TransCon CNP, a Sustained-Release C-Type Natriuretic Peptide Prodrug, a Potentially Safe and Efficacious New Therapeutic Modality for the Treatment of Comorbidities Associated with Fibroblast Growth Factor Receptor 3-Related Skeletal Dysplasias.

TransCon CNP is a C-type natriuretic peptide (CNP-38) conjugated via a cleavable linker to a polyethylene glycol carrier molecule, designed to provide sustained systemic CNP levels upon weekly subcutaneous administration. TransCon CNP is in clinical development for the treatment of comorbidities associated with achondroplasia. In both mice and cynomolgus monkeys, sustained exposure to CNP via TransCon CNP was more efficacious in stimulating bone growth than intermittent CNP exposure. TransCon CNP was well tolerated with no adverse cardiovascular effects observed at exposure levels exceeding the expected clinical therapeutic exposure. At equivalent dose levels, reductions in blood pressure and/or an increase in heart rate were seen following single subcutaneous injections of the unconjugated CNP-38 molecule or a daily CNP-39 molecule (same amino acid sequence as Vosoritide, USAN:INN). The half-life of the daily CNP-39 molecule in cynomolgus monkey was estimated to be 20 minutes, compared with 90 hours for CNP-38, released from TransCon CNP. C max for the CNP-39 molecule (20 µg/kg) was approximately 100-fold higher, compared with the peak CNP level associated with administration of 100 µg/kg CNP as TransCon CNP. Furthermore, CNP exposure for the daily CNP-39 molecule was only evident for up to 2 hours postdose (lower limit of quantification 37 pmol/l), whereas TransCon CNP gave rise to systemic exposure to CNP-38 for at least 7 days postdose. The prolonged CNP exposure and associated hemodynamically safe peak serum concentrations associated with TransCon CNP administration are suggested to improve efficacy, compared with short-lived CNP molecules, due to better therapeutic drug coverage and decreased risk of hypotension. SIGNIFICANCE STATEMENT: The hormone C-type natriuretic peptide (CNP) is in clinical development for the treatment of comorbidities associated with achondroplasia, the most common form of human dwarfism. The TransCon Technology was used to design TransCon CNP, a prodrug that slowly releases active CNP in the body over several days. Preclinical data show great promise for TransCon CNP to be an effective and well-tolerated drug that provides sustained levels of CNP in a convenient once-weekly dose, while avoiding high systemic CNP bolus concentrations that can induce cardiovascular side effects.

Two-step methodology for high-yield routine radiohalogenation of peptides: (18)F-labeled RGD and octreotide analogs.

UNLABELLED: Routine application of (18)F-labeled peptides for quantitative in vivo receptor imaging of receptor-expressing tissues and quantification of receptor status using PET is limited by the lack of appropriate radiofluorination methods for routine large-scale synthesis of (18)F-labeled peptides. To satisfy this demand, a new (18)F-labeling methodology based on the chemoselective oxime formation between an unprotected aminooxy-functionalized peptide and an (18)F-labeled aldehyde or ketone was investigated and optimized with respect to peptide conjugation. METHODS: 4-[(18)F]Fluorobenzaldehyde ([(18)F]FB-CHO) was prepared from the 4-formyl-N,N,N-trimethylanilinium precursor via direct no-carrier-added (18)F-fluorination (dimethyl sulfoxide, 60 degrees C, 15 min) and purified using a cation-exchange/reversed-phase cartridge system. Radiochemical yields (RCYs) of N-(4-[(18)F]fluorobenzylidene)oxime ([(18)F]FBOA) formation with various aminooxy-modified peptides such as minigastrin, RGD, and octreotate analogs were investigated as a function of reaction time and temperature, peptide concentration, and pH. Biodistribution studies were performed with an [(18)F]FBOA-RGD dimer ((c(RGDfE)HEG)(2)-K-Dpr-[(18)F]FBOA, 60 and 120 min after injection) and a gylcosylated [(18)F]FB-Tyr(3)-octreotate (Gluc-S-Dpr([(18)F]FBOA)TOCA), 10 and 60 min after injection) using M21 and M21L human melanoma and AR42J rat pancreatic tumor-bearing nude mice, respectively. RESULTS: [(18)F]FB-CHO was obtained in a nonoptimized RCY of 50% within 30 min. At low peptide concentrations (0.5 mmol/L), optimal [(18)F]FBOA-labeling efficiencies (60%-80%) were obtained within 15 min at 60 degrees C and pH 2-3, independently of the peptide used, affording the [(18)F]FBOA-peptides in overall RCYs of up to 40% (from end of bombardment) after purification. Both (c(RGDfE)HEG)(2)-K-Dpr-[(18)F]FBOA and Gluc-S-Dpr([(18)F]FBOA)TOCA showed pharmacokinetics suitable for early (

RGD modified polymers: biomaterials for stimulated cell adhesion and beyond.

Since RGD peptides (R: arginine; G: glycine; D: aspartic acid) have been found to promote cell adhesion in 1984 (Cell attachment activity of fibronectin can be duplicated by small synthetic fragments of the molecule, Nature 309 (1984) 30), numerous materials have been RGD functionalized for academic studies or medical applications. This review gives an overview of RGD modified polymers, that have been used for cell adhesion, and provides information about technical aspects of RGD immobilization on polymers. The impacts of RGD peptide surface density, spatial arrangement as well as integrin affinity and selectivity on cell responses like adhesion and migration are discussed.

Photoswitched cell adhesion on surfaces with RGD peptides.

Coating of surfaces by RGD peptides is well-known. Herein we describe the possibility to switch cell adhesion properties by changing the distance and orientation of the RGD peptides to the surface. A set of RGD peptides of the type cyclo(-RGDfK-) was synthesized containing the photoswitchable 4-[(4-aminophenyl)azo]benzocarbonyl central unit as spacer between the acrylamide anchor and the RGD peptide. PMMA (poly methyl methacrylate) surfaces were coated with these peptides. Control of adhesion stimulation by irradiation with 366 or 450 nm light could be achieved.

Multimeric cyclic RGD peptides as potential tools for tumor targeting: solid-phase peptide synthesis and chemoselective oxime ligation.

The alpha v beta 3 integrin receptor plays an important role in human metastasis and tumor-induced angiogenesis. Targeting this receptor may provide information about the receptor status of the tumor and enable specific therapeutic planning. Solid-phase peptide synthesis of multimeric cyclo(-RGDfE-)-peptides is described, which offer the possibility of enhanced integrin targeting due to polyvalency effects. These peptides contain an aminooxy group for versatile chemoselective oxime ligation. Conjugation with para-trimethylstannylbenzaldehyde results in a precursor for radioiododestannylation, which would allow them to be used as potential tools for targeting and imaging alpha v beta 3-expressing tumor cells. The conjugates were obtained in good yield without the need of a protection strategy and under mild conditions.