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Therapeutic Monoclonal Antibodies to...

Galant, Natalie Julianne.

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Therapeutic Monoclonal Antibodies to Detect and Halt ATTR Cardiac Amyloidosis and Neuropathy.

Record Type:	Electronic resources : Monograph/item
Title/Author:	Therapeutic Monoclonal Antibodies to Detect and Halt ATTR Cardiac Amyloidosis and Neuropathy./
Author:	Galant, Natalie Julianne.
Published:	Ann Arbor : ProQuest Dissertations & Theses, : 2018,
Description:	128 p.
Notes:	Source: Dissertations Abstracts International, Volume: 80-01, Section: B.
Contained By:	Dissertations Abstracts International80-01B.
Subject:	Biochemistry. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=10791467
ISBN:	9780438188303

Therapeutic Monoclonal Antibodies to Detect and Halt ATTR Cardiac Amyloidosis and Neuropathy.
Galant, Natalie Julianne.

Therapeutic Monoclonal Antibodies to Detect and Halt ATTR Cardiac Amyloidosis and Neuropathy. - Ann Arbor : ProQuest Dissertations & Theses, 2018 - 128 p.

Source: Dissertations Abstracts International, Volume: 80-01, Section: B.

Thesis (Ph.D.)--University of Toronto (Canada), 2018.

This item is not available from ProQuest Dissertations & Theses.

Transthyretin (prealbumin, TTR) is an abundant serum protein which transports vitamin A and thyroid hormone T4 throughout the body. Although TTR normally forms stable soluble homotetrameric complexes, point mutations and unknown pathological conditions can favour the dissociation of the TTR tetramer into misfolded monomers which can aggregate and accumulate as transthyretin amyloid (ATTR) throughout the body, particularly in the heart and peripheral nerves. Cardiac ATTR deposition leads to cardiomyopathy, heart failure, and death; nerve deposition causes neuropathy. At present, endomyocardial biopsy is the only method for conclusively diagnosing ATTR amyloidosis and no FDA-approved pharmacotherapies exist. The only treatment option is organ transplantation (heart and/or liver) for a subset of eligible patients. This thesis focuses on the development of conformation-specific polyclonal/monoclonal antibodies which can potentially diagnose/treat both hereditary and wild-type ATTR amyloidosis, through their ability to specifically recognize and bind to disease-associated forms of TTR via a cryptotope (an epitope normally buried and inaccessible in the native protein, but exposed in its altered conformation). These monoclonal antibodies (mAbs) were demonstrated in vitro to specifically bind misfolded TTR, inhibit fibril formation, induce phagocytic clearance of non-native and aggregated TTR, and specifically recognize TTR amyloid in diseased heart tissue. We further investigated the mechanism of mAb-mediated inhibition of fibrillogenesis using immunogold transmission electron microscopy (IGEM). This high resolution imaging technique confirmed this cryptotope to be an effective antibody target due to its exposure within both pathological TTR misfolding intermediates and end-point insoluble TTR fibrils. In addition to their ability to recognize TTR aggregates in vitro, these monoclonal antibodies demonstrated the ability to specifically recognize soluble, misfolded TTR aggregates in vivo in the plasma of transgenic ATTR mouse models. These results further support the use of monoclonal antibodies to target pathological protein conformations as potentially effective immunotherapies for ATTR amyloidosis.

ISBN: 9780438188303Subjects--Topical Terms:

518028
Biochemistry.

Therapeutic Monoclonal Antibodies to Detect and Halt ATTR Cardiac Amyloidosis and Neuropathy.
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502 $a Thesis (Ph.D.)--University of Toronto (Canada), 2018.
506 $a This item is not available from ProQuest Dissertations & Theses.
506 $a This item must not be sold to any third party vendors.
520 $a Transthyretin (prealbumin, TTR) is an abundant serum protein which transports vitamin A and thyroid hormone T4 throughout the body. Although TTR normally forms stable soluble homotetrameric complexes, point mutations and unknown pathological conditions can favour the dissociation of the TTR tetramer into misfolded monomers which can aggregate and accumulate as transthyretin amyloid (ATTR) throughout the body, particularly in the heart and peripheral nerves. Cardiac ATTR deposition leads to cardiomyopathy, heart failure, and death; nerve deposition causes neuropathy. At present, endomyocardial biopsy is the only method for conclusively diagnosing ATTR amyloidosis and no FDA-approved pharmacotherapies exist. The only treatment option is organ transplantation (heart and/or liver) for a subset of eligible patients. This thesis focuses on the development of conformation-specific polyclonal/monoclonal antibodies which can potentially diagnose/treat both hereditary and wild-type ATTR amyloidosis, through their ability to specifically recognize and bind to disease-associated forms of TTR via a cryptotope (an epitope normally buried and inaccessible in the native protein, but exposed in its altered conformation). These monoclonal antibodies (mAbs) were demonstrated in vitro to specifically bind misfolded TTR, inhibit fibril formation, induce phagocytic clearance of non-native and aggregated TTR, and specifically recognize TTR amyloid in diseased heart tissue. We further investigated the mechanism of mAb-mediated inhibition of fibrillogenesis using immunogold transmission electron microscopy (IGEM). This high resolution imaging technique confirmed this cryptotope to be an effective antibody target due to its exposure within both pathological TTR misfolding intermediates and end-point insoluble TTR fibrils. In addition to their ability to recognize TTR aggregates in vitro, these monoclonal antibodies demonstrated the ability to specifically recognize soluble, misfolded TTR aggregates in vivo in the plasma of transgenic ATTR mouse models. These results further support the use of monoclonal antibodies to target pathological protein conformations as potentially effective immunotherapies for ATTR amyloidosis.
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