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- Title
A potent peptide-steroid conjugate accumulates in cartilage and reverses arthritis without evidence of systemic corticosteroid exposure.
- Authors
Cook Sangar, Michelle L.; Girard, Emily J.; Hopping, Gene; Yin, Chunfeng; Pakiam, Fiona; Brusniak, Mi-Youn; Nguyen, Elizabeth; Ruff, Raymond; Gewe, Mesfin M.; Byrnes-Blake, Kelly; Nairn, Natalie W.; Miller, Dennis M.; Mehlin, Christopher; Strand, Andrew D.; Mhyre, Andrew J.; Correnti, Colin E.; Strong, Roland K.; Simon, Julian A.; Olson, James M.
- Abstract
Peptide targeting prevents toxicity: Treatments that target anti-arthritic drugs to joints can help avoid systemic toxicity. Cook Sangar et al. identified a cystine-dense peptide that accumulates in cartilage. Imaging agents conjugated to the peptide distributed to cartilage in rodents when delivered systemically and bound to human cartilage explants ex vivo. Conjugating the steroid triamcinolone acetonide to the peptide alleviated inflammation in the joints of a rat model of collagen-induced rheumatoid arthritis without systemic toxicity, suggesting that the conjugate could have potential joint-targeting therapeutic utility. On-target, off-tissue toxicity limits the systemic use of drugs that would otherwise reduce symptoms or reverse the damage of arthritic diseases, leaving millions of patients in pain and with limited physical mobility. We identified cystine-dense peptides (CDPs) that rapidly accumulate in cartilage of the knees, ankles, hips, shoulders, and intervertebral discs after systemic administration. These CDPs could be used to concentrate arthritis drugs in joints. A cartilage-accumulating peptide, CDP-11R, reached peak concentration in cartilage within 30 min after administration and remained detectable for more than 4 days. Structural analysis of the peptides by crystallography revealed that the distribution of positive charge may be a distinguishing feature of joint-accumulating CDPs. In addition, quantitative whole-body autoradiography showed that the disulfide-bonded tertiary structure is critical for cartilage accumulation and retention. CDP-11R distributed to joints while carrying a fluorophore imaging agent or one of two different steroid payloads, dexamethasone (dex) and triamcinolone acetonide (TAA). Of the two payloads, the dex conjugate did not advance because the free drug released into circulation was sufficient to cause on-target toxicity. In contrast, the CDP-11R–TAA conjugate alleviated joint inflammation in the rat collagen–induced model of rheumatoid arthritis while avoiding toxicities that occurred with nontargeted steroid treatment at the same molar dose. This conjugate shows promise for clinical development and establishes proof of concept for multijoint targeting of disease-modifying therapeutic payloads.
- Publication
Science Translational Medicine, 2020, Vol 12, Issue 533, p1
- ISSN
1946-6234
- Publication type
Article
- DOI
10.1126/scitranslmed.aay1041