English Diana P, Bellone Stefania, Schwab Carlton L, Roque Dana M, Lopez Salvatore, Bortolomai Ileana, Cocco Emiliano, Bonazzoli Elena, Chatterjee Sudeshna, Ratner Elena, Silasi Dan-Arin, Azodi Masoud, Schwartz Peter E, Rutherford Thomas J, Santin Alessandro D
Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut.
Cancer. 2015 Feb 1;121(3):403-12. doi: 10.1002/cncr.29062. Epub 2014 Sep 23.
Solitomab is a novel, bispecific, single-chain antibody that targets epithelial cell adhesion molecule (EpCAM) on tumor cells and also contains a cluster of differentiation 3 (CD3) (T-cell coreceptor) binding region. The authors evaluated the in vitro activity of solitomab against primary chemotherapy-resistant epithelial ovarian carcinoma cell lines as well as malignant cells in ascites.
EpCAM expression was evaluated by flow cytometry in 5 primary ovarian cancer cell lines and in 42 fresh ovarian tumor cell cultures in ascites from patients with mainly advanced or recurrent, chemotherapy-resistant disease. The potential activity of solitomab against EpCAM-positive tumor cells was evaluated by flow cytometry, proliferation, and 4-hour chromium-release, cell-mediated cytotoxicity assays.
EpCAM expression was detected by flow cytometry in approximately 80% of the fresh ovarian tumors and primary ovarian tumor cell lines tested. EpCAM-positive, chemotherapy-resistant cell lines were identified as resistant to natural killer cell-mediated or T-cell-mediated killing after exposure to peripheral blood lymphocytes in 4-hour chromium-release assays (mean±standard error of the mean, 3.6%±0.7% of cells killed after incubation of EpCAM-positive cell lines with control bispecific antibody). In contrast, after incubation with solitomab, EpCAM-positive, chemotherapy-resistant cells became highly sensitive to T-cell cytotoxicity (mean±standard error of the mean, 28.2%±2.05% of cells killed; P<.0001) after exposure to peripheral blood lymphocytes. Ex vivo incubation of autologous tumor-associated lymphocytes with EpCAM-expressing malignant cells in ascites with solitomab resulted in a significant increase in T-cell activation markers and a reduction in the number of viable ovarian tumor cells in ascites (P<.001).
Solitomab may represent a novel, potentially effective agent for the treatment of chemotherapy-resistant ovarian cancers that overexpress EpCAM.
Solitomab是一种新型双特异性单链抗体，可靶向肿瘤细胞上的上皮细胞黏附分子（EpCAM），还包含一个分化簇3（CD3）（T细胞共受体）结合区域。作者评估了Solitomab对原发性化疗耐药上皮性卵巢癌细胞系以及腹水中恶性细胞的体外活性。
通过流式细胞术评估5种原发性卵巢癌细胞系以及42例主要为晚期或复发性化疗耐药疾病患者腹水中新鲜卵巢肿瘤细胞培养物中的EpCAM表达。通过流式细胞术、增殖和4小时铬释放细胞介导的细胞毒性试验评估Solitomab对EpCAM阳性肿瘤细胞的潜在活性。
在大约80%的测试新鲜卵巢肿瘤和原发性卵巢肿瘤细胞系中通过流式细胞术检测到EpCAM表达。在4小时铬释放试验中，EpCAM阳性、化疗耐药细胞系在暴露于外周血淋巴细胞后被鉴定为对自然杀伤细胞介导或T细胞介导的杀伤具有抗性（EpCAM阳性细胞系与对照双特异性抗体孵育后，平均±平均标准误差，3.6%±0.7%的细胞被杀死）。相比之下，与Solitomab孵育后，EpCAM阳性、化疗耐药细胞在暴露于外周血淋巴细胞后对T细胞细胞毒性变得高度敏感（平均±平均标准误差，28.2%±2.05%的细胞被杀死；P<0.0001）。用Solitomab对腹水中表达EpCAM的恶性细胞进行自体肿瘤相关淋巴细胞的体外孵育导致T细胞活化标志物显著增加，腹水中存活的卵巢肿瘤细胞数量减少（P<0.001）。
Solitomab可能是一种用于治疗过表达EpCAM的化疗耐药卵巢癌的新型潜在有效药物。
