Investigational immunotherapeutics for B-cell malignancies

Abstract

The use of rituximab-based chemoimmunotherapy regimens has remarkably improved the response rates, long-term outcomes, and quality of life of patients with B-cell malignancies. However, a substantial number of patients exhibit either primary or acquired resistance to rituximab, which suggests that novel immunotherapeutics with distinct mechanisms of action are necessary. A series of monoclonal antibodies with specificity against different surface antigens expressed on malignant B cells (eg, CD22, CD23, CD40, CD70) and novel immunotherapeutics (eg, bispecific monoclonal antibodies, small-modular immunopharmaceuticals, T-cell engagers) are currently in clinical or final preclinical stages of development. Although these agents offer reason for optimism, considerable challenges lie ahead in establishing their real clinical value, as well as in integrating them into current therapeutic algorithms for patients with B-cell malignancies. This review describes some of the most promising investigational immunotherapeutics for the treatment of B-cell malignancies.

Fig 1.

Structure of the CD37–small-modular immunopharmaceutical (SMIP). The CD37-SMIP (G28-1 scFv-Ig) was generated using variable regions (V_L and V_H) from the G28-1 hybridoma and engineered constant regions encoding human IgG₁ domains (hinge, CH₂, and CH₃). CD37 is commonly expressed in chronic lymphocytic leukemia and other mature B-cell malignancies. CD37-SMIP mediated apoptosis and antibody-dependent cellular cytotoxicity, but not complement-dependent cytotoxicity, against CD37⁺ B-cell lymphoma cell lines. IgG1, immunoglobulin G1.

Fig 2.

Schema of the mechanism of action of blinatumomab (MT103/MEDI-538), a bispecific T-cell engager (BiTE). BiTE antibodies, unlike conventional monoclonal antibodies, are capable of directly activating T cells to seek out and destroy cancer cells by transiently tethering resting T cells to cancer cells. Blinatumomab has dual specificity for CD19, expressed on chronic lymphocytic leukemia cells and non-Hodgkin's lymphoma cells, and CD3, present on the surface of all T cells.