Monoclonal antibodies (mAbs) have become a mainstay of therapy for many cancers. However, antibody therapy is not completely effective in some applications due to loss of the target surface antigen on cancer cells. Such mAb-induced “escape variants” are no longer sensitive to the therapeutic mAb therapy. It was observed that the escape variants carried covalently bound complement activation fragments, especially C3d. NIH inventors have generated several C3d-specific mouse and rabbit monoclonal antibodies to re-target cells that have escaped from mAb therapy. Proof of principle for this “one-two punch” approach in preclinical models indicates that these C3d specific antibodies can potentiate the anti-tumor activity of therapeutic mAbs and eliminate antigen loss variants that survive after antibody therapy. This approach can enhance mAb-dependent cancer cells killing in an additive or even synergistic way, and will play a prominent role in filling an unmet cancer immunotherapeutic need specially for patients with refractory and relapsed diseases.