Abstract 3232: Pharmacokinetic analysis of anti-PD-1 and PD-L1 antibodies and evaluation of their anti-tumor effects
Authors: Hatakeyama Hiroto , Kurino Taiki , Matsuda Reiko , Suzuki Hiroyuki , Terui Ayu , Uehara Tomoya , Arano Yasushi , Hisaka Akihiro 
Published: August 2019

Objective: Recently anti-PD-1 antibodies (aPD-1 Abs), anti-PD-L1 (aPD-1) Abs have been approved. 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 aPD-1/PD-L1 Abs labeled with radioisotopes (In-111/I-125) and evaluated the relationship between PK and therapeutic effects.

Method: Abs were labeled with In-111 via chelate agents, and labeled with I-125 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 radio activities in organs were measured by a gamma counter. The accumulation of Abs were expressed as % of injected dose/g organs. Because In-111 tends to be accumulated in organs due to poor permeability and I-125 was eliminated from organs rapidly due to high permeability, the ratio of I-125 and In-111 could reflect the degradation of Abs after cellular uptake. In pharmacological studies, Abs were intraperitoneally injected into tumor-bearing mice at doses of 50 to 200 μg (2.5 to 10 mg/kg) at day 5, 8, and 12 after tumor-inoculation. Tumor volume was evaluated to evaluate tumor progression.

Result and Discussion: aPD-1 Ab showed anti-tumor effect in both MC38 and MM48 tumor models in a dose-dependent manner. On the other hand, aPD-L1 Abs showed lower anti-tumor effect in MC38 models, and negligible effect in MM48 tumor bearing mice at tested doses. According to PK studies, it was observed that aPD-L1 Abs were largely accumulated in normal tissues, especially in the spleen, liver, and kidney, and degraded rapidly compared with aPD-1 Abs, resulting that the blood concentration and distribution in tumors of aPD-L1 Abs tended to be low. Moreover, aPD-L1 Abs showed more rapid degradation in both tumors than aPD-1 Ab.

Conclusion: aPD-L1 Ab showed less anti-tumor effect in tested tumor models due to less distribution and faster degradation in tumors than aPD-1 Ab. Collectively, the PK of aPD-1/PD-L1 Abs which 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, Reiko Matsuda, Hiroyuki Suzuki, Ayu Terui, Tomoya Uehara, Yasushi Arano, Akihiro Hisaka. Pharmacokinetic analysis of anti-PD-1 and PD-L1 antibodies and evaluation of their anti-tumor effects [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3232.