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Therapeutic Targets and New Directions for Antibodies Developed for Ovarian Cancer King’s Research Portal DOI: 10.1080/19420862.2016.1219005 Document Version Publisher's PDF, also known as Version of record Link to publication record in King's Research Portal Citation for published version (APA): Bax, H. J., Josephs, D. H., Pellizzari, G., Spicer, J. F., Montes, A., & Karagiannis, S. N. (2016). Therapeutic targets and new directions for antibodies developed for ovarian cancer. Mabs, 8(8), 1437-1455. https://doi.org/10.1080/19420862.2016.1219005 Citing this paper Please note that where the full-text provided on King's Research Portal is the Author Accepted Manuscript or Post-Print version this may differ from the final Published version. If citing, it is advised that you check and use the publisher's definitive version for pagination, volume/issue, and date of publication details. 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Download date: 30. Sep. 2021 mAbs ISSN: 1942-0862 (Print) 1942-0870 (Online) Journal homepage: http://www.tandfonline.com/loi/kmab20 Therapeutic targets and new directions for antibodies developed for ovarian cancer Heather J. Bax, Debra H. Josephs, Giulia Pellizzari, James F. Spicer, Ana Montes & Sophia N. Karagiannis To cite this article: Heather J. Bax, Debra H. Josephs, Giulia Pellizzari, James F. Spicer, Ana Montes & Sophia N. Karagiannis (2016) Therapeutic targets and new directions for antibodies developed for ovarian cancer, mAbs, 8:8, 1437-1455, DOI: 10.1080/19420862.2016.1219005 To link to this article: https://doi.org/10.1080/19420862.2016.1219005 © 2016 The Author(s). Published with license by Taylor & Francis Group, LLC© Heather J. Bax, Debra H. Josephs, Giulia Pellizzari, James F. Spicer, Ana Montes, and Sophia N. Karagiannis Accepted author version posted online: 05 Aug 2016. Published online: 10 Sep 2016. Submit your article to this journal Article views: 1546 View related articles View Crossmark data Citing articles: 1 View citing articles Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=kmab20 MABS 2016, VOL. 8, NO. 8, 1437–1455 http://dx.doi.org/10.1080/19420862.2016.1219005 REVIEW Therapeutic targets and new directions for antibodies developed for ovarian cancer Heather J. Baxa,b, Debra H. Josephsa,b, Giulia Pellizzaria,b, James F. Spicerb, Ana Montesc, and Sophia N. Karagiannisa aSt. John’s Institute of Dermatology, Division of Genetics and Molecular Medicine, Faculty of Life Sciences and Medicine, King’s College London & NIHR Biomedical Research Center at Guy’s and St. Thomas’ Hospital and King’s College London, Guy’s Hospital, King’s College London, London, UK; bDivision of Cancer Studies, Faculty of Life Sciences and Medicine, King’s College London, Guy’s Hospital, London, UK; cDepartment of Medical Oncology, Guy’s and St Thomas’ NHS Foundation Trust, London, UK ABSTRACT ARTICLE HISTORY Antibody therapeutics against different target antigens are widely used in the treatment of different Received 8 June 2016 malignancies including ovarian carcinomas, but this disease still requires more effective agents. Improved Revised 25 July 2016 understanding of the biological features, signaling pathways, and immunological escape mechanisms Accepted 27 July 2016 involved in ovarian cancer has emerged in the past few years. These advances, including an appreciation KEYWORDS of the cross-talk between cancer cells and the patient’s immune system, have led to the identification of Antibodies; clinical trials; new targets. In turn, potential antibody treatments with various mechanisms of action, including immune immunotherapy; immune activation or toxin-delivery, that are directed at these targets have been developed. Here, we identify checkpoint; molecular- established as well as novel targets for antibodies in ovarian cancer, and discuss how they may provide targeting; ovarian cancer; fresh opportunities to identify interventions with enhanced therapeutic potential. tumor-associated antigen; tumor-promoting molecule; vaccine Introduction or no expression on normal cells. Often TAAs are involved in the activation of signaling transduction pathways that support It is estimated that »22,280 American women will receive new unregulated growth or division of cancer cells. This