Soluble ligands are important targets for therapy of cancers and other diseases. Therapeutic monoclonal antibodies (mAb) against such ligands block their interactions with corresponding receptors but do not enhancetheirremovalfromthecirculationandcanincreasetheirhalf-livesbecauseofthelonghalf-livesofthe antibodies. We have hypothesized that mAbs targeting two or more nonoverlapping epitopes on the same ligandcouldformoligomericantibody–ligandcomplexesthatcanbindtocellsexpressingFcgammareceptors (FcgRs)withhighavidityleadingtotheirfastandirreversibleremovalfromthecirculation.Insulin-likegrowth factorII(IGF-II)isanexampleofsuchligandsandanimportanttargetforhumancancertherapy.Weidentified two mAbs, m610.27 and m630.3, which bound to nonoverlapping epitopes on IGF-II with nanomolar affinity, and generated a bispecific antibody, m660. m660 inhibited the interaction of human IGF-II (hIGF-II) with the human breast cancer cell line MCF-7, hIGF-II–mediated IGF receptor type I and insulin receptor phosphorylation,andcellgrowth.InthepresenceofhIGF-II,largecomplexesofm660wereformedthatboundtoFcgRIIexpressing BJAB cells much more efficiently than the monospecific antibody–hIGF-II complexes and were presumably phagocytosed by phorbol 12-myristate 13-acetate–stimulated macrophage-like U937 cells. A mixture of m610.27 and m630.3 exhibited similar properties. To our knowledge, these mAbs are the first reported to target nonoverlapping epitopes on a cancer-related ligand and could represent a novel class of candidate therapeutics against cancers. This approach could also be used to irreversibly eliminate other disease-related soluble ligands. Mol Cancer Ther; 11(7); 1400–10. 2012 AACR.