Conjugation of 10 kDa Linear PEG onto Trastuzumab Fab′ Is Sufficient to Significantly Enhance Lymphatic Exposure while Preserving in Vitro Biological Activity

• DOI: 10.1021/acs.molpharmaceut.5b00749
• Publication Date: 2016-02-12T17:14:33Z
• Authors: Linda J. Chan; David B. Ascher; Rajbharan Yadav; Jürgen B. Bulitta; Charlotte C. Will...; Christopher J. H....; Cornelia B. Lande...; Lisa M. Kaminskas
• Keywords: PEGylation

The lymphatic system is a major conduit by which many diseases spread and proliferate. There therefore increasing interest in promoting better drug targeting. Further, antibody fragments such as Fabs have several advantages over full length monoclonal antibodies but are subject to rapid plasma clearance, can limit the exposure activity of against lymph-resident diseases. This study explored ideal PEGylation strategies maximize biological using trastuzumab Fab′ model. Specifically, was conjugated with single linear 10 or 40 kDa PEG chains at hinge region. led 3–4-fold reduction binding affinity HER2, antiproliferative HER2-expressing BT474 cells preserved. Lymphatic pharmacokinetics were then examined thoracic lymph duct cannulated rats after intravenous subcutaneous dosing 2 mg/kg, data evaluated via population pharmacokinetic modeling. displayed limited exposure, conjugation improved approximately 11- 5-fold (15% dose collected 30 h) (9%) administration, respectively. Increasing molecular weight kDa, however, had no significant impact on (14%) administration only doubled (18%) when compared PEG-Fab′. suggests that minimal has potential enhance Fab′s diseases, while benefit achieved very large PEGs.