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Increasing ADCC

Hung C Tran, Zesheng Wan, Michael A Sheard, Jianping Sun, Jeremy R Jackson, Jemily Malvar, Yibing Xu, Larry Wang, Richard Sposto, Eugene S Kim, Shahab Asgharzadeh, Robert C Seeger
PURPOSE: Immunotherapy of high-risk neuroblastoma using the anti-GD2 antibody dinutuximab induces antibody-dependent cell-mediated cytotoxicity (ADCC). Galunisertib, an inhibitor of TGFβR1, was examined for its ability to enhance the efficacy of dinutuximab in combination with human ex vivo activated NK (aNK) cells against neuroblastoma. EXPERIMENTAL DESIGN: TGFB1 and TGFBR1 mRNA expression was determined for 249 primary neuroblastoma tumors by microarray analysis...
October 10, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Beate Hintersteiner, Nico Lingg, Evelyne Janzek, Oliver Mutschlechner, Hans Loibner, Alois Jungbauer
It has previously been shown for individual antibodies, that the microheterogenity pattern can have a significant impact on various key characteristics of the product. The aim of this study to get a more generalized understanding of the importance of microheterogeneity. For that purpose, the charge variant pattern of various different commercially available therapeutic mAb products was compared using Cation-Exchange Chromatography with linear pH gradient antigen affinity, Fc-receptor affinity, antibody dependent cellular cytotoxicity (ADCC) and conformational stability...
October 18, 2016: Biotechnology Journal
M Burgess, S Mapp, R Mazzieri, C Cheung, L Chambers, S R Mattarollo, P Mollee, D Gill, N A Saunders
Resistance to therapeutic antibodies in chronic lymphocytic leukaemia (CLL) is common. In this study, we show that therapeutic antibodies against CD62L (CD62L-Ab) or CD20 (obinutuzumab) were able to induce antibody-dependent cell-mediated cytotoxicity (ADCC) and phagocytosis (ADP) in primary cultures of CLL cells. CLL cells derived from patients with active disease requiring treatment displayed resistance to these antibodies, whereas patients with stable disease were sensitive. Using enrichment strategies and transcriptomic analyses, we show that antibody-dependent tumour cell killing was FcγR-dependent and mediated by macrophages...
October 17, 2016: Oncogene
Hongmei Wang, Jianmin Liu, Xuemei Hu, Shanshan Liu, Baojun He
BACKGROUND Hepatocellular carcinoma (HCC) causes many deaths worldwide every year, especially in Asia. It is characterized by high malignancy, recurrence, and short survival time. Inflammation is closely related to the initiation and development of HCC. Tumor necrosis factor-α (TNF-α), an essential inflammatory mediator, has been studied as a potential therapy target in many cancers. However, its potential role in HCC diagnosis and therapy is still unclear. MATERIAL AND METHODS In our study, we detected the TNF-α expression in both human HCC tumor tissue and HCC cell lines HepG2 and HuH7...
October 14, 2016: Medical Science Monitor: International Medical Journal of Experimental and Clinical Research
Martin R Goodier, Chiara Lusa, Sam Sherratt, Ana Rodriguez-Galan, Ron Behrens, Eleanor M Riley
Cross-linking of FcγRIII (CD16) by immune complexes induces antibody-dependent cellular cytotoxicity (ADCC) by natural killer (NK) cells, contributing to control of intracellular pathogens; this pathway can also be targeted for immunotherapy of cancerous or otherwise diseased cells. However, downregulation of CD16 expression on activated NK cells may limit or regulate this response. Here, we report sustained downregulation of CD16 expression on NK cells in vivo after intramuscular (but not intranasal) influenza vaccination...
2016: Frontiers in Immunology
Capucine L Grandjean, Fabricio Montalvao, Susanna Celli, David Michonneau, Beatrice Breart, Zacarias Garcia, Mario Perro, Olivier Freytag, Christian A Gerdes, Philippe Bousso
Anti-CD20 monoclonal antibodies (mAbs) represent an effective treatment for a number of B cell malignancies and autoimmune disorders. Glycoengineering of anti-CD20mAb may contribute to increased anti-tumor efficacy through enhanced antibody-dependent cellular cytotoxicity (ADCC) and phagocytosis (ADP) as reported by in vitro studies. However, where and how glycoengineered Ab may potentiate therapeutic responses in vivo is yet to be elucidated. Here, we have performed mouse liver transplants to demonstrate that the liver is sufficient to mediate systemic B cells depletion after anti-CD20 treatment...
