Human and mouse PD-L1: similar molecular structure, but different druggability profiles

Katarzyna Magiera-Mularz; Justyna Kocik; Bogdan Musielak; Jacek Plewka; Dominik Sala; Monika Machula; Przemyslaw Grudnik; Malgorzata Hajduk; Marcin Czepiel; Maciej Siedlar; Tad A Holak; Lukasz Skalniak

doi:10.1016/j.isci.2020.101960

Human and mouse PD-L1: similar molecular structure, but different druggability profiles

iScience. 2020 Dec 24;24(1):101960. doi: 10.1016/j.isci.2020.101960. eCollection 2021 Jan 22.

Affiliations

¹ Department of Organic Chemistry, Faculty of Chemistry, Jagiellonian University, Gronostajowa 2, 30-387 Krakow, Poland.
² Malopolska Center of Biotechnology Jagiellonian University, Gronostajowa 7, 30-387 Krakow, Poland.
³ Department of Clinical Immunology, Institute of Pediatrics, Jagiellonian University Medical College, Wielicka 265, 30-663 Krakow, Poland.

Abstract

In the development of PD-L1-blocking therapeutics, it is essential to transfer initial in vitro findings into proper in vivo animal models. Classical immunocompetent mice are attractive due to high accessibility and low experimental costs. However, it is unknown whether inter-species differences in PD-L1 sequence and structure would allow for human-mouse cross applications. Here, we disclose the first structure of the mouse (m) PD-L1 and analyze its similarity to the human (h) PD-L1. We show that mPD-L1 interacts with hPD-1 and provides a negative signal toward activated Jurkat T cells. We also show major differences in druggability between the hPD-L1 and mPD-L1 using therapeutic antibodies, a macrocyclic peptide, and small molecules. Our study indicates that while the amino acid sequence is well conserved between the hPD-L1 and mPD-L1 and overall structures are almost identical, crucial differences determine the interaction with anti-PD-L1 agents, that cannot be easily predicted in silico.

Keywords: Immunology; Therapeutics.