Date on Master's Thesis/Doctoral Dissertation

5-2021

Document Type

Doctoral Dissertation

Degree Name

Ph. D.

Department

Pharmacology and Toxicology

Degree Program

Pharmacology and Toxicology, PhD

Committee Chair

Matoba, Nobuyuki

Committee Co-Chair (if applicable)

Palmer, Kenneth

Committee Member

Palmer, Kenneth

Committee Member

Telang, Sucheta

Committee Member

Yan, Jun

Committee Member

Miller, Donald

Author's Keywords

biologics; drug development; cancer glycobiology; antibodies; plant-made pharmaceuticals

Abstract

This dissertation explores the anticancer activity of Avaren-Fc (AvFc), a novel lectin-Fc fusion protein or “lectibody” targeting cancer and virus-associated high-mannose glycans. Previously, we have shown that AvFc recognizes a broad selection of established cancer cell lines from a wide array of tissue types, can potently induce antibody-dependent cell-mediated cytotoxicity (ADCC) against them, and exhibits anti-cancer activity in vivo. However, the exact mechanism of action remains elusive. We hypothesized that the primary mechanism of action is through Fc-mediated effector functions, and the purpose of this dissertation is to explore this question through the use of Fc variants that either increase or decrease ADCC activity relative to the WT molecule using the B16F10 murine melanoma model. Chapters 1 and 2 give a comprehensive overview of glycosylation and its role in cancer and disease, the molecule AvFc, the mechanism of action of the various Fc-mediated effector functions, and the current status of plant-made cancer biologics. Chapter 4 discusses the efficacy of AvFc in a human liver chimeric mouse model of HCV infection, which helped not only to establish AvFc’s activity in vivo but also demonstrated its safety and feasibility as a drug candidate. The bulk of the data obtained regarding the anticancer activity of AvFc are contained in Chapter 5, which establishes that Fc-mediated functions are the primary mechanisms of action and that AvFc administration is associated with the recruitment of FcγR-bearing cells to the tumor microenvironment. Interestingly, these studies also indicated that the presence of pre-existing immunity in the presence of anti-drug antibodies to AvFc did not obviate its activity in vivo. Further exploration of the anticancer activity of AvFc is detailed in Chapter 6, which discusses the use of AvFc as a therapeutic for ovarian cancer (OVCA) and details its in vitro and in vivo activities. The results presented herein provide evidence to suggest that cancer-associated high-mannose glycans may be a viable pharmacological target and that AvFc is a unique and potent first-in-class agent with significant anticancer capabilities through recognition of this glycobiomarker, warranting its further development as a therapeutic against cancers with limited therapeutic options such as OVCA.

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