Abstract 1805: Dual-payload TME-activated ADC platform
Authors: Cheng Liu, Yuan Liu, Rui Zhang
Journal: Cancer Research (2025)

Abstract The combination of Antibody-Drug Conjugates (ADCs) and Immuno-Oncology (IO) agents is regarded as one of the most exciting and promising trends in the rapidly evolving field of cancer treatment. Affinity Biopharma has developed the Tumor MicroEnviroment Activated (TMEA) platform, with proprietary TMEA linkers applicable in both Small Molecule Drug Conjugates (SMDCs), ADCs and dual-payload ADCs. The TMEA linkers could achieve extracellular activation of payloads in the Tumor MicroEnviroment (TME) by a tumor-specific protease Legumain (AEP), which is an acid endopeptidase with tumor site over-expression and a strict specificity for one particular amino acid (Asn), making it a first-in-class, highly specific and pan-solid tumor target in novel drug design. Compared to GGFG linkers cleaved by lysosomal enzymes such as cathepsins B and L, the TMEA linkers exhibited superior stability in human plasma at 37°C, and demonstrated higher cleavage efficiency under identical condition in tumor homogenates (pH=6.5), generating a remarkably clean cleavage profile with minimal to no inactive intermediates. Such advantageous characteristics of TMEA linkers could be supported by a TMEA-SMDC drug Legubicin in clinical trial that releases payload Doxorubicin. For dual-payload TMEA-ADCs, each hydrophilic TMEA linker is paired with two insoluble payloads such as TLR7/8 agonists and topoisomerase I inhibitors, which show similar maximum tolerated doses (MTD) in mice as linker-single-payload. Dual-payload TMEA-ADCs have effectively addressed the CMC challenges and enabled homogenous formation of 8-DAR dual-payload design. In various PBMCs-CDX models, dual-payload TMEA-ADCs such as IMD526 (HER2-ADC), IMD2126 (PD-L1-ADC) and IMD2113 (EGFR&amp;TROP2-ADC) have displayed significant dose-dependent antitumor activities and induced complete tumor regressions with no observable toxicities. Compared to mono- or combo treatments with single-payload ADCs, IMD526 validated its superiority in the in-vivo CT26-HER+ syngeneic mouse model, and long-term elimination of detectable tumors was achieved with IMD526 both alone and combined with IMD101 (a TMEA-Cytokine releasing IL-2). In tumor re-challenge studies, mice that were cured exhibited immune memory and were resistant to tumor re-implantation. In non-human primate (NHP) studies, dual-payload TMEA-ADCs showed excellent stability in circulation and a strong safety profile, indicating a greatly expanded therapeutic window. And different from the tumor cell endocytosis activation by GGFG-DXd ADCs, the bio-distribution of TMEA-ADCs resulted in faster and higher levels of payload accumulation in the tumor local tissues. In summary, by integrating antibody targeting, TME activation, cytotoxic therapy, and I/O therapy into one single molecule, the dual-payload TMEA-ADCs has demonstrated the synergistic effects of ADCs conjugated with 16 insoluble payloads from 2 distinct mechanisms of action in tumor models. Citation Format: Cheng Liu, Yuan Liu, Rui Zhang. Dual-payload TME-activated ADC platform [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 1805.