October 4, 2016: Scientific Reports
Maria F Mercogliano, Mara De Martino, Leandro Venturutti, Martín A Rivas, Cecilia J Proietti, Gloria Inurrigarro, Isabel Frahm, Daniel H Allemand, Ernesto Gil Deza, Sandra Ares, Felipe G Gercovich, Pablo Guzmán, Juan C Roa, Patricia V Elizalde, Roxana Schillaci
Although trastuzumab administration improved the outcome of HER2-positive breast cancer patients, resistance events hampered its clinical benefits. We demonstrated that TNFα stimulation in vitro induces trastuzumab resistance in HER2-positive breast cancer cell lines. Here, we explored the mechanism of TNFα-induced trastuzumab resistance and the therapeutic strategies to overcome it. Trastuzumab-sensitive breast cancer cells, genetically engineered to stably overexpress TNFα, and de novo trastuzumab-resistant tumors, were used to evaluate trastuzumab response and TNFɑ-blocking antibodies effectiveness respectively...
October 3, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Wei-Wei Deng, Lei Wu, Lin-Lin Bu, Jian-Feng Liu, Yi-Cun Li, Si-Rui Ma, Guang-Tao Yu, Liang Mao, Wen-Feng Zhang, Zhi-Jun Sun
P21 activated kinase 2 (PAK2) is a member of Group I PAKs family and highly expressed in various cancers. Current studies have demonstrated that PAK2 played a pivotal role in tumor progression. However, the role of PAK2 in salivary adenoid cystic carcinoma is still unclear. This study aims to explore the expression and the function of PAK2 in AdCC. Human salivary gland tissue microarray, including 18 normal salivary glands (NSG), 12 pleomorphic adenoma (PMA) and 72 AdCC, and immunohistochemistry were used to evaluate the expression of PAK2...
2016: American Journal of Translational Research
Elisa Cappuzzello, Anna Tosi, Paola Zanovello, Roberta Sommaggio, Antonio Rosato
Cytokine-induced Killer (CIK) cells are a heterogeneous population of ex vivo expanded T lymphocytes capable of MHC-unrestricted antitumor activity, which share phenotypic and functional features with both NK and T cells. Preclinical data and initial clinical studies demonstrated their high tolerability in vivo, supporting CIK cells as a promising cell population for adoptive cell immunotherapy. In this study, we report for the first time that CIK cells display a donor-dependent expression of CD16, which can be engaged by trastuzumab or cetuximab to exert a potent antibody-dependent cell-mediated cytotoxicity (ADCC) against ovarian and breast cancer cell lines, leading to an increased lytic activity in vitro, and an enhanced therapeutic efficacy in vivo...
August 2016: Oncoimmunology
Shanshan Chen, Xuechun Li, Rongming Chen, Mingang Yin, Qiuhong Zheng
Natural killer (NK) cells, discovered ~40 years ago, are believed to be the most effective cytotoxic lymphocytes to counteract cancer; however, adoptive NK cell therapy in vivo has encountered certain limitations, including a lack of specificity. The drug cetuximab can mediate antibody dependent cell mediated cytotoxicity (ADCC) activity through NK cells in vivo, and has been approved for the first-line treatment of epidermal growth factor receptor (EGFR)-positive metastatic colorectal cancer (CRC). However, the ADCC activity of adoptive NK cells, induced by cetuximab in a nude mouse CRC xenograft model, has not been previously reported...
September 2016: Oncology Letters
John O Richards, Alex J Albers, Thomas S Smith, Judy A Tjoe
Tumor-targeting antibodies have been successful in the treatment of various types of cancers. Antibodies engage the immune system with their Fc, stimulating immune cell effector function. In the clinic, FcγRIIIa polymorphisms with higher affinity for the Fc of antibodies were shown to improve response rates and overall survival. Efforts have been made to modify the Fc to enhance affinity to Fc receptors and thereby improve effector function. An alternative for improving immune effector function may be to increase the level of tumor antigen expression...
