AFM24 engages CD16A (FcγRIIIa) on NK cells and macrophages with much higher affinity than monoclonal antibodies (mAbs), triggering NK cell-mediated ADCC and macrophage-mediated ADCP. AFM24's mode of action is highly differentiated from current EGFR-targeting treatment options since it does not rely on inhibition of the EGFR signaling pathway, thus rendering AFM24 insensitive to the mutational status (e.g. KRAS, BRAF) of the tumor. Indeed, the efficacy of currently marketed EGFR inhibitors is limited by i) toxicities arising from blocking of EGFR signaling in healthy tissues and ii) by the occurrence of intrinsic or acquired resistances of the tumor to EGFR-targeting inhibitors. With its distinctive mode of action profile, AFM24 is a novel treatment option for a wide range of EGFR+ patient populations including hard-to-treat patients. In preclinical assays AFM24 added up to 20% more ADCC and up to 6-fold more ADCP towards NSCLC, CRC, HNSCC and ccRCC cell lines with a wide range of EGFR densities when compared to EGFR-targeting mAbs. This superior effect of AFM24 was most pronounced towards target cell lines with low EGFR density or EGFR signaling pathway mutations, such as KRAS. AFM24's efficacy was assessed in a xenograft mouse model using different human EGFR+ cell lines such as the TNBC cell line MDA-MB-231 and an adoptively transferred, cytokine-stimulated and expanded NK cell product. This combination of AFM24 with an NK cell product demonstrated a significant dose-dependent and differentiated reduction in tumor outgrowth as compared to mice treated with NK cell product alone. This model allows for systematic screening of future IO-combination regimens, such as checkpoint inhibitors. Moreover, prevalence and activity of innate and adaptive immune cells were assessed in tumor explants of patients with EGFR+ malignancies. These data will be instrumental to guide the clinical development of AFM24 in monotherapy and combination therapies. In conclusion and considering the previously reported good safety profile in cynomolgus monkeys, the presented data shows AFM24's potential to become a novel treatment option for patients with EGFR+ cancers overcoming limitations of available EGFR-targeting therapies by fully exploiting the potential of the innate immune system. AFM24 is currently being investigated in a phase 1/2a study, NCT04259450, in EGFR+ tumors.

Citation Format: Jens Pahl, Gabriele Hintzen, Uwe Reusch, Torsten Haneke, Christian Breunig, Sheena Pinto, Cassandra Choe-Juliak, Andreas Harstrick, Wolfgang Fischer, Arndt Schottelius, Joachim Koch, Erich Rajkovic. AFM24 is a novel, highly potent, tetravalent bispecific EGFR/CD16A-targeting Innate Cell Engager (ICE®) designed for the treatment of EGFR-positive malignancies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1881.