Autolytic degradation of ocriplasmin: a complex mechanism unraveled by mutational analysis

作者：Noppen B; Fonteyn L; Aerts F; De Vriese A; De Maeyer M; Le Floch F; Barbeaux P; Zwaal R; Vanhove M^*

来源：Protein Engineering Design and Selection, 2014, 27(7): 215-223.

DOI：10.1093/protein/gzu015

• autolysis
• Jetrea(A (R))
• ocriplasmin variants
• posterior vitreous detachment
• symptomatic vitreomacular adhesion

Ocriplasmin, a truncated form of plasmin, is commercialized in the USA and in Europe under the trade name Jetrea(A (R)), and indicated for the treatment of symptomatic vitreomacular adhesion and vitreomacular traction including when associated with macular hole a parts per thousand currency sign400 A mu m, respectively. We have shown in a previous study that ocriplasmin undergoes autolytic degradation when injected in eye vitreous, which leads to its rapid inactivation. In order to investigate this process further, we have introduced in ocriplasmin a variety of amino acid substitutions within or in the immediate vicinity of the three major autolytic cleavage sites. We demonstrate here that autolytic inactivation of ocriplasmin is a sequential process where initial cleavage occurs primarily between residues 156 and 157. Reduction or even blocking of autolysis can be achieved by mutating a limited number of key residues. In this study, we also report the identification of a series of ocriplasmin variants with improved resistance to autolysis and unimpaired catalytic activity. Such variants represent useful tools for the exploration of therapeutic approaches aiming at non-surgical resolution of vitreomacular adhesion.

• 出版日期2014-7