Researcher ORCID Identifier

0000-0003-3263-3120

Date Degree Awarded

Spring 5-13-2022

Degree Type

Open Access Dissertation

Degree Name

PHD in Applied Life Sciences

First Thesis/Dissertation Advisor

Dr. Rachita Sumbria

Second Thesis/Dissertation Advisor

Dr. Animesh Ray

Third Thesis/Dissertation Advisor

Dr. Karen Parfitt

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Abstract

The development of a neurotherapeutic for the treatment of Alzheimer’s Disease (AD) is challenging due to limited endpoint efficacy. Erythropoietin (EPO), a hematopoietic neurotrophin, is a potential therapeutic for AD but has limited blood-brain barrier (BBB) permeability. A chimeric fusion protein of EPO bound to the transferrin receptor monoclonal antibody (cTfRMAb) can act as a molecular trojan horse for brain drug delivery, shuttling EPO into the brain via the transvascular route. However, cTfRMAbs have Fc-effector function adverse effects, and removal of the Fc N-linked glycosylation site by substituting Asn with Gly (cTfRMAb-N292G-EPO) reduces this Fc effector function. Hence, developing this therapeutic for the treatment of AD is the central goal of the present dissertation.

In previous studies, the cTfRMAb-N292G-EPO protein displayed a higher-than- expected clearance and lower plasma concentrations compared to the non-mutant

protein. The first objective was to determine the dosage in which the clearance

mechanisms are saturated to get plasma exposure comparable to the non-mutant protein while maintaining a favorable safety profile through intraperitoneal and subcutaneous parenteral routes of administration. Previous studies also showed that the BBB-penetrating cTfRMAb-EPO reduces amyloid-beta (Aβ) in transgenic mice, but the neuroprotective effects on tau pathology are not known. The second objective was to investigate the effects of chronic dosing of the cTfRMAb-N292G-EPO fusion protein in a PS19 mouse model of tauopathy. Radiolabeled molecules are the gold standard for measuring brain protein concentration. However, radioactive particles may be potentially hazardous for investigators. The last objective was to develop an alternative method to radiolabeled molecules for measuring cTfRMAb concentration. The method developed in this dissertation is the Amicon Concentration Method, which concentrates brain homogenate samples. Our results demonstrated that although cTfRMAb-N292G-EPO is efficacious in Tauopathic mice, high doses of cTfRMAb-N292G-EPO are needed to equate to comparable plasma exposure to the nonmutant protein. This increase in dose leads to hematologic adverse effects similar to those associated with high-dose recombinant EPO treatment. The data obtained from the groundwork for future studies using the non-mutant cTfRMAb-EPO at low doses in multiple AD mouse models that combine different hallmarks of AD pathology.

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© 2022 Joshua Yang

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