Abstract A015: JAB-BX600, a first-in-class EGFR-directed antiboEdy drug conjugate delivering a novel KRAS G12D inhibitor

Abstract

In contrast to non-small cell lung cancer and pancreatic cancer, KRAS inhibitors exhibited limited single agent activities in colorectal cancer (CRC), largely owing to EGFR-mediated adaptive MAPK pathway reactivation and intratumor heterogeneity. JAB-BX600, a humanized, EGFR-targeted antibody-drug conjugate (ADC) with a KRAS G12D inhibitor (JAB-22G82) as payload with a drug-to-antibody ratio (DAR) of 8, represents a revolutionary module for synergistic dual-node signaling blockade. In the current study, the therapeutic potential of JAB-BX600 in CRC and other solid tumors including PDAC with KRAS G12D mutation was evaluated. The KRAS G12D inhibitor JAB-22G82 used as ADC payload was developed through Jacobio’s proprietary Induced Allosteric Drug Discovery Platform (IADDP). The binding affinity of JAB-22G82 for GDP-KRAS G12D was determined by SPR. The internalization efficacy of JAB-BX600 was evaluated by flow cytometry. The inhibitory effect of both JAB-22G82 and JAB-BX600 on cell viability was evaluated by a luminescence-based assay. The plasma stability of JAB-BX600 across species was evaluated by LC-MS/MS. In vivo anti-tumor efficacy of JAB-BX600 was evaluated in both cell line-derived xenograft (CDX) and patient-derived xenograft (PDX) models. The pharmacokinetics (PK) and safety profiles of JAB-BX600 in cynomolgus monkeys were obtained. The KRAS G12D inhibitor JAB-22G82 (payload) exhibited high binding affinity for KRAS G12D with KD of 14.5 fM, and high potency to inhibit cell viability with subnanomolar IC50s in most KRAS G12D mutant tumor cells tested. JAB-BX600 and the unconjugated EGFR antibody exhibited comparable potent EGFR binding, efficient internalization, and antibody-dependent cellular cytotoxicity (ADCC) induction in tumor cells. Remarkably, JAB-BX600 inhibited cell viability with IC50s at the 10 pM level across most tumor cell lines tested, and exhibited >2000-fold selectivity against normal human skin cells, indicating less skin toxicity. A single administration of JAB-BX600 at 3 mg/kg induced tumor regression in both CRC and PDAC animal models, with high intratumoral payload distribution and minimal payload release in plasma. Finally, JAB-BX600 with dosing up to 60 mg/kg exhibited an overall favorable tolerability profile in cynomolgus monkeys. JAB-BX600 exhibits potent anti-tumor activity in KRAS G12D-mutant tumor models and a favorable preclinical safety profile. These results support further clinical development of JAB-BX600 as a promising therapeutic strategy for KRAS G12D-driven cancers, particularly CRC and PDAC. The IND will be submitted in 2026. Peng Wang, Fangjie Liu, Xiaoyu Liu, Haijun Li, Xueting He, Amin Li, Andrea Wang-Gillam, Xin Sun, Yiwei Lin, Yanping Wang. JAB-BX600, a first-in-class EGFR-directed antiboEdy drug conjugate delivering a novel KRAS G12D inhibitor [abstract]. In: Proceedings of AACR Drug Discovery and Development (AACR D3) Conference; 2026 Jul 21-24; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(14_Suppl):Abstract nr A015.