota, United States of America.
Adria Bykowski
AB
Jonas
Biothera Pharmaceuticals Inc., Eagan, Minnesota, United States of America.
Xiaohong
X
Qiu
Biothera Pharmaceuticals Inc., Eagan, Minnesota, United States of America.
Nadine R
NR
Ottoson
Biothera Pharmaceuticals Inc., Eagan, Minnesota, United States of America.
Richard M
RM
Walsh
Biothera Pharmaceuticals Inc., Eagan, Minnesota, United States of America.
Keith B
KB
Gorden
Biothera Pharmaceuticals Inc., Eagan, Minnesota, United States of America.
Ben
B
Harrison
Biothera Pharmaceuticals Inc., Eagan, Minnesota, United States of America.
Peter J
PJ
Maimonis
Biothera Pharmaceuticals Inc., Eagan, Minnesota, United States of America.
Steven M
SM
Leonardo
Biothera Pharmaceuticals Inc., Eagan, Minnesota, United States of America.
Kathleen E
KE
Ertelt
Biothera Pharmaceuticals Inc., Eagan, Minnesota, United States of America.
Michael E
ME
Danielson
Biothera Pharmaceuticals Inc., Eagan, Minnesota, United States of America.
Kyle S
KS
Michel
Biothera Pharmaceuticals Inc., Eagan, Minnesota, United States of America.
Mariana
M
Nelson
Biothera Pharmaceuticals Inc., Eagan, Minnesota, United States of America.
Jeremy R
JR
Graff
Biothera Pharmaceuticals Inc., Eagan, Minnesota, United States of America.
Myra L
ML
Patchen
Biothera Pharmaceuticals Inc., Eagan, Minnesota, United States of America.
Nandita
N
Bose
D000936:Antigen-Antibody Complex / Q000276:immunology / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D057809:HEK293 Cells; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects; D016177:Macrophage-1 Antigen / Q000378:metabolism; D017452:Receptors, IgG / Q000378:metabolism; D047071:beta-Glucans / Q000737:chemistry / Q000276:immunology / Q000494:pharmacology*
D000936:Antigen-Antibody Complex; D000970:Antineoplastic Agents; D016177:Macrophage-1 Antigen; D017452:Receptors, IgG; D047071:beta-Glucans