Modelling bispecific monoclonal antibody interaction with two cell membrane targets indicates the importance of surface diffusion

Sengers, B. G., McGinty, S. , Nouri, F. Z., Argungu, M., Hawkins, E., Hadji, A., Weber, A., Taylor, A. and Sepp, A. (2016) Modelling bispecific monoclonal antibody interaction with two cell membrane targets indicates the importance of surface diffusion. mAbs, 8(5), pp. 905-916. (doi: 10.1080/19420862.2016.1178437) (PMID:27097222) (PMCID:PMC4968105)

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We have developed a mathematical framework for describing a bispecific monoclonal antibody interaction with two independent membrane-bound targets that are expressed on the same cell surface. The bispecific antibody in solution binds either of the two targets first, and then cross-links with the second one whilst on the cell surface, subject to rate-limiting lateral diffusion step within the lifetime of the monovalently engaged antibody-antigen complex. At experimental densities, only a small fraction of the free targets is expected to lie within the reach of the antibody binding sites at any time. Using ordinary differential equation and Monte Carlo simulation-based models, we validated this approach against an independently published anti-CD4/CD70 DuetMab experimental data set. As a result of dimensional reduction, the cell surface reaction is expected to be so rapid that, in agreement with the experimental data, no monovalently bound bispecific antibody binary complexes accumulate until cross-linking is complete. The dissociation of the bispecific antibody from the ternary cross-linked complex is expected to be significantly slower than that from either of the monovalently bound variants. We estimate that the effective affinity of the bivalently bound bispecific antibody is enhanced for about four orders of magnitude over that of the monovalently bound species. This avidity enhancement allows for the highly specific binding of anti-CD4/CD70 DuetMab to the cells that are positive for both target antigens over those that express only one or the other We suggest that the lateral diffusion of target antigens in the cell membrane also plays a key role in the avidity effect of natural antibodies and other bivalent ligands in their interactions with their respective cell surface receptors.

Item Type:Articles
Additional Information:This publication represents the work carried out by the authors at the UK QSP workshop at AstraZeneca Alderley Park 14-17th Sept 2015, and we wish to express our thanks both to the 15 organising committee (led by Dr. Marcus Tindall, Reading University), as well as the host organization for supporting this remarkable academia-industry collaboration event. We also wish to thank our colleagues for reading the manuscript and making invaluable suggestions. Dr Sengers received funding from the BBSRC (BB/L020823/1). Dr McGinty would like to acknowledge the funding provided by EPSRC under grant numbers EP/J007242/1 and EP/J007579/1.
Glasgow Author(s) Enlighten ID:Mcginty, Dr Sean
Authors: Sengers, B. G., McGinty, S., Nouri, F. Z., Argungu, M., Hawkins, E., Hadji, A., Weber, A., Taylor, A., and Sepp, A.
College/School:College of Science and Engineering > School of Engineering > Biomedical Engineering
Journal Name:mAbs
Publisher:Taylor & Francis
ISSN (Online):1942-0870
Published Online:20 April 2016
Copyright Holders:Copyright © 2016 The Authors
First Published:First published in mAbs 8(5):905-916
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
579501Optimal Design of Drug Eluting StentsSimon KennedyEngineering & Physical Sciences Research Council (EPSRC)EP/J007579/1RI CARDIOVASCULAR & MEDICAL SCIENCES