Abstract B160: Comparative analysis of pharmacokinetics and antitumor effect between anti-PD-1 and anti-PD-L1 in mice models

Introduction: Anti-PD-1 antibodies (αPD-1 Abs) are currently used in cancer immunotherapy that block the interaction between PD-1 and PD-L1. In addition to anti-PD-1 Abs, anti-PD-L1 (αPD-L1) Abs have also been approved to inhibit the PD-1/PD-L1 axis. However, the difference between both Abs in pharmacokinetics and anti-tumor effects have not been fully understood. In this study, we analyzed the difference between both Abs in blood concentration, biodistribution and degradation in tumor-bearing mice by using αPD-1/PD-L1 Abs labeled with radioisotopes (111In/125I) and evaluated the relationship between PK and therapeutic effects. Methods: Abs were labeled with 111In via chelate agents, and labeled with 125I through covalent bond. Tumor bearing mice were prepared by s.c. inoculation with mouse colon cancer MC38 cells or mouse breast cancer MM48 cells. The labeled Abs were intraperitoneally injected into tumor-bearing mice. Tumors and organs were harvested at several time points after the injection, and radioactivities in organs were measured by a gamma counter. The accumulation of Abs was expressed as % of injected dose/g organs. Because 111In tends to be accumulated in organs due to poor permeability and 125I was eliminated from organs rapidly due to high permeability, the ratio of 125I and 111In could reflect the degradation of Abs after cellular uptake. In pharmacologic studies, Abs were intraperitoneally injected into tumor-bearing mice at day 5, 8, and 12 after tumor-inoculation. Tumor volume was evaluated to evaluate tumor progression. Results and Discussion: It was observed that αPD-L1 Ab was largely accumulated in normal tissues, especially in the spleen and liver and degraded rapidly compared with αPD-1 Ab, resulting that the blood concentration and distribution in tumors of αPD-L1 Ab tended to be low in both tumor-bearing mice models. Moreover, αPD-L1 Ab showed lower antitumor effect due to less delivered aPD-L1 Ab to tumors than aPD-1 Ab. Collectively, the PK of αPD-1/PD-L1 Abs that target the same axis were not equivalent and the selectivity of expression of target molecules in both normal tissues and tumors should be considered to optimize their therapeutic efficacy. Citation Format: Hiroto Hatakeyama, Taiki Kurino, Hiroyuki Suzuki, Ayu Terui, Tomoya Uehara, Yasushi Arano, Akihiro Hisaka. Comparative analysis of pharmacokinetics and antitumor effect between anti-PD-1 and anti-PD-L1 in mice models [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr B160.