Selective recruitment of γδ T cells by a bispecific antibody for the treatment of acute myeloid leukemia
Rajkumar Ganesan, Vijaykumar Chennupati, Balaji Ramachandran, Michael Riis Hansen, Sanjaya Singh, Iqbal S. Grewal
Abstract
Abstract Despite significant progress over the last few decades in the treatment of acute myeloid leukemia (AML), there still remains a major unmet medical need for this disease. Immunotherapy approaches for redirecting pan CD3 + T cells to target leukemia blasts have shown limited efficacy in clinical trials and often accompanied with severe toxicity in AML patients. We designed an alternative engager molecule (Anti-TRGV9/anti-CD123), a bispecific antibody that can simultaneously bind to the Vγ9 chain of the Vγ9Vδ2 + γδ T cell receptor and to AML target antigen, CD123, to selectively recruit Vγ9 + γδ T cells rather than pan T cells to target AML blasts. Our results suggest that prototypic bispecific antibodies (a) selectively activate Vγ9 + γδ T cells as judged by CD69 and CD25 surface expression, and intracellular Granzyme B expression, (b) selectively recruit Vγ9 + γδ T cells into cell–cell conjugate formation of γδ T cells with tumor cells indicating selective and effective engagement of effector and target tumor cells, and (c) mediate γδ T cell cytotoxicity (in vitro and in vivo) against tumor antigen-expressing cells. Collectively, these findings suggest that selectively redirecting Vγ9 + γδ T cells to target AML blasts has a potential for immunotherapy for AML patients and favors further exploration of this concept.