Development of ICT01, a first-in-class, anti-BTN3A antibody for activating V gamma 9V delta 2 T cell-mediated antitumor immune response

Gamma delta T (gamma delta T) cells are among the most potent cytotoxic lymphocytes. Activating anti-butyrophilin 3A (BTN3A) antibodies prime diverse tumor cell types to be killed by V gamma 9V delta 2 T cells, the predominant gamma delta T cell subset in peripheral circulation, by mechanisms independent of tumor antigen-major histocompatibility complex (MHC) complexes. In this report, we describe the development of a humanized monoclonal antibody, ICT01, with sub-nanomolar affinity for the three isoforms of BTN3A. We demonstrate that ICT01-activated V gamma 9V delta 2 T cells kill multiple tumor cell lines and primary tumor cells, but not normal healthy cells, in an efficient process requiring approximately 20% target occupancy. We show that ICT01 activity is dependent on BTN3A and BTN2A but independent of the phosphoantigen (pAg)-binding B30.2 domain. ICT01 delays the growth of hematologic and solid tumor xenografts and prolongs survival of NOD/SCID/IL2r gamma(null) (NSG) mice adoptively transferred with human V gamma 9V delta 2 T cells. In single- and multiple-dose safety studies in cynomolgus macaques that received up to 100 mg/kg once weekly, ICT01 was well tolerated. With respect to pharmacodynamic endpoints, ICT01 selectively activated V gamma 9V delta 2 T cells without affecting other BTN3A-expressing lymphocytes such as alpha beta T or B cells. A first-in-human, phase 1/2a, open-label, clinical study of ICT01 was thus initiated in patients with advanced-stage solid tumors (EVICTION: NCT04243499; EudraCT: 2019-003847-31). Preliminary results show that ICT01 was well tolerated and pharmacodynamically active in the first patients. Digital pathology analysis of tumor biopsies of a patient with melanoma suggests that ICT01 may promote immune cell infiltration within the tumor microenvironment.