(T-079) A mechanistic QSP model of CRS allows for quantitative assessment of dose priming of CD3 bispecific antibody (BsAb) therapeutics.

Kristin Bompiani-Myers, PhD – Senior Principal Scientist Biology, Oncology Research Unit, Pfizer Oncology Division, Pfizer Inc.; Mohamed Elmeliegy, PhD, MBA – Director Clinical Pharmacology, Clinical Pharmacology and Translational Sciences, Pfizer Oncology Division, Pfizer Inc, San Diego, CA; Maria Josic, PhD – Senior Scientist, Oncology Research Unit, Pfizer Oncology Division, Pfizer Inc; Cynthia Musante, PhD – VP & Global Head, Pharmacometrics & Systems Pharmacology, Translational Clinical Sciences, Pfizer Inc; Blerta Shtylla, PhD – QSP Group Lead & Research Fellow, Pharmacometrics & Systems Pharmacology, Translational Clinical Sciences, Pfzier Inc; Kamrine Poels, PhD – Senior Quantitative Systems Pharmacologist, Pharmacometrics & Systems Pharmacology, Translational Clinical Sciences, Pfizer Inc

Objectives: Cytokine release syndrome (CRS) is a systemic inflammatory response that occurs after the administration of T cell engaging therapies such as bispecific antibodies (BsAbs) and results in elevated circulating cytokine levels and in some rare cases secondary organ dysfunction1. To decrease risk and severity, current management strategies involve step-up dosing and premedication. A quantitative systems pharmacology (QSP) model of CRS could streamline the development of innovative medicines by assessing different dose priming strategies and dose regimens.   

 

Methods: We developed a mechanistic QSP model capturing bispecific-receptor binding dynamics and cytokine release for multiple BsAbs4-5. The model was calibrated with in vitro cell assays2-3, mouse PK-PD studies2, and non-human primate (NHP) PK-PD studies. Global sensitivity analysis was performed to investigate model robustness and key drivers for preclinical to clinical translation.  



Results: The calibrated model reproduces two salient behaviors: i) a dose priming effect on cytokine release yielding cytokine peak reduction and ii) systemic cytokine rebound induced by extension of the interval between doses. A global sensitivity analysis (GSA) identified key model features driving the dose priming effect. 

 

Conclusions: Our CRS QSP model captures key cytokine dynamics observed from in vitro and in vivo studies of BsAb therapeutic interventions. The model can support future drug development by informing questions such as the selection of optimal dosing regimens that minimize potential CRS risk for pivotal clinical trials.   

Citations:
[1] Shimabukuro-Vornhagen A, et al. J Immunother Cancer. (2018);6(1):56. 

[2] Li J, et al. Sci Transl Med. (2019);11(508) 

[3] Leclercq G, et al OncoImmunology. (2022);11(1):2039432 



[4] Chen X, et al. Clin Tranl Sci (2019);12, 600-608. 

[5] Trendel N, et al. Sci Signaling (2021) 14 (666).