August 29, 2016: Cancer Immunology, Immunotherapy: CII
Cristiana Lo Nigro, Vincenzo Ricci, Daniela Vivenza, Cristina Granetto, Teresa Fabozzi, Emanuela Miraglio, Marco C Merlano
AIM: To reviewing genetic and epigenetic make-up of metastatic colorectal cancers (mCRCs) addicted to epidermal growth factor receptor (EGFR) signalling. METHODS: The present study summarizes the potential value of prognostic and predictive biomarkers in selecting mCRC patients treated with anti-EGFR therapy. A meta-analysis was performed using a systematic search of PubMed, Medline and Web of Science to identify eligible papers until March 21(st), 2016 using these following terms: ''colorectal cancer'', "predictive biomarkers'', "anti-EGFR therapy", "KRAS", "NRAS'', "PIK3CA", "TP53", "PTEN", ''EGFR", "MET", "HER2", "epiregulin", "amphiregulin", "prognostic biomarkers", "BRAF", "miRNA" and "antibody-dependent cell-mediated cytotoxicity (ADCC) activity"...
August 14, 2016: World Journal of Gastroenterology: WJG
Aneta Schieferdecker, Ofer Shoshani, Benedikt Westner, Dov Zipori, Boris Fehse, Nicolaus Kröger, Francis Ayuk
INTRODUCTION: Multiple myeloma is still incurable in most cases. Polyclonal anti T lymphocyte globulins (ATG) have been reported to kill human myeloma cells in vitro and in mouse models. METHODS: Anti-human-myeloma globulins (AMG) were produced by immunizing rabbits with human myeloma cell lines RPMI-8226 (AMG-8226) or KMS-12-BM (AMG-12-BM). Cytotoxicity of the polyclonal antibodies was analyzed in vitro and in a xenograft NOD-SCID mouse model. RESULTS: Both AMG had stronger cytotoxicity against myeloma cells compared to ATG...
August 22, 2016: Oncotarget
Tristan Legris, Christophe Picard, Dilyana Todorova, Luc Lyonnet, Cathy Laporte, Chloé Dumoulin, Corinne Nicolino-Brunet, Laurent Daniel, Anderson Loundou, Sophie Morange, Stanislas Bataille, Henri Vacher-Coponat, Valérie Moal, Yvon Berland, Francoise Dignat-George, Stéphane Burtey, Pascale Paul
Although kidney transplantation remains the best treatment for end-stage renal failure, it is limited by chronic humoral aggression of the graft vasculature by donor-specific antibodies (DSAs). The complement-independent mechanisms that lead to the antibody-mediated rejection (ABMR) of kidney allografts remain poorly understood. Increasing lines of evidence have revealed the relevance of natural killer (NK) cells as innate immune effectors of antibody-dependent cellular cytotoxicity (ADCC), but few studies have investigated their alloreactive potential in the context of solid organ transplantation...
2016: Frontiers in Immunology
Johannes S Gach, Andrea Gorlani, Emmanuel Y Dotsey, Juan C Becerra, Chase T M Anderson, Baiba Berzins, Philip L Felgner, Donald N Forthal, Steven G Deeks, Timothy J Wilkin, Joseph P Casazza, Richard A Koup, Christine Katlama, Brigitte Autran, Robert L Murphy, Chad J Achenbach
Little is known about the humoral immune response against DNA prime-recombinant adenovirus 5 (rAd5) boost HIV vaccine among HIV-infected patients on long-term suppressive antiretroviral therapy (ART). Previous studies emphasized cellular immune responses; however, current research suggests both cellular and humoral responses are likely required for a successful therapeutic vaccine. Thus, we aimed to understand antibody response and function induced by vaccination of ART-treated HIV-1-infected patients with immune recovery...
