In Vitro Properties of MEDI4212, a Human Anti-IgE Antibody for the Treatment of Allergic Asthma

Suzanne Cohen1, Per-Olof Eriksson2, Karin Von Wachenfeldt2, Sofia Persdotter2, Helena Ekdahl2, Phillip Monk4, Scott Kaclamp3, Siobhan O’Brian1, Chris Lloyd1, Mats Carlsson2, Claire Dobson1, Sarah Oakley1, Dorothy Sims1, Isabelle de Mendez1, Ian Anderson1. 1MedImmune Ltd, Cambridge, United Kingdom, 2AstraZeneca R&D, Lund, Sweden, 3MedImmune, Hayward, United States, 4Synairgen, Southampton, United Kingdom.

The key role played by IgE during allergic responses is well documented and clinically precedented. Here we describe the characteristics of a high affinity anti-IgE antibody (MEDI4212), currently in preclinical development for moderate/severe allergic asthma.

HuFcϵRI transfected RBL or LAD2 cells were incubated with IgE ± MEDI4212. Bound IgE was cross-linked using a commercial anti-IgE and cell activation detected using calcium signalling or β-hexosaminidase release. Effect of MEDI4212 on IgE/CD23 interaction was assessed by incubation of IL-4 stimulated IM9 cells with IgE ± MEDI4212 and bound IgE detected by flow cytometry. Effects on IgE production in human B cells (differentiated with APC + IL-4, ± MEDI4212) was evaluated by flow cytometry. Serum free-IgE was measured using ELISA.

MEDI4212 inhibited the IgE-induced calcium signalling of RBL cells with an IC50 of 0.084nM (95%CI 0.073-0.096, n = 11), but did not crosslink IgE bound to the cells. MEDI4212 concentration-dependently inhibited FcϵRI induced β-hexosaminidase release from the human mast cell line LAD2 with an IC50 of 0.025nM (95%CI 0.016-0.035, n = 4). In addition to blocking the binding of IgE to FcϵRI, MEDI4212 prevented the binding of IgE to CD23 on the surface of IM9 cells, and was able to concentration-dependently inhibit B cell IgE production with an IC50 of 8nM (95%CI 6-10, n = 3). In line with these data, MEDI4212 was able to effectively deplete free IgE from human sera in vitro.

MEDI4212 is a novel, highly potent human IgG that binds specifically to IgE and inhibits IgE binding to FcϵRI and CD23. With its higher potency, MEDI4212 offers potential to expand the current anti-IgE therapy patient group to encompass individuals with high serum IgE.