MAC-8001: A KRAS-targeting molecular glue-antibody conjugate with robust antitumor activity in KRAS-mutant cancers

Background KRAS mutations are among the most frequent oncogenic drivers, occurring in approximately 10-15% of all human cancers and in over 90% of pancreatic ductal adenocarcinomas (PDAC). Although KRAS G12C inhibitors have achieved clinical success, the majority of KRAS mutations (>85%), predominantly G12D and G12V, remain without approved targeted therapies. Recently, several G12D/V-selective inhibitors and pan-RAS molecular glues (MGs) have emerged as promising strategies to address this unmet need. Converting KRAS-targeting MGs into molecular glue-antibody conjugates (MACs) offers an attractive avenue to further optimize their therapeutic window by limiting systemic exposure, improving pharmacokinetics, and enhancing clinical translatability. Methods A series of KRAS-modulating MG payloads were developed through structure-based optimization and subsequently site-specifically conjugated to an anti-B7H3 antibody via a cleavable linker, yielding the conjugate MAC-8001. The conjugate was characterized by reversed-phase liquid chromatography (RPLC) and size-exclusion chromatography (SEC) to determine its drug-to-antibody ratio (DAR) and aggregation profile, respectively. The capacity of the payloads to interfere with RAS-BRAF RBD interactions was evaluated using a TR-FRET assay. In vitro antiproliferative activities were evaluated across cancer cell lines harboring KRAS G12C/D/V mutations, while in vivo efficacy and pharmacodynamic responses were examined in corresponding xengraft models. Results The conjugate exhibited a DAR of approximately 8.0 with no detectable aggregation. MAC-8001 demonstrated potent and selective inhibition of KRAS-mutant cancer cells (IC₅₀ <10 nM) compared with KRAS wild-type counterparts, accompanied by pronounced, dose-dependent suppression of downstream p-ERK and p-AKT signaling. Consistent with its scaffold-derived mechanism, TR-FRET assays confirmed that the payloads disrupted RAS-BRAF interactions, thereby attenuating MAPK signaling. In xenograft mouse models, a single intravenous dose of MAC-8001 produced durable antitumor responses, achieving over 90% tumor growth inhibition. Moreover, MAC-8001 was well-tolerated, without body-weight loss or detectable systemic toxicity. Conclusions MAC-8001 represents a potent KRAS-targeting MAC that selectively inhibits KRAS-driven signaling and exhibits robust antitumor efficacy both in vitro and in vivo . The modular design of this MAC platform allows straightforward adaptation to other tumor-associated antigens, such as TROP2, thereby broadening its translational potential across RAS-driven malignancies. Collectively, these findings establish a novel therapeutic paradigm that may overcome the inherent limitations of systemic KRAS modulation.