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Updated: Jul 15, 2026
An Organotypic High Throughput System for Characterization of Drug Sensitivity of Primary Multiple Myeloma Cells
Published on: July 15, 2015
Quantitative systems pharmacology modeling sheds light into the dose response relationship of a trispecific T cell
R E Abrams1,2, K Pierre3, N El-Murr4
1Sanofi, 55 Corporate Dr, Bridgewater, NJ, 08807, USA.
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.
Insights
A novel trispecific antibody targeting multiple myeloma (MM) shows improved T-cell activation and tumor killing. This bispecific T-cell engager (TCE) demonstrates enhanced efficacy by engaging CD3, CD28, and CD38, offering new hope for relapsed and refractory MM patients.
Area of Science:
- Immunology
- Pharmacology
- Oncology
Background:
- Relapsed and refractory multiple myeloma (RRMM) presents limited therapeutic options post-standard care.
- Bispecific T-cell engagers (TCEs) are emerging therapies for MM, designed to activate T-cells and induce tumor cell killing.
- Novel TCEs are being developed to enhance T-cell engagement and anti-myeloma activity.
Purpose of the Study:
- To investigate the mechanism of a novel trispecific TCE that targets CD3, CD28, and CD38.
- To evaluate how this trispecific TCE enhances T-cell activation, proliferation, and cytolytic activity against multiple myeloma cells.
- To develop a quantitative systems pharmacology (QSP) model to understand the drug's dose-response relationship.
Main Methods:
- Utilized computational and experimental approaches to study T-cell and myeloma cell interactions.
- Developed a rule-based QSP model trained on T-cell activation, cytotoxicity, and cytokine data.
- Analyzed dose-response curves and predicted the impact of cellular interactions on efficacy.
Main Results:
- The trispecific TCE (targeting CD3-CD28-CD38) demonstrated increased T-cell killing capacity against MM cells.
- QSP model predictions indicated a plateau in killing at higher doses, differing from typical bispecific TCE bell-shaped curves.
- Tumor cell synapse formation and competition for engagement with T-cells were identified as key drivers of the dose-response.
Conclusions:
- The CD28 co-stimulatory domain on the trispecific antibody significantly enhances anti-myeloma efficacy.
- The study proposes "effective" receptor occupancy as a metric to assess the potency of novel TCEs.
- Findings provide insights into optimizing TCE design and predicting therapeutic outcomes in multiple myeloma.
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