Development of an antibody that neutralizes soluble IgE and eliminates IgE expressing B cells

Abstract

Immunoglobulin E (IgE) plays a key role in allergic asthma and is a clinically validated target for monoclonal antibodies. Therapeutic anti-IgE antibodies block the interaction between IgE and the Fc epsilon (Fcε) receptor, which eliminates or minimizes the allergic phenotype but does not typically curtail the ongoing production of IgE by B cells. We generated high-affinity anti-IgE antibodies (MEDI4212) that have the potential to both neutralize soluble IgE and eliminate IgE-expressing B-cells through antibody-dependent cell-mediated cytotoxicity. MEDI4212 variants were generated that contain mutations in the Fc region of the antibody or alterations in fucosylation in order to enhance the antibody's affinity for FcγRIIIa. All MEDI4212 variants bound to human IgE with affinities comparable to the wild-type (WT) antibody. Each variant was shown to inhibit the interaction between IgE and FcεRI, which translated into potent inhibition of FcγRI-mediated function responses. Importantly, all variants bound similarly to IgE at the surface of membrane IgE expressing cells. However, MEDI4212 variants demonstrated enhanced affinity for FcγRIIIa including the polymorphic variants at position 158. The improvement in FcγRIIIa binding led to increased effector function in cell based assays using both engineered cell lines and class switched human IgE B cells. Through its superior suppression of IgE, we anticipate that effector function enhanced MEDI4212 may be able to neutralize high levels of soluble IgE and provide increased long-term benefit by eliminating the IgE expressing B cells before they differentiate and become IgE secreting plasma cells.

FCGR2A and FCGR3A Genotypes Correlate with Farletuzumab Response in Patients with First-Relapsed Ovarian Cancer Exhibiting Low CA125

“…Previous studies have reported that these changes affect IgG binding affinity to either receptor, whereby the FCGR2A -131H allele has a higher binding affinity than 131R, especially for IgG2a, and the FCGR3A -158V allele has a higher binding affinity than the 158F allele to IgG 1 and IgG2a [Warmerdam et al, 1991;Koene et al, 1997;Bruhns et al, 2009;Schneider-Merck et al, 2010;Smith and Clatworthy, 2010]. Nyborg et al [2016] demonstrated that FCGR3A-158V has an approximately 10-fold higher affinity for IgG 1 than FCGR3A-158F (0.502 vs. 4.963 μ M , respectively). In both cases, it was reported that the higher affinity allele results in enhanced immune-effector activity of host cells in in vitro assays [Wu et al, 1997].…”

Targeting IgE in allergic disease

“…Recently, modified versions of the monoclonal anti-IgE antibody MEDI4212 with improved binding to FcyRIIIA have been engineered. While the reactivity against IgE remained unchanged the elimination of IgE expressing B-cells in vitro was significantly increased [44]. The afucosylated variant of MEDI4212 decreased serum IgE levels in a humanized mouse model to a higher degree than the fucosylated variant [44].…”

“…While the reactivity against IgE remained unchanged the elimination of IgE expressing B-cells in vitro was significantly increased [44]. The afucosylated variant of MEDI4212 decreased serum IgE levels in a humanized mouse model to a higher degree than the fucosylated variant [44]. No clinical human data is currently available for the afucosylated variant of MEDI4212.…”

Monoclonal antibodies: the new magic bullets for allergy: IUPHAR Review 17

“…Much effort has been made also to target B‐cell‐associated membrane IgE to eradicate a priori the IgE‐expressing B‐cells so that they will not differentiate into IgE‐secreting plasma cells, thus reducing the amount of total free IgE (Chen et al, ; Chowdhury et al, ). However, because these Abs, currently in clinical trials, bind to a specific region proximal to the membrane, do not neutralize soluble, circulating IgE and do not block the interaction between IgE and FcεRI, no real interruption of the allergic cascade will take place, thus showing that membrane IgE is not worth targeting (Nyborg et al, ).…”