Abstract
CA-170 is currently the only small-molecule modulator in clinical trials targeting PD-L1 and VISTA proteins – important negative checkpoint regulators of immune activation. The reported therapeutic results to some extent mimic those of FDA-approved monoclonal antibodies overcoming the limitations of the high production costs and adverse effects of the latter. However, no conclusive biophysical evidence proving the binding to hPD-L1 has ever been presented. Using well-known in vitro methods: NMR binding assay, HTRF and cell-based activation assays, we clearly show that there is no direct binding between CA-170 and PD-L1. To strengthen our reasoning, we performed control experiments on AUNP-12 – a 29-mer peptide, which is a precursor of CA-170. Positive controls consisted of the well-documented small-molecule PD-L1 inhibitors: BMS-1166 and peptide-57.
Highlights
Alongside chemo- and radiotherapy, surgery, and other “targeted treatments”, cancer immunotherapy is regarded as the fifth pillar of cancer treatment, mainly due to a rapid development of potent immune checkpoint-blocking (ICB) therapeutic inhibitors [1,2,3,4]
CA-170 Does Not Bind to human PD-L1 (hPD-L1) According to the Nuclear magnetic resonance (NMR) Binding Assay
As the reference positive controls for the NMR binding small-molecule BMS-1166 developed by Bristol-Myers Squibb, which bind strongly to hPD-L1 at assay, we show the NMR spectra of the well-known hPD-L1 binders: macrocyclic peptide-57 and equimolar concentrations (Figure S3.) (Adapted from Skalniak et al, Oncotarget, 2017 [42])
Summary
Alongside chemo- and radiotherapy, surgery, and other “targeted treatments”, cancer immunotherapy (called immuno-oncology) is regarded as the fifth pillar of cancer treatment, mainly due to a rapid development of potent immune checkpoint-blocking (ICB) therapeutic inhibitors [1,2,3,4]. These therapies unleash the native immune system by overcoming tumor-induced immunosuppression demonstrating impressive results. Programmed cell death protein 1 (known as PD-1 and CD279) and its naturally occurring ligand PD-L1 (B7-H1, CD274) are transmembrane glycoprotein receptors characterized by β-sandwich immunoglobulin-like extracellular domains (seven β-strands organized in two sheets connected via a disulfide bridge) (Figure 1A) [9,10]. Its extracellular IgV domain is followed by a transmembrane region and an intracellular tail, which contains two tyrosine-based immunoreceptor signaling motifs: the switch motif (ITSM), and the inhibitory motif (ITIM) [13]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
