Clarifying the precise effector phenotypes elicited upon engagement of FcγRIIa or FcγRI by monocytes and macrophages using engineered Fc domains with absolute selectivity for either CD32 or CD64

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Presentation Time: 03:15 PM - 04:30 PM
Poster Board Number: B566
Abstract ID: 4636

Presenting Author:
Katia George , Graduate Research Assistant at Univ. of Texas, Austin

Abstract:

Humans encode 6 different effector Fcγ receptors (FcγRs) whose expression varies greatly among different cells. The expression of multiple FcγRs by most effector cells, including most notably macrophages and monocytes, has cofounded our understanding of the precise functional role of each receptor and to what degree it contributes to a particular IgG effector function such as ADCP, cytokine release etc. To address this problem, we have engineered a set of IgG1 Fc domains that bind to a single effector FcγR with absolute, or near absolute, selectivity and in some cases with a range of affinities, both physiological and supraphysiological.  Our investigation reveals that CD64 and CD32 can independently initiate downstream effector functions such as (a) antibody-dependent phagocytosis of immune complexes, (b) trogocytosis of opsonized cancer cells, and (c) cytokine release. Primary immune cell in vitro assays and state-of-the-art single cell imaging experiments reveal that CD64 and CD32 exhibit different kinetics (i.e. speed and duration) of phagocytosis. The analysis of FcγR function using engineered antibodies with selective Fcs highlights several differences with earlier studies in which receptor function was evaluated by F(ab')2 -induced crosslinking.