Abstract 2888: DB-1418, a bispecific antibody-drug conjugate (ADC) targeting EGFR and HER3, demonstrates superior and broad antitumor efficacy and favorable safety in preclinical models

Background: EGFR and HER3 are co-overexpressed in a spectrum of tumors, including lung, breast, gastrointestinal, renal cell, ovarian, bladder, and prostate cancers. Importantly, HER3 expression is further enhanced upon inhibition of EGFR, suggesting that simultaneous targeting of both EGFR and HER3 could enhance tumor selectivity and improve therapeutic efficacy in EGFR tyrosine kinase inhibitors resistant tumors. This hypothesis has been supported by the clinical data of BL-B01D1, a bispecific ADC currently in clinical development. Here, we developed a differentiated bispecific ADC with stronger antitumor activity in preclinical studies. Methods: We generated DB-1418, an asymmetric IgG-like bispecific ADC, featuring a Fab arm targeting EGFR with medium affinity and a scFv arm targeting HER3 with high affinity. The antibody is conjugated to a linker-payload L101P1021 at a drug-to-antibody ratio (DAR) of 6. Results: The bispecific antibody showed low affinity on EGFR-only or HER3-only cell lines but demonstrated high affinity on tumor cells co-expressing both EGFR and HER3 compared to the parent monospecific antibodies. It also showed higher internalization capacity than the parent monospecific antibodies. DB-1418 exhibited broad anti-tumor activity across different expression levels of EGFR and HER3. Superior tumor inhibition was observed compared to a BL-B01D1 analog, based on both equal molar and mass concentrations. In the EGFR-dominant CAL-27 model, DB-1418 demonstrated a significant tumor growth inhibition (TGI) of 83% at a dose of 1.9 mg/kg Q3W, whereas the BL-B01D1 analog achieved only a 73% TGI at a dose of 3 mg/kg Q3W. In the HER3-dominant SW-620 model, DB-1418 treatment at a dose of 10 mg/kg Q3W resulted in complete tumor regression in 4 out of 5 mice and persisted up to 63 days after administration, whereas the BL-B01D1 analog at the same dose level and frequency failed to inhibit tumor growth. Notably, in an osimertinib-resistant NSCLC xenograft model with the C797S mutation, DB-1418 induced tumor regression with a TGI of 98% at a dose of 6 mg/kg Q3W, significantly higher than the BL-B01D1 analog at 6 mg/kg Q3W (TGI of 68%, p<0.01). DB-1418 demonstrated in vitro plasma stability in human, monkey, and rat models. In cynomolgus monkeys, the dose-range finding study showed favorable safety, with the highest non-severely toxic dose (HNSTD) reaching up to 45 mg/kg. Conclusion: DB-1418 has shown promising pharmacological and pharmacokinetic properties, differentiated from the current clinical trial bispecific ADC targeting EGFR and HER3, with a broader therapeutic window. DB-1418 offers additional treatment options for patients who have developed resistance to EGFR tyrosine kinase inhibitors (TKIs) and addresses other unmet medical needs. Citation Format: Yunhua Zhou, Jun Yao, Rong Shi, Yang Qiu, Haiqing Hua. DB-1418, a bispecific antibody-drug conjugate (ADC) targeting EGFR and HER3, demonstrates superior and broad antitumor efficacy and favorable safety in preclinical models [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 2888.