Abstract B123: Preclinical evaluation of FS102: A HER2-specific Fcab with a novel mechanism of action.

HER2 is a validated oncogenic target which is overexpressed in many cancers. Although the approved HER2-specific biologics have improved the standard of care of HER2-positive breast and gastric cancers, a significant unmet medical need exists due to intrinsic or acquired resistance. By randomizing two loops in the CH3 domain of an IgG1 Fc fragment, we generated a HER2-specific Fcab™ (Fc fragment with antigen binding), called FS102, which binds HER2 with high affinity (2 nM), and recognizes an epitope that does not overlap with the epitopes of trastuzumab or pertuzumab. FS102 has a favorable t1/2 of ∼ 60 hours in mice. Biophysical characterization has shown the Fcab to have suitable properties to be developed as a therapeutic. To assess if interactions with the unique HER2 epitope could translate into clinically relevant pharmacological activities, we conducted in vitro and in vivo characterization of FS102 in comparison to trastuzumab monotherapy or trastuzumab-pertuzumab combination therapy. Using the HER2-positive breast cell line SKBr3 as an in vitro model system, we determined the effect of FS102 on HER2 downregulation, cellular proliferation, cell cycle progression, and apoptosis. Both FS102 and trastuzumab were internalized efficiently by SKBr3 cells, but only the former induced profound reduction in cell surface and total HER2 protein levels. Trastuzumab and FS102 both reduced SKBr3 cell proliferation by approximately 50% upon 5 days treatment. However the two agents achieved this inhibition via distinct mechanisms of action (MOA). Consistent with published data, trastuzumab induced G1 cell cycle arrest, while FS102 showed no effect on cell cycle progression. Instead, FS102 significantly induced apoptosis as measured by caspase activity and a loss of membrane integrity, an effect not observed upon exposure to trastuzumab. FS102 displays potent anti-tumor effects in HER2 overexpressing patient-derived xenograft (PDX) murine models, which are positive for a clinically relevant biomarker. Significant tumor inhibition has been observed in gastric, colorectal and breast PDX models. This includes complete tumor regression in 3 out of 8 models evaluated. Moreover, FS102 is significantly more effective than trastuzumab when tested in the biomarker-positive subset of PDX tumors. In one of these PDX model systems, where the tumors were refractory to trastuzumab-pertuzumab combination treatment, subsequent FS102 treatment reversed tumor growth and ultimately led to complete regression of the tumor. The results indicate that FS102 may have the potential to overcome resistance to conventional HER2 therapy in a biomarker-defined patient subpopulation, and that the Fcab technology is an attractive platform to generate novel biologics with unique antigen recognition and MOA. Additional studies are underway to further elucidate the FS102-induced ErbB receptor degradation pathway. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B123. Citation Format: Sarah Batey, Kinmei Leung, Robert Rowlands, Samine Isaac, Joana Carvalho, Sarah Weller, Mateusz Wydro, Miguel Gaspar, Melanie Medcalf, Robert Pegram, Vicky Drewett, Mihriban Tuna, John Haurum, Haijun H. Sun. Preclinical evaluation of FS102: A HER2-specific Fcab with a novel mechanism of action. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B123.