Bispecific Antibodies: A Review of Development, Clinical Efficacy and Toxicity in B-Cell Lymphomas

Abstract

The treatment landscape of B-cell lymphomas is evolving with the advent of novel agents including immune and cellular therapies. Bispecific antibodies (bsAbs) are molecules that recognise two different antigens and are used to engage effector cells, such as T-cells, to kill malignant B-cells. Several bispecific antibodies have entered early phase clinical development since the approval of the CD19/CD3 bispecific antibody, blinatumomab, for relapsed/refractory acute lymphoblastic leukaemia. Novel bsAbs include CD20/CD3 antibodies that are being investigated in both aggressive and indolent non-Hodgkin lymphoma with encouraging overall response rates including complete remissions. These results are seen even in heavily pre-treated patient populations such as those who have relapsed after chimeric antigen receptor T-cell therapy. Potential toxicities include cytokine release syndrome, neurotoxicity and tumour flare, with a number of strategies existing to mitigate these risks. Here, we review the development of bsAbs, their mechanism of action and the different types of bsAbs and how they differ in structure. We will present the currently available data from clinical trials regarding response rates, progression free survival and outcomes across a range of non-Hodgkin lymphoma subtypes. Finally, we will discuss the key toxicities of bsAbs, their rates and management of these adverse events.

Trial watch: intratumoral immunotherapy

“…For instance, blinatumomab binds to CD19 on leukemia cells and can engage T cells through binding to their CD3 ( Table 1 ). 127 To our knowledge, there were no clinical trials initiated these past 3 y involving intratumoral delivery of bispecific antibodies.…”

Dual Targeting of Multiple Myeloma Stem Cells and Myeloid-Derived Suppressor Cells for Treatment of Chemotherapy-Resistant Multiple Myeloma

“…Neurotoxicity is a treatment-emergent adverse event (AE) for BsABs, and it is often associated with CRS (77). The signs and symptoms vary from patient to patient and include headache, tremor, confusion, expressive and nominal dysphasia, impaired attention, apraxia, and lethargy occurring as early and common manifestations (77)(78)(79). Consensus grading criteria were developed by the ASTCT based on the use of the Immune Effector Cell-Associated Encephalopathy (ICE) screening tool (78).…”

“…Neurotoxicity is a treatment-emergent adverse event (AE) for BsABs, and it is often associated with CRS ( 77 ). The signs and symptoms vary from patient to patient and include headache, tremor, confusion, expressive and nominal dysphasia, impaired attention, apraxia, and lethargy occurring as early and common manifestations ( 77 – 79 ).…”

Development of a reporter gene method to measure the bioactivity of anti-CD38 × CD3 bispecific antibody

“…Bispecific antibody (bsAb)—a class of artificial mAb that can simultaneously bind to two different epitopes or antigens—is expected to provide additional functions compared with a typical mAb for the inhibition of tumors. With the scientific efforts in development in the past a few decades, there are currently four bsAb drugs lunched on markets, >100 academic and industry-derived molecules in clinical development and many more projects under preclinical development [ 3 ]. Among these bsAbs, over 80% of the projects are clinically indicated for cancers, and ~50% of which are T cell-redirecting bsAbs (T-bsAbs; [ 4–8 ]).…”