ArticleScientific reports2022
Quantitative systems pharmacology modeling sheds light into the dose response relationship of a trispecific T cell engager in multiple myeloma.
Article in Scientific reports, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed, 14 citations in OpenAlex.
- Clinical Validation of a QSP Model for ISB 2001, a Trispecific T Cell Engager to Support Optimal FIH Study Design in RRMM Patients.Clinical pharmacology and therapeutics · 2026Trial
- Virtual clinical trials of anti-PD-1 and anti-CTLA-4 immunotherapy in advanced hepatocellular carcinoma using a quantitative systems pharmacology model.Journal for immunotherapy of cancer · 2022Trial
- Patient-Specific Determinants of Response to BCMA- and GPRC5D-Targeted CAR T-Cell Therapy in Multiple Myeloma: A QSP Analysis of Clinical Trial and Real-World Data.Clinical pharmacology and therapeutics · 2026Article
- Translating B-Cell and Plasma-Cell Targeting from Oncology to Autoimmunity: Modalities, Quantitative Bridging, and a Development Roadmap.Clinical pharmacology and therapeutics · 2026Review
- TPP-45142-an Anti-HER2 T-cell Engager-Designed for Selective HER2-Low Cancer Immunotherapy.Molecular cancer therapeutics · 2026Article
- Emerging precision medicine in multiple myeloma: clinical and preclinical landscape of T cell, natural killer cell, and macrophages engaging multi-specific antibodies.Frontiers in immunology · 2026Review
- An Overview on T-Cell Engagers: The Current Position in Both the Biological and Mathematical Context.Computational and structural biotechnology journal · 2026Review
- Foundational Principles for the Quantitative Translation of T-Cell Therapeutics for Hematologic Malignancies and Immunology.Clinical pharmacology and therapeutics · 2026Review
- Leveraging quantitative systems pharmacology modeling for elranatamab regimen optimization in relapsed or refractory multiple myeloma.NPJ systems biology and applications · 2025Article
- Perspective of usingFrontiers in immunology · 2025Review
- ISB 2001 trispecific T cell engager shows strong tumor cytotoxicity and overcomes immune escape mechanisms of multiple myeloma cells.Nature cancer · 2024Article
- Article
- Realizing the promise of Project Optimus: Challenges and emerging opportunities for dose optimization in oncology drug development.CPT: pharmacometrics & systems pharmacology · 2024Review
- Development of bispecific T cell engagers: harnessing quantitative systems pharmacology.Trends in pharmacological sciences · 2023Review
- Monoclonal Antibodies: The Greatest Resource to Treat Multiple Myeloma.International journal of molecular sciences · 2023Review
- Review
Corrections and comments
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Authors and funding
14 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
In relapsed and refractory multiple myeloma (RRMM), there are few treatment options once patients progress from the established standard of care. Several bispecific T-cell engagers (TCE) are in clinical development for multiple myeloma (MM), designed to promote T-cell activation and tumor killing by binding a T-cell receptor and a myeloma target. In this study we employ both computational and experimental tools to investigate how a novel trispecific TCE improves activation, proliferation, and cytolytic activity of T-cells against MM cells. In addition to binding CD3 on T-cells and CD38 on tumor cells, the trispecific binds CD28, which serves as both co-stimulation for T-cell activation and an additional tumor target. We have established a robust rule-based quantitative systems pharmacology (QSP) model trained against T-cell activation, cytotoxicity, and cytokine data, and used it to gain insight into the complex dose response of this drug. We predict that CD3-CD28-CD38 killing capacity increases rapidly in low dose levels, and with higher doses, killing plateaus rather than following the bell-shaped curve typical of bispecific TCEs. We further predict that dose-response curves are driven by the ability of tumor cells to form synapses with activated T-cells. When competition between cells limits tumor engagement with active T-cells, response to therapy may be diminished. We finally suggest a metric related to drug efficacy in our analysis-"effective" receptor occupancy, or the proportion of receptors engaged in synapses. Overall, this study predicts that the CD28 arm on the trispecific antibody improves efficacy, and identifies metrics to inform potency of novel TCEs.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.