Influence of the Dissociation Rate Constant on the Intra-tumor Distribution of Antibody-drug Conjugate Against Tissue Factor

Antibody-drug conjugates (ADCs) are currently considered to be promising agents for cancer therapy. However, especially in solid tumors, the uneven distribution of ADCs would decrease their efficacy in clinical studies. We suggest that in addition to optimizing ADC components, such as the linker structure and anticancer agent, it is necessary to consider the distribution of the ADC within tumor tissue. In this study, we established three kinds of anti-tissue factor (TF) ADCs: 1849ADC with a low k, 444ADC with an intermediate k, and 1084ADC with a high k. All three of the anti-TF ADCs exhibited almost the same in vitro cytotoxicity and pharmacological and biochemical characteristics, although the binding kinetics parameters differed. In vivo, all ADCs exerted equivalent antitumor effects against small BxPC3 tumors. However, on larger BxPC3 tumors, 1084ADC (higher k) exerted higher antitumor activity than 1849ADC (lower k). Furthermore, immunofluorescence staining indicated that 1084ADC was distributed throughout the whole tumor, whereas 1849ADC was mainly localized close to tumor vessels. We conclude that the ADC with a higher k increased the antitumor effect of because it penetrated and distributed evenly throughout the entire solid tumor. These findings highlight the importance of the k of a mAb in ADC design.