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https://www.readbyqxmd.com/read/28332900/fc-or-not-fc-that-is-the-question-antibody-fc-receptor-interactions-are-key-to-universal-influenza-vaccine-design
#1
Sinthujan Jegaskanda, Hillary A Vanderven, Adam K Wheatley, Stephen J Kent
A universal vaccine that provides long-lasting protection from both epidemic and pandemic influenza viruses remains the "holy grail" of influenza vaccine research. Though virus neutralization assays are the current benchmark of measuring vaccine effectiveness, it is clear that Fc-receptor functions can drastically improve the effectiveness of antibodies and vaccines in vivo. Antibodies that kill virus-infected cells and/or elicit an antiviral environment, termed antibody-dependent cellular cytotoxicity (ADCC)-mediating antibodies, provide a link between the innate and adaptive immune response...
March 23, 2017: Human Vaccines & Immunotherapeutics
https://www.readbyqxmd.com/read/28332312/antitumor-activity-of-chlpmab-2-a-human-mouse-chimeric-cancer-specific-antihuman-podoplanin-antibody-via-antibody-dependent-cellular-cytotoxicity
#2
Mika K Kaneko, Shinji Yamada, Takuro Nakamura, Shinji Abe, Yasuhiko Nishioka, Akiko Kunita, Masashi Fukayama, Yuki Fujii, Satoshi Ogasawara, Yukinari Kato
Human podoplanin (hPDPN), a platelet aggregation-inducing transmembrane glycoprotein, is expressed in different types of tumors, and it binds to C-type lectin-like receptor 2 (CLEC-2). The overexpression of hPDPN is involved in invasion and metastasis. Anti-hPDPN monoclonal antibodies (mAbs) such as NZ-1 have shown antitumor and antimetastatic activities by binding to the platelet aggregation-stimulating (PLAG) domain of hPDPN. Recently, we developed a novel mouse anti-hPDPN mAb, LpMab-2, using the cancer-specific mAb (CasMab) technology...
March 23, 2017: Cancer Medicine
https://www.readbyqxmd.com/read/28331095/divergent-requirement-of-fc-fc%C3%AE-r-interactions-for-in-vivo-protection-against-influenza-viruses-by-two-pan-h5-hemagglutinin-antibodies
#3
Shuangshuang Wang, Huanhuan Ren, Wenbo Jiang, Honglin Chen, Hongxing Hu, Zhiwei Chen, Paul Zhou
Recent studies have shown that Fc-FcγR interactions are required for in vivo protection against influenza viruses by broadly reactive anti-HA stem, but not virus strain-specific, anti-receptor binding site (RBS), antibodies (Abs). Since only a few Abs recognizing epitopes in the head region but outside the RBS have been tested against single challenge virus strains, it remains unknown whether Fc-FcγR interactions are required for in vivo protection by Abs recognizing epitopes outside the RBS, and whether the requirement is virus strain-specific or epitope-specific...
March 22, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28331088/bst-2-expression-modulates-small-cd4-mimetic-sensitization-of-hiv-1-infected-cells-to-adcc
#4
Jonathan Richard, Jérémie Prévost, Benjamin von Bredow, Shilei Ding, Nathalie Brassard, Halima Medjahed, Mathieu Coutu, Bruno Melillo, Frédéric Bibollet-Ruche, Beatrice H Hahn, Daniel E Kaufmann, Amos B Smith, Joseph Sodroski, Daniel Sauter, Frank Kirchhoff, Katrina Gee, Stuart J Neil, David T Evans, Andrés Finzi
Antibodies recognizing conserved CD4-induced (CD4i) epitopes on HIV-1 Env and able to mediate antibody-dependent cellular cytotoxicity (ADCC) have been shown to be present in sera from most HIV-1-infected individuals. These antibodies preferentially recognize Env in its CD4-bound conformation. CD4 downregulation by Nef and Vpu dramatically reduces exposure of CD4i HIV-1 Env epitopes and therefore reduce the susceptibility of HIV-1-infected cells to ADCC mediated by HIV+ sera. Importantly, this mechanism of immune evasion can be circumvented with small-molecule CD4-mimetics (CD4mc) which are able to transition Env into the CD4-bound conformation and sensitize HIV-1-infected cells to ADCC mediated by HIV+ sera...
