Inhibitory FcyRIIb (CD32b) becomes activated by therapeutic mAb in both cis and trans and drives internalization according to antibody specificity

Abstract

A major feature that distinguishes type I from type II anti-CD20 monoclonal antibodies (mAbs) and reduces their therapeutic efficacy is the tendency to internalize from the cell surface. We have shown previously that the extent of internalization correlates with the capacity of type I mAb to simultaneously engage both CD20 and the inhibitory Fc? receptor, Fc?RIIb, in a bipolar configuration. Here, we investigated whether mAbs directed at other B-cell surface receptors also engaged Fc?RIIb and whether this interaction promoted internalization. Most mAbs engaged and activated Fc?RIIb, with the strength of activation related to the level of mAb bound to the cell surface. However, engagement did not affect internalization of most mAb-ligated receptors, either in cell lines or primary chronic lymphocytic leukemia cells with the exception of CD19 and CD38. Furthermore, at high cell concentrations/density both cis and trans interactions between cell-surface bound mAb and Fc?RIIb were evident, but trans interactions did not inhibit type I anti-CD20 mAb-mediated internalization. These data identify that Fc?RIIb is engaged by many mAbs in both cis and trans configurations, triggering its activation, but that internalization via Fc?RIIb occurs for only a select subset. These findings have implications when designing new antibody-based therapeutics.

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Identifiers

ORCID for A.T. Vaughan: orcid.org/0000-0001-6076-3649

ORCID for S.A. Beers: orcid.org/0000-0002-3765-3342

ORCID for S.H. Lim: orcid.org/0000-0002-2768-4858

ORCID for A. Roghanian: orcid.org/0000-0003-1316-4218

ORCID for M.S. Cragg: orcid.org/0000-0003-2077-089X

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