SSEA4抗體和Globo H抗體在乳癌的結合效果

Abstract

先前研究指出globo-系列鞘醣脂 (SSEA3, SSEA4, Globo H) 大量表現在許多癌症，且它們涉及與癌症生長和轉移相關的訊息傳遞路徑。SSEA4和Globo H皆為SSEA3的下游產物，已被指出可能會與不同的蛋白作用來作訊息傳遞，造成乳癌增生。因此，使用SSEA4抗體和Globo H抗體作聯合治療，可能會是更有效的治療方式。另外，在老鼠實驗中，此聯合治療已證實對於抑制腫瘤生長能產生協同作用。為了更了解此協同作用，我們進行體外實驗，探討SSEA4抗體和Globo H抗體在抗原結合和抗體依賴的細胞介導的細胞毒性作用上之結合效果。在本研究中，我們發現MC813-70 (SSEA4抗體) 會影響VK9 (Globo H抗體) 結合抗原。此外，此組合所誘導的抗體依賴的細胞介導的細胞毒性作用與只有SSEA4抗體誘導的作用程度相似，顯示SSEA4在乳癌是個主要的標靶。此研究中，我們建立了染色訊號與抗體依賴的細胞介導的細胞毒性作用的關聯性。此結果能作為伴隨式診斷的一個平台，根據病人的抗原表現量預測聯合治療的效果，另外也可應用在藥物研發，評估其他不同抗體或抗體策略。

Previous studies have shown that the globo-series glycosphingolipids (SSEA3, SSEA4, and Globo H) are expressed in many cancers and involved in the signaling pathways that promote cancer proliferation and metastasis. SSEA4 and Globo H, the downstream products of SSEA3, were shown to interact with different proteins in the signaling pathway in breast cancer proliferation, providing a direction for combination therapy using anti-SSEA4 and anti-Globo H antibodies. Moreover, the combination was shown to induce better tumor suppression in mice inoculated with breast cancer cell lines. To further understand the effect in vivo, we focused on the combined effect of the two antibodies in antigen binding and antibody dependent cellular cytotoxicity (ADCC) induction in vitro. Here, we report that the antigen binding of VK9 (anti-Globo H antibody) was influenced by MC813-70 (anti-SSEA4 antibody). In addition, we have also found that combination of both antibodies induced similar effector cell activation as did anti-SSEA4 antibodies alone in reporter-based ADCC assay, indicating that SSEA4 is perhaps a major target in breast cancer due to its high expression. Furthermore, we have established the correlation between staining signal and ADCC response. These findings can serve as a platform in future companion studies to predict therapy outcome based on patients’ expression levels as well as to evaluate other antibodies or antibody strategies for drug development.