| First Author | Cho HM | Year | 2010 |
| Journal | Cancer Res | Volume | 70 |
| Issue | 24 | Pages | 10121-30 |
| PubMed ID | 21159634 | Mgi Jnum | J:167605 |
| Mgi Id | MGI:4868633 | Doi | 10.1158/0008-5472.CAN-10-1047 |
| Citation | Cho HM, et al. (2010) Delivery of NKG2D ligand using an anti-HER2 antibody-NKG2D ligand fusion protein results in an enhanced innate and adaptive antitumor response. Cancer Res 70(24):10121-30 |
| abstractText | NKG2D ligands link the innate and adapative immune response by activating the receptors expressed on effector cells of both the innate (NK) and adaptive immune systems (CD8(+) T cells). In this study, we explored the potential therapeutic utility of this intersection by fusing the murine NKG2D ligand Rae-1beta to the 3' end of an anti-HER2 IgG3 antibody containing an intact Fc domain (anti-HER2 IgG3-Rae-1beta), thereby targeting an NK cell activation signal to HER2+ breast tumor cells. The antitumor efficacy of this anti-HER2-Rae-1beta fusion protein was examined in a mouse mammary tumor model engineered to express HER2 (EMT6-HER2 cells). We observed an enhanced cytotoxic response of NK effectors against EMT-HER2 cells in vitro. Mice implanted on one flank with EMT6-HER2 cells and contralaterally with control EMT6 cells exhibited rapid regression of EMT6-HER2 tumors but delayed regression of contralateral EMT6 tumors. IFNgamma was implicated, given a lack of antitumor efficacy in IFNgamma(-/-) mice. Depletion of either NK cells or CD8(+) T cells abrogated tumor growth inhibition, suggesting essential roles for each in the observed antitumor activity. Mice rejecting EMT6-HER2 tumors after anti-HER2-Rae-1beta treatment showed markedly decreased tumor growth when rechallenged with EMT6-HER2 or EMT6 cells, whereas both EMT6 and EMT6-HER2 cells grew in control mice, indicating the development of an adaptive memory response. Our findings demonstrate that administration of an antibody-NKG2D ligand fusion protein can enhance innate and adaptive immune antitumor responses, also evoking additional nontargeted antigens to enhance the potential clinical utility of this approach. |
