A next-generation CD8-selective tri-specific T cell engager targeting CDH17 with enhanced efficacy and reduced toxicity

T cell engagers (TCEs) have already achieved remarkable clinical potential. However, severe toxicities such as cytokine release syndrome (CRS) have led to the failure of many TCE candidates in clinical trials. In addition, because Treg cells also express the TCR-CD3 complex, TCEs can inadvertently activate Treg cells, thereby substantially suppressing anti-tumor immune responses. To address these problems, a CD8-biased TCE has been developed that strongly activates CD8+T cells while minimally activating CD4+T cells and Treg cells, thereby reducing toxicity and improving therapeutic efficacy. However, CD8+T cell activation requires help from CD4+T cells; without this assistance, the effector function of CD8+T cells is limited. Therefore, we have developed an first-in-class next-generation TCE based on NKG2D. NKG2D is highly expressed on CD8+T cells but is rarely expressed on CD4+T cells and Tregs, providing inherent selectivity for CD8+T-cell activation. Moreover, NKG2D delivers a costimulatory signal that restores the function of CD8+T cells without CD4+T-cell help. Here, we present a tri-specific TCE, CDH17×CD3×NKG2D (FPE026). FPE026 binds to and activates CD8+T cells, but not CD4+T cells or Treg cells. It effectively mediates T cell-driven killing of CDH17-positive tumor cells while inducing much lower levels of cytokines, such as TNF-alpha and IL-6, compared with traditional TCEs. In addition, compared with the CDH17×TCR×CD8 construct, FPE026 exhibits stronger cytotoxic activity. Furthermore, FPE026 demonstrates significant anti-tumor activity in the AsPC-1 subcutaneous xenograft model, with limited cytokine elevation in serum. Together, these findings highlight FPE026 as a promising next-generation TCE candidate that combines enhanced CD8+ T cell selectivity and potent anti-tumor efficacy with an improved safety profile.