Whole-Body Physiologically Based Pharmacokinetic Modeling Framework for Tissue Target Engagement of CD3 Bispecific Antibodies
<b>Background</b>: T-cell-engaging bispecific (TCB) antibodies represent a promising therapy that utilizes T-cells to eliminate cancer cells independently of the major histocompatibility complex. Despite their success in hematologic cancers, challenges such as cytokine release syndrome (...
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MDPI AG
2025-04-01
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| Online Access: | https://www.mdpi.com/1999-4923/17/4/500 |
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| author | Monica E. Susilo Stephan Schaller Luis David Jiménez-Franco Alexander Kulesza Wilhelmus E. A. de Witte Shang-Chiung Chen C. Andrew Boswell Danielle Mandikian Chi-Chung Li |
| author_facet | Monica E. Susilo Stephan Schaller Luis David Jiménez-Franco Alexander Kulesza Wilhelmus E. A. de Witte Shang-Chiung Chen C. Andrew Boswell Danielle Mandikian Chi-Chung Li |
| author_sort | Monica E. Susilo |
| collection | DOAJ |
| description | <b>Background</b>: T-cell-engaging bispecific (TCB) antibodies represent a promising therapy that utilizes T-cells to eliminate cancer cells independently of the major histocompatibility complex. Despite their success in hematologic cancers, challenges such as cytokine release syndrome (CRS), off-tumor toxicity, and resistance limit their efficacy in solid tumors. Optimizing biodistribution is key to overcoming these challenges. <b>Methods</b>: A physiologically based pharmacokinetic (PBPK) model was developed that incorporates T-cell transmigration, retention, receptor binding, receptor turnover, and cellular engagement. Preclinical biodistribution data were modeled using two TCB formats: one lacking tumor target binding and another with target arm binding, each with varying CD3 affinities in a transgenic tumor-bearing mouse model. <b>Results</b>: The PBPK model successfully described the distribution of activated T-cells and various TCB formats. It accurately predicted preclinical biodistribution patterns, demonstrating that higher CD3 affinity leads to faster clearance from the blood and increased accumulation in T-cell-rich organs, often reducing tumor exposure. Simulations of HER2-CD3 TCB doses (0.1 µg to 100 mg) revealed monotonic increases in synapse AUC within the tumor. A bell-shaped dose-Cmax relationship for synapse formation was observed, and Tmax was delayed at higher doses. Blood PK was a reasonable surrogate for tumor synapse at low doses but less predictive at higher doses. <b>Conclusions</b>: We developed a whole-body PBPK model to simulate the biodistribution of T-cells and TCB molecules. The insights from this model provide a comprehensive understanding of the factors affecting PK, synapse formation, and TCB activity, aiding in dose optimization and the design of effective therapeutic strategies. |
| format | Article |
| id | doaj-art-28e40148b1f842ee9bfdc1369a4ccb35 |
| institution | OA Journals |
| issn | 1999-4923 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceutics |
| spelling | doaj-art-28e40148b1f842ee9bfdc1369a4ccb352025-08-20T02:18:10ZengMDPI AGPharmaceutics1999-49232025-04-0117450010.3390/pharmaceutics17040500Whole-Body Physiologically Based Pharmacokinetic Modeling Framework for Tissue Target Engagement of CD3 Bispecific AntibodiesMonica E. Susilo0Stephan Schaller1Luis David Jiménez-Franco2Alexander Kulesza3Wilhelmus E. A. de Witte4Shang-Chiung Chen5C. Andrew Boswell6Danielle Mandikian7Chi-Chung Li8Genentech, Inc., South San Francisco, CA 94080, USAESQlabs GmbH, Am Sportplatz 7, 26683 Saterland, GermanyESQlabs GmbH, Am Sportplatz 7, 26683 Saterland, GermanyESQlabs GmbH, Am Sportplatz 7, 26683 Saterland, GermanyESQlabs GmbH, Am Sportplatz 7, 26683 Saterland, GermanyGenentech, Inc., South San Francisco, CA 94080, USAGenentech, Inc., South San Francisco, CA 94080, USAGenentech, Inc., South San Francisco, CA 94080, USAGenentech, Inc., South San Francisco, CA 94080, USA<b>Background</b>: T-cell-engaging bispecific (TCB) antibodies represent a promising therapy that utilizes T-cells to eliminate cancer cells independently of the major histocompatibility complex. Despite their success in hematologic cancers, challenges such as cytokine release syndrome (CRS), off-tumor toxicity, and resistance limit their efficacy in solid tumors. Optimizing biodistribution is key to overcoming these challenges. <b>Methods</b>: A physiologically based pharmacokinetic (PBPK) model was developed that incorporates T-cell transmigration, retention, receptor binding, receptor turnover, and cellular engagement. Preclinical biodistribution data were modeled using two TCB formats: one lacking tumor target binding and another with target arm binding, each with varying CD3 affinities in a transgenic tumor-bearing mouse model. <b>Results</b>: The PBPK model successfully described the distribution of activated T-cells and various TCB formats. It accurately predicted preclinical biodistribution patterns, demonstrating that higher CD3 affinity leads to faster clearance from the blood and increased accumulation in T-cell-rich organs, often reducing tumor exposure. Simulations of HER2-CD3 TCB doses (0.1 µg to 100 mg) revealed monotonic increases in synapse AUC within the tumor. A bell-shaped dose-Cmax relationship for synapse formation was observed, and Tmax was delayed at higher doses. Blood PK was a reasonable surrogate for tumor synapse at low doses but less predictive at higher doses. <b>Conclusions</b>: We developed a whole-body PBPK model to simulate the biodistribution of T-cells and TCB molecules. The insights from this model provide a comprehensive understanding of the factors affecting PK, synapse formation, and TCB activity, aiding in dose optimization and the design of effective therapeutic strategies.https://www.mdpi.com/1999-4923/17/4/500T-cell engaging bispecificTCBPBPKimmune synapseexposure–responsedose optimization |
| spellingShingle | Monica E. Susilo Stephan Schaller Luis David Jiménez-Franco Alexander Kulesza Wilhelmus E. A. de Witte Shang-Chiung Chen C. Andrew Boswell Danielle Mandikian Chi-Chung Li Whole-Body Physiologically Based Pharmacokinetic Modeling Framework for Tissue Target Engagement of CD3 Bispecific Antibodies Pharmaceutics T-cell engaging bispecific TCB PBPK immune synapse exposure–response dose optimization |
| title | Whole-Body Physiologically Based Pharmacokinetic Modeling Framework for Tissue Target Engagement of CD3 Bispecific Antibodies |
| title_full | Whole-Body Physiologically Based Pharmacokinetic Modeling Framework for Tissue Target Engagement of CD3 Bispecific Antibodies |
| title_fullStr | Whole-Body Physiologically Based Pharmacokinetic Modeling Framework for Tissue Target Engagement of CD3 Bispecific Antibodies |
| title_full_unstemmed | Whole-Body Physiologically Based Pharmacokinetic Modeling Framework for Tissue Target Engagement of CD3 Bispecific Antibodies |
| title_short | Whole-Body Physiologically Based Pharmacokinetic Modeling Framework for Tissue Target Engagement of CD3 Bispecific Antibodies |
| title_sort | whole body physiologically based pharmacokinetic modeling framework for tissue target engagement of cd3 bispecific antibodies |
| topic | T-cell engaging bispecific TCB PBPK immune synapse exposure–response dose optimization |
| url | https://www.mdpi.com/1999-4923/17/4/500 |
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