An updated patent review on PD-1/PD-L1 antagonists (2022-present)

ABSTRACT

Introduction

PD-L1, via its interactions with PD-1, constitutes a key immune checkpoint that allows cancer cells to escape immune surveillance. Targeting PD-1/PD-L1 with monoclonal antibodies (mAbs) led to spectacular success in clinical oncology. However, the inherent limitations of mAbs and increasing findings about immune-related adverse events (iRAEs) prompted intense research in the field of small-molecule inhibitors of PD-L1.

Areas covered

This review covers inhibitors of PD-L1 reported in patents published in the online databases of the World Intellectual Property Organization and European Patent Office in the 2022–2023 period. This review provides a landscape of available inhibitors, including their chemical structures, activity, and stage of development.

Expert opinion

Small-molecule inhibitors impairing PD-L1/PD-1 interaction represent an attractive alternative to mAbs. In recent years, the field of small-molecule and macrocyclic inhibitors targeting PD-L1 has grown rapidly. The majority (if not all) of small-molecule inhibitors developed recently, similarly to their predecessors, act through a dimerization mechanism of PD-L1, followed by its internalization into the cytosol. In contrast, macrocyclic peptides act purely through a competition mechanism known as protein–protein interaction inhibitors. The ongoing clinical trials should ultimately reveal which strategy has real clinical potential and may complement or even replace mAbs-based therapies.

KEYWORDS:

• Cancer
• immunotherapy
• PD-L1
• PD-1
• small-molecules
• macrocyclic peptides

Article highlights

• PD-L1 is an established therapeutic target for cancer immunotherapy.

• Small-molecule PD-L1 inhibitors are a rapidly growing group of compounds.

• Ten PD-L1 inhibitors have entered phase I/II clinical trials.

• A few combinations of small-molecule inhibitors with other agents emerged recently in clinical trials.

• This review covers PD-L1 immunomodulators published in patents over the past 2 years.

Declaration of interest

The authors have no relevant affiliations or financial relationships with any organization or entity with the subject matter or materials discussed in the manuscript. This includes consultancies, employment, expert testimony, honoraria, stock options or ownership, grants or patents received or pending.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Author contributions

W Uzar, B Kaminska, H Rybka, and R Kitel collected the data. W Uzar, B Kaminska, H Rybka, K Magiera-Mularz and R Kitel wrote the draft of the paper. R Kitel was responsible for conceptualization, data analysis, organization and preparation of the final version of manuscript. L Skalniak provided the funding, participated in organizing the work of the team and in proofreading of the Introduction. All authors have read and agreed to the final version of the manuscript.

Additional information

Funding

The research was supported by a grant from the Faculty of Chemistry under the Strategic Programme Excellence Initiative at Jagiellonian University (U1U/W20/NO.17.06 to R.K.). The work was funded by the National Science Centre, Poland - Grant numbers 2021/42/E/NZ7/00422 (to L.S.) and 2018/31/D/NZ7/01900 (to K.M.M.)