Blinatumomab: A novel, bispecific, T-cell engaging antibody

Abstract

Blinatumomab is approved as an option for Ph chromosome-negative relapsed or refractory B-cell precursor ALL and is a needed addition to the limited treatment options for this difficult-to-treat patient population. Two Phase II clinical trials resulted in impressive results when using blinatumomab as a single agent, resulting in the drug's approval.

Integrated Pharmacokinetic/Pharmacodynamic Model of a Bispecific CD3xCD123 DART Molecule in Nonhuman Primates: Evaluation of Activity and Impact of Immunogenicity

“…The decrease in T-cell counts likely represents cell migration toward tissues or an increased adhesion of the cells to blood vessels, triggered by the binding of the drug to CD3. The later increase in T-cell counts following MGD006 exposure is thought to be due to stimulation by subsequent cytokine release (19). Lymphocyte trafficking is a phenomenon that has been well described with an indirect pharmacokinetic/pharmacodynamic model following the administration of corticosteroids in humans (36,37).…”

“…However, anti-drug antibodies were developed in 70% of the animals (17). Similar to blinatumomab, MGD006 results in circulating T-lymphocyte cell trafficking, which may be triggered by monovalent binding of the compound to CD3 (19). The objectives of this study were to (i) develop a pharmacokinetic model for MGD006 disposition in monkeys, (ii) develop pharmacodynamic models to link MGD006 exposure with T-cell trafficking and CD123 þ cell depletion, and (iii) evaluate the impact of ADA development on these outcomes.…”

Antibody darts on target for acute myelogenous leukemia

“…Antibodies have been used alone, but can be engineered linking them to toxins or to T lymphocytes, either joined to the zeta chain of the T cell receptor (chimeric antigen receptors), or through bi-specific antibodies binding T cells by anti CD3 to the lymphoid target through, for example the anti CD19 variable portion [reviewed in (1)]. Clinical trials clearly confirm the power of strategies which bring T cells with their cytotoxic potency into close proximity with surface antigen targets on the malignant cell (2)(3)(4).…”

Targeting CD19: the good, the bad, and CD81

“…Second, antithrombin is an important direct inhibitor of thrombin and other coagulation proteases. 3 Finally, the propagation phase is regulated by the protein C anticoagulant pathway. 4 As thrombin is generated, it binds to endothelial cell surface thrombomodulin, and its specificity is redirected from fibrinogen cleavage to protein C activation.…”