The rationale behind targeting these proteins was that (1) they could enable targeting of diverse tumor types, and (2) the proteins were not rapidly turned over or internalized upon ligand/reagent binding or via constitutive endocytosis, as is the case for PSMA, EGFR, Her2, and transferrin receptor (TfR).116, 117, 118, 119, 120, 121 The anti-VEGF/anti-4-1BB bsApt ([1 + 2]; Figure 3B) showed anti-tumor effects at a dose five times lower than monovalent aptamer or mAb against 4-1BB (150 pmol versus 800 pmol). Here, FOLH1 is linked to neoplasm.