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Proquest Dissertations RICE UNIVERSITY Gd@C60-(ZME-018) Immunoconjugate Targeting of A375 Melanoma Cells by Christopher Scott Berger A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE Master of Arts Approved Thesis Committee: Lon J. Wilson, Chairman Professor of Chemistry W. Edward Billups Professor of Chemistry ^1 -u Ronald J. Parry Professor of Chemistry HOUSTON, TEXAS MAY 2010 UMI Number: 1486027 All rights reserved INFORMATION TO ALL USERS The quality of this reproduction is dependent upon the quality of the copy submitted. In the unlikely event that the author did not send a complete manuscript and there are missing pages, these will be noted. Also, if material had to be removed, a note will indicate the deletion. UMT Dissertation Publishing UMI 1486027 Copyright 2010 by ProQuest LLC. All rights reserved. This edition of the work is protected against unauthorized copying under Title 17, United States Code. ProQuest LLC 789 East Eisenhower Parkway P.O. Box 1346 Ann Arbor, Ml 48106-1346 Abstract Gd@C6o-(ZME-018) Immunoconjugate Targeting of A375 Melanoma Cells by Christopher Scott Berger For the first time, C6o-monoclonal antibody (mAb) immunoconjugates have been determined to internalize into target cells using water-soluble Gd3+-ion-filled fullerenes (Gd@Ceo(OH)x). Separate conjugations of Gd@C6o(OH)x with the antibody ZME-018 and a murine antibody mixture (MulgG) took place in a 1:5 mAb:Gd@C6o ratio. Quanitative analysis of the immunoconjugates was established using inductively-coupled plasma mass spectrometry (ICP-MS) and UV-Vis spectrometry (Gd@C6o+C6o). Enzyme- linked immunosorbent assays (ELISA) show little change in the specific binding of the ZME-018 once conjugated. Each immunoconjugate was exposed to two cancer cell lines, A375m (a ZME-018-specific line), and T24, a bladder carcinoma line. Internalization of the immunoconjugate was measured at various timepoints, after which the cells were harvested and digested with 25% HCIO3 for Gd3+ analysis by ICP-MS. ICP-MS results show immunoconjugate internalization peaked in the first hour of exposure of the cells with a large dropoff occuring in the subsequent hour. These are the first results demonstrating the practicality of a cancer therapy based on Fullerene Immunotherapy (FIT). Acknowledgements While the work in this thesis is my own, none of it would have been possible without the enormous amount of help and effort from my friends and collaborators. The first people I would like to thank are Freddy Nguyen and Dan Heller; ever since our Owlchemy days at Rice, we have never lost our love for chemistry. It was Dan in particular who helped start me on my journey toward graduate school on a windswept platz in Vienna in the summer of 2003. Also, I'd like to thank Drs. Robert Curl and Robert Willcott, who in their own respects have always kept their contagious loves for Rice, science and students for more than 50 years, an example I hope to live up to. To all the Wilsonites, both past and present. The best research group at Rice, they are less a group and more a family. To Theodora Greene, for providing such an amazing resource for organic chemists. To my friends and family, who always believed I could do it (even when I wasn't so sure) and who always seemed interested in my research, even when they had no clue what I was talking about. To our collaborators at M. D. Anderson, Dr. Rosenblum and Bill Marks and all the patience, kindness and attention they've given me these past 4 years. It's been a true pleasure working with Bill, a fellow Kansas Citian. To the members of my committee, Drs. Lon Wilson, Ed Billups and Ronald Parry for taking time out of their busy schedules to sit on my committee. Finally, I want to thank my advisor, Dr. Lon Wilson. Little could I have imagined the journey I would undertake with him when I first took CHEM 351 in the Fall of 1998, but I've always enjoyed it. Table of Contents Introduction page 1 Experiment page 7 Results and Discussion page 8 Further Research page 15 References page 20 Appendix page 22 List of Figures Figure 1. Diagrams of an Antibody. page 4 Figure 2. ELISA Tests of Gd@C6o-Immunoconjugates page 10 Figure 3. UV-Vis Spectrum of mAbs and Immunoconjugates page 12 Figure 4. TEM Immunoconjugate Images page 13 Figure 5. Gd@C6o-mAb Immunoconjugate Internalization into Cells page 15 List of Tables Table I. ICP-MS Results for Immunoconjugates page 11 Table II. Cell internalization for Immunoconjugates over time page 14 1 Introduction The birth of modern passive immunization began in two stages. First, in 1888, Emile Roux and Alexandre Yersin of the Pasteur Institute proved the existence of diphtheria toxin by injecting the cell-free sera of Corynebacterium diphtheriae into lab animals. Though no infection was possible, the lab animals soon developed symptoms of diphtheria, proving the cause of symptoms were not directly from the diphtheria bacteria, but instead from the toxins they release. The second stage was completed two years later when Roux and Yersin's colleagues at the Pasteur Institute, Emil