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Nonclinical Pharmacokinetics and Pharmacodynamics Characterization of Anti-CD79b/CD3 T Cell-Dependent Bispecific Antibody Using a Surrogate Molecule: A Potential Therapeutic Agent for B Cell Malignancies
The T cell-dependent bispecific (TDB) antibody, anti-CD79b/CD3, targets CD79b and CD3 cell-surface receptors expressed on B cells and T cells, respectively. Since the anti-CD79b arm of this TDB binds only to human CD79b, a surrogate TDB that binds to cynomolgus monkey CD79b (cyCD79b) was used for pr...
Autores principales: | , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9147001/ https://www.ncbi.nlm.nih.gov/pubmed/35631556 http://dx.doi.org/10.3390/pharmaceutics14050970 |
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author | Yadav, Rajbharan Sukumaran, Siddharth Zabka, Tanja S. Li, Jinze Oldendorp, Amy Morrow, Gary Reyes, Arthur Cheu, Melissa Li, Jessica Wallin, Jeffrey J. Tsai, Siao Sun, Laura Wang, Peiyin Ellerman, Diego Spiess, Christoph Polson, Andy Stefanich, Eric G. Kamath, Amrita V. Ovacik, Meric A. |
author_facet | Yadav, Rajbharan Sukumaran, Siddharth Zabka, Tanja S. Li, Jinze Oldendorp, Amy Morrow, Gary Reyes, Arthur Cheu, Melissa Li, Jessica Wallin, Jeffrey J. Tsai, Siao Sun, Laura Wang, Peiyin Ellerman, Diego Spiess, Christoph Polson, Andy Stefanich, Eric G. Kamath, Amrita V. Ovacik, Meric A. |
author_sort | Yadav, Rajbharan |
collection | PubMed |
description | The T cell-dependent bispecific (TDB) antibody, anti-CD79b/CD3, targets CD79b and CD3 cell-surface receptors expressed on B cells and T cells, respectively. Since the anti-CD79b arm of this TDB binds only to human CD79b, a surrogate TDB that binds to cynomolgus monkey CD79b (cyCD79b) was used for preclinical characterization. To evaluate the impact of CD3 binding affinity on the TDB pharmacokinetics (PK), we utilized non-tumor-targeting bispecific anti-gD/CD3 antibodies composed of a low/high CD3 affinity arm along with a monospecific anti-gD arm as controls in monkeys and mice. An integrated PKPD model was developed to characterize PK and pharmacodynamics (PD). This study revealed the impact of CD3 binding affinity on anti-cyCD79b/CD3 PK. The surrogate anti-cyCD79b/CD3 TDB was highly effective in killing CD79b-expressing B cells and exhibited nonlinear PK in monkeys, consistent with target-mediated clearance. A dose-dependent decrease in B cell counts in peripheral blood was observed, as expected. Modeling indicated that anti-cyCD79b/CD3 TDB’s rapid and target-mediated clearance may be attributed to faster internalization of CD79b, in addition to enhanced CD3 binding. The model yielded unbiased and precise curve fits. These findings highlight the complex interaction between TDBs and their targets and may be applicable to the development of other biotherapeutics. |
format | Online Article Text |
id | pubmed-9147001 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-91470012022-05-29 Nonclinical Pharmacokinetics and Pharmacodynamics Characterization of Anti-CD79b/CD3 T Cell-Dependent Bispecific Antibody Using a Surrogate Molecule: A Potential Therapeutic Agent for B Cell Malignancies Yadav, Rajbharan Sukumaran, Siddharth Zabka, Tanja S. Li, Jinze Oldendorp, Amy Morrow, Gary Reyes, Arthur Cheu, Melissa Li, Jessica Wallin, Jeffrey J. Tsai, Siao Sun, Laura Wang, Peiyin Ellerman, Diego Spiess, Christoph Polson, Andy Stefanich, Eric G. Kamath, Amrita V. Ovacik, Meric A. Pharmaceutics Article The T cell-dependent bispecific (TDB) antibody, anti-CD79b/CD3, targets CD79b and CD3 cell-surface receptors expressed on B cells and T cells, respectively. Since the anti-CD79b arm of this TDB binds only to human CD79b, a surrogate TDB that binds to cynomolgus monkey CD79b (cyCD79b) was used for preclinical characterization. To evaluate the impact of CD3 binding affinity on the TDB pharmacokinetics (PK), we utilized non-tumor-targeting bispecific anti-gD/CD3 antibodies composed of a low/high CD3 affinity arm along with a monospecific anti-gD arm as controls in monkeys and mice. An integrated PKPD model was developed to characterize PK and pharmacodynamics (PD). This study revealed the impact of CD3 binding affinity on anti-cyCD79b/CD3 PK. The surrogate anti-cyCD79b/CD3 TDB was highly effective in killing CD79b-expressing B cells and exhibited nonlinear PK in monkeys, consistent with target-mediated clearance. A dose-dependent decrease in B cell counts in peripheral blood was observed, as expected. Modeling indicated that anti-cyCD79b/CD3 TDB’s rapid and target-mediated clearance may be attributed to faster internalization of CD79b, in addition to enhanced CD3 binding. The model yielded unbiased and precise curve fits. These findings highlight the complex interaction between TDBs and their targets and may be applicable to the development of other biotherapeutics. MDPI 2022-04-30 /pmc/articles/PMC9147001/ /pubmed/35631556 http://dx.doi.org/10.3390/pharmaceutics14050970 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Yadav, Rajbharan Sukumaran, Siddharth Zabka, Tanja S. Li, Jinze Oldendorp, Amy Morrow, Gary Reyes, Arthur Cheu, Melissa Li, Jessica Wallin, Jeffrey J. Tsai, Siao Sun, Laura Wang, Peiyin Ellerman, Diego Spiess, Christoph Polson, Andy Stefanich, Eric G. Kamath, Amrita V. Ovacik, Meric A. Nonclinical Pharmacokinetics and Pharmacodynamics Characterization of Anti-CD79b/CD3 T Cell-Dependent Bispecific Antibody Using a Surrogate Molecule: A Potential Therapeutic Agent for B Cell Malignancies |
title | Nonclinical Pharmacokinetics and Pharmacodynamics Characterization of Anti-CD79b/CD3 T Cell-Dependent Bispecific Antibody Using a Surrogate Molecule: A Potential Therapeutic Agent for B Cell Malignancies |
title_full | Nonclinical Pharmacokinetics and Pharmacodynamics Characterization of Anti-CD79b/CD3 T Cell-Dependent Bispecific Antibody Using a Surrogate Molecule: A Potential Therapeutic Agent for B Cell Malignancies |
title_fullStr | Nonclinical Pharmacokinetics and Pharmacodynamics Characterization of Anti-CD79b/CD3 T Cell-Dependent Bispecific Antibody Using a Surrogate Molecule: A Potential Therapeutic Agent for B Cell Malignancies |
title_full_unstemmed | Nonclinical Pharmacokinetics and Pharmacodynamics Characterization of Anti-CD79b/CD3 T Cell-Dependent Bispecific Antibody Using a Surrogate Molecule: A Potential Therapeutic Agent for B Cell Malignancies |
title_short | Nonclinical Pharmacokinetics and Pharmacodynamics Characterization of Anti-CD79b/CD3 T Cell-Dependent Bispecific Antibody Using a Surrogate Molecule: A Potential Therapeutic Agent for B Cell Malignancies |
title_sort | nonclinical pharmacokinetics and pharmacodynamics characterization of anti-cd79b/cd3 t cell-dependent bispecific antibody using a surrogate molecule: a potential therapeutic agent for b cell malignancies |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9147001/ https://www.ncbi.nlm.nih.gov/pubmed/35631556 http://dx.doi.org/10.3390/pharmaceutics14050970 |
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