Development of a Target cell-Biologics-Effector cell (TBE) complex-based cell killing model to characterize target cell depletion by T cell redirecting bispecific agents

Abstract

T-cell redirecting bispecific antibodies (bsAbs) or antibody-derived agents that combine tumor antigen recognition with CD3-mediated T cell recruitment are highly potent tumor-killing molecules. Despite the tremendous progress achieved in the last decade, development of such bsAbs still faces many challenges. This work aimed to develop a mechanism-based pharmacokinetic/pharmacodynamic (PK/PD) modeling framework that can be used to assist the development of T-cell redirecting bsAbs. A Target cell-Biologics-Effector cell (TBE) complex-based cell killing model was developed using in vitro and in vivo data, which incorporates information on binding affinities of bsAbs to CD3 and target receptors, expression levels of CD3 and target receptors, concentrations of effector and target cells, as well as respective physiological parameters. This TBE model can simultaneously evaluate the effect of multiple system-specific and drug-specific factors on the T-cell redirecting bsAb exposure–response relationship on a physiological basis; it reasonably captured multiple reported in vitro cytotoxicity data, and successfully predicted the effect of some key factors on in vitro cytotoxicity assays and the efficacious dose of blinatumomab in humans. The mechanistic nature of this model uniquely positions it as a knowledge-based platform that can be readily expanded to guide target selection, drug design, candidate selection and clinical dosing regimen projection, and thus support the overall discovery and development of T-cell redirecting bsAbs.

Mechanistic Quantitative Pharmacology Strategies for the Early Clinical Development of Bispecific Antibodies in Oncology

“…For example, it may be difficult to determine whether a dose close to the projected efficacious dose is ineffective due to being on the right‐hand side of the bell‐shaped response and when to stop dose escalation. The bell‐shaped relationship has been confirmed preclinically for CD3 bsAbs 34,35 and mechanistic modeling can be used to predict it and to optimize variables to minimize its impact on efficacy and toxicity. For example, Schropp et al .…”

“…The complex MoA of bsAbs and the distinct conditions of preclinical in vivo models demands an integrated analysis to translate to the clinic. QSP modeling and simulation approaches can incorporate and systematically analyze in vitro , preclinical, and clinical data to simultaneously assess the individual effect of, as well as the dynamic interactions among, various factors 34 . Some examples of the use of QSP models to translate preclinical data to the clinic are emerging in the literature for the CD3 bsAbs.…”

Target‐Mediated Drug Disposition Model for Bispecific Antibodies: Properties, Approximation, and Optimal Dosing Strategy

“…In the future, the model and its approximation can be extended with (i) TC effects on target cells, (ii) T cell rebound phenomena, and (iii) integration of local geometrical structures on the cell surface for the cross‐linking binding reactions . Inclusion of geometrical structures leads to mathematical models of the form Eqs.…”

“…In the future, the model and its approximation can be extended with (i) TC effects on target cells, 28 (ii) T cell rebound phenomena, 31 and (iii) integration of local geometrical…”

“…We observed that sometimes representation Eqs. 15,17,[25][26][27][28][29][30] caused convergence issues in MONOLIX and, therefore, we suggest using the representation Eqs. 15-23.…”