Past, present, and future of anti-IgE biologics

Abstract

About 20 years after the identification of immunoglobulin E (IgE) and its key role in allergic hypersensitivity reactions against normally harmless substances, scientists have started inventing strategies to block its pathophysiological activity in 1986. The initial concept of specific IgE targeting through the use of anti-IgE antibodies has gained a lot of momentum and within a few years independent research groups have reported successful generation of first murine monoclonal anti-IgE antibodies. Subsequent generation of optimized chimeric and humanized versions of these antibodies has paved the way for the development of therapeutic anti-IgE biologicals as we know them today. With omalizumab, there is currently still only one therapeutic anti-IgE antibody approved for the treatment of allergic conditions. Since its application is limited to the treatment of moderate-to-severe persistent asthma and chronic spontaneous urticaria, major efforts have been undertaken to develop alternative anti-IgE biologicals that could potentially be used in a broader spectrum of allergic diseases. Several new drug candidates have been generated and are currently assessed in pre-clinical studies or clinical trials. In this review, we highlight the molecular properties of past and present anti-IgE biologicals and suggest concepts that might improve treatment efficacy of future drug candidates.

Keywords: IgE; allergy treament; anti-IgE; b cells; basophils; biologics; mast cells.

Fig. 1. Chronological appearance of anti-IgE compounds.

Following the discovery of IgE various anti-IgE compounds have been reported. The years of their appearance (blue) are marked on the timeline (grey arrow). The inter-relationship between different anti-IgE compounds is highlighted with arrows (dotted black). TES-C21: monoclonal murine anti-IgE antibody; TESC-2/ CGP51901: monoclonal chimeric mouse/human anti-IgE antibody; TNX-901: humanized monoclonal anti-IgE antibody; rhuMAb-E25/ omalizumab: humanized monoclonal anti-IgE antibody; GE2: fusion protein of IgG1-Fc_3–4 and IgE-Fc_2–4; DE53-Fc: fusion protein of anti-IgE DARPin and IgG1-Fc_3–4; XmAb7195: humanized affinity maturated version of parental omalizumab antibody; CMAB007: omalizumab biosimilar; ligelizumab: high-affinity version of TNX-901; quilizumab: afucosylated humanized monoclonal anti-IgE (EMPD) antibody; MEDI4212: afucosylated monoclonal anti-IgE antibody; bi53_79: bispecific disruptive anti-IgE DARPin; 39D11: anti-IgE nanobody; 026 sdab: humanized affinity maturated anti-IgE nanobody.

Fig. 2. Binding characteristics and modes-of-action of omalizumab.

a) Schematic overview of omalizumab (blue), FcεRIα (left panel) and FcεRII/CD23 (right panel) binding sites as well as their relative overlap on IgE-Fc_3–4 (purple). b) Omalizumab mediated inhibition of free IgE binding to FcεRI or CD23. c) Omalizumab mediated accelerated dissociation of pre-formed IgE:FcεRI and IgE:CD23 complexes. d) Potential mechanisms leading to suppression of IgE production by omalizumab.

Fig. 3. Binding characteristics and modes-of-action of different anti-IgE antibodies.

a) Schematic overview of ligelizumab (blue), FcεRIα (left panel) and FcεRII/CD23 (right panel) binding sites as well as their relative overlap on IgE-Fc_3–4 (purple). b) Two mechanisms of quilizumab mediated suppression of IgE production through induction of B-cell apoptosis or antibody dependent cellular cytotoxicity (ADCC). Afucosylation of quilizumab is indicated with stars. c) Mechanisms of MEDI4212 mediated neutralization of free IgE and suppression of IgE production through induction of B-cell apoptosis or antibody dependent cellular cytotoxicity (ADCC). Afucosylation of MEDI4212 is indicated with stars. d) XmAb7195 mediated neutralization of free IgE and suppression of IgE production through co-aggregation of mIgE and FcγRIIb on B-cells. Mutations in the antibody Fc-part are indicated with dots.

Fig. 4. Modes-of-action of potential future anti-IgE drug candidates.

a) Mechanisms of DARPin bi53_79 mediated inhibition of IgE-binding to FcεRI and CD23, suppression of IgE production and active disruption of pre-formed IgE:FcεRI complexes. b) 8D6 mediated inhibition of IgE-binding to FcεRI, binding of IgE complexes to CD23 and suppression of IgE production. c) GE2 mediated suppression of allergic effector cell activation through co-aggregation of FcεRI with FcγRIIb and suppression of IgE production by co-aggregation of CD23 with FcγRIIb. d) 026 sdab mediated inhibition of IgE-binding to FcεRI and CD23 and active disruption of pre-formed IgE:FcεRI complexes.