Abstract 6832: SYS6041, a next-generation Folate Receptor α-targeted antibody-drug conjugates for the treatment of FRα-expressing malignancies

Abstract Folate Receptor α(FRα)exhibits an increased expression on cell surfaces in multiple solid tumors, including ovarian, lung, endometrial cancer, with limited expression in normal tissues. Recently, an antibody drug conjugate (ADC) with a microtubule inhibitor (MTI) payload, was approved by FDA for FRα-expressing platinum-resistant ovarian cancer. However, it can cause severe ocular toxicities and show therapeutic efficacies only in patients with high expression. In order to address the unmet needs of additional patient populations, we sought to develop a next generation FRα-targeting ADC, SYS6041, actively targeting tumors with a broad range of FRα expression, especially moderate or low expression levels. SYS6041 was developed adopting a novel ADC platform with a camptothecin-based topoisomerase 1 inhibitor payload, Exatecan, tethered to a cleavable linker. The drug-to-antibody ratio standed 8.0. Upon binding to FRα, SYS6041 underwent receptor-mediated internalization. Subsequent proteolytic cleavage released the cytotoxic payload Exatecan, leading to DNA strand breaks and consequently disrupting DNA replication and transcription. SYS6041 demonstrated potent cytotoxicities against FRα expressing cancer cell-lines and effective bystander activities towards tumor cells without FRα expression. It demonstrated superior antitumor effects across ovarian endometrial and lung cancer CDX models compared to the MTI-ADC especially in models with low or moderate FRα expression, with a minimum effect dose(MED) at 0.75 mg/kg. In a FRα moderate ovarian PDX model with Olaparib resistance, SYS6041 significantly inhibited tumor growth at 3 mg/kg, whereas the MTI-ADC showed no inhibitory effect at 6 mg/kg. Furthermore, Exatecan demonstrated a significant enrichment in the tumors of mice bearing tumors, achieving a tumor-to-blood ratio of 182 following a dosage of 6 mg/kg of SYS6041.SYS6041 exhibited a stable PK profile with AUC of Exatecan less than 0.01% of that of total Exatecan in ADC. In a GLP toxicity study in cynomolgus monkey, SYS6041 demonstrated an encouraging tolerability with an HNSTD of 50 mg/kg, and favorable PK and DAR stability, and presented a good tolerability profile with therapeutic window (TW)>66 (HNSTD/MED). In conclusion, the distinct mode of action along with the proprietary drug-linker platform resulted in an excellent in-vivo antitumor potency and safety, which supports the potential of SYS6041 as a novel therapeutic agent that may help address unmet needs in patients with moderate and low FRα expressing malignancies. Citation Format: Jieru Liu, Huan Li, Mo Dan, Xiwu Hui, Bin Yao, Yang Zhang, Linlin Xiao, Bin Kang, Can Yuan, Bin Bao, Miaomiao Wei, Chunqing Qu, Yanling Li, Wei Yang. SYS6041, a next-generation Folate Receptor α-targeted antibody-drug conjugates for the treatment of FRα-expressing malignancies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6832.