MONOCLONAL ANTIBODY-MEDIATED TUMOR TARGETING AND DRUG DELIVERY TO SOLID TUMORS Public Deposited

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  • March 20, 2019
Creator
  • Glatt, Dylan
    • Affiliation: Eshelman School of Pharmacy, Division of Pharmacoengineering and Molecular Pharmaceutics
Abstract
  • Antibody-drug conjugates (ADCs) are an emerging class of targeted anticancer therapeutics. Premised on Paul Ehrlich’s magic bullet hypothesis and clinical need to improve the tumor selectivity of anticancer drugs, ADCs marry the tumor homing properties of monoclonal antibodies (mAbs) with the cell-killing properties of cytotoxic agents like chemotherapy. Conceptually, this is achieved by simultaneously improving the therapeutic effects and diminishing the toxic effects of the cytotoxic agent, thereby increasing the therapeutic index compared to standard chemotherapy. Recent FDA-approvals of ADCETRIS® (2011) and KADCYLA® (2013), as well as the FDA breakthrough designation of inotuzumab ozogamicin (2015), inspire confidence in ADCs to continue advancing state-of-the-art cancer treatment. New research in cancer biology influences trends in ADC design. Advances in antibody engineering, linker design, and bioconjugation continue to improve the chemistry, manufacturing, and control of ADCs. Despite hurdles, herculean efforts brought ADCs from a research-phase concept to an FDA-approved clinical treatment in less than three decades. The objective of this dissertation research was to develop an antibody-drug conjugate therapy for solid tumors cancer therapy. Achieving that goal demanded a deep exploration of the many complex yet innately interdependent physical, chemical, and biological barriers that protect our bodies from the daily barrage of pathogens but also shield diseases like cancer, HIV/AIDS, and Alzheimer’s from the drugs we use for treatment. Uptake and exposure of tumor-targeting mAb by solid tumors is influenced by specific molecular properties of the mAb, like antigen affinity, internalization rate, and circulating half-life, the nature of tumor-associated antigen, and the unique tumor pathophysiology and its microenvironment. Intermediate affinity tumor-targeting mAb were discovered to display superior tumor-targeting features than low- or high-affinity mAb to the tumor-associated antigen CD44, a novel cancer stem cell marker, and the epidermal growth factor receptor (EGFR), a hallmark tumor cell biomarker. Pharmaceutical properties of tumor-targeting mAb were attenuated by fragmentation, yielding exceptionally sensitive EGFR tumor imaging agents, and chemical conjugation, enabling tumor-cell specific homing, internalization, and delivery of docetaxel to a solid tumor. In a culminating study, an anti-EGFR mAb-docetaxel bioconjugate demonstrated tumor cell-specific anticancer activity in vitro and durable tumor regression in tumor-bearing mice in vivo.
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Rights statement
  • In Copyright
Advisor
  • Jay, Michael
  • Mumper, Russell J.
  • Jarstfer, Michael
  • Luft, James Christopher
  • Parrott, Matthew
Degree
  • Doctor of Philosophy
Degree granting institution
  • University of North Carolina at Chapel Hill Graduate School
Graduation year
  • 2016
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