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OBJECTIVES Imprime PGG (Imprime), is a soluble ß-1,3/1,6 immunomodulatory glucan, being developed in combination with monoclonal antibody therapy for multiple oncologic indications. To date, limited studies exist on the recognition and immunomodulatory activities of soluble glucans on the human immune system. Although yeast ß-glucans have been shown to be capable of binding human cells through leukocyte complement receptor 3 (CR3, Mac-1, αM ß2 integrin), the key components for this event were not elucidated. Here, we demonstrate that Imprime, a soluble carbohydrate pathogen associated molecular pattern (PAMP), is recognized by only certain human cells expressing CR3 (i.e., bind to CR3-expressing myeloid cells, but not to CR3 expressing NK cells) and requires opsonization by complement components. Inactivation of serum complement components resulted in loss of binding and function. Surprisingly, not all healthy donor myeloid cells were capable of binding Imprime despite the presence of complement components. Looking into potential reasons for differential binding led to a strong correlation between being a high-Imprime binder and having a high-natural anti-ß glucan titer. Both, in vitro and in vivo feasibility studies in humans demonstrate the potential for converting a low-Imprime binder to a high-binder with anti-ß-glucan antibodies. Given the preclinical requirement for Imprime binding to myeloid cells for antitumor effects, we propose that assessing Imprime binding to blood immune cells could be a predictive biomarker, and enriching for high-binder patients or converting low-binders to high-binders by treating with high-titer plasma or IVIG, would enhance therapeutic efficacy. • Determine the characteristics of Imprime PGG binding to immune subsets in human whole blood (WB) • Correlate Imprime PGG binding to function • Identify a predictive biomarker to screen for those patients with the highest potential to respond to Imprime PGG therapy in the clinic Figure 5. Requirements for Imprime PGG Binding to Human Myeloid Cells. As demonstrated in the past, Imprime PGG bound to human neutrophils and monocytes only in the presence of normal (i.e. serum with intact complement) but not heat-inactivated, “complement deficient” serum. Likewise, Imprime PGG binding requires “CR3” and was not detected on CR3-blocked cells. Requirements for Imprime PGG Binding to Human Myeloid Cells in Whole Blood Citrate in normal human serum 10mg/ml of Imprime PGG in normal human serum 10mg/ml of Imprime PGG in heatinactivated serum 10mg/ml of Imprime PGG in normal human serum + anti-CR3 blocking antibody

frontiers in immunology

A NOVEL MECHANISM FOR RECOGNITION OF A SMALL MOLECULE CARBOHYDRATE IMMUNOTHERAPEUTIC BY HUMAN MYELOID CELLS: POTENTIAL FOR MODULATION OF EFFICACY IN THE CLINIC