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Sarah L Buchan, Mohannad Fallatah, Stephen M Thirdborough, Vadim Y Taraban, Anne Rogel, Lawrence J Thomas, Christine A Penfold, Li-Zhen He, Michael A Curran, Tibor Keler, Aymen Al-Shamkhani
Purpose: PD-1 checkpoint blockade has revolutionized the field of cancer immunotherapy, yet the frequency of responding patients is limited by inadequate T-cell priming secondary to a paucity of activatory dendritic cells (DC). DC signals can be bypassed by CD27 agonists, and we therefore investigated if the effectiveness of anti-PD-1/L1 could be improved by combining with agonist anti-CD27 monoclonal antibodies (mAb). Experimental Design: The efficacy of PD-1/L1 blockade or agonist anti-CD27 mAb was compared with a dual-therapy approach in multiple tumor models...
May 15, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Anna H Turaj, Khiyam Hussain, Kerry L Cox, Matthew J J Rose-Zerilli, James Testa, Lekh N Dahal, H T Claude Chan, Sonya James, Vikki L Field, Matthew J Carter, Hyung J Kim, Jonathan J West, Lawrence J Thomas, Li-Zhen He, Tibor Keler, Peter W M Johnson, Aymen Al-Shamkhani, Stephen M Thirdborough, Stephen A Beers, Mark S Cragg, Martin J Glennie, Sean H Lim
Monoclonal antibodies (mAbs) can destroy tumors by recruiting effectors such as myeloid cells, or targeting immunomodulatory receptors to promote cytotoxic T cell responses. Here, we examined the therapeutic potential of combining a direct tumor-targeting mAb, anti-CD20, with an extended panel of immunomodulatory mAbs. Only the anti-CD27/CD20 combination provided cures. This was apparent in multiple lymphoma models, including huCD27 transgenic mice using the anti-huCD27, varlilumab. Detailed mechanistic analysis using single-cell RNA sequencing demonstrated that anti-CD27 stimulated CD8+ T and natural killer cells to release myeloid chemo-attractants and interferon gamma, to elicit myeloid infiltration and macrophage activation...
December 11, 2017: Cancer Cell
Anna Wasiuk, James Testa, Jeff Weidlick, Crystal Sisson, Laura Vitale, Jenifer Widger, Andrea Crocker, Lawrence J Thomas, Joel Goldstein, Henry C Marsh, Tibor Keler, Li-Zhen He
CD27, a member of the TNFR superfamily, is constitutively expressed in most T cells and plays crucial roles in T cell effector functions. The costimulation and antitumor activity of CD27 agonistic Abs have been well documented in mouse models. Clinical testing of a human IgG1 anti-CD27 Ab, varlilumab (clone 1F5), is ongoing in cancer patients. In this study, we set out to further understand CD27 as an immunomodulatory target and to address the mechanism of antitumor efficacy using different IgG isotypes of 1F5 in human CD27 -transgenic mice...
December 15, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
Elina Alaterre, Sébastien Raimbault, Jean-Michel Garcia, Thierry Rème, Guilhem Requirand, Bernard Klein, Jérôme Moreaux
BACKGROUND: Multiple myeloma (MM) is an incurable disease characterized by clonal plasma cell (PC) proliferation within the bone marrow (BM). Next-generation flow cytometry has become the reference tool to follow minimal residual disease (MRD). We developed a new simpler and cheaper flow cytometry method to analyze bone marrow samples in patients with MM. METHODS: To identify and characterize abnormal PCs, we designed a simple panel composed of anti-CD38, antikappa, and antilambda light chain antibodies, combined with two antibody pools with the same fluorophore (anti-CD19 and anti-CD27 for the negative pool and anti-CD56, anti-CD117, and anti-CD200 antibodies for the positive pool)...
September 2, 2017: Cytometry. Part B, Clinical Cytometry
Alexey Teplyakov, Galina Obmolova, Thomas J Malia, Gary L Gilliland
CD27 is a T-cell and B-cell co-stimulatory glycoprotein of the tumor necrosis factor (TNF) receptor superfamily that is dependent on the availability of the TNF-like ligand CD70. Therapeutic approaches to treating autoimmune diseases and cancers with antagonistic and agonistic anti-CD27 monoclonal antibodies (mAbs), respectively, have recently been developed. Mouse anti-human CD27 mAb 2177 shows potency in neutralizing CD70-induced signaling; however, it does not block the binding of soluble CD70. To provide insight into the mechanism of action of the mAb, the crystal structure of the CD27 extracellular domain in complex with the Fab fragment of mAb 2177 was determined at 1...
May 1, 2017: Acta Crystallographica. Section F, Structural Biology Communications
Howard A Burris, Jeffrey R Infante, Stephen M Ansell, John J Nemunaitis, Geoffrey R Weiss, Victor M Villalobos, Branimir I Sikic, Matthew H Taylor, Donald W Northfelt, William E Carson, Thomas R Hawthorne, Thomas A Davis, Michael J Yellin, Tibor Keler, Timothy Bullock
Purpose CD27, a costimulatory molecule on T cells, induces intracellular signals that mediate cellular activation, proliferation, effector function, and cell survival upon binding to its ligand, CD70. Varlilumab is a novel, first-in-class, agonist CD27 antibody that stimulates the CD27 pathway, which results in T-cell activation and antitumor activity in tumor models. This first-in-human, dose-escalation and expansion study evaluated the safety, pharmacology, and activity of varlilumab in patients with advanced solid tumors...