March 22, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28323750/humoral-responses-against-hiv-in-male-genital-tract-role-in-sexual-transmission-and-perspectives-for-preventive-strategies
#5
Amandine Gagneux-Brunon, Nicolas Rochereau, Elisabeth Botelho-Nevers, Frédéric Lucht, Bruno Pozzetto, Stéphane Paul, Thomas Bourlet
Most new HIV infections occur via sexual routes. The induction of protective anti-HIV antibodies in genital mucosa is an important step towards reducing HIV transmission. Mucosal anti-HIV antibodies may play a dual role by either protecting against HIV transmission or facilitating it. Protective properties against HIV of mucosal IgGs and IgAs exhibiting neutralizing or antibody dependent cell-mediated cytotoxicity (ADCC) activities have been described in highly exposed seronegative individuals (HESN). Conversely, some IgGs may facilitate the crossing of HIV free particles through epithelial barriers by transcytosis...
March 18, 2017: AIDS
https://www.readbyqxmd.com/read/28322167/hiv-specific-adcc-new-technologies-to-study-adcc-and-importance-for-the-hiv-vaccine-field
#6
Bruce D Wines, Hugh Billings, Milla R Mclean, Stephen J Kent, P Mark Hogarth
There is now intense interest in the role of HIV-specific antibodies and the engagement of FcγR functions in the control and prevention of HIV infection. The RV144 vaccine study, natural progression cohorts, and macaque studies all point to a role for antibody dependent cellular cytotoxicity (ADCC) in the control of HIV. However, reliable assays that can be reproducibly used across different laboratories to measure ADCC and other Fc-dependent functions of antibodies are limited. We recently developed a novel ELISA-based assay to detect the binding of viral antigen-specific antibodies to the ectodomains of homo-dimeric Fcγ receptors...
March 20, 2017: Current HIV Research
https://www.readbyqxmd.com/read/28318221/crystal-structure-of-a-homogeneous-igg-fc-glycoform-with-the-n-glycan-designed-to-maximize-the-antibody-dependent-cellular-cytotoxicity
#7
Chia-Lin Chen, Jen-Chi Hsu, Chin-Wei Lin, Chia-Hung Wang, Ming-Hung Tsai, Chung-Yi Wu, Chi-Huey Wong, Che Ma
N-glycosylation on IgG modulates Fc conformation and effector functions. An IgG-Fc contains a human sialo-complex type (hSCT) glycan of biantennary structure with two α2,6-sialylations and without core-fucosylation is an optimized glycoform developed to enhance the antibody dependent cellular cytotoxicity (ADCC). hSCT modification not only enhances the binding affinity to Fc receptors in the presence of antigen, but also in some cases provides gain-of-function effector activity. We used enzymatic glyco-engineering to prepare an IgG-Fc with homogeneous hSCT attached to each CH2 domain, and solved its crystal structure...
March 20, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28317093/non-neutralizing-epitopes-induce-robust-hcv-specific-antibody-dependent-cd56-nk-cell-responses-in-chronic-hcv-infected-patients
#8
Lu Long, Manxue Jia, Xueying Fan, Hua Liang, Jiahua Wang, Liyan Zhu, Zhe Xie, Tao Shen
NK cell-mediated antibody-dependent cellular cytotoxicity (NK-ADCC) is of considerable interest in viral infection. However, little is known about NK-ADCC responses in chronic hepatitis C virus (HCV) infection. In this study, impaired nonspecific antibody-dependent CD56(+) NK cell responses were observed in chronic HCV infection, as shown by decreased degranulation (extracellular CD107a expression) and IFN-γ production in response to antibody-bound P815 cells. A peptide pool composed of epitopes recognized by anti-HCV-E1/E2 antibodies could induce pronounced HCV-specific antibody-dependent NK cell responses in sera from approximately half of the chronic HCV carriers...
