Preclinical development of LUA005: A differentiated bivalent EGFR/cMET bispecific ADC displays strong anti-cancer efficacy and a wider therapeutic window

Background Compensatory functions between EGFR- and cMET-mediated signaling contribute to resistance to either EGFR- or cMet-targeting agents such as osimertinib. The frequent co-expression of these two targets in solid tumors supports dual targeting strategy, evidenced by the approved bispecific antibody amivantamab. Several EGFR-cMET antibody-drug conjugates (ADCs) have entered clinical trials. While most bispecific ADCs targeting EGFR and cMET use a 1+1 format, we designed and generated LUA005 with bivalent arms for each target. It exhibits low affinity but high avidity to EGFR, coupled with high-affinity to cMET. This design aims to minimize on-target off-tumor toxicity while ensuring robust efficacy across heterogeneous tumors, including those with low EGFR expression. Here, we report the preclinical characterizations of LUA005 as an EGFR/c-Met bispecific ADC with differentiated properties. Methods LUA005 was built on the QILU's proprietary novel topoisomerase-1 inhibitor platform, conjugated via a hydrophilic cleavable linker to yield a uniform DAR 8 product. The payload displayed nanomolar activity across various cancer cell lines and much faster systematic clearance than Dxd in vitro , to reduce systematic toxicity. Benchmark ADCs were included for comparison. Results In vitro , LUA005 exhibited strong cytotoxicity against tumor cell lines but minimal killing of normal keratinocytes, indicating a wider therapeutic window than benchmarks. Meanwhile, LUA005 demonstrated superior antitumor activity compared to benchmarks across a spectrum of CDX models with different EGFR and cMET expression levels, highlighting its potential to address tumor heterogeneity. LUA005 also demonstrated remarkable efficacy in a series of patient-derived xenograft (PDX) models, including those resistant to osimertinib, cetuximab, or immunotherapy. Meanwhile, LUA005 was well tolerated in Cyno monkeys, with HNSTD up to 60 mpk Q3W for three times repeated dosing in NHP toxicity study, without obvious on-target toxicity or ILD, consistent with our molecule design. LUA005 demonstrated favorable PK profile in cyno monkeys, with high stability and limited free drug release in circulation. Conclusions LUA005, an EGFR/cMET bispecific ADC with differentiated molecular design, demonstrated superior antitumor efficacy with enhanced therapeutic index. Preclinical studies warranted its further development into clinical trials, which are anticipated to start in early 2026.