Draft Preview of Abstract #951007
THIS COPY IS A DRAFT ONLY. YOUR FINAL PRINTOUT WILL BE AVAILABLE AT TIME OF SUBMISSION.

Note: The accuracy of your abstract is your responsibility. Please proofread your abstract carefully before submitting it. After submission, no corrections will be allowed.
 

ATS 2009 · San Diego
International Conference
Abstract Number: 951007
Contact/Presenting Author: Emma S. Cohen
Department/Institution:  Respiratory, Inflammation and Autoimmunity Biology, MedImmune Ltd
Address:  Granta Park
City/State/Zip/Country:  Cambridge, CB21 6GH, United Kingdom
Phone: +44 1223 898534   Fax: +44 1223 471472   E-mail:  cohense@medimmune.com
ATS member: No   Student or in training: No
Funding Source: AstraZeneca R&D

Abstract Category: 01.09 - Allergic Mechanisms
Presentation format: Poster Only
Preview Disclosure
Travel Award: No
Publication of email address: No

I confirm that all authors listed on this abstract have knowledge of the abstract submission: Yes


Title: In Vitro Properties Of MEDI-4212, A Human Anti-IgE Antibody For The Treatment Of Allergic Asthma

E S Cohen, PhD1, P-O F Eriksson, PhD2, K Von Wachenfeldt, PhD2, I de Mendez, PhD1, D Sims1, S Oakley, PhD1, C Dobson, PhD1, S Persdotter2, H Ekdahl2, M Azimi2, U Alkner2, P Monk, PhD4, S Klakamp3, S OBrian, PhD1, C Lloyd1, M Carlsson, PhD2, A Coyle, PhD3 and I Anderson, PhD1. 1MedImmune Ltd, United Kingdom; 2AstraZeneca R&D, Sweden; 3MedImmune, United States and 4Synairgen, United Kingdom.

Rationale: 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 (MEDI-4212), currently in preclinical development for moderate/severe allergic asthma.
Methods:HuFcRI transfected RBL or LAD2 cells were incubated with IgE MEDI-4212. Bound IgE was cross-linked using a commercial anti-IgE and cell activation detected using calcium signalling or -hexosaminidase release. Effect of MEDI-4212 on IgE/CD23 interaction was assessed by incubation of IL-4 stimulated IM9 cells with IgE MEDI-4212 and bound IgE detected by flow cytometry. Effects on IgE production in human B cells (differentiated with APC + IL-4, MEDI-4212) was evaluated by flow cytometry. Serum free-IgE was measured using ELISA.
Results: MEDI-4212 inhibited the IgE-induced calcium signalling of RBL cells with an IC50 of 0.084nM (95%CI 0.063-0.11), but did not crosslink IgE bound to the cells. MEDI-4212 concentration-dependently inhibited FcRI induced -hexosaminidase release from the human mast cell line LAD2 with an IC50 of 0.04nM. In addition to blocking the binding of IgE to FcRI, MEDI-4212 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 1.6nM. In line with these data, MEDI-4212 was able to effectively deplete free IgE from human sera in vitro.
Conclusions: MEDI-4212 is a novel, highly potent human IgG that binds specifically to IgE and blocks IgE binding to FcRI and CD23. With its higher potency, MEDI-4212 offers the potential over current anti-IgE therapy to expand the patient group to encompass individuals with high serum IgE.