March 20, 2017: Clinical and Experimental Immunology
https://www.readbyqxmd.com/read/28314374/hiv-1-consensus-envelope-induced-broadly-binding-antibodies
#9
R Ryan Meyerhoff, Richard M Scearce, Damon F Ogburn, Brad Lockwood, Joy Pickeral, Masa Kuraoka, Kara Anasti, Joshua Eudailey, Amanda Eaton, Melissa Cooper, Kevin Wiehe, David C Montefiori, Georgia D Tomaras, Guido Ferrari, S Munir Alam, Hua-Xin Liao, Bette Korber, Feng Gao, Barton F Haynes
Antibodies that cross-react with multiple HIV-1 envelopes (Envs) are useful reagents for characterizing Env proteins and for soluble Env capture and purification assays. We previously reported ten murine monoclonal antibodies induced by group M consensus Env, CON-6 immunization. Each demonstrated broad cross-reactivity to recombinant Envs. Here we characterized the Env epitopes to which they bind. Seven mapped to linear epitopes in gp120, five at the Env N-terminus and two at the Env C-terminus. One antibody, 13D7, bound at the gp120 N-terminus (aa 30-42), reacted with HIV-1-infected CD4+ T cells, and when expressed in a human IgG1 backbone, mediated ADCC...
March 17, 2017: AIDS Research and Human Retroviruses
https://www.readbyqxmd.com/read/28298635/novel-mutations-in-crygc-are-associated-with-congenital-cataracts-in-chinese-families
#10
Zilin Zhong, Zehua Wu, Liyun Han, Jianjun Chen
Congenital cataract (CC), responsible for about one-third of blindness in infants, is a major cause of vision loss in children worldwide. 10-25% of CC cases are attributed to genetic causes and CC is a clinically and genetically highly heterogeneous lens disorder in children. Autosomal dominant (AD) inheritance is the most commonly pattern. 195 unrelated non-syndromic ADCC families in this study are recruited from 15 provinces of China. Sanger sequencing approach followed by intra-familial co-segregation, in Silico analyses and interpretation of the variations according to the published guidelines of American College of Medical Genetics (ACMG), were employed to determine the genetic defects...
March 15, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28296619/drifts-in-adcc-related-quality-attributes-of-herceptin%C3%A2-impact-on-development-of-a-trastuzumab-biosimilar
#11
Seokkyun Kim, Jinsu Song, Seungkyu Park, Sunyoung Ham, Kyungyeol Paek, Minjung Kang, Yunjung Chae, Heewon Seo, Hyung-Chan Kim, Michael Flores
A biosimilar product needs to demonstrate biosimilarity to the originator reference product, and the quality profile of the latter should be monitored throughout the period of the biosimilar's development to match the quality attributes of the two products that relate to efficacy and safety. For the development of a biosimilar version of trastuzumab, the reference product, Herceptin®, was extensively characterized for the main physicochemical and biological properties by standard or state-of-the-art analytical methods, using multiple lots expiring between March 2015 and December 2019...
March 15, 2017: MAbs
https://www.readbyqxmd.com/read/28289219/modulating-igg-effector-function-by-fc-glycan-engineering
#12
Tiezheng Li, David J DiLillo, Stylianos Bournazos, John P Giddens, Jeffrey V Ravetch, Lai-Xi Wang
IgG antibodies contain a conserved N-glycosylation site on the Fc domain to which a complex, biantennary glycan is attached. The fine structures of this glycan modulate antibody effector functions by affecting the binding affinity of the Fc to diverse Fc receptor family members. For example, core fucosylation significantly decreases antibody-dependent cellular cytotoxicity (ADCC), whereas terminal α2,6-sialylation plays a critical role in the anti-inflammatory activity of human i.v. immunoglobulin therapy...
