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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.
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.
Afiliação
  • Yadav R; Preclinical and Translational Pharmacokinetics and Pharmacodynamics, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
  • Sukumaran S; Preclinical and Translational Pharmacokinetics and Pharmacodynamics, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
  • Zabka TS; Safety Assessment, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
  • Li J; Safety Assessment, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
  • Oldendorp A; Safety Assessment, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
  • Morrow G; Safety Assessment, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
  • Reyes A; Preclinical and Translational Pharmacokinetics and Pharmacodynamics, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
  • Cheu M; BioAnalytical Sciences, Genentech Inc., South San Francisco, CA 94080, USA.
  • Li J; Oncology Biomarker Development (OBD), Genentech Inc., South San Francisco, CA 94080, USA.
  • Wallin JJ; Oncology Biomarker Development (OBD), Genentech Inc., South San Francisco, CA 94080, USA.
  • Tsai S; Biochemical and Cellular Pharmacology, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
  • Sun L; Translational Oncology Department, Genentech Inc., South San Francisco, CA 94080, USA.
  • Wang P; Translational Oncology Department, Genentech Inc., South San Francisco, CA 94080, USA.
  • Ellerman D; Antibody Engineering, Genentech Inc., South San Francisco, CA 94080, USA.
  • Spiess C; Antibody Engineering, Genentech Inc., South San Francisco, CA 94080, USA.
  • Polson A; Translational Oncology Department, Genentech Inc., South San Francisco, CA 94080, USA.
  • Stefanich EG; Preclinical and Translational Pharmacokinetics and Pharmacodynamics, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
  • Kamath AV; Preclinical and Translational Pharmacokinetics and Pharmacodynamics, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
  • Ovacik MA; Preclinical and Translational Pharmacokinetics and Pharmacodynamics, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
Pharmaceutics ; 14(5)2022 Apr 30.
Article em En | MEDLINE | ID: mdl-35631556
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.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Tipo de estudo: Prognostic_studies Idioma: En Revista: Pharmaceutics Ano de publicação: 2022 Tipo de documento: Article País de afiliação: Estados Unidos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Tipo de estudo: Prognostic_studies Idioma: En Revista: Pharmaceutics Ano de publicação: 2022 Tipo de documento: Article País de afiliação: Estados Unidos