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Evaluation of Antibody-based Therapeutics in B cell Malignancies

Rafiq, Sarwish
http://rave.ohiolink.edu/etdc/view?acc_num=osu1338321515

Abstract Details

2012, Doctor of Philosophy, Ohio State University, Integrated Biomedical Science Graduate Program.
Monoclonal antibodies therapy for B cell malignancies evolved vastly over the past few decades. Since its approval as the first therapeutic antibody for cancer, rituximab has improved outcome in virtually all CD20+ malignancies it was tested. However, despite its successes, most patients become resistant to rituximab therapy and novel therapeutic targets and agents are needed. Intelligently engineered antibodies and antibody-based protein therapeutics for the treatment of leukemia have newly emerged. These engineered variants enhance various mechanisms of action of antibodies. They include the next generation CD20-directed antibodies, as well as therapies directed at new therapeutic targets such as CD19 and CD37 for Acute Lymphoblastic Leukemia (ALL) and Chronic Lymphocytic Leukemia (CLL). Understanding the benefits and properties of these engineered variants is vital before they can be moved to the clinic. XmAb-5574 is an amino acid engineered anti-CD19 antibody that mediates superior NK cell-dependent Antibody-dependent Cellular Cytotoxicity (ADCC) against ALL and CLL cells as compared to the currently utilized anti-CD20 and anti-CD52 therapies. SMIP-016GV is a glyco-engineered novel mono-specific protein therapeutic against CD37 that mediates superior NK cell-mediated ADCC at low concentrations and low antigen density. It represents a second generation molecule that is more potent than the parent compound against both CLL and ALL patient cells. Finally, the next generation of anti-CD20 antibodies are coming in to the clinic and are engineered for specific functions. Ofatumumab has enhanced complement activation, while GA101 is a novel Type II antibody that is Fc engineered. GA101 shows enhanced activation of NK cells and ADCC. However, it shows diminished activation of monocytes, as well as decreased Antibody-dependent Cellular Phagocytosis (ADCP) and monocyte/macrophage cytokine release. In addition, it shows decreased recruitment of Fc gamma ReceptorIIa to signaling lipid rafts. These results question the importance of specific types of engineering and which cells are the most important for therapeutic antibody efficacy in vivo. The newly emerging therapies described above are adding to the armamentarium available to clinicians of specific biological therapies against B cell malignancies and giving insight into the mechanism of action of therapeutic antibodies.
John C. Byrd, MD (Advisor)
Natarajan Muthusamy, PhD, DVM (Advisor)
Susheela Tridandapani, PhD (Committee Member)
William E. Carson, MD (Committee Member)
Oncology; Therapy
CD37; CD20; Protein Therapeutics; Antibody Therapeutics

Recommended Citations

Citations

  • Rafiq, S. (2012). Evaluation of Antibody-based Therapeutics in B cell Malignancies [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1338321515

    APA Style (7th edition)

  • Rafiq, Sarwish. Evaluation of Antibody-based Therapeutics in B cell Malignancies. 2012. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1338321515.

    MLA Style (8th edition)

  • Rafiq, Sarwish. "Evaluation of Antibody-based Therapeutics in B cell Malignancies." Doctoral dissertation, Ohio State University, 2012. http://rave.ohiolink.edu/etdc/view?acc_num=osu1338321515

    Chicago Manual of Style (17th edition)

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© 2012, all rights reserved.
This open access ETD is published by The Ohio State University and OhioLINK.