Tumor uptake of pegylated diabodies: Balancing systemic clearance and vascular transport
| Autor: | William Dall'acqua, Kevin L Allen, Keith W Rickert, Jason White, Kim Rosenthal, Ping Tsui, Norman C. Peterson, Qing Li, Chris Lloyd, Xizhe Gao, M. Jack Borrok, Herren Wu |
|---|---|
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
medicine.drug_class Mice Nude Pharmaceutical Science Vascular transport Polyethylene glycol Monoclonal antibody Polyethylene Glycols Mice 03 medical and health sciences chemistry.chemical_compound Drug Delivery Systems 0302 clinical medicine Antigen Pharmacokinetics Cell Line Tumor Neoplasms PEG ratio medicine Animals Humans Tissue Distribution Immunoglobulin Fragments biology Biological Transport Molecular Weight 030104 developmental biology chemistry Positron-Emission Tomography 030220 oncology & carcinogenesis Hydrodynamics biology.protein Biophysics PEGylation Female Antibody Half-Life |
| Zdroj: | Journal of Controlled Release. 279:126-135 |
| ISSN: | 0168-3659 |
| DOI: | 10.1016/j.jconrel.2018.04.013 |
| Popis: | The accumulation, dissemination and clearance of monoclonal antibody-based therapeutics or imaging reagents targeting tumor associated antigens is governed by several factors including affinity, size, charge, and valency. Tumor targeting antibody fragments have distinct advantages over intact monoclonal antibodies such as enhanced penetration within the tumor and rapid accumulation but are subject to rapid clearance. Polyethylene glycol (PEG)-modified antibody fragments can provide a way to balance tumor penetration and accumulation with improved serum persistence. In this study, we use a diabody, the dimeric antibody fragment, targeting the 5T4 antigen to assess the impact of PEGs of distinct size and shape on tumor accumulation and pharmacokinetics (PK). We show that PEG-modified diabodies improved the PK of the parental diabody from a half-life of 40 min to over 40 h for the higher molecular weight PEG conjugated diabodies. This improvement correlates with the increasing hydrodynamic size of pegylated diabodies, and can serve as a better predictor of the PK behavior of pegylated molecules than molecular weight alone. Tumor uptake profiles determined by quantitative PET imaging differed significantly based on PEG size and shape with diabody-PEG5K showing peak accumulation early on, but with the larger diabody-PEG20K showing better sustained tumor uptake at later time points. In addition, we demonstrate that a diabody-PEG20K-B with a hydrodynamic radius (Rh) of 6 nm had superior tumor uptake than the larger diabody-PEG40K-B with Rh of 12 nm, indicating that beyond 6 nm, larger pegylated diabodies have a slower tumor uptake rate while having comparable clearance kinetics. Our data demonstrate that pegylated diabodies with Rh of ~6 nm have an optimal size and PK profile for tumor uptake. Understanding the impact of pegylation on PK and tumor uptake could facilitate the development of pegylated diabodies as therapeutics. |
| Databáze: | OpenAIRE |
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