Hyaluronic Acid-Antibody Fragment Bioconjugates for Extended Ocular Pharmacokinetics

被引：13

作者：

Famili, Amin ^{[1
]}

Crowell, Susan R. ^{[2
]}

Loyet, Kelly M. ^{[3
]}

Mandikian, Danielle ^{[2
]}

Boswell, C. Andrew ^{[2
]}

Cain, David ^{[1
]}

Chan, Joyce ^{[3
]}

Comps-Agrar, Laetitia ^{[3
]}

Kamath, Amrita ^{[2
]}

Rajagopal, Karthikan ^{[1
]}

机构：

[1] Genentech Inc, Drug Delivery Dept, San Francisco, CA 94080 USA

[2] Genentech Inc, Preclin & Translat Pharmacokinet Dept, San Francisco, CA 94080 USA

[3] Genentech Inc, Biochem & Cellular Pharmacol Dept, San Francisco, CA 94080 USA

来源：

BIOCONJUGATE CHEMISTRY | 2019年 / 30卷 / 11期

关键词：

ENDOTHELIAL GROWTH-FACTOR; RANIBIZUMAB; CLEARANCE; PEGYLATION; MODEL; SIZE;

D O I：

10.1021/acs.bioconjchem.9b00475

中图分类号：

Q5 [生物化学];

学科分类号：

071010 ; 081704 ;

摘要：

Treatment of ocular diseases associated with neovascularization currently requires frequent intravitreal injections of antivascular endothelial growth factor (anti-VEGF) therapies. Reducing the required frequency of anti-VEGF injections and associated clinical visits may improve patient adherence to the prescribed treatment regimen and improve outcomes. Herein, we explore conjugation of rabbit and fragment antibodies (Fab) to the biopolymer hyaluronic acid (HA) as a half-life modifying strategy, and assess the impact on Fab biophysical properties and vitreal pharmacokinetics. HA-Fab conjugates of three distinct molecular weights and hydrodynamic radii (RH) were assessed for in vivo pharmacokinetic performance relative to unconjugated Fab after intravitreal injection in rabbits. Covalent conjugation to HA did not significantly alter the thermal stability or secondary or tertiary structure, or diminish the potency of the Fab, thereby preserving its pharmacological properties. Conjugation to HA did significantly slow the in vivo clearance of Fab from the rabbit vitreous in an R-H-dependent manner. Compared to free Fab (observed vitreal half-life of 2.8 days), HA-Fab conjugates cleared with observed half-lives of 7.6, 10.2, and 18.3 days for 40 kDa, 200 kDa, and 600 kDa HA conjugates, respectively. This work elucidates a possible strategy for long-acting delivery of proteins intended for the treatment of chronic posterior ocular diseases.

引用

页码：2782 / 2789

页数：8

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