Cutting Edge: FcγRIII (CD16) and FcγR1 (CD64) Are Responsible for Anti-Glycoprotein 75 Monoclonal Antibody TA99 Therapy for Experimental Metastatic B16 Melanoma

mAb therapy for experimental metastatic melanoma relies on activating receptors for the Fc portion of IgG (Fc-gamma R). Opposing results on the respective contribution of mouse Fc-gamma RI, Fc-gamma RIII, and Fc-gamma RIV have been reported using the gp75-expressing B16 melanoma and the protective anti-gp75 mAb TA99. We analyzed the contribution of Fc-gamma Rs to this therapy model using bioluminescent measurement of lung metastases loads, novel mouse strains, and anti-Fc-gamma R blocking mAbs. We found that the TA99 mAb-mediated effects in a combination therapy using cyclophosphamide relied on activating Fc-gamma Rs. The combination therapy, however, was not more efficient than mAb therapy alone. We demonstrate that Fc-gamma RI and, unexpectedly, Fc-gamma RIII contributed to TA99 mAb therapeutic effects, whereas Fc-gamma RIV did not. Therefore, Fc-gamma RIII and Fc-gamma RI are, together, responsible for anti-gp75 mAb therapy of B16 lung metastases. Our finding that mouse Fc-gamma RIII contributes to Ab-induced tumor reduction correlates with clinical data on its human functional equivalent human Fc-gamma RIIIA (CD16A). The Journal of Immunology, 2012, 189: 5513-5517.