June 20, 2017: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
Galina Obmolova, Alexey Teplyakov, Thomas J Malia, Nicole Wunderler, Deborah Kwok, Linda Barone, Raymond Sweet, Tatiana Ort, Michael Scully, Gary L Gilliland
CD27 is a T and B cell co-stimulatory protein of the TNF receptor superfamily dependent on the availability of the TNF-like ligand CD70. Two anti-CD27 neutralizing monoclonal antibodies were obtained from mouse hybridoma and subsequently humanized and optimized for binding the target. The two antibodies are similar in terms of their CD27-binding affinity and ability to block NF-κB signaling, however their clearance rates in monkeys are very different. The pharmacokinetics profiles could be epitope dependent...
March 2017: Molecular Immunology
Miguel F Sanmamed, Fernando Pastor, Alfonso Rodriguez, Jose Luis Perez-Gracia, Maria E Rodriguez-Ruiz, Maria Jure-Kunkel, Ignacio Melero
T and natural killer (NK) lymphocytes are considered the main effector players in the immune response against tumors. Full activation of T and NK lymphocytes requires the coordinated participation of several surface receptors that meet their cognate ligands through structured transient cell-to-cell interactions known as immune synapses. In the case of T cells, the main route of stimulation is driven by antigens as recognized in the form of short polypeptides associated with major histocompatibility complex (MHC) antigen-presenting molecules...
August 2015: Seminars in Oncology
Si-Ming Wei, Jin-Xuan Fei, Feng Tao, Hang-Li Pan, Qing Shen, Li Wang, Yu-Jia Wu, Li Zhou, Sheng-Xin Zhu, Wei-Bin Liao, Hua Ji, Zhao-Liang Xin
In the current study, we investigated whether anti-CD27 monoclonal antibody can enhance the antitumor efficacy of a dendritic cell-based vaccine in prostate cancer-bearing mice. The overall therapeutic effect of a dendritic cell-based vaccine for prostate cancer remains moderate. A prostate cancer model was established by subcutaneous injection of RM-1 tumor cells into male C57BL/6 mice on day 0. After 4 days, tumor-bearing mice were treated with RM-1 tumor lysate-pulsed dendritic cells (i.e., dendritic cell-based vaccine), anti-CD27 monoclonal antibody, or a combination of RM-1 tumor lysate-pulsed dendritic cells with anti-CD27 monoclonal antibody...
January 2015: International Surgery
Sarah Buchan, Teresa Manzo, Barry Flutter, Anne Rogel, Noha Edwards, Lei Zhang, Shivajanani Sivakumaran, Sara Ghorashian, Ben Carpenter, Clare Bennett, Gordon J Freeman, Megan Sykes, Michael Croft, Aymen Al-Shamkhani, Ronjon Chakraverty
Exhaustion of chronically stimulated CD8(+) T cells is a significant obstacle to immune control of chronic infections or tumors. Although coinhibitory checkpoint blockade with anti-programmed death ligand 1 (PD-L1) Ab can restore functions to exhausted T cell populations, recovery is often incomplete and dependent upon the pool size of a quiescent T-bet(high) subset that expresses lower levels of PD-1. In a model in which unhelped, HY-specific CD8(+) T cells gradually lose function following transfer to male bone marrow transplantation recipients, we have explored the effect of shifting the balance away from coinhibition and toward costimulation by combining anti-PD-L1 with agonistic Abs to the TNFR superfamily members, OX40 and CD27...
January 1, 2015: Journal of Immunology: Official Journal of the American Association of Immunologists
Xiang-Ying Huang, Shuang-Qing Yu, Zhan Cheng, Jing-Rong Ye, Ke Xu, Xia Feng, Yi Zeng
OBJECTIVE: To establish a simple and practical method for screening of Env-specific monoclonal antibodies from HIV-1 infected individuals. METHODS: Human B cells were purified by negative sorting from PBMCs and memory B cells were further enriched using anti-CD27 microbeads. Gp120 antigen labbled with biotin was incubated with memory B cells to specifically bind IgG on cells membrane. The memory B cells expressing the Env-specific antibody were harvested by magnetic beads separating, counted and diluted to the level of single cell in each PCR well that loading with catch buffer containing RNase inhibitor to get RNAs...