March 13, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28281922/a-high-performance-non-radioactive-potency-assay-for-measuring-cytotoxicity-a-full-substitute-of-the-chromium-release-assay-targeting-the-regulatory-compliance-objective
#13
Alexis Rossignol, Véronique Bonnaudet, Béatrice Clémenceau, Henri Vié, Laurent Bretaudeau
Standardized and biologically relevant potency assays are required by the regulatory authorities for the characterization and quality control of therapeutic antibodies. As critical mechanisms of action (MoA) of antibodies, the antibody-dependent cell-meditated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) must be characterized by appropriate potency assays. The current reference method for measuring cytotoxicity is the (51)Cr-release method. However, radioactivity handling is difficult to implement in an industrial context because of environmental and operator protection constraints...
February 8, 2017: MAbs
https://www.readbyqxmd.com/read/28275508/targeting-cd47-the-achievements-and-concerns-of-current-studies-on-cancer-immunotherapy
#14
COMMENT
Yuting Huang, Yuchi Ma, Peng Gao, Zhi Yao
Targeting CD47 is in the spotlight of cancer immunotherapy. Blocking CD47 triggers the recognition and elimination of cancer cells by the innate immunity. There are three CD47 antagonists in phase I clinical trials, but their potential efficacies are highly controversial. We raise our concern that NOD-based xenograft hosts tend to overestimate, while syngeneic mouse models could substantially underestimate the efficacy of anti-CD47 therapy. Such discrepancy may be resulted from specific reagent that alters CD47 clustering, and the highly variable avidities of interspecies and intraspecies CD47-SIRPα interaction...
February 2017: Journal of Thoracic Disease
https://www.readbyqxmd.com/read/28274143/avelumab-combining-immune-checkpoint-inhibition-and-antibody-dependent-cytotoxicity
#15
Gerhard Hamilton, Barbara Rath
Immune checkpoint inhibition holds great promise for selected tumors. The human monoclonal antibody (mAB) avelumab is directed to programmed death ligand-1 (PD-L1) and is supposed to inhibit the immunosuppressive PD-L1/PD-1 interaction and, furthermore, effect antibody-dependent cytotoxicity (ADCC) lysis of tumor cells. Areas covered: This article presents an overview of the current means to activate the antitumor immune defense by targeting PD-1 or PD-L1 with mABs and their possible role in ADCC-mediated tumor cell elimination...
April 2017: Expert Opinion on Biological Therapy
https://www.readbyqxmd.com/read/28265581/impact-of-desensitization-on-antiviral-immunity-in-hla-sensitized-kidney-transplant-recipients
#16
Mieko Toyoda, Bong-Ha Shin, Shili Ge, James Mirocha, David Thomas, Maggie Chu, Edgar Rodriguez, Christine Chao, Anna Petrosyan, Odette A Galera, Ashley Vo, Jua Choi, Alice Peng, Joseph Kahwaji, Stanley C Jordan
Viral infections represent significant morbidity and mortality factors in kidney transplant recipients, with CMV, EBV, and BKV infections being most common. Desensitization (DES) with IVIg and rituximab with/without plasma exchange followed by kidney transplantation with alemtuzumab induction increased successful transplant rates in HLA-sensitized patients but may represent an increased risk for viral infections due to severe lymphocyte depletion. Here, we report on the posttransplant viral infection status in 372 DES versus 538 non-DES patients...
