Definition

A T-cell engaging (TCE) bispecific antibody against both the tumor-associated antigen (TAA) B7-H4 (V-set domain-containing T-cell activation inhibitor 1; VTCN1; B7x; B7S1) and the costimulatory receptor 4-1BB (CD137; tumor necrosis factor receptor superfamily member 9; TNFRSF9), with potential checkpoint inhibitory, immunostimulating and antineoplastic activities. Upon administration, anti-B7-H4/anti-4-1BB bispecific antibody ABL103 targets and binds to both B7-H4 expressed on the surface of tumor cells and 4-1BB expressed on immune cells, including activated T lymphocytes, natural killer (NK) cells and NK-T cells. This crosslinks B7-H4-expressing tumor cells and 4-1BB-expressing T cells, NK cells and NK-T-cells, and activates 4-1BB signaling locally in the tumor microenvironment (TME) only when in the presence of B7-H4 expressing cells. This induces cytotoxic T-lymphocyte (CTL) proliferation, cytokine production and promotes a CTL-mediated anti-tumor immune response against tumor cells, induces NK-mediated tumor cell killing, and suppresses the immunosuppressive activity of regulatory T cells (Tregs). In addition, the blockage of B7-H4 by ABL103 directly prevents B7-H4-mediated inhibition of T cells. B7-H4, a member of the B7 family of immune modulators, is upregulated in a variety of tumor cell types and negatively regulates T-cell immune responses. B7-H4 expression in normal tissues is quite limited. 4-1BB, a surface glycoprotein of the tumor necrosis factor receptor superfamily, is an inducible costimulatory receptor that plays a key role in T-cell proliferation, survival and cytolytic activity.