Development of an antibody that neutralizes soluble IgE and eliminates IgE expressing B cells.
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.
MedImmune LLC, Gaithersburg, MD, USA.
Andrew C
AC
Nyborg
MedImmune LLC, Gaithersburg, MD, USA.
Anna
A
Zacco
MedImmune LLC, Gaithersburg, MD, USA.
Rachel
R
Ettinger
MedImmune LLC, Gaithersburg, MD, USA.
M
M
Jack Borrok
MedImmune LLC, Gaithersburg, MD, USA.
Jie
J
Zhu
MedImmune LLC, Gaithersburg, MD, USA.
Tom
T
Martin
MedImmune LLC, Gaithersburg, MD, USA.
Rob
R
Woods
MedImmune LLC, Gaithersburg, MD, USA.
Christine
C
Kiefer
MedImmune LLC, Gaithersburg, MD, USA.
Michael A
MA
Bowen
MedImmune Ltd, Milstein Building, Granta Park, Cambridge, UK.
E
E
Suzanne Cohen
MedImmune LLC, Gaithersburg, MD, USA.
Ronald
R
Herbst
MedImmune LLC, Gaithersburg, MD, USA.
Herren
H
Wu
MedImmune LLC, Gaithersburg, MD, USA.
Steven
S
Coats
D000818:Animals; D000888:Antibodies, Anti-Idiotypic / Q000494:pharmacology*; D057134:Antibodies, Neutralizing / Q000494:pharmacology*; D000920:Antibody-Dependent Cell Cytotoxicity / Q000187:drug effects; D001402:B-Lymphocytes / Q000187:drug effects / Q000378:metabolism*; D016466:CHO Cells; D002118:Calcium / Q000378:metabolism; D015550:Cell Degranulation / Q000187:drug effects; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D006224:Cricetinae; D003412:Cricetulus; D006801:Humans; D007073:Immunoglobulin E / Q000276:immunology*; D011485:Protein Binding / Q000187:drug effects; D051381:Rats; D017452:Receptors, IgG / Q000378:metabolism; D012995:Solubility
D000888:Antibodies, Anti-Idiotypic; D057134:Antibodies, Neutralizing; C496124:FCGR3A protein, human; D017452:Receptors, IgG; C026408:anti-IgE antibodies; D007073:Immunoglobulin E; D002118:Calcium