Bispecific antibodies in haematological malignancies

Abstract

Bispecific antibodies (bsAbs) combine the binding sites of two monoclonal antibodies in one molecule. The close proximity of a tumor specific antigen and an effector cell antigen results in a targeted activation of effector cells. The mechanism is similar to the chimeric antigen receptor (CAR) T-cells, recently approved in two haematologic cancers. CAR T-cells and bsAb represent the most powerful tools for major-histocompatibility complex (MHC) independent T-cell immune response against cancer. In contrast to CAR T-cells, bsAbs are "off the shelf" drugs. As a drawback, the efficacy is dependent on a prolonged application. More than 40 years of intensive research generate a plethora of bispecific constructs with a remarkable difference in manufacturability, stability, half-life time and receptor affinity. Blinatumomab was the first approved bsAb in relapsed and refractory acute lymphoblastic leukemia. By the mature experience of blinatumomab in more than 10 clinical trials over more than one decade, we learned some lessons on how to use this new principle. The efficacy is higher in patients with less tumor burden, suggesting the use as consolidation more than for initial debulking. Main resistance mechanisms are extramedullary relapses and the expression of the inhibitory PD-L1 molecule, suggesting the value of combination with checkpoint inhibitors. CD19 loss is infrequent after blinatumomab, preserving the option for alternative CD19-direct treatments. New bsAbs in lymphoma, myeloma and acute myeloid leukemia enter phase-I trials, together with many new constructs in solid cancer.

Keywords: Acute lymphoblastic leukemia; Bispecific antibodies; Bispecific t-cell engager; Blinatumomab; Cytokine release syndrome; Neurotoxicity; Non-hodgkin lymphoma.