Cancer immunotherapy with immune checkpoint inhibitors which enhances T-cell regulatory pathways has provided unprecedented benefit to cancer patients. Programmed death 1 ligand (PD-L1) being expressed by cancer cells binds to programmed death-1 (PD-1) to avoid anti-tumor activity of immune cells. Antibodies to disrupt the interaction have been developed for cancer therapeutics. YBL-006 is a new anti-PD-1 human IgG4 monoclonal antibody. Here, we described in vitro & in vivo studies to evaluate pharmacological effect of YBL-006 along with non-clinical studies of pharmacokinetics, toxicokinetics & tissue cross reactivity (TCR). YBL-006 was bound specifically to human PD-1 among receptors of B7 family by ELISA. When affinity to recombinant PD-1 of various species was measured using surface plasmon response system, KD of YBL-006 was 0.372 nM to human PD-1 & 0.070 nM to cynomolgus monkey PD-1 which is higher affinity than nivolumab (1.37 nM & 2.50 nM) & pembrolizumab (1.44 nM & 0.817 nM). It did bind to mouse PD-1 with less affinity than to human PD1, while nivolumab & pembrolizumab did not bind to mouse PD-1. YBL-006 was able to inhibit interaction between PD-1 & both PD-L1 & PD-L2 which was confirmed in competitive binding assay. Inhibition of PD-1 by YBL-006 increased the level of IFN-γ in a mixed lymphocyte reaction model. In a syngeneic mouse model of MC38 colon cancer, weight of tumors in mice treated with YBL-006 was less than that in mice with human IgG control by 25%. In a humanized mouse model (miXeno mouse) of HCC827 non-small cell lung cancer, volume of tumors in YBL-006-treated mice was smaller (35 % less comparing to control mice) than that in nivolumab-treated mice (24 % less). Pharmacokinetic analysis in monkey showed that exposures to YBL-006 increased dose-dependently & in a dose-proportional manner. Maximum mean serum concentrations (Cmax) of YBL-006 were reached (Tmax) between 0.5- & 1.0-hour post onset of infusion & YBL-006 mean serum concentrations slowly declined at a mean estimated t1/2 value of 70.8~110 hours. Clearance & mean volume of distribution suggest that YBL-006 was mainly distributed throughout the blood. In 1-month IV infusion toxicity study in monkey, there was no toxicity when they were infused up to 100 mg/kg/dose of YBL-006, but anti-drug antibody was observed (7 out of 22 monkeys). There was no potential toxicity in TCR study. YBL-006 is an anti-PD-1 antibody with high affinity, promising anti-tumor activity in animal models, & favorable safety profile. First-in-human phase I trial to investigate the safety & efficacy of YBL-006 in advanced solid cancer will be held in 2020.

Citation Format: Jaebong Yoon, Hyunmi Lee, Eunyoung Jeon, Jinsil Lee, Eunyoung Shim, Hyunju Lee, Eunjin Lee, Younggyu Cho, Bumchan Park, Hanseung Lee, Youngwoo Park. Preclinical characterization of YBL-006, a fully human anti-PD-1 antibody being ready for clinical studies [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3367.