Potent Therapeutic Activity Against Peritoneal Dissemination and Malignant Ascites by the Novel Anti-Folate Receptor Alpha Antibody KHK2805.
Potent Therapeutic Activity Against Peritoneal Dissemination and Malignant Ascites by the Novel Anti-Folate Receptor Alpha Antibody KHK2805.
复制标题
DOI：
10.1016/j.tranon.2017.06.007
复制
发表时间：
2017-10
影响因子：
5
通讯作者：
Nakamura K
中科院分区：
文献类型：
--
作者：
Ando M;Nagata K;Nihira K;Suzuki Y;Kanda Y;Adachi M;Kubota T;Kameyama N;Nakano M;Ando H;Yamano K;Ishii T;Nakai R;Nakamura K
许多卵巢癌患者常出现腹膜转移伴恶性腹水。然而，在肿瘤对化疗产生耐药性后，关于控制这些症状的医疗需求仍未得到满足。我们开发了一种新型抗叶酸受体α（FOLR1）人源化抗体KHK 2805，该抗体具有增强的抗体依赖性细胞毒性（ADCC）和补体依赖性细胞毒性（CDC）。本研究的主要目的是评估KHK 2805的抗肿瘤活性是否足以在临床前模型中用于治疗铂耐药卵巢癌的腹膜播散和恶性腹水。在此，在卵巢癌细胞系和患者来源的样品中评价了KHK 2805的ADCC和CDC。在铂耐药腹膜播散的SCID小鼠模型中评价KHK 2805的抗肿瘤活性。结果，KHK 2805在新表位处显示出与FOLR1的高亲和力特异性结合。KHK2805对卵巢癌细胞株具有较强的ADCC和CDC活性。此外，原代铂耐药恶性腹水细胞对KHK 2805的自体ADCC敏感。患者来源的血清和恶性腹水诱导KHK 2805的CDC。KHK 2805显著降低了腹腔播散的SCID小鼠的总肿瘤负荷和腹水量，并显著延长了其生存期。此外，通过免疫组织化学，亲代大鼠抗体强烈染色浆液性和透明细胞型卵巢肿瘤。总体而言，KHK 2805对卵巢癌细胞系和患者来源的细胞都显示出细胞毒性。这些转化研究结果表明，KHK 2805可能是一种新的治疗药物，铂耐药卵巢癌腹膜播散和恶性腹水。
Many ovarian cancer patients often show peritoneal metastasis with malignant ascites. However, unmet medical needs remain regarding controlling these symptoms after tumors become resistant to chemotherapies. We developed KHK2805, a novel anti-folate receptor α (FOLR1) humanized antibody with enhanced antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC). The primary aim of the present study was to evaluate whether the anti-tumor activity of KHK2805 was sufficient for therapeutic application against peritoneal dissemination and malignant ascites of platinum-resistant ovarian cancer in preclinical models. Here, both the ADCC and CDC of KHK2805 were evaluated in ovarian cancer cell lines and patient-derived samples. The anti-tumor activity of KHK2805 was evaluated in a SCID mouse model of platinum-resistant peritoneal dissemination. As results, KHK2805 showed specific binding to FOLR1 with high affinity at a novel epitope. KHK2805 exerted potent ADCC and CDC against ovarian cancer cell lines. Furthermore, primary platinum-resistant malignant ascites cells were susceptible to autologous ADCC with KHK2805. Patient-derived sera and malignant ascites induced CDC of KHK2805. KHK2805 significantly reduced the total tumor burden and amount of ascites in SCID mice with peritoneal dissemination and significantly prolonged their survival. In addition, the parental rat antibody strongly stained serous and clear cell-type ovarian tumors by immunohistochemistry. Overall, KHK2805 showed cytotoxicity against both ovarian cancer cell lines and patient-derived cells. These translational study findings suggest that KHK2805 may be promising as a novel therapeutic agent for platinum-resistant ovarian cancer with peritoneal dissemination and malignant ascites.
登录
查看更多内容
影响因子：
28.5
作者：
Mellor JD;Brown MP;Irving HR;Zalcberg JR;Dobrovic A
通讯作者：
Dobrovic A
影响因子：
11.2
作者：
Natsume, Akito;In, Mika;Niwa, Rinpei
通讯作者：
Niwa, Rinpei
影响因子：
4.7
作者：
Armstrong, Deborah K.;White, Allen J.;Coleman, Robert L.
通讯作者：
Coleman, Robert L.
DOI：
10.1007/s13402-011-0052-6
发表时间：
2012-02
期刊：
Cellular oncology (Dordrecht, Netherlands)
影响因子：
--
作者：
Crane LM;Arts HJ;van Oosten M;Low PS;van der Zee AG;van Dam GM;Bart J
通讯作者：
Bart J
影响因子：
3.6
作者：
KLEIN, E;DIRENZO, L;YEFENOF, E
通讯作者：
YEFENOF, E