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Potent Therapeutic Activity Against Peritoneal Dissemination and Malignant Ascites by the Novel Anti-Folate Receptor
Munetoshi Ando1, Keiko Nagata1, Kaito Nihira2
1Oncology R&D Unit, Kyowa Hakko Kirin Co., Ltd., Japan.
Abstract:
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.
Insights
A new antibody, KHK2805, shows promise in treating platinum-resistant ovarian cancer with peritoneal metastasis and ascites by leveraging enhanced antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC). This therapy effectively reduced tumor burden and prolonged survival in preclinical models.
Area of Science:
- Oncology
- Immunology
- Pharmacology
Background:
- Ovarian cancer frequently presents with peritoneal metastasis and malignant ascites, posing significant treatment challenges, especially upon developing resistance to chemotherapy.
- Existing therapies offer limited options for managing these advanced-stage symptoms in platinum-resistant ovarian cancer.
Purpose of the Study:
- To evaluate the therapeutic potential of KHK2805, a novel humanized antibody targeting folate receptor alpha (FOLR1), against peritoneal dissemination and malignant ascites in platinum-resistant ovarian cancer models.
- To assess the antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) of KHK2805 in relevant preclinical settings.
Main Methods:
- KHK2805's binding affinity and epitope specificity to folate receptor alpha (FOLR1) were determined.
- ADCC and CDC activities of KHK2805 were assessed using ovarian cancer cell lines and patient-derived malignant ascites cells.
- The in vivo anti-tumor efficacy of KHK2805 was evaluated in a SCID mouse model of platinum-resistant ovarian cancer peritoneal dissemination.
- Immunohistochemistry was used to evaluate the expression of FOLR1 in ovarian tumor tissues.
Main Results:
- KHK2805 demonstrated high-affinity, specific binding to FOLR1 at a novel epitope.
- The antibody induced potent ADCC and CDC in ovarian cancer cell lines and patient-derived malignant ascites cells.
- In vivo studies showed that KHK2805 significantly reduced tumor burden and ascites volume, prolonging survival in mice.
- Immunohistochemistry confirmed FOLR1 expression in serous and clear cell ovarian tumors.
Conclusions:
- KHK2805 exhibits significant anti-tumor cytotoxicity against both established ovarian cancer cell lines and patient-derived cells, including platinum-resistant ascites cells.
- The findings support KHK2805 as a potential novel therapeutic agent for platinum-resistant ovarian cancer with peritoneal dissemination and malignant ascites.
