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McWilliams Dissertation 11-28-2016.pdf (2.62 MB)

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Restoring Innate NK-cell Immunity with Antibody Therapeutics in CLL B-Cell Malignancy

McWilliams, Emily Mary
http://rave.ohiolink.edu/etdc/view?acc_num=osu1479863842166353

Abstract Details

2016, Doctor of Philosophy, Ohio State University, Biomedical Sciences.
Chronic Lymphocytic Leukemia (CLL) is the most prevalent adult leukemia with estimations in the US of over 18, 900 newly diagnosed cases and 4,600 deaths for 2016. Patients suffer from profound defects in immune function, with secondary infection a leading cause of morbidity and mortality that is further exacerbated by frontline therapy. A deeper understanding of CLL-associated immunosuppression is needed in order to overcome immune compromise. Enhancing Natural Killer (NK) effector functions has emerged as a promising immunotherapy. NK cells are innate immune effectors that survey and kill pathogen-infected or malignant cells. These cells are a major component of anti-tumor response especially with monoclonal antibody therapeutics (mAbs) that engage NKs and mediate tumor killing. Activating NK anti-tumor functions depends on a tightly regulated network of inhibitory and activating receptors that detect “self” antigens, which are severely deregulated in CLL leading to tumor escape. MAbs that activate NK anti-tumor immunity represent a promising chemotherapy-free therapeutic option that would not only spare patients’ immune systems but even enhance the anti-tumor response. Antibodies generated by glyco-engineering have improved capacity to recruit and activate NK anti-tumor response. Defucosylation is a form of glyco-engineering that removes a fucose moiety at the CH2 locus within the antibody constant region (Fc) and raises the affinity between antibody and NK resulting in more effective NK-mediated killing of targeted cancer cells. B-cell activation factor (BAFF) ligating to BAFF receptor (BAFF-R) triggers critical pro-survival signals in B cells and blocking this interaction represents a novel target for immunotherapy. Glyco-engineered anti-BAFF-R activated superior NK antibody-dependent cellular cytotoxicity (ADCC) over CD20 antibodies including glyco-engineered obinutuzumab, and activated additional innate immune response as demonstrated by TNFa release by monocytes and macrophages, and induction of antibody cellular phagocytosis (ADCP). Anti-BAFF-R antagonizes BAFF-mediated protection of CLL cells from apoptosis and blocks NF-¿B signaling, as shown both in bulk protein analysis and at the single-cell level. Similarly, BAFF signaling was observed in CLL B-cells treated with ibrutinib, which blocks Bruton’s tyrosine kinase (Btk), a mediator of B-cell receptor (BCR) signaling cascades, and this was antagonized by anti-BAFF-R pretreatment. In vivo, anti-BAFF-R treatment rapidly cleared peripheral blood and synergistically combined with ibrutinib to provide survival advantage in a murine CLL model. CLL patient NK-cell counts correlates with stage of disease and time to treatment, and are severely dysfunctional. CLL B-cells overexpress HLA-E, a MHC class I molecule that differentiates “self” from “non-self,” and leads to NK cell inhibition by binding NKG2A. NKG2A, the primary inhibitory receptor on NKs, has garnered much attention as a promising target of antibody therapy to alleviate NK cell suppression, especially as anti-NKG2A, monalizumab, is entering phase II clinical trials in various cancers. NKG2A is expressed on CD56+ CD16+ NKs, and blocking NKG2A with monalizumab is sufficient to restore NK-killing capacity indicating the significance of HLA-E/NKG2A driving tumor escape in CLL. These findings demonstrate the impact of NK-cell dysfunction in CLL, and the novel therapeutic approaches of glyco-engineering and antigen selection to generate effective antibody-therapy. Together, these studies deepen our understanding of NK cell immunosuppression in CLL and contributes to the development of rational combination therapies to eradicate tumor and enhance anti-tumor response.
John C. Byrd (Advisor)
Natarajan Muthusamy (Advisor)
Virginia Sanders (Committee Member)
Susheela Tridandapani (Committee Member)
156 p.
Biomedical Research
CLL; antibody therapeutics; NK cells; immunotherapy; immunosuppression

Recommended Citations

Citations

  • McWilliams, E. M. (2016). Restoring Innate NK-cell Immunity with Antibody Therapeutics in CLL B-Cell Malignancy [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1479863842166353

    APA Style (7th edition)

  • McWilliams, Emily. Restoring Innate NK-cell Immunity with Antibody Therapeutics in CLL B-Cell Malignancy. 2016. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1479863842166353.

    MLA Style (8th edition)

  • McWilliams, Emily. "Restoring Innate NK-cell Immunity with Antibody Therapeutics in CLL B-Cell Malignancy." Doctoral dissertation, Ohio State University, 2016. http://rave.ohiolink.edu/etdc/view?acc_num=osu1479863842166353

    Chicago Manual of Style (17th edition)

osu1479863842166353
454
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This open access ETD is published by The Ohio State University and OhioLINK.