Bifunctional Antibodies: Preclinical and Clinical Applications

Abstract

Treating malignancies with antibody-based immunotherapy has revolutionized the concept of targeted therapy. Rituximab and Trastuzumab, two monoclonal antibodies approved in the 1990s by the FDA, elucidated the potential of harnessing the immune system to eliminate transformed cells. As with any cancer therapy, a significant proportion of patients relapse, driving the development of nontraditional antibody-based therapies. Therefore, in an effort to enhance the ability of antibodies to retarget immune cells toward cancer cells, bispecic antibodies were born. Created through a variety of techniques they conform to an assortment of structures, recapitulating the basic structure of an antibody or deconvoluting the antigen-binding domains into unique designs. The European Union's approval in 2009 of Catumaxomab, a bispecic antibody that links cells of the innate and adaptive immune system to EpCAM + cells for the treatment of malignant ascites, marks the first clinically approved dual-targeting antibody. Blinatumomab, a bispecic T-cell engager BiTE), links T-cells directly to malignant cells, activating target-cell apoptosis through perforin-granzyme release. Early clinical results of Blinatumomab show a remarkable 80 % response rate in a heavily pretreated ALL patient subgroup. These enticing clinical results represent the forefront of the bispecic antibody field but evidence exists that point to the clinical success of numerous bispecificantibody formats. Although it is unknown which format will exhibit the highest clinical efficacy, it is clear that dual-targeting antibodies represent the future of immunotherapy for the treatment of cancer.