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6 General discussion and Future Prospects | 149 Bispecific antibodies In the last decade, several bispecific and trispecific Ab platforms, simultaneously targeting immune cells and tumor cells, have been developed in the field of cancer immunotherapy 53 . To date, the majority of bispecific Abs that has been developed targets T cells, whereas only a limited number of bispecific approaches targets NK cells 54 . Affimed is a clinical stage pharmaceutical company developing bifunctional antibodies that recruit immune cells such as T and NK cells to tumor sites. These bispecifics (TandAbs) are tetravalent in nature, thus offering four binding sites, two aimed at tumor antigens and two aimed at immune cells. Currently, Affimed’s AFM13 that targets CD30 on cancer cells and CD16a on NK cells is in clinical phase II testing in patients with Hodgkin’s lymphoma. In phase I studies AFM13 was found to be safe and well tolerated, and resulted in an overall response rate of 23%. Furthermore, AFM13 treatment resulted in an increase in NK cell activation and a decrease in soluble CD30 levels in peripheral blood (NCT01221571) 55 . Further, two other bispecific CD16a based tumor targeting antibodies are in preclinical phase development, i.e. AFM22 and AFM24 that bind to EGFRvIII expressed by several solid tumors, including glioblastoma (GBM), and wild-type EGFR respectively. Another promising NK cell focused bispecific platform is developed by AvidBiotics to target tumors that evade NK killing via downregulation or shedding of the NKG2D ligand MICA, which is a major limiting step in NK mediated tumor targeting. To overcome this, AvidBiotics designed MicAbody proteins that bind to the NK cell NKG2D receptor with high affinity. Further, this MicAbody was engineered with an additional binding site to target tumor antigens of interest, thus enabling recruitment of NK cells to tumors 56 . NK cell checkpoint inhibitors Another strategy to increase NK cell functionality is the disruption or blocking of NK inhibitory signals. Innate Pharma is a clinical stage pharmaceutical company currently focused on developing NK cell checkpoint inhibitors. Lirilumab (IPH2102/ BMS 986015) is a fully humanized IgG 4 anti-KIR mAb against the inhibitory KIRs KIR2DL1, L2 and L3, which are expressed predominantly on NK cells and on some T cells. Lirilumab induced significant anti-tumor activity of NK cells against HLA-C expressing tumor cells, contributing to increased survival in lirilumab treated mice 57 . Similar to KIRs, the NK cell inhibitory receptor NKG2A binds to its ligand HLA-E on tumor cells resulting in an inhibition of NK cell function. HLA-E is overexpressed in colon, cervical and ovarian cancers, thus serving as an escape mechanism for NK killing in these tumors 58,59 . The anti-NKG2A mAb monalizumab, was developed to block the interaction between NKG2A and HLA-E and is currently under clinical investigation. IPH4102, which targets KIR3DL2, is under phase I clinical investigation in cutaneous T cell lymphoma (CTCL). Clinical trials testing lirilumab, monalizumab and IPH4102 are listed in Table 1.