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Monoclonal Antibody and Liposomal Nanoparticle-based Targeting Therapies for Chronic Lymphocytic Leukemia

Mao, Yicheng
http://rave.ohiolink.edu/etdc/view?acc_num=osu1354299911

Abstract Details

2012, Doctor of Philosophy, Ohio State University, Pharmacy.
Chronic Lymphocytic Leukemia (CLL), representing 30% of leukemia, remains the most common hematologic malignancy in the western world. It is diagnosed by peripheral blood immunophenotyping with co-expression of biomarkers, such as CD5, CD19, CD20 and CD23, on B cell surface and with more than 5,000 B lymphocytes in one μl. The first-line treatment for CLL includes monotherapy or combined chemotherapy of alkylating agents (e.g. chlorambucil and cyclophosphamide), purine analogues (e.g. fludarabine and cladribine) and monoclonal antibody based immunotherapy (e.g. rituximab and alemtuzumab) CD20 directed therapeutic antibodies such as rituximab and ofatumumab are widely used in CLL therapy. However, there are still limitations of currently existing first-line treatments for CLL due to nonspecific cytotoxicity induced by drug or relapse caused by immunotherapy. Therefore, it is crucial to develop therapies that are efficiently and specifically targeting to the malignant B-CLL cells. Herein, we explore monoclonal antibody (mAb) and liposomal nanoparticles-based therapeutic strategies for CLL with the goal to achieve efficient and directed drug/gene delivery with minimal side effects. Firstly, a relatively new antibody, anti-CD37, was combined with one of the two classical antibodies, anti-CD19 or anti-CD20 to form dual-ligand immunoliposome (dILPs) delivery systems to show higher targeted delivery efficiency and more cytotoxicity to CLL cells compared to single-ligand immunoliposomes (sILPs). Among all combined dILPs, CD19/CD37 dILPs demonstrated the highest delivery efficiency to primary B cells from CLL patients. The improvement in specificity and efficiency made by dILPs revealed the advantages of combining mAbs with complementary features such as high expression level, unique specificity and fast internalization. A novel anti-ROR1 mAb, 2A2-IgG based immunoliposome (ILPs) delivery system specifically targeting to B-CLL cells was developed and tested. Besides investigating dILPs and 2A2-IgG based ILPs without any drug, two small molecule drugs, FTY720 and OSU2S, with potent therapeutic efficacy but significant side effect due to off-target selection were formulated into liposomes to realize targeted delivery and used as model drugs to further evaluate the delivery systems. Drug loaded in liposomes with or without antibody targeting provided different pharmacokinetics profiles compared with free drug in vivo and showed improved targeted delivery, enhanced killing efficiency and reduced the off-target killing of T lymphocytes in vitro. Additionally, characterization of liposomal FTY720 and OSU-2S were also presented with physical-chemical characterization studies and pharmacokinetics evaluation. In addition to drug delivery, mAb targeted liposomal nanoparticle systems can also deliver oligodeoxynucleotides to CLL cells, which was demonstrated with an in vivo study of anti-CD20 targeted lipoplex nanoparticle containing ODN G3139 in SCID mice engrafted with Raji cells. Overall, this study explored liposomal nanoparticles-based therapies using inserted new mAb and dual mAb for both targeting and therapeutic functions. Our results proved their advantages of delivering drug or gene, providing evidence of potential new strategies for CLL treatment.
Robert J. Lee, PhD (Advisor)
Natarajan Muthusamy, PhD, DVM (Advisor)
L. James Lee, PhD (Committee Member)
John. C Byrd, MD (Committee Member)
Mitch A. Phelps, PhD (Committee Member)
Pharmaceuticals
Chronic Lymphocytic Leukemia; Monoclonal Antibody; Liposomal Nanoparticles; Targeted Therapeutics;

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Citations

  • Mao, Y. (2012). Monoclonal Antibody and Liposomal Nanoparticle-based Targeting Therapies for Chronic Lymphocytic Leukemia [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1354299911

    APA Style (7th edition)

  • Mao, Yicheng. Monoclonal Antibody and Liposomal Nanoparticle-based Targeting Therapies for Chronic Lymphocytic Leukemia. 2012. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1354299911.

    MLA Style (8th edition)

  • Mao, Yicheng. "Monoclonal Antibody and Liposomal Nanoparticle-based Targeting Therapies for Chronic Lymphocytic Leukemia." Doctoral dissertation, Ohio State University, 2012. http://rave.ohiolink.edu/etdc/view?acc_num=osu1354299911

    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.