Definition

A designed ankyrin repeat proteins (DARPin)-based agent targeting the tumor-associated protein fibroblast activation protein (FAP) and the T-cell co-stimulatory immune receptor 4-1BB (CD137; tumor necrosis factor receptor superfamily member 9; TNFRSF9), with potential immunomodulating and antineoplastic activities. Upon administration, the FAP/4-1BB-targeting DARPin MP0310 targets and binds to both FAP, localized on tumor stromal cells, and 4-1BB, expressed on a variety of leukocyte subsets including activated T lymphocytes and natural killer (NK) cells. The simultaneous binding of FAP and 4-1BB results in local clustering of FAP-expressing tumor stromal cells and 4-1BB-expressing T cells, and local immune cell activation through the promotion of T-cell activation, cytokine release and T-cell-mediated anti-tumor immune responses. 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. FAP is abundantly expressed by cancer associated fibroblasts in the majority of solid tumors. Compared to antibodies, DARPins are small in size, have favorable pharmacokinetics and allow for both high affinity binding and efficacy.