MAC-8001: A KRAS-targeting molecular glue-antibody conjugate with robust antitumor activity in KRAS-mutant cancers
Presenter: Carlos Chai, PhD Session: Antibody Technologies and Platforms 1 Time: 4/20/2026 9:00:00 AM → 4/20/2026 12:00:00 PM
Authors
Feilong Sun , Shuaishuai Chi , Carlos Chai , Yi Chen , Xuan Zhang DaCure Therapeutics, Shanghai, China
Abstract
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 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.
Disclosure
F. Sun, None.. S. Chi, None.. C. Chai, None.. Y. Chen, None.. X. Zhang, None.
Cited in
Control: 5791 · Presentation Id: 5493 · Meeting 21436