Abstract
With the advent of checkpoint inhibitor treatment for various cancer types, the optimization of drug selection, pharmacokinetics and biomarker assays is an urgent and as yet unresolved dilemma for clinicians, pharmaceutical companies and researchers. Drugs which inhibit cytotoxic T-lymphocyte associated protein-4 (CTLA-4), such as ipilimumab and tremelimumab, programmed cell death protein-1 (PD-1), such as nivolumab and pembrolizumab, and programmed cell death ligand-1 (PD-L1), such as atezolizumab, durvalumab and avelumab, each appear to have varying pharmacokinetics and clinical activity in different cancer types. Each drug differs in terms of dosing, which becomes an issue when drug comparisons are attempted. Here, we examine the various checkpoint inhibitors currently used and in development. We discuss the antibodies and their protein targets, their pharmacokinetics as measured in various tumor types, and their binding affinities to their respective antigens. We also examine the various dosing regimens for these drugs and how they differ. Finally, we examine new developments and methods to optimize delivery and efficacy in the field of checkpoint inhibitors, including non-fucosylation, prodrug formations, bispecific antibodies, and newer small molecule and peptide checkpoint inhibitors.
Highlights
Checkpoint inhibitors (CPIs) induce an anti-tumor immune response by antagonizing suppressive immune checkpoint regulatory pathways
PL120131 was shown to act as a competitive inhibitor of programmed cell death ligand-1 (PD-L1) by associating with the binding groove on PD-1, and to reverse the apoptotic signal induced by soluble PD-L1 in Jurkat cells and primary lymphocytes
The peptide molecule TPP-1 has a high affinity for human PD-L1, and, in a mouse model, could decrease tumor growth by 56% compared with control peptide-treated mice, by re-activating T cells through blocking the PD-1/PD-L1 interaction [103]
Summary
Checkpoint inhibitors (CPIs) induce an anti-tumor immune response by antagonizing suppressive immune checkpoint regulatory pathways. The advent of antibodies targeting programmed cell death protein-1 (PD-1), programmed cell death protein ligand-1 (PD-L1) and cytotoxic T-lymphocyte associated protein-4 (CTLA-4) has led to the development of drugs targeting these pathways in the last 10 years. Their variable pharmacokinetics and response rates has led to efforts to optimize these drugs, as well as to develop new drugs targeting other checkpoint pathways. We describe efforts to enhance the delivery and formulation of CPIs, while attempting to minimize the immune-related adverse events (irAEs) associated with these treatments
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