| الوصف: |
Antibody drug conjugate (ADC) is a novel class of therapeutic agent which recently showed great success in both solid tumour and blood cancer. ADCs deliver potent cytotoxic payloads to tumour via cancer specific monoclonal antibodies. A few ADCs are currently evaluated in clinical trials for high grade serous ovarian cancer (HGSOC). However, most of them target FOLR1-alpha, a conventional HGSOC target which also expresses in vital organs including lungs. Thus, it is desirable to discover more specific antigen targets, and these new targets will be the foundation for the next-generation ADC for HGSOC.We propose that ovarian tumour specificity of an ADC target could contributed by three factors: 1. Lineage (e.g. fallopian tube marker FOLR1); 2. DNA amplification (e.g. ERBB2); 3. Other carcinogenesis process including epigenetic reprogramming. Then, by combining the GTEX, TCGA dataset with our own WES, long-reads RNA-sequencing and Mass spectrometry-based proteomics cohort, an array of differentially expressed genes in HGSOC tumours are identified. Out of over 50 candidates, two most promising targets are chosen for monoclonal antibodies (mAbs) production and subsequent ADC development. First, the affinity and specificity of the mAbs were confirmed by ELISA, flow cytometry and immunofluorescence. The cellular internalisation characteristics of these antibodies are confirmed by a fluorescence-based assay. Then, ADCs for these two targets are produced by conjugating monomethyl auristatin E payload to the mAbs via a cleavable linker. Finally, both ADCs show highly target-specific and sub-nanomolar cytotoxicity in model ovarian cancer cell lines. In conclusion, we identify a panel of HGSOC-specific ADC targets and develop two ADCs candidates for further pre-clinical and clinical investigations. Citation Format: Ruisi Fu, Hantao Lou, Ning Wang, Dongnan Yan, Clara Tresserras-Segura, Haonan Lu, Eric Aboagye. Development of an antibody-drug conjugate panel targeting high grade serous ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 455. |
