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Humoral Immune Response to Melanoma: Discovery and Evaluation of Anti-Melanoma Antibodies

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Humoral Immune Response to Melanoma: Discovery and Evaluation of Anti-Melanoma Antibodies This electronic thesis or dissertation has been downloaded from the King’s Research Portal at https://kclpure.kcl.ac.uk/portal/ Humoral immune response to melanoma: discovery and evaluation of anti-melanoma antibodies Gilbert, Amy Awarding institution: King's College London The copyright of this thesis rests with the author and no quotation from it or information derived from it may be published without proper acknowledgement. END USER LICENCE AGREEMENT Unless another licence is stated on the immediately following page this work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International licence. https://creativecommons.org/licenses/by-nc-nd/4.0/ You are free to copy, distribute and transmit the work Under the following conditions: Attribution: You must attribute the work in the manner specified by the author (but not in any way that suggests that they endorse you or your use of the work). Non Commercial: You may not use this work for commercial purposes. No Derivative Works - You may not alter, transform, or build upon this work. Any of these conditions can be waived if you receive permission from the author. Your fair dealings and other rights are in no way affected by the above. Take down policy If you believe that this document breaches copyright please contact [email protected] providing details, and we will remove access to the work immediately and investigate your claim. Download date: 07. Oct. 2021 This electronic theses or dissertation has been downloaded from the King’s Research Portal at https://kclpure.kcl.ac.uk/portal/ Title: Humoral immune response to melanoma: discovery and evaluation of anti-melanoma antibodies Author: Amy Gilbert The copyright of this thesis rests with the author and no quotation from it or information derived from it may be published without proper acknowledgement. END USER LICENSE AGREEMENT This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported License. http://creativecommons.org/licenses/by-nc-nd/3.0/ You are free to: Share: to copy, distribute and transmit the work Under the following conditions: Attribution: You must attribute the work in the manner specified by the author (but not in any way that suggests that they endorse you or your use of the work). Non Commercial: You may not use this work for commercial purposes. No Derivative Works - You may not alter, transform, or build upon this work. Any of these conditions can be waived if you receive permission from the author. Your fair dealings and other rights are in no way affected by the above. Take down policy If you believe that this document breaches copyright please contact [email protected] providing details, and we will remove access to the work immediately and investigate your claim. Humoral immune response to melanoma: discovery and evaluation of anti-melanoma antibodies Amy Eileen Gilbert A thesis submitted for the degree Doctor of Philosophy King’s College, London Abstract Melanoma, a potentially lethal form of skin cancer, is widely thought to be immunogenic in nature. While numerous studies have examined T cell-mediated immune responses to melanoma and their therapeutic potential, there has been less focus on B cell-mediated immune responses and the tumor-reactive antibodies they produce. The aim of this work was three-fold: (1) to develop a methodology to detect antibodies secreted by human B cells that recognize melanoma cell surface proteins; (2) to evaluate the mature B cell repertoire of individuals with melanoma for antibody subclass composition and the presence and prevalence of anti-tumor antibodies; and (3) to study patient-derived antibodies and two engineered antibodies recognizing melanoma cells for their propensity to activate immune effector cells and their capacity to kill or restrict the growth of tumor cells. As part of this thesis, a novel tumor cell-based ELISA was developed for the detection of tumor-reactive antibodies. Utilizing this new assay, the presence and prevalence of melanoma-reactive IgG antibodies derived from ex vivo cultured peripheral blood B cells from a cohort of 21 patients with melanoma (Stage I, n=1; Stage II, n=8; Stage III, n=6; Stage IV, n=6) were compared to those from healthy volunteers (n=10). While B cells from melanoma patients secreted IgG antibody concentrations comparable to those from healthy volunteer B cell cultures, a significantly increased reactivity of antibodies derived from patients to primary and metastatic melanoma cells was measured compared to healthy volunteers (P<0.001). Interestingly, there was a significant reduction in antibody responses to melanoma with advancing disease stage that was not found to be solely due to a -i- reduction in the B cell memory compartment size. Comparing IgG antibody subclass distribution among cutaneous tumors, patient lymph nodes and peripheral blood B cells all isolated from individuals with metastatic disease, elevated proportions of IgG4 subclass antibodies were observed in cutaneous tumors which present a novel finding of this thesis. These findings point to differentially polarized humoral immune responses in cutaneous tumor microenvironments. Lastly, an antibody derived from a patient was then selected and preliminary evaluations of reactivity and specificity to a range of melanoma cell lines and primary human melanocytes were conducted. Using a live cell imaging cytotoxicity assay, this patient-derived melanoma-specific antibody was observed to kill melanoma cells via antibody-mediated cellular cytotoxicity. Additionally, two engineered monoclonal antibodies recognizing a melanoma associated antigen were found to partially restrict tumor cell migration and adhesion and to kill melanoma cells via antibody-dependent cellular cytotoxicity or phagocytosis. In summary, examining the humoral immune response to melanoma and the effector function of antibodies targeting melanoma cells provides insight into the discovery of new therapeutic strategies for the treatment of melanoma. -ii- Table of Contents Abstract ............................................................................................................................................................ i Table of Contents .......................................................................................................................................iii Table of Figures .......................................................................................................................................... xi List of Tables ............................................................................................................................................. xvi Acknowledgements ............................................................................................................................. xviii Abbreviations ............................................................................................................................................. xx Chapter 1: Introduction....................................................................................................................... 1 1.1 Antibodies ............................................................................................................................. 2 1.1.1 The Role of Antibodies in the Adaptive Immune Response................... 2 1.1.2 Antibody Structure and Fc Effector Function ............................................... 8 1.1.3 Therapeutic Mechanisms of Action of Monoclonal Antibodies ......... 12 1.1.4 Monoclonal Antibodies for the Treatment of Cancer ............................. 17 1.1.5 Monoclonal Antibody Production ................................................................... 21 1.1.5.1 Historical Perspectives on the Production of Antibody Therapeutics .......................................................................................................................... 21 1.1.5.2 Strategies to Discover Human Antibodies from Patient B cells . 27 1.2 Melanoma ........................................................................................................................... 32 1.2.1 Therapy for Metastatic Melanoma .................................................................. 34 1.2.2 Immunotherapeutic Approaches for the Treatment of Melanoma . 37 1.2.3 Melanoma Antigens Recognized by the Immune System .................... 42 1.2.3.1 HMW-MAA ........................................................................................................... 44 -iii- 1.3 Immune Responses to Cancer .................................................................................. 48 1.3.1 Humoral Responses to Melanoma................................................................... 49 1.3.2 Mechanisms of Immune Evasion in Tumors .............................................. 52 1.3.3 Th2 Responses in Cancer and Activation of Alternative Humoral Immunity ...................................................................................................................................... 55 1.3.3.1 Preclinical Evaluations of Tumor-specific Antibodies of the IgE Class ................................................................................................................................... 57 1.4 Hypotheses and Aims ................................................................................................... 62 Chapter 2: Materials and Methods .............................................................................................
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