Bispecific Siglec-15/T cell antibody (STAB) activates T cells and suppresses pancreatic ductal adenocarcinoma and non-small cell lung tumors <i>in vivo</i>

<b>Rationale:</b> Siglec-15 (S15) is a membrane-associated antigen overexpressed across various cancer types, and also induces immunosuppression. We believe this makes S15 a promising target for cellular immunotherapy of solid tumors characterized by an immunosuppressive tumor microenvironment, but this remains underexplored to date. <b>Method:</b> We engineered a bispecific antibody that simultaneously binds S15 on tumor cells and CD3 on T cells in the popular IgG-scFv format; we termed this molecule STAB. <b>Results:</b> <i>In vitro</i>, STAB induced marked proliferation of CD3+ T cells in human PBMCs, and mediated effective killing of Panc-1 pancreatic ductal adenocarcinoma (PDAC) and H460 non-small cell lung cancer (NSCLC) cells in co-culture studies with PBMCs or CD3+ T cells. In NSG mice with human PDAC and NSCLC tumors, STAB effectively suppressed tumor growth and prolonged survival, in sharp contrast to mice receiving either anti-S15 or anti-CD3 mAbs alone. STAB increased activated T cells in both tumor and circulation, as well as reduced the stromal barrier-a key hallmark of PDAC. <b>Conclusion:</b> Our results underscore STAb as a promising therapeutic molecule to be investigated further for PDAC and NSCLC, and potentially other S15-positive solid tumors.