Bispecific Antibodies in Hematological Malignancies: A Scoping Review

Abstract

Bispecific T-cell engagers (BiTEs) and bispecific antibodies (BiAbs) have revolutionized the treatment landscape of hematological malignancies. By directing T cells towards specific tumor antigens, BiTEs and BiAbs facilitate the T-cell-mediated lysis of neoplastic cells. The success of blinatumomab, a CD19xCD3 BiTE, in acute lymphoblastic leukemia spearheaded the expansive development of BiTEs/BiAbs in the context of hematological neoplasms. Nearly a decade later, numerous BiTEs/BiAbs targeting a range of tumor-associated antigens have transpired in the treatment of multiple myeloma, non-Hodgkin's lymphoma, acute myelogenous leukemia, and acute lymphoblastic leukemia. However, despite their generally favorable safety profiles, particular toxicities such as infections, cytokine release syndrome, myelosuppression, and neurotoxicity after BiAb/BiTE therapy raise valid concerns. Moreover, target antigen loss and the immunosuppressive microenvironment of hematological neoplasms facilitate resistance towards BiTEs/BiAbs. This review aims to highlight the most recent evidence from clinical trials evaluating the safety and efficacy of BiAbs/BiTEs. Additionally, the review will provide mechanistic insights into the limitations of BiAbs whilst outlining practical applications and strategies to overcome these limitations.

Keywords: CAR-T; antibodies; bispecific antibody; hematological cancer; leukemia; lymphoma; multiple myeloma.

Figure 1

This figure depicts the main bispecific antibodies in ongoing clinical trials for the treatment of multiple myeloma. The bispecific antibodies are outlined according to their target myeloma-associated antigen, including BCMA, GPRC5D, FcRH5, and CD38. The figure also outlines the key strategies to overcome bispecific antibody resistance. One of the key strategies includes the synergistic combination of bispecific antibodies with other bispecific antibodies, monoclonal antibodies, or antibody–drug conjugates in order to target multiple antigens simultaneously. The second strategy to overcome resistance is relevant to the main class of bispecific antibodies in multiple myeloma, i.e., BCMA-targeting bispecific antibodies. This strategy involves using gamma-secretase inhibitors such as nirogacestat to prevent the cleavage of membrane-bound BCMA into soluble BCMA, thereby increasing the expression of BCMA on the surfaces of myeloma cells. Finally, the third strategy involves the use of immunomodulatory agents, immune checkpoint inhibitors, and daratumumab to modulate the tumor microenvironment and shift the repertoire of T cells by reducing the number of immunosuppressive regulatory T cells and exhausted T cells.

Figure 2

This figure outlines the mechanism of action of blinatumomab, the main bispecific T-cell engager utilized in the treatment of acute lymphoblastic leukemia. Blinatumomab binds to the CD19 antigen expressed on neoplastic B lymphoblasts along with the CD3 receptor expression on T cells, resulting in subsequent T-cell-mediated lysis of the leukemic cell. The figure also outlines some of the potential applications of blinatumomab therapy in acute lymphoblastic leukemia. This includes its use for relapsed/refractory disease, in addition to its incorporation in induction and consolidation regimens for different subtypes of acute lymphoblastic leukemia. The figure also illustrates the key mechanisms of resistance associated with blinatumomab therapy, including (1) antigen escape and loss of CD19 expression; (2) myeloid lineage switch after blinatumomab therapy, which has been reported in cases of KMT2A(MLL)-rearranged acute lymphoblastic leukemia, resulting in the development of acute myelogenous leukemia; (3) the immunosuppressive microenvironment in acute lymphoblastic leukemia is associated with an increased percentage of regulatory T cells along with a lower frequency of CD8+/CD3+ T cells, thereby facilitating resistance to blinatumomab.

Figure 3

This figure outlines the advantages and disadvantages of the potential target antigens in the development of bispecific antibodies for the treatment of acute myelogenous leukemia. These target antigens, which are expressed on leukemic stem cells and myeloblasts, include CD33, CD123, CLL-1, and FLT-3.

Figure 4

This figure outlines the features of primary toxicities associated with bispecific T-cell engaging therapy in hematological malignancies. These primary toxicities include neurotoxicity/immune effector cell-associated neurotoxicity syndrome, cytokine release syndrome, infections, and hematologic toxicity.