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

ABSTRACT

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.

KEYWORDS:

• Programmed death-1
• PD-1
• PD-L1
• immune checkpoint
• T-cell exhaustion
• immune-oncology

Article highlights

• Targeting the immune checkpoint inhibitor pathway is a highly promising new therapeutic modality to fight cancer.

• PD-1/PD-L1 directed checkpoint inhibitor therapy of malignant tumors is a breakthrough in oncology.

• Structure-based design of PD-1/PD-L1 antagonists is achievable now.

• Three general non-mAb PD-1/PD-L1 antagonists are currently known, peptidic direct PD-1 antagonists, small molecule PD-L1 dimerizer, and small molecules of unknown mode-of-action.

• Small molecules and peptides can potentially reduce irAEs, lead to higher efficacy and to a larger number of responders.

Acknowledgement

K.M.M.supported by the Foundation for Polish Science (FNP)

Declaration of interest

AD is a cofounder of SMIO BV. TH is a shareholder of SMIO BV. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

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

Additional information

Funding

S.S. is grateful for a postdoctoral fellowship from KWF [Grant Agreement No. 10504]. The work in the PIs laboratory was financially supported from the NIH [NIH 2R01GM097082-05] and by the Innovative Medicines Initiative Joint Undertaking under grant agreement no. 115489, resources of which are composed of financial contribution from the European Union’s Seventh Framework Programme [FP7/2007-2013] and EFPIA companies’ in-kind. Moreover, funding has also been received from the European Union’s Horizon 2020 research and innovation program under MSC ITN ‘Accelerated Early stage drug dIScovery’ (AEGIS), grant agreement No 675555. This work has been supported by Grant UMO-2012/06/A/ST5/00224 to T.A.H. from the National Science Centre, Poland. This work has also received funding from the European Union’s Horizon 2020 research and innovation program under the Marie Sklodowska Curie grant agreement No. 713482.