specificity diagnoses of ovarian cancer in 2016, and an estimated 14,240 in expression and role in pro-tumoral functions make TAAs deaths from the disease will occur in this year.1 Standard therapy is promising antibody targets, allowing tumor cells to be specifi- a combination of maximal surgical cytoreductive and taxane- and cally marked for immune cell destruction or blockade of platinum-based chemotherapeutic agents. Nevertheless, relapse is tumor-associated signaling, which impedes malignant function, common after first-line treatment. Despite investigations of novel invasiveness and survival. chemotherapeutic regimes, targeted and other therapies, there have been no significant improvements in clinical outcomes or cure rates, with current 5-year overall survival rates at only 45%.2 Given that ovarian cancer is known to be immunogenic and CA125 high numbers of infiltrating immune cells, including effector CA125 (MUC16), an extremely large, 2500–5000 kDa, mucin- cells such as T cells and macrophages, are associated with like surface glycoprotein, is expressed in greater than 95% of improved survival rates,3 antibody-based therapies are thought non-mucinous stage III/IV epithelial ovarian cancers (EOCs) to offer promise. Monoclonal antibody immunotherapies may and in 50–80% of ovarian tumors overall. CA125 is thought to redirect these effector cells against cancer and mediate specific support tumor-associated immune escape in the tumor microen- and potent anti-tumor immune responses, with the aim of vironment (TME).4,5 High CA125 expression correlates with restricting tumor growth and improving disease course. Here, protection against cytolytic killing by natural killer (NK) cells, we focus on established and emerging new targets for antibody which is linked to reduced activating immune synapses between treatments in ovarian carcinoma, and we discuss monoclonal NK and target cells, and thus decreased cell adhesion.5 This may antibodies that have been studied in patients with this disease. be because the NK synaptic cleft requires a distance of 10–50 nm between NK and cancer cells, which is thought to be disrupted bythelarge(upto24,000aminoacid)proteinbackboneof Targets for antibody treatments CA125 that can protrude from ovarian tumor cells by up to 1– 5mm. 5 However, given the heterogeneity of the size of CA125 Tumor-associated antigens reported, which may be a result of the biological source of the Tumor-associated antigens (TAAs) are surface-associated mol- molecules studied or differing biological methods used to charac- ecules or receptors expressed by tumor cells, which have limited terize them,6 or significant variation in the extent of protein CONTACT Sophia N. Karagiannis [email protected] St. John’s Institute of Dermatology, Division of Genetics and Molecular Medicine, Faculty of Life Sciences and Medicine, King’s College London & NIHR Biomedical Research Centre at Guy’s and St. Thomas’s Hospitals and King’s College London, Guy’s Hospital, Tower Wing, 9th Floor, London, SE1 9RT, United Kingdom. Published with license by Taylor & Francis Group, LLC © Heather J. Bax, Debra H. Josephs, Giulia Pellizzari, James F. Spicer, Ana Montes, and Sophia N. Karagiannis This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0/), which permits unrestricted use, distribu- tion, and reproduction in any medium, provided the original work is properly cited. The moral rights of the named author(s) have been asserted. 1438 H. J. BAX ET AL. glycosylation,5 thedegreeofimmuneescapeaswellasotherbio- expression is maintained in metastatic disease,13 and EpCAM logical functions of CA125-expressing tumor cells may vary. overexpression is prognostic of reduced overall survival (OS) in It has also been suggested that inhibition may be due to a ovarian cancer.14 Expression on epithelial carcinomas is at the CA125-induced reduction in NK cell expression of the Fc activat- cell surface, whereas in normal epithelial tissues, EpCAM is ing receptor, CD16.4 In fact, NK cells from patients with EOCs expressed basolaterally and is protected by tight junctions, have shown significant reduction in CD16 expression compared to making this an attractive target for anti-cancer therapy. NK cells from healthy donors. A down-regulation of activatory
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