Abstract 347: Novel EGFR x cMET bispecific ADC GQ1033 and DLL3-ADC GQ1030 demonstrated promising therapeutic efficacy in preclinical studies

Abstract Background: Lung cancer is the leading cause of cancer deaths globally, with NSCLC comprising around 85% and SCLC about 15%. Several tyrosine kinase inhibitors (TKIs) have been approved for NSCLC. However, TKIs favor the emergence of resistant cells, ultimately resulting in tumor relapse. EGFR and cMET are co-expressed oncoproteins, with cMET playing a pivotal role in resistance to EGFR TKI in NSCLC. SCLC commonly develops disease relapse and resistance following first-line platinum-based chemotherapy, leading to a poor 5-year overall survival of below 7%. DLL3, an inhibitory Notch ligand, is selectively expressed on the surface of SCLC cells and represents a validated therapeutic target. Methods: Traditional ADC discovery relies on rational design, which often limits diversity and may exclude promising candidates due to the complexity of ADCs. Existing conjugation technologies are not well-suited for diversity-oriented synthesis (DOS), as they involve multi-step processes, low versatility, and inconsistent quality. Our proprietary enzymatic site-specific conjugation platforms, iGDC™ and iLDC™, enable high-throughput synthesis of diverse ADC libraries. Using the platforms, we created a broad ADC library targeting EGFR x cMET and DLL3, combining antibodies with various formats, different linkers, and payloads like MMAE, Eribulin, Exatecan, Lurbinectedin, and TopoIx. The resulting ADCs were rigorously evaluated using in vitro cytotoxicity assays and in vivo PDX subclinical trials. Through this process, we developed GQ1033 and GQ1030, next-generation ADCs specifically targeting EGFR x cMET and DLL3, respectively. Results: GQ1033 showed potent cytotoxicity in the HCC827 cell line and complete tumor regression at a single 4 mg/kg dose in the NCI-H1975 CDX model. In an osimertinib-resistant NSCLC PDX trial, involving ∼10 models with diverse EGFR/cMET expression levels, GQ1033 demonstrated robust antitumor activity with an overall ORR of ∼70%. GQ1030 displayed strong cytotoxicity in DLL3-positive cancer cell lines, with no off-target effects in DLL3-negative cells. In vivo, GQ1030 exhibited robust antitumor activity in the SHP-77 CDX model at a single dose of 2.5 mg/kg. In a PDX trial involving over 10 SCLC models randomly chosen without consideration of DLL3 expression, GQ1030 demonstrated best-in-class potential with an ORR of ∼80%. The selected lead ADCs did not necessarily possess the highest antibody affinities or the most potent payloads. Furthermore, ADCs with higher DARs did not consistently demonstrate significant efficacy advantages. Conclusions: GQ1033 and GQ1030, developed through high-throughput screening leveraging our iGDC™ and iLDC™ platforms, have demonstrated encouraging efficacy in preclinical studies, suggesting a broader therapeutic index. These next-gen ADCs hold potential as innovative treatments for lung cancers. Citation Format: Sipeng Li, Yajun Sun, Meijun Xiong, Chong Liu, Yanwen Feng, Zengyan Mu, Xinju Gao, Yu Han, Paul H. Song, Gang Qin. Novel EGFR x cMET bispecific ADC GQ1033 and DLL3-ADC GQ1030 demonstrated promising therapeutic efficacy in preclinical studies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 347.