Abstract 596: Development and assessment of a novel tumor microenvironment activable linker (TMALIN) ADC platform for solid tumor treatments

Abstract Antibody-drug conjugates (ADC) are one of the fastest growing anticancer drugs, which bring cytotoxic drugs into tumors while avoiding high systemic toxicities. To date, all commercial ADCs use intracellular lysosomal cleavage mechanisms for payload release to kill tumor cells which is often limited by the low tumor antigen expression. To this end, a novel systemically stable and extracellular tumor microenvironment activable linker-payload technology platform has been developed. Preclinical assessments demonstrated that the highly hydrophilic linker-payload, which showed limited impact on the hydrophilicity of antibody, prolonged the retention time in vivo and eventually enhanced the in vivo potency of ADC. The linker-payload is stable with less than 2% payload drop-off after 28-day incubation in plasma under physiological conditions in vitro. The high stability was also illustrated by GLP cynomolgus monkey studies and preliminary clinical trial data, with the overlap of ADC and TAb PK profile. Furthermore, a battery in vitro and in vivo cell line-derived xenograft (CDX) mouse model studies showed the linker-payload is stable in normal tissues but efficiently releases the payload in tumor tissues. The ADCs using TMALIN platform elucidated significant anti-tumor activity advantages when compared with those marketed ADCs targeting the same antigen, besides showing an acceptable safety profile in pivotal NHP studies without lung/liver/kidney toxicities. 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. Continued clinical validation work is underway for several pipeline candidates as well as investigation into other target areas. Citation Format: Jiaqiang Cai, Shuai Song, Qing Zong, Qigang Liu, Jian Xu. Development and assessment of a novel tumor microenvironment activable linker (TMALIN) ADC platform for solid tumor treatments [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 596.