Abstract 5654: Novel ALDC and ADC with TMEAlinker and eribulin payload demonstrate excellent safety and efficacy in preclinical evaluation.

Abstract Overexpression of extracellular legumain in the tumor microenvironment (TME) plays a critical role in tumor invasion and metastasis. TMEAlinkers (TME-activated linkers) are legumain-activated linkers with clinical proof-of-concept (POC) from the phase 3 study of legubicin (an albumin drug conjugate, ALDC). Leveraging this TMEAlinker platform, eribulin can be conjugated to albumin or antibodies via TMEAlinker to generate novel ALDCs and ADCs. QHL-1848 is a TMEAlinker-based ALDC carrying eribulin as payload. In both in vitro and in vivo studies, QHL-1848 exhibited markedly improved safety data compared with the free payload. In human plasma at 37 °C, only ∼0.5% of free eribulin was released after 7 days of incubation, indicating high plasma stability. The maximum tolerated dose (MTD) of QHL-1848 was 0.491 µmol/kg (QWx4) in dogs, displaying a significantly superior safety profile relative to eribulin (MTD = 0.054 µmol/kg, QWx3 in dogs). In murine HT1080 xenograft models, QHL-1848 achieved complete tumor regression of large (750 mm3) tumors with a dosing regimen of 1 µmol/kg given 3 times. IMD2128, a bispecific ADC targeting EGFR/c-Met, is conjugated with eribulin via TMEAlinker at a drug-to-antibody ratio (DAR) of 2. IMD2128 demonstrated potent curative antitumor activities across multiple xenograft models, including lung and pancreatic carcinomas, achieving complete tumor elimination with a single dose of 3.75 mg/kg. Remarkably, IMD2128 retained efficacy in models resistant to DXd-based ADCs. In cynomolgus monkeys, IMD2128 was well tolerated with a highest nonseverely toxic dose (HNSTD) over 16 mg/kg, showing a superior safety profile compared to VC linker-eribulin based ADCs (e.g., MORAb-202, HNSTD = 1.95 mg/kg). Pharmacokinetic studies in monkeys revealed a Cmax of 291.07 µmol/mL for IMD2128 ADC versus a Cmax of 0.0000823 µmol/mL for free eribulin (Cmax ratio ≈ 3.54 × 106 : 1), confirming strong linker stability in circulation. Together, these findings highlight the versatility of the TMEAlinker platform for developing both ALDCs and ADCs with eribulin payloads, demonstrating excellent safety and efficacy in preclinical evaluations. Citation Format: Tao Chen, Cheng Liu, Yuan Liu. Novel ALDC and ADC with TMEAlinker and eribulin payload demonstrate excellent safety and efficacy in preclinical evaluation [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 5654.