Development of a Target cell-Biologics-Effector cell (TBE) complex-based cell killing model to characterize target cell depletion by T cell redirecting bispecific agents
Open accessAbstract
T-cell redirecting bispecific antibodies (bsAbs) or antibody-derived agents that combine tumor antigen recognition with CD3-mediated T cell recruitment are highly potent tumor-killing molecules. Despite the tremendous progress achieved in the last decade, development of such bsAbs still faces many challenges. This work aimed to develop a mechanism-based pharmacokinetic/pharmacodynamic (PK/PD) modeling framework that can be used to assist the development of T-cell redirecting bsAbs. A Target cell-Biologics-Effector cell (TBE) complex-based cell killing model was developed using in vitro and in vivo data, which incorporates information on binding affinities of bsAbs to CD3 and target receptors, expression levels of CD3 and target receptors, concentrations of effector and target cells, as well as respective physiological parameters. This TBE model can simultaneously evaluate the effect of multiple system-specific and drug-specific factors on the T-cell redirecting bsAb exposure-response relationship on a physiological basis; it reasonably captured multiple reported in vitro cytotoxicity data, and successfully predicted the effect of some key factors on in vitro cytotoxicity assays and the efficacious dose of blinatumomab in humans. The mechanistic nature of this model uniquely positions it as a knowledge-based platform that can be readily expanded to guide target selection, drug design, candidate selection and clinical dosing regimen projection, and thus support the overall discovery and development of T-cell redirecting bsAbs.
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The optimal clinical dose of epcoritamab can be informed by levels of target engagement and trimer formation.
“Therefore, the optimal clinical dose of epcoritamab can be informed by levels of target engagement and trimer formation. 4 , 5”
From Semimechanistic Physiologically‐Based Pharmacokinetic/Pharmacodynamic Model Informing Epcoritamab Dose Selection for Patients With <scp>B‐Cell</scp> Lymphomas (2022) · cites this paper as [4]
The Discussion (page unavailable in our copy) says the TBE-complex model has the potential to predict efficacious dose ranges and dosing regimens for T-cell-redirecting bispecific antibodies using binding and engagement properties. The Results apply it to blinatumomab in humans, not epcoritamab. Thus the general dosing rationale is supported, but the epcoritamab-specific claim is not established by this paper. (LLM, conf=0.87)
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- Authors
- Jiang, X., Chen, X., Carpenter, T. J., Wang, J., Zhou, R., Davis, H. M., Heald, D. L., & Wang, W.
- Affiliations
- Biologics Development Sciences, Janssen Biotherapeutics, Janssen Research & Development, LLC, Spring House, PA, USA
- Swarthmore College (US)
- Corresponding author
- Wang, Weirong
- Venue
- mAbs
- Publisher
- Informa UK Limited
- Published
- 2018-08-18
- Volume
- 10
- Issue
- 6
- Pages
- 876-889
- ISSN
- 1942-0862 (ISSN-L)
- 1942-0870
- PMC
- PMC6152432
- OpenAlex
- W2818868381
- Cited by
- 60
- References
- 61
- Citations by year
- 2026: 4 · 2025: 11 · 2024: 4 · 2023: 12 · 2022: 7 · 2021: 6 · 2020: 11 · 2019: 2 · 2018: 2
- FWCI
- 3.63
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by-nc-nd
- Locations
- mAbs (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Funders
- Janssen Research & Development, LLC
- Topics
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Monoclonal and Polyclonal Antibodies Research
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Keywords
- pharmacokinetic-pharmacodynamic modeling, exposure-response relationship, blinatumomab, T cell recruitment, in vitro cytotoxicity, target selection
- MeSH terms
- Algorithms, Antibodies, Monoclonal, Antibody-Dependent Cell Cytotoxicity, Biological Products, Humans, T-Lymphocytes, CD3 Complex, Antibodies, Bispecific, Models, Immunological, Cell Line, Tumor, Precursor Cell Lymphoblastic Leukemia-Lymphoma
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