Immunomodulators targeting the PD‐1/PD‐L1 protein‐protein interaction: From antibodies to small molecules

Abstract

Cancer immunotherapy has made great strides in the recent decade, especially in the area of immune checkpoint blockade. The outstanding efficacy, prolonged durability of effect, and rapid assimilation of anti-PD-1 and anti-PD-L1 monoclonal antibodies in clinical practice have been nothing short of a medical breakthrough in the treatment of numerous malignancies. The major advantages of these therapeutic antibodies over their small molecule counterparts have been their high binding affinity and target specificity. However, antibodies do have their flaws including immune-related toxicities, inadequate pharmacokinetics and tumor penetration, and high cost burden to manufacturers and consumers. These limitations hinder broader clinical applications of the antibodies and have heightened interests in developing the alternative small molecule platform that includes peptidomimetics and peptides to target the PD-1/PD-L1 immune checkpoint system. The progress on these small molecule alternatives has been relatively slow compared to that of the antibodies. Fortunately, recent structural studies of the interactions among PD-1, PD-L1, and their respective antibodies have revealed key hotspots on PD-1 and PD-L1 that may facilitate drug discovery efforts for small molecule immunotherapeutics. This review is intended to discuss key concepts in immuno-oncology, describe the successes and shortcomings of PD-1/PD-L1 antibody-based therapies, and to highlight the recent development of small molecule inhibitors of the PD-1/PD-L1 protein-protein interaction.

Targeting B7‐1 in immunotherapy

“…This includes mAbs targeting CTLA‐4 (tremelimumab), TIM‐3 (LY3321367, MBG453, MEDI9447, TSR‐022), LAG‐3 (BMS‐986016, LAG525), B7‐H3 (enoblituzumab, 8H9), GITR (TRX‐518, BMS‐986156, MK‐4166, INCAGN01876, GWN323), and OX40 (9B12, MOXR 0916, PF‐04518600, MEDI0562, INCAGN01949, GSK3174998) to name a few . Despite their significant therapeutic efficacies, mAbs have some important limitations such as their complex production process, instability, high treatment cost, need for intravenous administration, long half‐lives, low bioavailability, immunogenicity, poor localization, inability to penetrate solid tumors, and irAEs . Small‐molecule inhibitors, in contrast, can overcome these limitations throughout their high membrane permeability, easy manufacturing, better stability, lower treatment costs, and possibilities for oral administration .…”

“…Despite their significant therapeutic efficacies, mAbs have some important limitations such as their complex production process, instability, high treatment cost, need for intravenous administration, long half‐lives, low bioavailability, immunogenicity, poor localization, inability to penetrate solid tumors, and irAEs . Small‐molecule inhibitors, in contrast, can overcome these limitations throughout their high membrane permeability, easy manufacturing, better stability, lower treatment costs, and possibilities for oral administration . Therefore, there has been growing attraction toward the development of small‐molecule inhibitors for immune checkpoints.…”

<p>Research Status and Outlook of PD-1/PD-L1 Inhibitors for Cancer Therapy</p>

“…KN035 is the only PD-L1 with subcutaneous formulation antibody, which is currently in clinical trials in the United States, China and Japan. 142 CA-170, developed by Aurigene and Curis, is the only small-molecule antagonist for PD-L1 and VISTA in clinical trials so far. The compound is currently in phase 1 clinical trials in patients with mesothelioma.…”

iRGD Peptide as a Tumor-Penetrating Enhancer for Tumor-Targeted Drug Delivery

“…After decades of continuous efforts to translate laboratory findings into clinical practice, FDA approved the use of ipilimumab for advanced melanoma treatment [ 186 ]. Since then, there has been an increasing interest in immunotherapy, specifically on PD-1/PDL-1 axis targeting advanced cancer stages [ 187 ].…”