von Behring and Kitasato Shibasaburo, immunized lab animals with heat-attenuated forms of diptheria and tetanus. Sera collected from these animals was injected into infected animals with manifested symptoms. The result was surprising, for the antitoxins in the sera relieved symptoms and eventually led to recovery from an infection that would previously have been fatal. By mass-producing the diphtheria antitoxin in horses, Behring's "serum therapy" eventually became treatment for humans in 1896, as the first immunity-based treatment since Jenner's smallpox vaccine developed a century before. As serum therapies appeared for other bacterial diseases, hope from this new therapy helped treat an entire generation. In the wake of this revolutionary therapy, Paul Ehrlich, a medical great who assisted Emil von Behring in his development of a diphtheria serum, made a prediction whose concept has been a goal of medical treatment for over a century. He noted that certain strains of infectious bacteria were susceptible to staining from different dyes, a precursor to Gram staining. He reasoned if dyes are capable of targeting and binding to 2 material in cell walls, it must be possible to find toxic materials that would preferentially target foreign bacteria in an infected patient over native tissue. This "magic bullet" would then provide a targeted therapy, capable of patient treatment with little to no side effects. This magic bullet concept of a targeted therapeutic persists to this day. It is estimated that only 1 of every 100,000 molecules administered to a patient locally reaches its intended destination. The simple goal of targeted therapies is to produce high concentrations of therapeutic in the appropriate biological area, thus reducing patient side effects while allowing higher pharmaceutical doses to be administered. The development of cell-targeted agents for imaging and therapeutic applications in medicine is accelerating. Cytokines, growth factor and kinase inhibitors and monoclonal antibodies (mAbs) all show promise for their ability to deliver payloads to the surface and the cytoplasm of targeted cancer cells,1 as well as other more exotic materials such as RGD (arginine-glycine-aspartic acid) peptides and chlorotoxin from the Deathstalker scorpion Leiurus quinquestriatus. However, by far the most versatile and successful class of targeting agents to show targeting capabilities for specific cancers currently are monoclonal antibodies (mAb). The study of antibodies and their role in immune response began with Emil von Behring and continued with Paul Ehrlich, but their potential as a therapy was not possible until the development of a method for producing large quantities of antibodies all recognizing the same cellular epitope. 3 By the early 1970s, research had revealed the role of antibodies in the immune system and many of the mechanisms by which B-cells identify antigens and stimulate immune responses. Investigation of paraproteins in multiple myeloma cases revealed, however, that cancerous B-cells deriving from a single sample produce monoclonal antibodies instead of the normal sample of polyclonal antibodies. In 1975, Niels Kaj Jerne, Cesar Milstein and Georges Kohler successfully fused antibody-producing myeloma cells with spleen cells from immunized mice producing a specific antigen. The resulting hybridomas can be cloned, are immortal and after sufficient incubation, begin to secrete a single product: monoclonal antibodies binding to the specific antigen from spleen cells. Antibodies, also known as immunoglobulins, are an integral components in the animalian immune system. These agents contain at least four subunits: two identical light chains (~23 kDa) and two identical heavy chains (mass ranging from 53-75 kDa). These subunits combine together through disulfide bonds and non-covalent interactions to form a Y-shaped symmetric molecule. It has now become regular laboratory practice to use the enzyme papain to proteolyze antibodies into the two identical Fab fragments, which serve as the antigen-binding "arms" of the Y-shaped antibody, from the single Fc fragment, which composes the antibody "stem". 4 Heavy chain Constant region Figure 1. Diagrams of an Antibody. Using a patient's own cellular identification system to target cancer with immunoconjugates has the potential to become a potent anticancer therapy in personalized medicine.2 To date, three immunoconjugates have been FDA-approved for clinical use. Two murine mAbs target the B-cell glycoprotein CD20 to treat non- Hodgkin's lymphomas with p-emitting radionuclides. Ibritumomab tiuxetan is the IgGl- K mAb radiolabeled with either 90Y or mIn,3 while Tositumomab is the second agent, which is an IgG2a-A, mAb radiolabeled with 131I.4 Gemtuzumab ozogamicin, a third immunoconjugate, is a humanized, anti-CD33 IgG4-K mAb covalently derivatized with cytotoxic calicheamicin for use in the treatment of acute myelogenous leukemia.5 These immunoconjugates must internalize effectively within target cells for optimal therapeutic efficacy.
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