2016: PloS One
Erin M Bertino, Elizabeth L McMichael, Xiaokui Mo, Prashant Trikha, Melanie Davis, Bonnie Paul, Michael Grever, William E Carson, Gregory A Otterson
mAbs can induce antibody-dependent cellular cytotoxicity (ADCC) via the innate immune system's ability to recognize mAb-coated cancer cells and activate immune effector cells. Lenalidomide is an immunomodulatory agent with the capacity to stimulate immune cell cytokine production and ADCC activity. This phase I trial evaluated the combination of cetuximab with lenalidomide for the treatment of advanced colorectal and head and neck squamous cell cancers (HNSCC). This trial included patients with advanced colorectal cancer or HNSCC...
September 2016: Molecular Cancer Therapeutics
Donatella Negri, Maria Blasi, Celia LaBranche, Robert Parks, Harikrishnan Balachandran, Michelle Lifton, Xiaoying Shen, Thomas Denny, Guido Ferrari, Maria Fenicia Vescio, Hanne Andersen, David C Montefiori, Georgia D Tomaras, Hua-Xin Liao, Sampa Santra, Barton F Haynes, Mary E Klotman, Andrea Cara
The design of an effective HIV-1 vaccine remains a major challenge. Several vaccine strategies based on viral vectors have been evaluated in preclinical and clinical trials, with largely disappointing results. Integrase defective lentiviral vectors (IDLV) represent a promising vaccine candidate given their ability to induce durable and protective immune responses in mice after a single immunization. Here, we evaluated the immunogenicity of a SIV-based IDLV in nonhuman primates. Six rhesus monkeys were primed intramuscularly with IDLV-Env and boosted with the same vector after 1 year...
July 26, 2016: Molecular Therapy: the Journal of the American Society of Gene Therapy
Elizabeth L McMichael, Alena C Jaime-Ramirez, Kristan D Guenterberg, Eric Luedke, Lakhvir S Atwal, Amanda Campbell, Zhiwei Hu, Armika S Tatum, Sri Vidya Kodadasula, Xiaokui Mo, Susheela Tridandapani, Mark Bloomston, E Christopher Ellison, Terence M Williams, Tanios Bekaii-Saab, William E Carson
PURPOSE: Alternative strategies to EGFR blockage by mAbs is necessary in order to improve the efficacy of therapy in patients with locally advanced or metastatic pancreatic cancer. One such strategy includes the use of NK cells to clear cetuximab-coated tumor cells, as need for novel therapeutic approaches to enhance the efficacy of cetuximab is evident. We show that IL-21 enhances NK cell-mediated effector functions against cetuximab-coated pancreatic tumor cells irrespective of KRAS mutation status...
July 19, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Sinthujan Jegaskanda, Catherine Luke, Heather D Hickman, Mark Y Sangster, Wendy F Wieland-Alter, Jacqueline M McBride, Jon W Yewdell, Peter F Wright, John Treanor, Carrie M Rosenberger, Kanta Subbarao
BACKGROUND: Nonneutralizing antibodies (Abs) involved in antibody-dependent cellular cytotoxicity (ADCC) may provide some protection from influenza virus infection. The ability of influenza vaccines to induce ADCC-mediating Abs (ADCC-Abs) in adults and children is unclear. METHODS: We quantified ADCC-Abs in serum samples from adults who received a dose of inactivated subunit vaccine (ISV) targeting monovalent 2009 pandemic influenza A(H1N1) virus or live-attenuated influenza vaccine (LAIV) or who had laboratory-confirmed influenza A(H1N1) virus infection...
September 15, 2016: Journal of Infectious Diseases
John Pradeep Veluchamy, Jan Spanholtz, Marleen Tordoir, Victor L Thijssen, Daniëlle A M Heideman, Henk M W Verheul, Tanja D de Gruijl, Hans J van der Vliet
The ability of Natural Killer (NK) cells to kill tumor targets has been extensively studied in various hematological malignancies. However, NK cell therapy directed against solid tumors is still in early development. Epidermal Growth Factor Receptor (EGFR) targeted therapies using monoclonal antibodies (mAbs) such as cetuximab and panitumumab are widely used for the treatment of metastatic colorectal cancer (mCRC). Still, the clinical efficacy of this treatment is hampered by mutations in RAS gene, allowing tumors to escape from anti-EGFR mAb therapy...
2016: PloS One
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