γδ T cell activation by bispecific antibodies

Bispecific antibodies have been successfully introduced into clinical application. gamma delta T cells are of special interest for tumor immunotherapy, due to their recognition of pyrophosphates that are overproduced by many tumor cells resulting in HLA-nonrestricted tumor cell killing. Here we describe in detail a [(Her2)(2) x V gamma 9] tribody construct that targets human V gamma 9 T cells to HER2-expressing tumor cells. The direct comparison with other selective V gamma 9 T cell agonists including phosphoantigens and nitrogen-containing bisphosphonates revealed the superiority of the [(Her2)2 x V gamma 9] tribody in triggering gamma delta T cell-mediated tumor cell killing with negligible induction of gamma delta T cell death. In contrast, phosphoantigens and bisphosphonates are potent inducers of gamma delta T cell proliferation but less efficient enhancers of gamma delta T cell-mediated tumor cell killing. Collectively, our data identify unique properties of a gamma delta T cell-targeting [(Her2)(2) x V gamma 9] tribody which make it an attractive candidate for clinical application in gamma delta T cell-based tumor immunotherapy. (C) 2015 Elsevier Inc. All rights reserved.