2017: Journal of Immunology Research
https://www.readbyqxmd.com/read/28239472/analyses-of-the-peripheral-immunome-following-multiple-administrations-of-avelumab-a-human-igg1-anti-pd-l1-monoclonal-antibody
#17
Renee N Donahue, Lauren M Lepone, Italia Grenga, Caroline Jochems, Massimo Fantini, Ravi A Madan, Christopher R Heery, James L Gulley, Jeffrey Schlom
BACKGROUND: Multiple anti-PD-L1/PD-1 checkpoint monoclonal antibodies (MAb) have shown clear evidence of clinical benefit. All except one have been designed or engineered to omit the possibility to mediate antibody-dependent cell-mediated cytotoxicity (ADCC) as a second potential mode of anti-tumor activity; the reason for this is the concern of lysis of PD-L1 positive immune cells. Avelumab is a fully human IgG1 MAb which has been shown in prior in vitro studies to mediate ADCC versus a range of human tumor cells, and clinical studies have demonstrated anti-tumor activity versus a range of human cancers...
2017: Journal for Immunotherapy of Cancer
https://www.readbyqxmd.com/read/28236750/targeting-nk-cell-checkpoints-for-cancer-immunotherapy
#18
REVIEW
Aura Muntasell, Maria C Ochoa, Luna Cordeiro, Pedro Berraondo, Ascension López-Díaz de Cerio, Mariona Cabo, Miguel López-Botet, Ignacio Melero
Natural Killer (NK) cells are cytotoxic lymphocytes specialized in early defense against virus-infected and transformed cells. NK-cell function is regulated by activating and inhibitory surface receptors recognizing their ligands on transformed cells. Modulation of NK numbers and/or function by a variety of agents such as cytokines and monoclonal antibodies may result in enhanced anti-tumor activity. Recombinant cytokines (i.e., IL-15 and IL-2), antibodies blocking inhibitory receptors (i.e., KIR, NKG2A and TIGIT) and agonists delivering signals via CD137, NKG2D and CD16 stand out as the most suitable opportunities...
February 22, 2017: Current Opinion in Immunology
https://www.readbyqxmd.com/read/28231426/engineering-of-anti-cd133-tri-specific-molecule-capable-of-inducing-nk-expansion-and-driving-antibody-dependent-cell-mediated-cytotoxicity-adcc
#19
Jörg U Schmohl, Martin Felices, Felix Oh, Alexander J Lenvik, Aaron M Lebeau, Jayanth Panyam, Jeffrey S Miller, Daniel A Vallera
Purpose: The selective elimination of cancer stem cells (CSCs) in tumor patients is a crucial goal because CSCs cause drug refractory relapse. To improve the current conventional bispecific immune-engager platform, a 16133 BiKE, consisting of scFvs binding FcγRIII (CD16) on NK cells and CD133 on carcinoma cells, was first synthesized and a modified IL-15 crosslinker capable of stimulating NK effector cells was introduced. Materials and Methods: DNA shuffling and ligation techniques were used to assemble and synthesize the 1615133 trispecific NK cell engager (TriKE)...
February 20, 2017: Cancer Research and Treatment: Official Journal of Korean Cancer Association
https://www.readbyqxmd.com/read/28225449/ifn-%C3%AE-augments-natural-killer-mediated-antibody-dependent-cellular-cytotoxicity-of-hiv-1-infected-autologous-cd4-t-cells-regardless-of-major-histocompatibility-complex-class-1-downregulation
#20
Costin Tomescu, Pablo Tebas, Luis J Montaner
DESIGN: We have previously shown that IFN-α stimulation augments direct natural killer (NK) cell lysis of autologous CD4 primary T cells infected with certain HIV-1 isolates based upon major histocompatibility complex class 1 (MHC-1) downregulation capacity. Here, we investigated if antibody-dependent cellular cytotoxicity (ADCC) could trigger lysis of HIV-1 isolates that were resistant to direct NK lysis and if IFN-α prestimulation of NK cells could further enhance ADCC. METHODS: Using broadly neutralizing monoclonal antibodies against gp120 (VRC01 or PGV04) or plasma from HIV-1-infected patients (ART-suppressed or elite controller) to trigger ADCC, we measured NK cell chromium release cytotoxicity against HIV-1-infected autologous CD4 primary T cells and NK cell CD107a degranulation against gp120-coated CD4 T cells...
March 13, 2017: AIDS
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