Document resource
Background High-grade serous ovarian carcinoma (HGSOC) is the most aggressive type of epithelial ovarian cancer. Despite the development of numerous sophisticated strategies, the traits of HGSOC, such as its ability to metastasize, resist therapy, create an immunosuppressive environment, and recur frequently, significantly reduce treatment effectiveness. To develop a clinically relevant regimen, we hypothesized that enhancing the drug payloads of antibody-drug conjugates (ADCs) could substantially improve their effectiveness. Moreover, the therapeutic impact can be further heightened alongside appropriate immunomodulatory cytokines, intensifying the anti-tumor response.Methods Trastuzumab emtansine (T-DM1, KADCYLA) served as the lead ADC. To increase the drug payloads, we first engineered trastuzumab with our patented technology (PCT/US24/037314) using the super hydrophilic polymer, Poly (2-Methacryloyloxyethyl phosphorylcholine) (PMPC). The resultant ADC, T-DM1 PMPC, successfully reached a drug-antibody ratio exceedingly twice that of T-DM1, while preserving stability throughout manufacturing and in animals. To improve the immunosuppressive environment of tumors, we selected interleukins 7 and 12 (IL-7 and IL-12) as our immunomodulators. Both were connected to a tumor-targeting agent through fusion with a collagen-binding domain (CBD-IL-7 and CBD-IL-12). The effectiveness of T-DM1PMPC combined with CBD-IL-7 and CBD-IL-12 against human HGSOC tumors was evaluated in a xenografted ovarian cancer mouse model, with or without humanization. Tumor burden changes were assessed using bioluminescent imaging and survival rates. Tissue samples were collected at the endpoint and analyzed for immune cell profiles.Results Tissue imaging revealed that ovaries with tumors in humanized mice indicated a scarcity of T cells. At the same time, numerous CD68+ macrophages showed positive staining for arginase 1, indicating an immunosuppressive environment in the ovarian tumors. A combinatorial approach utilizing T-DM1 PMPC alongside two CBD-immunomodulators effectively extended survival, irrespective of mouse-humanization status. Notably, the humanized mice exhibited a complete reduction of tumors just four weeks after receiving treatment.Conclusions Combination therapy resulted in superior management of HGSOC tumors in the presence of an active host immune system. In pursuit of future clinical applications, we are actively developing additional HGSOC models to assess the effectiveness of this combinatorial strategy.Acknowledgements CBD-IL-7 and CBD-IL-12 generated by Dr. Jun Ishihara, Imperial College London.Ethics Approval This study was approved by the Institutional Animal Care and Use Committee at the University of Alabama at Birmingham, APN 22788.