Cell . . . Multi-functional antibodies that target NKp46 activate the anti-tumor immunity of NK cells.

At present, tumor immunotherapy mainly focuses on enhancing the cytotoxic effect of T cells, ICB (Immune checkpoint blockade) targeted inhibitory pathway, car-t targeted activation pathway.bites (bispecific T cell engagers) are antibodies that can specifically recognize tumor antigen and CTL cell receptor (such as CD3) in two directions, promote the interaction between endogenous effector T cells and tumor cells, induce T cell activation and kill tumor cells [1].the promotion of T cell / target cell binding by bites is independent of MHC.cd3-cd19 bites have been successfully used in the treatment of CD19 + B-ALL [2].like car-t therapy, bites treatment usually leads to toxicity and is not effective for solid tumors.natural killer cells (NK cells) have killing function and promote anti-tumor effect.NK cells express a variety of activated receptors, such as CD16, NKG2D, SLAM family, NCR family, NKp30, NKp44 and NKp46, which are potential targets for inducing NK cell mediated anti-tumor immunity.so it has not been reported whether the multifunctional antibody targeting NK cells can improve the anti-tumor immunity and toxicity.recently, Eric Vivier and Laurent Gauthier from France published a paper on cell entitled multifunctional natural killer cell engagers targeting NKp46 trigger protective tumor immunity, which reported three functional nature killer cell engagers targeting NK activated receptors NKp46, CD16 and tumor antigen Nkces can activate NK cells, control the growth of solid tumors and invasive tumors, and have the pharmacokinetics similar to IgG antibody, and have no off target effect.three functional nkces provide new ideas for tumor treatment.the research team first detected the expression of NK activated receptors in tumors. NKp46 + lymphocytes were found in human colon cancer, head and neck cancer, kidney cancer, lung cancer, pancreatic cancer, and gastric cancer.in acute myeloid leukemia, breast cancer and lung cancer, it has been reported that NKp46 is persistently expressed and down regulated NKG2D, NKp30, NKp44 and other activated receptors.at the same time, there is no significant difference in the expression of NKp46 in various tumors and peripheral blood, which makes NKp46 a target to activate the anti-tumor immunity of NK cells in tumors.the soluble human NKp46 FC was used as an antigen to immunize mice. After screening, 14 kinds of anti-nkp46 mAbs were produced which combined with different parts of the extracellular domain of NKp46.secondly, the researchers used single chain variable fragment (scFv) technology to connect the Fab segment of anti-nkp46 with the tumor antigen recognition part to make bispecific nkce.three kinds of nkces targeting different parts of NKp46 can up regulate cd107 and CD69, activate NK cells, and promote tumor cell lysis.after further optimization, the nkce-1 form was obtained, which not only has the same NK activation ability and anti-tumor effect, but also has the similar pharmacokinetic characteristics of IgG1 in vivo, and has high affinity for FcRn binding, with a half-life of 11 days. subsequently, NKp46 / (FC) / cd20-nkce-1 was made and solid tumor model was established by using CD20 + Raji lymphama B cells to detect its anti-tumor effect. NKp46 / (FC) / cd20-nkce-1 significantly reduced the growth rate of solid tumors, controlled the tumor size, and promoted the infiltration or proliferation of NK cells in tumors. finally, the research team combined the CD16 mediated ADCC (anti body dependent cell mediated cytotoxicity) pathway with NKp46 to produce functional nkces that can simultaneously target NKp46, CD16 and tumor antigen, so as to further enhance the anti-tumor ability of nkces. the addition of CD16 significantly increased the tumor cell lysis ability and NK cell activation ability of nkces, and optimized the Fc receptor binding ability of CD16 to further enhance the anti-tumor function of nkces. in vivo experiments show that bispecific nkces or trifunctional nkces can significantly reduce tumor size and control tumor growth when used in the treatment of solid tumors or invasive tumors. Moreover, the anti-tumor effect of triple functional nkces is better than that of tumor antigen-specific monoclonal antibody, which has potential clinical development value. in a word, inspired by the bites technology, this paper developed a multifunctional antibody technology nkces for NK cell activation, which simultaneously targeted NKp46, CD16 and tumor antigen, increased the number of NK cells in tumor, promoted NK cell activation and ADCC, and enhanced anti-tumor immunity. provides an important reference for the development of the next generation of tumor immunotherapy molecule nkce. original link: plate maker: Ke reference 1. Slaney, C.Y., Wang, P., Darcy, P.K. & amp; Kershaw, M.H. cars versus bites: a comparison between T cell redirection strategies for cancer treatment. Cancer discov 8, 924-934 (2018). 2. SPIESS, C., Zhao, Q. & amp; Carter, P.J. Alternative molecular formats and therapeutic applications for bispecific antibodies. Mol Immunol 67, 95-106 (2015).