| First Author | Williams EL | Year | 2013 |
| Journal | J Immunol | Volume | 191 |
| Issue | 8 | Pages | 4130-40 |
| PubMed ID | 24026082 | Mgi Jnum | J:206279 |
| Mgi Id | MGI:5548294 | Doi | 10.4049/jimmunol.1301430 |
| Citation | Williams EL, et al. (2013) Immunotherapy targeting inhibitory Fcgamma receptor IIB (CD32b) in the mouse is limited by monoclonal antibody consumption and receptor internalization. J Immunol 191(8):4130-40 |
| abstractText | Genetic deficiency of the inhibitory Fc receptor, FcgammaRIIB (CD32b), has been shown to augment the activity of activatory FcgammaR and promote mAb immunotherapy. To investigate whether mAbs capable of blocking FcgammaRIIB have similar capacity, we recently generated a panel of specific anti-mouse FcgammaRIIB mAbs that do not cross-react with other FcRs, allowing us to study the potential of FcgammaRIIB as a therapeutic target. Previous work revealed a number of these mAbs capable of eliciting programmed cell death of targets, and in the present study we demonstrated their ability to promote target cell phagocytosis. However, in a variety of murine tumor models, anti-FcgammaRIIB mAbs demonstrated limited therapeutic activity despite optimized treatment regimens. Unexpectedly, we observed that the anti-FcgammaRIIB mAbs are rapidly and extensively consumed in vivo, both by the tumor and host cells, including B cells, leading to a precipitous loss from the circulation. Closer analysis revealed that the anti-FcgammaRIIB mAbs become extensively internalized from the cell surface within 24 h in vivo, likely explaining their suboptimal efficacy. Subsequent studies revealed that anti-FcgammaRIIB mAb immunotherapy was effective when used against FcgammaRIIB(+) tumors in FcgammaRIIB(-/-) recipients, indicating that consumption of the mAb by nontumor cells is the primary limitation of these reagents. Importantly, similar rates of internalization were not seen on human target cells, at least in vitro. These studies further highlight the need to determine the propensity of mAb therapeutics to internalize target receptors and also identify potential key differences between human and mouse cells in this respect. |
