Oleg Demin Jr (1), Dmitry Shchelokov (2)
(1) InSysBio, Russia, (2) Lomonosov Moscow State University, Russia
Objectives: A lot of bispecific T-cell engaging antibodies are in preclinical and clinical development for the treatment of various types of cancers. Kinetics of bispecific therapeutic antibody bound with its targets (trimer complex) is more complex than simple monospecific antibody bound with one target. Theoretically, the dependence of concentration of trimer complex on dose is bell-shaped. The aim of this work is to investigate dose response behavior of bispecific T-cell engaging antibodies under physiological conditions on the basis of B-cell acute lymphoblastic leukemia (B-ALL) treatment with blinatumomab, CD19/CD3 bispecific T-cell engaging antibody.
Methods: Developed QSP model consist of three parts: (1) physiologically-based pharmacokinetic (PBPK) model of blinatumomab including binding to target receptors – CD3 on T cells and CD19 on leukemic cells; (2) dynamics of normal cells (CD20 positive and CD20 negative B cell precursors, neutrophils, platelets) and leukemic cells during B-ALL progression without treatment; (3) specific lysis of CD19+ cells (both normal and leukemic cells) by CD3+ T cells in presence of blinatumomab. Model describes immunological synapse between CD3+ T cells and CD19+ cells, and formation of trimer complex of blinatumomab with CD3 and CD19 in synapse. Parameters of the model were identified on the basis of published in vitro and in vivo data on healthy subjects and adult relapse/refractory B-ALL patients, but not clinical data. Blinatumomab clinical data including pharmacokinetics and pharmacodynamics was used to validate the model. Also, in vitro data was used to implement variability in specific lysis of CD19+ cells in presence of blinatumomab.
Results: PBPK part of the model was able to reproduce clinical PK data on blinatumomab without fitting of clinical pharmacokinetics data. Pharmacodynamics of blinatumomab was validated against data on dynamics of CD19+ cells in blood of B-ALL patients. Model shows that there is no response at doses up to 8 ug/m^2/day, which is correspond to clinical data [1]. Duration of CD19+ cell depletion to the level below 1 cell per microliter was varied from 0.5 to 21 days for responders in the model as in clinical trials [2,3]. The threshold for activation of specific lysis in presence of blinatumomab was 253 nmol/L (corresponds to 38 trimer complexes in synapse) for CD4 T cells and 103 nmol/L (corresponds to 16 trimer complexes in synapse) for CD8 T cells. The decrease in concentration of trimer complex (bell-shaped behavior) can be observed only at doses starting from 10^6 ug/m^2/day, which correspond to steady state concentration in plasma – 47 ug/mL, whereas concentration of blinatumomab in plasma after administration of approved dose is about 700 pg/mL.
Conclusions: Developed model is able to reproduce pharmacokinetics and pharmacodynamics data of blinatumomab without fitting of clinical data. Model shows that threshold for activation of specific lysis of CD19+ cells in presence of blinatumomab is very low and bell shaped dose response can be observed only at very high non-physiological doses of blinatumomab.
References:
[1] Bargou et al. Science. 2008 Aug 15;321(5891):974-7
[2] Zugmaier et al. Blood. 2015 Dec 10;126(24):2578-84
[3] Klinger et al. Blood. 2012 Jun 28;119(26):6226-33
Reference: PAGE 28 (2019) Abstr 8801 [www.page-meeting.org/?abstract=8801]
Poster: Drug/Disease Modelling - Oncology