The CEA/CD3-bispecific antibody MEDI-565 (MT111) binds a nonlinear epitope in the full-length but not a short splice variant of CEA.

PloS One
Li PengS Hammond

Abstract

MEDI-565 (also known as MT111) is a bispecific T-cell engager (BiTE®) 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 F(326), T(328), N(333), V(388), G(389), P(390), E(392), I(408), and N(410). Two non-synonymous single-nucleotide polymorphisms (SNPs) (rs10407503, rs7249230) were identified in the epitope region, but they are found at low homozygosity rates. Searching the National Center for Biotechnology Information GenBank® database, we further identified a single, previously uncharacterized mRNA splice variant of CEA that lacks a portion of the N-terminal domain, the A1 and B1 domains, and a large portion of the A2 domain. Real-time quantitative polymerase chain reaction analysis of...Continue Reading

References

Mar 1, 1992·Diagnostic Microbiology and Infectious Disease·R S TsangM H Ng
Jul 1, 1986·British Journal of Cancer·P J HarwoodG T Rogers
Sep 1, 1989·Cancer Research·S HammarstromP Burtin
Apr 1, 1989·European Journal of Cancer & Clinical Oncology·V J RichardsonM E Gallant
Jul 1, 1988·Proceedings of the National Academy of Sciences of the United States of America·S A HeftaJ E Shively
Apr 29, 1987·Biochemical and Biophysical Research Communications·S OikawaH Nakazato
Jan 30, 1987·Biochemical and Biophysical Research Communications·S OikawaG Kosaki
Sep 1, 1994·The Journal of Histochemistry and Cytochemistry : Official Journal of the Histochemistry Society·Z R ShiS H Itzkowitz
Jul 18, 1995·Proceedings of the National Academy of Sciences of the United States of America·M MackP Kufer
Apr 1, 1994·International Journal of Cancer. Journal International Du Cancer·K A ChesterR H Begent
Dec 1, 1998·The Journal of Peptide Research : Official Journal of the American Peptide Society·B E KaplanJ E Shively
Jan 11, 2000·Tumour Biology : the Journal of the International Society for Oncodevelopmental Biology and Medicine·D C JetteM R Suresh
Mar 29, 2001·Tumour Biology : the Journal of the International Society for Oncodevelopmental Biology and Medicine·I SolassolA Pèlegrin
Dec 25, 2002·Tumour Biology : the Journal of the International Society for Oncodevelopmental Biology and Medicine·J BjernerO P Børmer
Apr 4, 2003·International Journal of Cancer. Journal International Du Cancer·Pauline WimbergerRainer Kimmig
Aug 12, 2003·Expert Review of Vaccines·Emina H Huang, Howard L Kaufman
Aug 17, 2005·Cancer Investigation·Mitchell J Goldstein, Edith Peterson Mitchell
Oct 11, 2005·Drug Discovery Today·Evelyn WolfPatrick A Baeuerle
Nov 23, 2005·Bioinformatics·Konstantin ArnoldTorsten Schwede
Oct 25, 2006·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Gershon Y LockerUNKNOWN ASCO
Apr 3, 2007·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Mark Rother
Sep 27, 2008·Breast Cancer Research and Treatment·Juliane WitthauerBarbara Mayer
Oct 24, 2008·International Journal of Clinical Oncology·Masahiro UeharaTakashi Fukutomi

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Citations

May 15, 2015·Expert Opinion on Biological Therapy·Julia StieglmaierDirk Nagorsen
Nov 28, 2012·Expert Opinion on Investigational Drugs·Jinbiao ZhanKeyi Wang
Feb 2, 2016·Cancer Biology & Therapy·Bin DongZhong Wang
Apr 30, 2013·Current Opinion in Chemical Biology·Stanley R Frankel, Patrick A Baeuerle
Aug 4, 2012·Biochemical Pharmacology·Chad MayHans-Peter Gerber
May 6, 2015·Cellular & Molecular Immunology·Andrew C NyborgSteven Coats
Sep 22, 2017·Journal of Hematology & Oncology·Shengnan YuKongming Wu
Jul 8, 2018·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Stijn J H WaaijerMarjolijn N Lub-de Hooge

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Datasets Mentioned

BETA
NM002483
CR749337

Methods Mentioned

BETA
xenograft
protein assay
flow cytometry
transfection
PCR
saturation binding

Clinical Trials Mentioned

NCT01284231

Software Mentioned

Fluidigm Real - Time PCR Analysis
SDS
Primer Express
GraphPad Prism
FACSDiva
SWISS
MODEL workspace
FlowJo
GraphPad

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