Abstract 2997: The tetravalent bispecific antibody AFM13 engages and primes innate immune cells for anti-cancer immunity

AFM13 is a tetravalent bispecific antibody with bivalent binding to both CD30 and CD16A. It has been shown to engage NK-cells through CD16A with high affinity and specificity, resulting in strong NK-cell cytotoxicity, and is currently being tested in Phase 2 monotherapy and in combination with pembrolizumab in Phase 1b clinical trials. We have previously shown that AFM13-dependent activation of NK-cell cytotoxicity towards CD30+ tumor cells is more pronounced than that of anti-CD30 mAbs. In addition, AFM13 enhances NK-cell sensitivity to low doses of IL-2 and IL-15, leading to an increased NK-cell proliferative potential. Here, we have extended the panel of phenotypic markers on NK-cells that are modulated after exposure to CD30+ tumor cells in the presence of AFM13. Targeting some of these markers may enable the development of novel combination therapies. Moreover, we have analyzed the kinetics of NK-cell responses to AFM13 exposure. Even though short-term exposure to AFM13 significantly enhanced NK-cell cytotoxicity, long-term exposure led to a partial, transient functionally exhausted phenotype in vitro, which could be fully restored by cytokine stimulation for several days in the absence of AFM13. Importantly, these recovered cells displayed high cytotoxicity towards CD30+ target cells in the presence of AFM13. Interestingly, the transient NK-cell exhaustion was not related to the expression of typical exhaustion markers or insufficient levels of perforin and granzyme. These data may warrant the development of novel metronomic application regimens of AFM13. Further studies imply that immune cells other than NK-cells are able to inhibit growth of CD30+ tumor cells in an AFM13-dependent manner. This appears to be strictly dependent on CD16A and a specific cytokine milieu. Taken together, AFM13 specifically enhances the cytotoxic, proliferative and cytokine-producing potential of NK-cells, parameters that can be utilized to monitor NK-cell responses during AFM13 therapy. Moreover, based on our data, engagement of CD16A+ cells to the tumor site might enable several innate immune effector functions within the tumor microenvironment for synergistic anti-tumor activity. Citation Format: Jens Pahl, Joachim Koch, Uwe Reusch, Thorsten Gantke, Adelheid Cerwenka, Martin Treder. The tetravalent bispecific antibody AFM13 engages and primes innate immune cells for anti-cancer immunity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2997. doi:10.1158/1538-7445.AM2017-2997