Mediation of Tumor Cell Death by Naked Antibodies

Most of the early monoclonal antibodies against target molecules on tumor cells for cancer therapy were naked antibodies without payloads. They can induce tumor cell death by the Fc-mediated effector functions of ADCC (antibody-dependent cellular cytotoxicity), ADCP (antibody-dependent cellular phagocytosis), and CDC (complement-dependent cytotoxicity) or by inhibiting the signaling pathway of growth hormone receptors on the tumor cell surface. The IgG1 subtype is usually chosen for eliminating tumor cells by ADCC and ADCP since it has a high affinity for the Fcγ receptors and is a potent activator of natural killer (NK) cells. Another approach has been to block the growth signals of angiogenesis (blood vessel formation) necessary for tumor nourishment. More recently, the use of antibodies directed against immune checkpoints on immune cells has made a major impact on the treatment of solid tumors. They have opened a window for treating cancers such as malignant melanomas that were previously resistant to therapy. Tumors that are particularly amenable to treatment with IC inhibitors are characterized by a high mutation rate and a significant number of tumor-infiltrating lymphocytes (TILs). However, not all patients with these so-called “hot” tumors respond due to the highly immunosuppressive tumor microenvironment. Recent advances in our understanding of these resistance mechanisms could provide new strategies for combining antibodies directed at ICs with other complementary therapeutic approaches.