Blinatumomab, a Bispecific T-cell Engager (BiTE®) for CD-19 Targeted Cancer Immunotherapy: Clinical Pharmacology and Its Implications

Abstract

Blinatumomab has unique pharmacokinetic and immunological features that require indication-dependent dosing regimens. Stepped dosing is required to achieve adequate efficacy and minimize cytokine release in diseases with high tumor burden.

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

“…32 First, in vitro cytotoxicity data of blinatumomab with multiple representative human B-cell tumor cell lines (Karpas-422, MEC-1 and Raji) and human PBMCs were used to develop the TBE model (Table 2, Figure S2). These cell lines have varied CD19 receptor expression levels and different sensitivities to T cells.…”

“…Blinatumomab plasma drug concentration information following the approved dosing regimen, i.e., continuous intravenous infusion at a 9 µg/day priming dose for 7 days and then 28 µg/day full dose treatments, was obtained from multiple clinical PK studies in patients with either ALL or non-Hodgkin’s lymphoma. 32 Following the 9 µg/day priming dose, blinatumomab plasma concentrations at steady state ranged between 167 – 277 pg/mL; following the 28 µg/day full dose, blinatumomab plasma concentrations at steady state ranged between 552 – 771 pg/mL. Bone marrow concentrations of blinatumomab following blinatumomab administrations were assumed to be about 30% of that in the plasma based on literature report.…”

“…SystemParameters (Unit)EstimationSE(%)Karpas-422 + PBMCsEC 50 (complex/tumor cell)0.01620γ0.8710τ Reference (hr)49.10Base (%)11.60Raji + PBMCsEC 50 (complex/tumor cell)0.0085γ0.933τ Reference (hr)36.81Base (%)1.0313MEC-1 + PBMCsEC 50 (complex/tumor cell)0.01360γ5 (fixed)NAτ Reference (hr)36.20

10.1080/19420862.2018.1480299-F0005Figure 5.Projection of exposure-response relationships of blinatumomab in blood (a) and bone marrow (b) for patients with acute lymphoblastic leukemia (ALL), using TBE model fitting results of in vitro cytotoxicity data from 4 different cell lines (Tables 1 and 2) and physiology & pathology information of ALL patients. Steady state plasma drug concentration information following the priming dose (9 µg/day light gray bar) and the full dose (28 µg/day, dark gray bar) was obtained from literature 32 . Steady state bone marrow drug concentrations following the priming dose (9 µg/day light gray bar) and the full dose (28 µg/day, dark gray bar) were projected under the assumption that drug exposure in bone marrow was about 30% of that in plasma 46

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“…Steady state plasma drug concentration information following the priming dose (9 µg/day light gray bar) and the full dose (28 µg/day, dark gray bar) was obtained from literature 32 . Steady state bone marrow drug concentrations following the priming dose (9 µg/day light gray bar) and the full dose (28 µg/day, dark gray bar) were projected under the assumption that drug exposure in bone marrow was about 30% of that in plasma 46 …”

Perspectives of Fc engineered antibodies in CD19 targeting immunotherapies in pediatric B-cell precursor acute lymphoblastic leukemia

“…2 , 24 Blinatumomab has the disadvantage that its molecule size is only 55 kDa, which results in unfavorable pharmacokinetic properties with a fast clearance from the blood and the body and an elimination half-life of approximately 2 hours. 2 , 29 Thus, blinatumomab treatment requires continuous infusion over several weeks in each cycle requiring special equipment and training of patients and health professionals. Also, both blinatumomab and CAR T cell therapy are enormously cost intensive.…”