The Development of Quantitative System Pharmacology (QSP) Model Platform to Guide Clinical Development of T cell Redirecting Engagers (TCEs)

Authors:: Poster Author(s)

Cheung, Yuen Kiu - FDA/CDER (Student); Jiang, Xiling - FDA/CDER (Mentor); Zhao, Miao - FDA/CDER; Feng, Zhou - FDA/CDER; Okusanya, Olanrewaju - FDA/CDER

Center:: Contributing Office

Center for Drug Evaluation and Research

Abstract

Poster Abstract

Background

In the past two decades, there has been a focus on bispecific antibodies (BsAbs) as a novel class of therapeutic agents. A subclass of BsAbs - T cell redirecting engagers (TCEs), which redirect effector cells (e.g., cytotoxic T cells) to tumor-associated/ -specific antigens toward targeted cell killings, have attracted tremendous interest in treating patients with hematological malignancies. Despite their promising efficacy profile, TCEs present significant potential risk of severe toxicities, notably cytokine release syndrome (CRS). Challenges arise throughout the development of TCEs in the past decades as the determinants for the activity of TCEs is multi-factorial. Therefore, the objective was to develop a quantitative system pharmacology (QSP) model platform to guide clinical development of TCEs by investigating multiple aspects, which included, the effects of numerous factors on the exposure-response relationship of TCEs, the influence of soluble target on the pharmacokinetics and pharmacodynamics (PK/PD) of TCEs, and the comparison of TCEs exposure in target tissues following intravenous (IV) vs. subcutaneous (SC) administrations.

Methods

This model platform consists of three mechanistic models: Target cell- Biologics-Effector cell (TBE) complex-based cell killing model, minimal physiological-based PK (mPBPK) model, and target-mediated drug disposition (TMDD) model. The model platform was utilized to perform simulations under multiple clinical scenarios to answer various review questions.

Results

Model platform was able to characterize three major aspects. Using blinatumomab as a model drug, the model platform was able to predict the cytotoxicity (i.e., efficacy) and cytokine release (i.e., safety) of TCEs, with different systemic- (e.g., non-Hodgkin’s lymphoma vs. acute lymphoblastic leukemia) and drug- (e.g., fixed dose vs. step dose) specific factors. In addition, the model was able to provide PK simulations comparison of TCEs in target tissues following IV vs. SC administrations. The model also demonstrated the PK/PD changes of TCEs with the presence of soluble target.

Conclusion

This model platform may serve as a useful tool to provide guidance on numerous key factors regarding the design optimization and dosing regimens of TCEs. Models within this platform can also be incorporated individually to other mechanistic models to further explore individual aspect, including evaluating the potential relationship among TCE dosing regimen, cytokine release and CRS occurrence.