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Humanization of a MUC16-Specific Mon...

White, Brandy R.

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Humanization of a MUC16-Specific Monoclonal Antibody and Characterization of the MUC16 Epitope.

Record Type:	Electronic resources : Monograph/item
Title/Author:	Humanization of a MUC16-Specific Monoclonal Antibody and Characterization of the MUC16 Epitope./
Author:	White, Brandy R.
Published:	Ann Arbor : ProQuest Dissertations & Theses, : 2019,
Description:	166 p.
Notes:	Source: Masters Abstracts International, Volume: 80-12.
Contained By:	Masters Abstracts International80-12.
Subject:	Biochemistry. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=13900504
ISBN:	9781392295601

Humanization of a MUC16-Specific Monoclonal Antibody and Characterization of the MUC16 Epitope.
White, Brandy R.

Humanization of a MUC16-Specific Monoclonal Antibody and Characterization of the MUC16 Epitope. - Ann Arbor : ProQuest Dissertations & Theses, 2019 - 166 p.

Source: Masters Abstracts International, Volume: 80-12.

Thesis (M.S.)--California State University, Fresno, 2019.

This item must not be sold to any third party vendors.

Pancreatic cancer is currently the fourth leading cause of cancer deaths in the United States and has a 5-year relative survival rate of less than 7%. Pancreatic ductal adenocarcinoma (PDAC) tumors currently make up approximately 90% of all pancreatic cancers. PDAC has long been treated with burdensome therapeutics including surgical resection, chemotherapy, and radiation. Therapeutic antibodies, on the other hand, tend to confer less severe side effects, but none are currently used for PDAC. One potential target of therapeutic antibodies in PDAC is a large membrane-bound mucin glycoprotein, mucin16 (MUC16). A mouse monoclonal antibody specific to a MUC16 tandem repeat epitope has recently been discovered. In mouse models, the antibody has shown great promise in reducing tumor size and metastasis of pancreatic tumors. Humans mount an immune response against foreign proteins, however, rendering the mouse antibody useless in clinic. This current work shows that the antibody treatment has been humanized and that the humanized antibody is similar to the parent mouse antibody in function and sensitivity using immunodetection assays. The protein crystal structure of this novel humanized antibody Fab is presented which highlights a Z-shaped binding groove created by the heavy and light chain complementarity determining region loops. The antibody was known to bind a specific 197 amino acid epitope, but this work has narrowed down the binding region to a smaller conformational epitope comprised of the SEA5 domain within the original epitope. Also, it was thought that the antibody binds an abnormally glycosylated region of the epitope but this work shows the antibody binds both glycosylated and non-glycosylated epitopes similarly. While the functions of MUC16 and its implications in cancer have been extensively studied over the last four decades, crystal structures of this glycoprotein have not been previously solved. Here, we present the first crystal structure of MUC16: the recombinant MUC16 SEA5 domain; and computational docking studies to show potential interactions between the Z-shaped binding groove of the antibody and the domain. This work paves the way for a potential deeper understanding of which residues on the MUC16 SEA5 domain contribute to PDAC metastasis and realizing these targets may reveal new drugs targets for this lethal disease.

ISBN: 9781392295601Subjects--Topical Terms:

518028
Biochemistry.

Humanization of a MUC16-Specific Monoclonal Antibody and Characterization of the MUC16 Epitope.
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520 $a Pancreatic cancer is currently the fourth leading cause of cancer deaths in the United States and has a 5-year relative survival rate of less than 7%. Pancreatic ductal adenocarcinoma (PDAC) tumors currently make up approximately 90% of all pancreatic cancers. PDAC has long been treated with burdensome therapeutics including surgical resection, chemotherapy, and radiation. Therapeutic antibodies, on the other hand, tend to confer less severe side effects, but none are currently used for PDAC. One potential target of therapeutic antibodies in PDAC is a large membrane-bound mucin glycoprotein, mucin16 (MUC16). A mouse monoclonal antibody specific to a MUC16 tandem repeat epitope has recently been discovered. In mouse models, the antibody has shown great promise in reducing tumor size and metastasis of pancreatic tumors. Humans mount an immune response against foreign proteins, however, rendering the mouse antibody useless in clinic. This current work shows that the antibody treatment has been humanized and that the humanized antibody is similar to the parent mouse antibody in function and sensitivity using immunodetection assays. The protein crystal structure of this novel humanized antibody Fab is presented which highlights a Z-shaped binding groove created by the heavy and light chain complementarity determining region loops. The antibody was known to bind a specific 197 amino acid epitope, but this work has narrowed down the binding region to a smaller conformational epitope comprised of the SEA5 domain within the original epitope. Also, it was thought that the antibody binds an abnormally glycosylated region of the epitope but this work shows the antibody binds both glycosylated and non-glycosylated epitopes similarly. While the functions of MUC16 and its implications in cancer have been extensively studied over the last four decades, crystal structures of this glycoprotein have not been previously solved. Here, we present the first crystal structure of MUC16: the recombinant MUC16 SEA5 domain; and computational docking studies to show potential interactions between the Z-shaped binding groove of the antibody and the domain. This work paves the way for a potential deeper understanding of which residues on the MUC16 SEA5 domain contribute to PDAC metastasis and realizing these targets may reveal new drugs targets for this lethal disease.
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