the ceacd3-bispecific antibody medi-565 (mt111) binds a nonlinear epitope in the full-length but not a short splice variant of ceaceacd3-bispecific抗体读出- 565(mt111)结合非线性抗原决定基在全身的但不是短接头东航的变体.pdfVIP

The CEA/CD3-Bispecific Antibody MEDI-565 (MT111) Binds a Nonlinear Epitope in the Full-Length but Not a Short Splice Variant of CEA 1. 2. 3 3 3 1 Li Peng , Michael D. Oberst , Jiaqi Huang , Philip Brohawn , Chris Morehouse , Kristen Lekstrom , 4 1 3 1 1 Patrick A. Baeuerle , Herren Wu , Yihong Yao , Steven R. Coats , William Dall’Acqua , 1 2 Melissa Damschroder *, Scott A. Hammond * 1 Department of Antibody Discovery and Protein Engineering, MedImmune LLC, Gaithersburg, Maryland, United States of America, 2 Preclinical Oncology, MedImmune LLC, Gaithersburg, Maryland, United States of America, 3 Translational Sciences, MedImmune LLC, Gaithersburg, Maryland, United States of America, 4 Amgen Research (Munich) GmbH, Munich, Germany Abstract MEDI-565 (also known as MT111) is a bispecific T-cell engager (BiTEH) antibody in development for the treatment of patients with cancers expressing carcinoembryonic antigen (CEA). MEDI-565 binds CEA on cancer cells and CD3 on T cells to induce T-cell mediated killing of cancer cells. To understand the molecular basis of human CEA recognition by MEDI-565 and how polymorphisms and spliced forms of CEA may affect MEDI-565 activity, we mapped the epitope of MEDI-565 on CEA using mutagenesis and homology modeling approaches. We found that MEDI-565 recognized a conformational epitope in the A2 domain comprised of amino acids 326–349 and 388–410, with critical residues F326, T328, N333, V388, G389, P390, E392, I408, and N410. Two non-synonymous single-nucleotide polymorphisms (SNPs) (r rs7249230) were identified in t