Abstract 5659: AFM24, a bispecific EGFR/CD16A innate cell engager with the potential to overcome resistance to current targeted treatments for EGFR-positive malignancies
Authors: Reusch Uwe , Damrat Michael , Wingert Susanne , Knackmuss Stefan H.J. , Mueller Thomas , Fucek Ivica , Schniegler-Mattox Ute , Ellwanger Kristina , Haneke Torsten , Strassz Andras , Fischer Wolfgang , Rajkovic Erich , Tesar Michael 
Published: September 2020

Abstract
The epidermal growth factor receptor (EGFR) is a prime target for cancer therapy across many solid tumor types, including CRC, NSCLC, breast, esophageal cancer, and SCCHN. Binding of EGFR by its ligand EGF induces cell proliferation, a process which is uncontrolled or constitutively active in many cancers. The development of anti-EGFR therapies such as monoclonal antibodies and tyrosine kinase inhibitors enabled clinicians to treat specific patient populations. Nevertheless, prognoses for patients remain unfavorable due to occurrence of intrinsic or acquired resistance via mutations of EGFR and/or downstream signaling factors such as KRAS and BRAF which are drivers of tumorigenesis. Inhibitors that target specific KRAS mutations, such as the G12C mutation (i.e. 14% of the most frequently observed in NSCLC and up to 5% in CRC), have shown early promising efficacy. While such drugs hold promise for specific mutations, there continues to be a need for new treatments with more differentiated and novel modes of action that utilize the power of the innate immune system, such as antibody dependent cellular cytotoxicity (ADCC) and antibody dependent cellular phagocytosis (ADCP).
Affimed has engineered the tetravalent bispecific EGFR- and CD16A-binding antibody AFM24 to engage and redirect innate immune cells such as NK cells and macrophages to EGFR+ tumor cells. In contrast to currently available EGFR-targeted therapies (e.g. cetuximab), this innate cell engager has been designed to exhibit a significantly reduced inhibition of EGFR signaling aiming for an improved safety profile, i.e. avoiding skin and gastro-intestinal toxicities. In vitro, AFM24 demonstrated high affinity binding to immune cells regardless of CD16A variants and potent killing of multiple EGFR+ tumor cell lines, carrying relevant KRAS or BRAF mutations via a different mode of action, namely ADCC and ADCP, rather than EGFR signaling inhibition. It was shown that AFM24's activity is independent of both, the EGFR cell surface expression level and the cellular origin of the respective cell lines. Cynomolgus toxicity studies revealed a very good safety profile, and no toxicity was observed after repeated administration (q7x28d, in total 5 infusions) of AFM24 up to 75 mg/kg. In contrast, EGFR-targeting mAbs (e.g. cetuximab) exhibited severe toxicities particularly in skin in toxicology studies when investigated with a similar dosing schedule.
Due to its potent activation of innate immunity and its beneficial safety/tolerability profile, AFM24 has the potential to become a novel treatment option for patients suffering from EGFR-expressing cancers and to overcome limitations of available EGFR-targeted therapies such as resistance and/or associated toxicities. AFM24 has cleared the IND and clinical investigations are planned in patients with cancers known to express EGFR.
Citation Format: Uwe Reusch, Michael Damrat, Susanne Wingert, Stefan H.J. Knackmuss, Thomas Mueller, Ivica Fucek, Ute Schniegler-Mattox, Kristina Ellwanger, Torsten Haneke, Andras Strassz, Wolfgang Fischer, Erich Rajkovic, Michael Tesar. AFM24, a bispecific EGFR/CD16A innate cell engager with the potential to overcome resistance to current targeted treatments for EGFR-positive malignancies [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5659.