Wen LiuFollow

Defense Date

6-6-2018

Graduation Date

Summer 8-11-2018

Availability

One-year Embargo

Submission Type

dissertation

Degree Name

PhD

Department

Pharmaceutics

School

School of Pharmacy

Committee Chair

Wilson S. Meng

Committee Member

Ellen S. Gawalt

Committee Member

James K. Drennen

Committee Member

Patrick Flaherty

Committee Member

Jelena M. Janjic

Keywords

Self-assembling peptides, bioaffinity interactions, hydrogels, sustained release, antibody, dL5_EAK, pG_EAK, EAK16-II

Abstract

The scope of illnesses that are being treated using monoclonal antibodies (mAbs) has been expanding from cancers to autoimmune diseases due to their high specificity to their molecular target. Because many of the new mAbs are aimed to modulate the immune system, an emerging concern is that patients with chronic illnesses are subjected to immune-related Adverse Events (irAEs). Loss of immunological tolerance to self-antigens or increased susceptibility to infections have been documented in some mAb treatments. Localized sustained release of mAb at disease sites might mitigate the risk of such toxicities. Antibody drugs are formulated typically for parenteral delivery because of degradative mechanisms in gastrointestinal tract. The assumption has been that systemic administration via the vascular compartment is the best or only option in achieving therapeutic drug concentrations at diseased tissues. This paradigm is being challenged as the benefit to risk ratio of exposing non-targeted tissues or organs is lower in many of the new mAb drugs. Direct local mAb administration to target tissues is enabled by biomaterials scaffolds in which drug retention at the intended sites can be modulated. This dissertation is focused on two bioaffinity hydrogels designed for administering mAbs locally. One was built on a fluorescent-based module: fluorogen activating protein dL5 and its fluorogenic partner malachite green (MG) for immobilizing IgG Fc binding molecule protein A/G into the hydrogel matrix. This design was shown to render sustained release of mAbs and detectable binding sites in vivo through a built-in imaging feature. The second design was built upon pG_EAK, a bifunctional polypeptide in which the IgG-binding domain was genetically fused to the self-assembling sequence (AEAEAKAK)3 (single amino acid code; hereafter “EAK”). The rationale was that reducing the number of interactions would enhance the translational prospect of the bioaffinity hydrogel. Sustained release and prolonged retention of IgG delivered in the pG_EAK gel were observed in vitro and in vivo in skin allografts. In conclusion, bioaffinity hydrogels built on dL5_EAK and pG_EAK are two injectable platforms on which IgG mAbs of different specificities can be localized and sustained in diseased tissues.

Language

English

Additional Citations

W. Liu, M.J. Saunders, C. Bagia, E.C. Freeman, Y. Fan, E.S. Gawalt, A.S. Waggoner, W.S. Meng, Local retention of antibodies in vivo with an injectable film embedded with a fluorogen-activating protein, Journal of Controlled Release, 230 (2016) 1-12.

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