Redirecting T cells to hematological malignancies with bispecific antibodies

Abstract

There is a need to improve outcomes for patients with recurrent and/or refractory hematological malignancies. Immunotherapy holds the promise to meet this need, because it does not rely on the cytotoxic mechanism of conventional therapies. Among different forms of immunotherapy, redirecting T cells to hematological malignancies with bispecific antibodies (BsAbs) is an attractive strategy. BsAbs are an "off-the-shelf" product that is easily scalable in contrast to adoptive T-cell therapies. Among these, the bispecific T-cell engager blinatumomab has emerged as the most successful BsAb to date. It consists of 2 single-chain variable fragments specific for CD19 present on B-cell malignancies and CD3 expressed on almost all T cells. Blinatumomab has shown potent antitumor activity as a single agent, particularly for acute lymphoblastic leukemia, resulting in its US Food and Drug Administration approval. However, although successful in inducing remissions, these are normally short-lived, with median response durations of <1 year. Nevertheless, the success of blinatumomab has reinvigorated the BsAb field, which is bustling with preclinical and clinical studies for not only B-cell-derived lymphoblastic leukemia and lymphoma but also acute myeloid leukemia and multiple myeloma. Here, we will review the successes and challenges of T-cell-targeted BsAbs for the immunotherapy of hematological malignancies with special focus on conducted clinical studies and strategies to improve their efficacy.

Figure 1.

Selected BsAb formats. BsAbs can be broadly divided into molecules that contain or do not contain an immunoglobulin G backbone with a functional Fc domain. BsABs can be created by chemical crosslinking 2 mAbs or recombinant DNA technology. Fab, fragment antigen binding; CH, heavy chain; CL, light chain; DART, dual-affinity retargeting; sc, single chain; scFv, single-chain variable fragment.