Immunotherapy using bispecific T cell engager (BiTE®) antibodies: preclinical and clinical experience in acute leukemia

BiTE antibodies are novel recombinant single chain Ig domain constructs that leverage the endogenous cytotoxic potential of polyclonal T cells to target malignant cells by utilizing the specific binding properties of variable domains from two different antibodies. Antibody-based immunotherapy represents a promising strategy in cancer. BiTE antibodies have demonstrated efficacy in hematologic malignancies, both preclinically and clinically. Two investigational BiTE antibodies are under development targeting leukemia. The most advanced BiTE antibody, Blinatumomab, directs cytotoxic T cells to CD19-expressing target cells. Blinatumomab has shown anti-leukemia activity in adult relapsed/refractory (r/r) B-precursor ALL. Its efficacy and toxicity was evaluated in a large confirmatory Phase II study. Patients with Ph-negative r/r ALL (N = 189; refractory; 1st relapse Given the anti-leukemia activity of single-agent Blinatumomab in a difficult-to-treat population with r/r ALL, another BiTE antibody targeting CD33, AMG 330, was developed for its suitability as immunotherapy in AML. To simulate the natural setting of target and T cells in AML patients, a long-term culture system was developed that supports the growth of primary AML cells ex-vivo for up to 5 weeks. AMG 330 activated and expanded residual autologous T cells within primary AML patient samples and eliminated CD33+ blasts even at very low effector to target ratios. The functional relevance of CD33 expression levels was shown by faster lysis kinetics of CD33 versus CD33 AML cell lines and primary AML cells in ex-vivo cytotoxicity assays. However, by extending the exposure time to AMG 330, potent anti-leukemic activity was observed in both CD33 and CD33 cells. AMG 330 treated T cells were shown to up-regulate the activation markers CD25, PD-1, TIM3 and LAG3, which was partially reversible after complete target cell elimination Clinical experience with Blinatumomab in ALL and ex-vivo activity of AMG 330 in primary AML samples supports further development of BiTE antibodies for targeted T cell-mediated immunotherapy of patients with malignancies.