Bispecific Monoclonal Antibody Therapy of B-Cell Malignancy

Bispecific monoclonal antibodies (bsAbs) that recognize CD3 with one arm and a tumor associated antigen with the other arm can retarget T-cells toward tumor cells in an MHC independent manner, thereby combining the specificity of monoclonal antibodies with the power of the cellular immune system. B-cell malignancies are particularly attractive as targets for anti-CD3-based bsAb therapy because of their sensitivity to other forms of antibody therapy, and the extent to which B-cells and T-cells communicate at the molecular level. BsAbs that recognize CD3 and a number of antigens on malignant B-cells have been shown in vitro to be capable of retargeting T-cells. In animal models of B-cell malignancy, bsAb can eliminate tumor loads that are resistant to unmodified monoclonal antibody therapy. Ongoing early clinical trials in advanced B-cell lymphoma indicate CD3-based bsAbs have significant biologic effects, and suggest they have anti-tumor activity as well. A number of significant questions relating to bsAb therapy of B-cell malignancies remain. It is unclear what role both endogenously produced and exogenously administered cytokines are likely to play. Further exploration of whether bsAb can induce T-cells to target to tumor will also be required before the true promise of this novel form of immunotherapy can be determined.