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      Target‐Mediated Drug Disposition Model for Bispecific Antibodies: Properties, Approximation, and Optimal Dosing Strategy

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          Abstract

          Bispecific antibodies (BsAbs) bind to two different targets, and create two binary and one ternary complex ( TC). These molecules have shown promise as immuno‐oncology drugs, and the TC is considered the pharmacologically active species that drives their pharmacodynamic effect. Here, we have presented a general target‐mediated drug disposition (TMDD) model for these BsAbs, which bind to two different targets on different cell membranes. The model includes four different binding events for BsAbs, turnover of the targets, and internalization of the complexes. In addition, a quasi‐equilibrium (QE) approximation with decreased number of binding parameters and, if necessary, reduced internalization parameters is presented. The model is further used to investigate the kinetics of BsAb and TC concentrations. Our analysis shows that larger doses of BsAbs may delay the build‐up of the TC. Consequently, a method to compute the optimal dosing strategy of BsAbs, which will immediately create and maintain maximal possible TC concentration, is presented.

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          Most cited references20

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          Application of dual affinity retargeting molecules to achieve optimal redirected T-cell killing of B-cell lymphoma.

          We describe the application of a novel, bispecific antibody platform termed dual affinity retargeting (DART) to eradicate B-cell lymphoma through coengagement of the B cell-specific antigen CD19 and the TCR/CD3 complex on effector T cells. Comparison with a single-chain, bispecific antibody bearing identical CD19 and CD3 antibody Fv sequences revealed DART molecules to be more potent in directing B-cell lysis. The enhanced activity with the CD19xCD3 DART molecules was observed on all CD19-expressing target B cells evaluated using resting and prestimulated human PBMCs or purified effector T-cell populations. Characterization of a CD19xTCR bispecific DART molecule revealed equivalent potency with the CD19xCD3 DART molecule, demonstrating flexibility of the DART structure to support T-cell/B-cell associations for redirected T cell-killing applications. The enhanced level of killing mediated by DART molecules was not accompanied by any increase in nonspecific T-cell activation or lysis of CD19(-) cells. Cell-association studies indicated that the DART architecture is well suited for maintaining cell-to-cell contact, apparently contributing to the high level of target cell killing. Finally, the ability of the CD19xTCR DART to inhibit B-cell lymphoma in NOD/SCID mice when coadministered with human PBMCs supports further evaluation of DART molecules for the treatment of B-cell malignancies.
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            Pharmacologic target-mediated drug disposition.

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              A "Trojan horse" bispecific-antibody strategy for broad protection against ebolaviruses.

              There is an urgent need for monoclonal antibody (mAb) therapies that broadly protect against Ebola virus and other filoviruses. The conserved, essential interaction between the filovirus glycoprotein, GP, and its entry receptor Niemann-Pick C1 (NPC1) provides an attractive target for such mAbs but is shielded by multiple mechanisms, including physical sequestration in late endosomes. Here, we describe a bispecific-antibody strategy to target this interaction, in which mAbs specific for NPC1 or the GP receptor-binding site are coupled to a mAb against a conserved, surface-exposed GP epitope. Bispecific antibodies, but not parent mAbs, neutralized all known ebolaviruses by coopting viral particles themselves for endosomal delivery and conferred postexposure protection against multiple ebolaviruses in mice. Such "Trojan horse" bispecific antibodies have potential as broad antifilovirus immunotherapeutics.
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                Author and article information

                Contributors
                johannes.schropp@uni-konstanz.de
                dshah4@buffalo.edu
                gilbert.koch@ukbb.ch
                Journal
                CPT Pharmacometrics Syst Pharmacol
                CPT Pharmacometrics Syst Pharmacol
                10.1002/(ISSN)2163-8306
                PSP4
                CPT: Pharmacometrics & Systems Pharmacology
                John Wiley and Sons Inc. (Hoboken )
                2163-8306
                08 January 2019
                March 2019
                : 8
                : 3 ( doiID: 10.1002/psp4.2019.8.issue-3 )
                : 177-187
                Affiliations
                [ 1 ] Department of Mathematics and Statistics University of Konstanz Konstanz Germany
                [ 2 ] Department of Pharmaceutical Sciences School of Pharmacy and Pharmaceutical Sciences State University of New York at Buffalo Buffalo New York USA
                [ 3 ] Paediatric Pharmacology and Pharmacometrics Research University of Basel Children's Hospital (UKBB) Basel Switzerland
                Author notes
                [*] [* ]Correspondence: Johannes Schropp ( johannes.schropp@ 123456uni-konstanz.de ), Dhaval K. Shah ( dshah4@ 123456buffalo.edu ), and Gilbert Koch ( gilbert.koch@ 123456ukbb.ch )
                [†]

                Shared first authorship. Both authors contributed equally.

                Article
                PSP412369
                10.1002/psp4.12369
                6430159
                30480383
                72446edf-62dd-44c1-97a8-cd666c832c25
                © 2019 The Authors CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals, Inc. on behalf of the American Society for Clinical Pharmacology and Therapeutics.

                This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

                History
                : 16 July 2018
                : 17 October 2018
                Page count
                Figures: 5, Tables: 2, Pages: 11, Words: 8487
                Funding
                Funded by: National Institutes of Health (NIH)
                Award ID: GM114179
                Award ID: AI138195
                Categories
                Article
                Research
                Articles
                Custom metadata
                2.0
                psp412369
                March 2019
                Converter:WILEY_ML3GV2_TO_NLMPMC version:5.6.1 mode:remove_FC converted:22.03.2019

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