Abstract 544: Anti-tumor efficacy and potential mechanism of action of a novel therapeutic humanized anti-Globo H antibody, OBI-888
Authors: Yu-Chi Chen, Ming-Chen Yang, Yi-Chien Tsai, Hui-Wen Chang, Chang-Lin Hsieh, Yu-Jung Chen, Kuang-Hsiu Lee, Jiann-Shiun Lai, I-Ju Chen
Journal: Cancer Research (2019)

Abstract Background: Globo H (GH) is a hexasaccharide expressed on various cancer types. We therefore designed OBI-888, a humanized monoclonal IgG1 antibody targeting GH, as a treatment for GH expressing cancers. This study evaluated OBI-888’s mechanisms of action (MOA) and in vivo efficacy. Methods: Antibody-dependent cell-mediated cytotoxicity (ADCC) and antibody-dependent cell-mediated phagocytosis (ADCP) were assessed by bioluminescent cell-based reporter assays. Binding affinity of OBI-888 to various FcγRs and complement-dependent cytotoxicity (CDC) were evaluated by ELISA-based binding assay. We studied the anti-immunosuppressive effect via Jurkat/NFAT-luciferase reporter based assay (Promega). In vivo anti-tumor efficacy of OBI-888 was measured in multiple GH expressing xenograft mouse models. The GH expression levels of tumor cells in xenograft models before tumor inoculation and after tumor excision were determined by flow cytometry and immunohistochemistry (IHC), respectively. The lymphocyte populations in tumor microenvironment were evaluated by IHC. Results: EC50 values of ADCC and ADCP activity were 4.68 and 29.15 μg/mL, respectively. In addition, OBI-888 demonstrated binding affinity to FcγRs, including FcγRI, FcγRIIA, FcγRIIB, FcγRIIIA, FCRN, and a low affinity genotype FcγRIIIA V176F. The EC50 of OBI-888 binding to C1q, the complement component required for CDC initiation, was 0.86 μg/mL. Addition of 5-40 μM GH ceramide (GH-cer) showed dose-dependent immunosuppresive effect on Jurkat/NAF-Luciferase cells. 8.7 μM of OBI-888 can reverse the inactivation of Jurkat/NAF-Luciferase cells induced by GH-cer. In GH positive (GH+) MCF7 (breast), HCC-1428 (breast), HPAC (pancreas), NCI-H526 (lung), and SW480 (colorectal) xenograft cancer models, OBI-888 exhibited tumor growth inhibition of 30-85%. Based on IHC, GH staining was observed on the immune cells at intra- and peri-tumor regions. OBI-888 reduced the population of M2 macrophage, but not that of pan-macrophage. Conclusions: Study demonstrated OBI-888’s ability to trigger ADCC, ADCP, and CDC, mechanisms by which antibody induces tumor lysis. ADCC was further supported by OBI-888’s binding affinity to multiple FcγRs, including a low affinity genotype which can potentially benefit those patients who belong to low affinity genotype. GH-cer showed immunosuppresive effect, as manifested by GH staining on the immune cells. OBI-888 has anti-immunosuppresive function to reverse the effect. In vivo tumor growth inhibition with decreased M2 population was observed in various GH+ xenograft models, suggesting the potential MOA through immune modulation. The aforementioned findings suggest that OBI-888 has substantial therapeutic potential to treat various types of cancer that express GH. A first-in-human (FIH) clinical trial of OBI-888 (NCT03573544) has been initiated. Citation Format: Yu-Chi Chen, Ming-Chen Yang, Yi-Chien Tsai, Hui-Wen Chang, Chang-Lin Hsieh, Yu-Jung Chen, Kuang-Hsiu Lee, Jiann-Shiun Lai, I-Ju Chen. Anti-tumor efficacy and potential mechanism of action of a novel therapeutic humanized anti-Globo H antibody, OBI-888 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 544.