Abstract Background: CEACAM5 and EGFR are highly expressed in several cancers, including colorectal, gastric, and lung, with greater specificity than in normal tissues. EGFR antibodies like cetuximab are standard first-line therapy for colorectal cancer (CRC) patients with wild-type KRAS, but are less effective in those with KRAS mutations, creating an unmet clinical need. ADCs targeting CEACAM5 or EGFR, such as M9140 and MRG003, are under clinical development for CRC; however, single-target ADCs have shown limited efficacy, likely due to variable antigen expression among patients. To address this, we developed RT023, a CEACAM5/EGFR bispecific ADC designed to treat patients positive for either marker, including those with KRAS mutations and those who relapse after EGFR antibody treatment. Methods: RT023 is an ADC composed of an anti-CEACAM5/anti-EGFR bispecific antibody and a DNA topoisomerase I inhibitor, exatecan, linked through a cleavable linker, with a homogeneous drug-to-antibody ratio (DAR) of 6. In vitro potency was measured through cytotoxicity assay. Its anti-tumor activities were evaluated in cell line-derived xenograft (CDX) models. Toxicity and pharmacokinetics of RT023 were assessed in cynomolgus monkey. Results: RT023 exhibited high affinity binding to CEACAM5 and EGFR. It had higher internalization rate than its respective parent monospecific antibodies, resulting in efficiently killing to tumor cells with a wide spectrum of CEACAM5 and EGFR expression levels. RT023 demonstrated superior tumor growth inhibition than M9140 and Cetuximab ADC in several CRC CDX models. In the EGFR-dominant HCT116 model, RT023 exhibited impressive tumor growth inhibition with a TGI of 88.5% after single dose of 0.77 mg/kg, whereas the Cetuximab ADC at the same molar dose achieved only a 58% TGI, and M9140 did not inhibit tumor growth. In the CEACAM5-dominant GP2D model, a single dose treatment of RT023 at 2.3 mg/kg resulted in 80% (4/5) complete tumor regression (CR), whereas M9140 treatment group only achieved 20% (1/5) CR. In the CEACAM5 /EGFR double-driven SW1116 model, RT023 induced tumor repression with a higher TGI than Cetuximab ADC (117% vs 105%) after two doses of 2.3 mg/kg, Q3W, and showed more durable anti-tumor effect than M9140 (64 days vs 47 days). RT023 was well tolerated in cynomolgus monkeys up to 30 mg/kg, with only minimal skin and hematological adverse effect. It also had a favorable PK profile with a half-life of approximately 120 hours. RT023 remained stable in circulation with less than 0.02% free drug release. Conclusion: RT023, with its unique bispecific design and differentiated features in affinity, linker-payload, has shown promising potential as a first-in-class ADC candidate for CRC treatment. Preclinical discovery studies have revealed favorable efficacy and toxicity profiles, supporting advancing RT023 into first-in-human studies. Citation Format: Shuting Huang, Lulu Zhou, Jingjing Cao, Lingli Bi, Qiang Fu, Xuan Wu, Aikun Xia, Jiaming Wang, Yue Deng, Yanghua Xu, Xin Wang, Wenli Shi, Honglin He, Yuyuan Yan, Ziyang Zhong. RT023, a first-in-class CEACAM5/EGFR targeted bispecific antibody drug conjugate (ADC) in colorectal cancer (CRC) abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 1718.
Huang et al. (Fri,) studied this question.