Aparna Mohan 1, Dinesh Bedathuru 1, Debomita Chakraborthy 1, Goutam Nair 1, Bhairav Paleja 1
1 Vantage Research (Lewes, USA)
OBJECTIVES
CD3 T-cell engagers (TCEs) pose a significant risk of cytokine release syndrome (CRS), making accurate first-in-human (FIH) dose selection essential for both safety and clinical efficiency. The objectives of this work are.
• To develop a mechanistically informed minimum anticipated biological effect level (MABEL) framework for TCEs using a quantitative systems pharmacology (QSP) model calibrated to preclinical mosunetuzumab data.
• To move beyond empirical EC10/EC20-based approaches by explicitly capturing the mechanistic drivers of cytokine release and target engagement.
• To evaluate whether model-informed predictions can support safer and more clinically meaningful FIH starting dose selection strategies.
METHODS
We refined a published CD3 TCE QSP platform model with mosunetuzumab-specific parameters to capture intravenous PK, trimer formation, and IL-6 dynamics. We explicitly modeled CD3-CD20-drug trimer formation as the proximal driver of IL-6 release, moving beyond plasma concentration driven frameworks. We calibrated the model using in vivo transgenic mouse and cynomolgous monkey data. We defined MABEL thresholds by trimer onset and detectable cytokine activity below CRS-relevant levels, and we ran low-dose simulations to estimate the model-derived MABEL. We then compared these results with reported clinical starting doses and escalation schemes.
RESULTS
Model simulations identified a MABEL dose that achieved subthreshold IL-6 induction at doses higher than the reported clinical starting dose of mosunetuzumab. This model-derived MABEL remained below in pre-defined IL-6 thresholds linked to clinically significant CRS, indicating its potential safety. Comparison highlighted that a model-guided approach could potentially reduce the number of subtherapeutic cohorts while maintaining safety, thereby enabling leaner FIH escalation.
CONCLUSION
We demonstrate that trimer-driven modeling provides a mechanistic framework for defining MABEL in TCEs. While both concentration and trimer-based models align at higher exposures, only the trimer-based approach captures the low-dose range critical for MABEL and supports biologically interpretable “what-if” simulations. Applied to mosunetuzumab, this approach strengthens justification for FIH starting doses and offers a reusable framework for efficient TCE development.
References:
1. Sun et al. Science translational medicine vol. 7,287 (2015): 287ra70.
2. Hosseini et al. NPJ Syst Biol Appl. 2020 Aug 28;6(1):28.
3. Shah and Betts. J et al. Journal of pharmacokinetics and pharmacodynamics vol. 39,1 (2012): 67-86.
Reference: PAGE 34 (2026) Abstr 11954 [www.page-meeting.org/?abstract=11954]
Poster: Drug/Disease Modelling - Oncology