Doctoral Dissertations

Author

Ke Li

Keywords and Phrases

Antibody drug conjugates; Cancer; Cetuximab-Staurosporine; Drug to antibody ratio; Positional isomer

Abstract

"Antibody drug conjugates (ADCs) are emerging therapeutic products specially designed for the treatment of cancers. Potent cytotoxic agents are linked to antibodies via linkers. Antibody drug conjugates, which take advantage of both antibodies and cytotoxic agents, showed high selectivity towards cancer cells. Cytotoxic agents are delivered to the cancer cells selectively and kill them from inside while leaving low or non-toxicity towards normal cells. Antibody drug conjugates are actually heterogeneous mixtures. The major heterogeneities mainly lie in the drug to antibody ratio (DAR) and drug linking positions, both of which potentially affect the therapeutic index of ADCs. In this research, we focused on the interchain cysteine linked ADCs, which are the most popular class. We first developed methods and characterized the drug linking position heterogeneity. Positional isomers of interchain cysteine linked ADCs were separated and their relative abundance was determined. In addition, novel LC/HRMS methods were developed for the accurate determination of the DAR with cleavable and non-cleavable linkers. Meanwhile, we also designed and synthesized new ADCs, namely Cetuximab-Staurosporine for EGFR over expressed Non-Small Cell Lung Cancer. The anticancer effects were evaluated on A549 human lung cancer cells"--Abstract, page iv.

Advisor(s)

Ma, Yinfa
Shi, Honglan

Committee Member(s)

Nam, Paul Ki-souk
Winiarz, Jeffrey G.
Lin, Zhongping (John)

Department(s)

Chemistry

Degree Name

Ph. D. in Chemistry

Comments

This research was supported by Frontage laboratories, Inc. and Missouri University of Science and Technology.

Publisher

Missouri University of Science and Technology

Publication Date

Fall 2019

Journal article titles appearing in thesis/dissertation

  • Characterization of Positional Isomers of Interchain Cysteine Linked Antibody-Drug Conjugates by High-Resolution Mass Spectrometry
  • Accurate Determination of Drug to Antibody Ratio of Interchain Cysteine Linked Antibody Drug Conjugates by LC-HRMS
  • Design, Synthesis and Toxicity Study of Cetuximab-Staurosporine on Non-Small Cell Lung Cancer Cells

Pagination

xii, 88 pages

Note about bibliography

Includes bibliographic references.

Rights

© 2019 Ke Li, All rights reserved.

Document Type

Dissertation - Open Access

File Type

text

Language

English

Thesis Number

T 11881

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