Abstract 4702: MediLink’s TMALIN ADC linker technology: Tumor microenvironment specific extracellular and intracellular double cleavage mechanism for better efficacy and expanded target space

Abstract Antibody-drug conjugates (ADC) are a type of the fastest growing anticancer drug modalities. However, the traditional ADC technologies constrain on therapeutic development, requiring overexpressed targets, high internalizing antigens and efficient intracellular processing. To this end, MediLink’s TMALIN platform was developed, with an irreversible pyrimidine coupling anchor and a valyl dipropyl-lysyl glycinamide-methylene (-VK*G-NHCH2-O-) cleavable sequence. The TMALIN platform is featured as a high hydrophilicity linker-payload, remarkable stability in circulation, coupled with an efficient payload release mechanism which is achieved through the cleavage both extracellularly in the tumor microenvironment and intracellularly within lysosomes. A site-specific and homogeneous conjugation using TMALIN platform provides highly stable ADC in circulation. It is evidenced by less than 2% payload drop-off after a 21-day incubation in plasma under physiological conditions in vitro. This feature is observed in over 7 ADCs developed using the TMALIN platform. Additionally, the high stability was also illustrated by the pharmacokinetic profiles in NHP studies and clinical trials, with the overlapped curves of ADC and TAb in all TMALIN platform-based ADCs. Apart from the stability, a battery of in vitro and in vivo studies showed the linker-payload efficiently releases the payload in both tumor cells and the tumor microenvironment. Due to the high stability in circulation and efficient cleavage within tumors, the TMALIN platform ADCs have shown promising efficacy and good safety windows in preclinical studies. In xenograft mouse models, including those with low antigen expression, these ADCs have demonstrated tumor regressions and good tolerability. This highlights the potential of the TMALIN platform in improving the efficacy of ADCs and expanding their therapeutic applications. Furthermore, favorable safety profiles have been observed in clinical trials and/or pivotal non-human primate (NHP) studies for ADCs developed using the TMALIN platform. No drug-related adverse effects in organs were identified including the lungs, liver, or kidneys for those ADCs. In summary, the TMALIN platform addresses the unmet need of ADCs by releasing the payload extracellularly in tumors and tumor microenvironments on top of the known intracellular lysosomal cleavage mechanisms. This enables the advancement of ADC development, and has the potential to expand the field of ADC therapy and improve patient outcomes. Citation Format: Tongtong Xue, Liang Xiao, Qigang Liu, Shuai Song, Ailin Shan, Xiaozhou Zhang, Sasha Stann, Jiaqiang Cai. MediLink’s TMALIN ADC linker technology: Tumor microenvironment specific extracellular and intracellular double cleavage mechanism for better efficacy and expanded target space [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4702.