Cutting Edge: FcgRIII (CD16) and FcgRI (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 (FcgR). Opposing results on the respective contribution of mouse FcgRI, FcgRIII, and FcgRIV have been reported using the gp75-expressing B16 melanoma and the protective anti-gp75 mAb TA99. We analyzed the contribution of FcgRs to this therapy model using bioluminescent measurement of lung metastases loads, novel mouse strains, and anti-FcgR blocking mAbs. We found that the TA99 mAb-mediated effects in a combination therapy using cyclophosphamide relied on activating FcgRs. The combination therapy, however , was not more efficient than mAb therapy alone. We demonstrate that FcgRI and, unexpectedly, FcgRIII contributed to TA99 mAb therapeutic effects, whereas FcgRIV did not. Therefore, FcgRIII and FcgRI are, together, responsible for anti-gp75 mAb therapy of B16 lung metastases. Our finding that mouse FcgRIII contributes to Ab-induced tumor reduction correlates with clinical data on its human functional equivalent human FcgRIIIA (CD16A). T umor cells can be specifically targeted using mAbs that bind to specific or overexpressed Ags on the tumor cell surface. Some of these mAbs can directly affect tumor growth or survival when their Fab portions are bound to their target, for example, trastuzumab targeting HER2/Neu. Some mAbs, however, target molecules that are not involved in tumor growth or survival. In most situations, however, mAbs bound to tumor cells enable the recruitment of phagocytic and cytotoxic immune cells bearing receptors for the Fc portion of IgG (FcgR). Activating FcgRs are indeed necessary for the protective effect of the mouse anti-gp75 mAb TA99 on the development of lung metastases of gp75-expressing B16F10 mouse melanoma cells (1). The contribution of FcgRs in the context of a therapy using a combination of chemotherapy and anti-gp75 mAb treatment has, however, not been investigated. and FcgRIV exist. All mouse activating FcgRs require the association of the FcRg subunit to be expressed and functional at the cell surface. The generation of FcRg 2/2 mice allowed for the discovery that activating FcgRs contribute primarily to the protective effect of mAb TA99 on B16 lung metastases (1). Since then, FcgRI 2/2 mice (2, 3), FcgRIII 2/2 mice (4), and FcgRIV 2/2 mice (5) have been reported; however, studies that have used these mice to identify the activating FcgR(s) responsible for the protective effect of mAb TA99 on B16 lung metastases report contradictory results. Whereas Nimmerjahn et al. (6) described a contribution of FcgRIV, but neither FcgRI nor …