Comparative pharmacology of the human CD19/CD3 Bispecific T-cell engager (BiTERTM) antibody blinatumomab with the hybrid murine surrogate CD19/CD3 BiTE antibody hyS103

Blinatumomab is a bispecific single-chain antibody of the BiTE RTM class that binds human CD19 (B-cells) and CD3 (T-cells). Blinatumomab directs T-cells to lyse B-cells and is in clinical trials for the treatment of B-cell malignancies. Alternative routes of administration are under consideration.A hybrid murine surrogate BiTE antibody, hyS103, was developed for use in human CD19 transgenic (CD19TG) mice as a potential pharmacologically-relevant species model for predicting human toxicity of blinatumomab. In vitro and in vivo pharmacology of hyS103 were assessed.HyS103 had a lower affinity to CD3, similar affinity to CD19 and a resulting potency that was lower than blinatumomab. Unexpectedly, hyS103 induced non-specific B-cell lysis and T-cell activation. CD19TG mice administered hyS103 were depleted of B-cells, and had measured T-cell activation and serum cytokines. HyS103-treated wild-type mice had non-specific B-cell depletion and T-cell activation. Because of these differences and non-specific activity, hyS103 may misrepresent human toxicity of blinatumomab.