Abstract LB263: BCG047, a novel heavy chain antibody-drug conjugate targeting FOLR1, demonstrates outstanding preclinical antitumor efficacy

Abstract Folate receptor 1 (FOLR1) is a GPI-anchored receptor crucial for folate transport. It has low expression in normal tissues but is abundant in tumors, especially ovarian cancers, making it an important therapeutic target. Elahere, an FRα-targeted ADC, improves progression-free survival in platinum-resistant ovarian cancer but is limited to patients with high FRα expression and poses safety concerns. This highlights the need for next-generation FRα-targeted ADCs that can treat patients with varying FOLR1 levels and use safer alternatives. By utilizing our fully human RenNano® mice, we identified an anti-FOLR1 VHH, HCAb-01, which recognizes a distinct FOLR1 epitope compared to the benchmark antibodies. It was shown to bind specifically to both human and monkey FOLR1 antigens, without recognizing other members of the FOLR family. HCAb-01 displayed a strong binding affinity for FOLR1 tumor cells with varying expression levels, suggesting its potential for effectively targeting cells with different levels of FOLR1 expression. Additionally, HCAb-01 demonstrated efficient internalization in tumor cells. HCAb-01 displayed favorable physicochemical properties and maintained consistent binding activity under stress conditions. Additionally, HCAb-01 demonstrated acceptable pharmacokinetics (PK) in C57BL/6 mice. We then conjugated HCAb-01 to BLD1102, a topoisomerase I inhibitor (TOP1i) based linker-payload, to generate a heavy-chain antibody-drug conjugate (HcADC), BCG047. BCG047 demonstrated potent efficacy in PDX models, particularly in an FOLR1-low model, outperforming the benchmark ADC. These data suggest that BCG047 is a promising therapeutic strategy targeting FOLR1, with the potential to expand the patient population benefiting from this treatment, particularly in low FOLR1 expression settings. To enhance pharmacokinetics and improve efficacy, modifications to BCG047 aimed at achieving a prolonged half-life are currently underway for further preclinical development. Citation Format: Benny Yang, Yifu Zhang, Yangyang Xu, Chengzhang Shang. BCG047, a novel heavy chain antibody-drug conjugate targeting FOLR1, demonstrates outstanding preclinical antitumor efficacy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(8_Suppl):Abstract nr LB263.