A patent review on PD-1/PD-L1 antagonists: small molecules, peptides, and macrocycles (2015-2018)

Shaabani, S., Huizinga, H. P. S., Butera, R., Kouchi, A., Guzik, K., Magiera-Mularz, K., Holak, T. A. & Domling, A., 2018, In : Expert Opinion on Therapeutic Patents. 28, 9, p. 665-678 14 p.

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  • A patent review on PD 1 PD L1 antagonists small molecules peptides and macrocycles 2015 2018

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Introduction: The protein-protein interaction PD1/PD-L1 is an important immune checkpoint and several recently approved monoclonal antibodies show promising anti cancer activities in the clinical practice. However, only a small percentage of cancer patients benefit from PD1/PD-L1 directed mAbs. Moreover, some patients experience immune related side effects upon treatment with these mAbs. Recently, several atomic-resolution structures of human PD1/PD-L1, and small molecules, peptides and mAbs with PD-L1 and PD1 open the field for structure based drug design. Small molecules and peptides targeting PD1/PD-L1 promise to enhance tumor activity while showing less immune related side effects.

Areas covered: We reviewed the small molecules classes and peptides targeting PD1/PD-L1.

Expert opinion: Currently approved PD1/PD-L1 directed therapeutics show room for improvement. Three classes of non mAb small molecule classes have been discovered so far: (cyclic) peptides as direct competitive PD1/PD-L1 antagonists; small molecules disrupting PD1/PD-L1 and inducing a PD-L1 dimerization; and a small molecule class of unknown mode-of-action. An example of the later group CA-170 is currently investigated in a Phase 1 trial in patients with advanced solid tumors and lymphomas. Potential advantages of small molecules over mAbs include high distribution and better tumor penetration, improved PK/PD, less side effects and oral bioavailability.

Original languageEnglish
Pages (from-to)665-678
Number of pages14
JournalExpert Opinion on Therapeutic Patents
Issue number9
Early online date10-Sep-2018
Publication statusPublished - 2018


  • Programmed death-1, PD-1, PD-L1, immune checkpoint, T-cell exhaustion, immune-oncology, IMMUNE CHECKPOINT, INHIBITORS

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