Abstract
Monoclonal antibodies have long in vivo half-lives and reach high concentrations in tumors but cannot access all regions in the tissue, whereas smaller ligands such as peptides distribute better but are limited by low concentrations due to fast renal clearance. A potential solution to this problem might be offered by peptide-based ligands that are conjugated to an albumin-binding tag, and thus have a long plasma half-life. Herein, we tested if a small ligand based on a bicyclic peptide (1.9 kDa) conjugated to an albumin-binding peptide (2.3 kDa) can diffuse into tissues. Although the peptide conjugate (4.6 kDa) was most of the time bound to the large protein serum albumin (66.5 kDa), it diffused deeply into tissues and reached high nanomolar concentrations in wide areas of solid tumors. Most of the peptide conjugate isolated from tumor tissue was found to be fully intact 24 hours after administration. Because of its noncovalent interaction with albumin, the bicyclic peptide might dissociate to diffuse to tumor regions that are not accessible to larger ligands. Bicyclic peptides having high binding affinity for targets of interest and being proteolytically stable can be evolved by phage display; in conjunction with albumin-binding tags, they offer a promising format to access targets in solid tumors.
Highlights
Solid tumors present many barriers to efficient delivery of therapeutics, to larger protein-based agents such as antibodies [1,2,3]
Two peptide formats were compared: bicyclic peptide UK18 and UK18 conjugated to the albumin-binding peptide SA21 (UK18-SA21; Fig. 1A)
The highest quantities of UK18 and UK18-SA21 were found in kidney, indicating renal clearance for both formats
Summary
Solid tumors present many barriers to efficient delivery of therapeutics, to larger protein-based agents such as antibodies [1,2,3]. If the activity of cancer therapeutics is based on antagonizing effects, and the therapeutics are unable to access all of the cells within a tumor, their effectiveness will be compromised. Size and circulation halflife were the factors that most strongly influenced extravasation and tissue penetration [5,6,7,8,9,10]. Large ligands such as antibodies have a long plasma half-life, and achieve over time relatively high concentrations in tumors but they tend to distribute heterogeneously and do not access all regions in tumor tissue.
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