April 2013: Chinese Journal of Experimental and Clinical Virology
A Hajas, S Barath, P Szodoray, B Nakken, P Gogolak, Z Szekanecz, E Zold, M Zeher, G Szegedi, E Bodolay
Mixed connective tissue disease (MCTD) is a systemic autoimmune disorder, characterized by the presence of antibodies to U1-RNP protein. We aimed to determine phenotypic abnormalities of peripheral B cell subsets in MCTD. Blood samples were obtained from 46 MCTD patients, and 20 controls. Using anti-CD19, anti-CD27, anti-IgD and anti-CD38 monoclonal antibodies, the following B cell subsets were identified by flow cytometry: (1) transitional B cells (CD19+CD27-IgD+CD38(high)); (2) naive B cells (CD19+CD27-IgD+CD38(low)); (3) non-switched memory B cells (CD19+CD27+IgD+); (4) switched memory B cells (CD19+CD27+IgD-); (5) double negative (DN) memory B cells (CD19+CD27-IgD-) and (6) plasma cells (CD19+CD27(high)IgD-)...
July 2013: Human Immunology
Hui-Min Wang, Ke Xu, Shuang-Qing Yu, Lin-Lin Ding, Hai-Yan Luo, Robin Flinko, George K Lewis, Xia Feng, Ji-Rong Shao, Yong-Jun Guan, Yi Zeng
To obtain protective human monoclonal antibody from HIV-1 infected person, we adapted a technology for isolating antigen specific monoclonal antibody from human memory B cells through in vitro B cell activation coupled with RT-PCT and expression cloning. Human B cells were purified by negative sorting from PBMCs of HIV-1 infected individuals and memory B cells were further enriched using anti-CD27 microbeads. Two hundred memory B cells per well were cultured in 96-well round-bottom plates Env-specific antibodies in supernatants were with feeder cells in medium containing EBV and CpG...
June 2012: Bing du Xue Bao, Chinese Journal of Virology
Drew J Roberts, Nathan A Franklin, Lara M Kingeter, Hideo Yagita, Alison L Tutt, Martin J Glennie, Timothy N J Bullock
The immune response to the tumor can be enhanced by targeting costimulatory molecules on T cells. As the CD70-CD27 costimulatory axis plays an important role in the activation, survival, and differentiation of lymphocytes, we have examined the efficacy of agonistic anti-CD27 antibodies as monotherapies for established melanoma in a murine model. We show that this approach leads to a substantial reduction in the outgrowth of both experimental lung metastases and subcutaneous tumors. Anti-CD27 treatment supports the maintenance of tumor-specific CD8(+) T cells within the tumor, reduces the frequency of FoxP3-expressing CD4(+) T cells within tumors, and potentiates the ability of NK1...
October 2010: Journal of Immunotherapy
Tamami Sakanishi, Hideo Yagita
CD27 plays an important role in T-cell co-stimulation and is also expressed on lymphomas. In the present study, we generated novel depleting and non-depleting monoclonal antibodies (mAbs) against mouse CD27 and characterized their co-stimulatory activity in vitro and anti-tumor effects in immune-competent mice bearing syngeneic T-cell lymphoma (EG7) expressing or lacking CD27. A profound anti-tumor effect was observed with a non-depleting mAb (RM27-3E5), but not with a depleting mAb (RM27-3C1), against either EG7/CD27(+) or EG7/CD27(-) tumors, which was associated with the induction of EG7-specific cytotoxic T lymphocytes (CTLs)...
March 19, 2010: Biochemical and Biophysical Research Communications
Karol Ratomski, Beata Zelazowska-Rutkowska, Jolanta Wysocka, Bozena Skotnicka, Edwina Kasprzycka, Elzbieta Hassmann-Poznańska
INTRODUCTION: Adenoid has particular meaning to develop of immunological response to inflammations in upper respiratory inclusive middle ear. The mining of antigen CD27 on lymphocytes T and B in creation of memory cells is still unclear. AIM: CD27 on lymphocytes T and B has a crucial role in development of immune response against inflammatory state. Aim of this study was evaluation functions of lymhocytes with expression CD27 in hypertrophied adenoid in children with otitis media with effusion...
May 2009: Otolaryngologia Polska
Sylvie Rusakiewicz, Geraldine Aubert, Richard E Clark, Alejandro J Madrigal, Anthony I Dodi, Paul J Travers
Soluble MHC-peptide complexes, commonly referred to as tetramers, have been shown to induce strong cross-linking of TCR and CD8, resulting in a vigorous activation followed by a rapid non-apoptotic CD8(+) T cell death. This has limited tetramer use for antigen-specific T cells isolation and cloning, as sorted tetramer positive cells were shown to possess compromised functional integrity. Here we show that the cross-linking of a secondary co-stimulatory signal into oligomeric MHC:peptide complexes prevents such cell death, and in contrast strongly stimulates antigen-specific T cell responses...
September 2009: Cancer Immunology, Immunotherapy: CII
Ai-Hua Liao, Li-Ping Liu, Wen-Ping Ding, Ling Zhang
PROBLEM: The aim of our study was to investigate the functional changes of human peripheral B-lymphocytes in healthy and pre-eclamptic pregnancies. METHOD OF STUDY: Twenty patients with pre-eclampsia and 15 healthy third-trimester pregnant women were recruited in this study. Peripheral blood mononuclear cells (PBMCs) were isolated and directly stained with fluorescein isothiocyanate (FITC)-labeled anti-CD27 monoclonal antibody (mAb) and phycoerythrin (PE)-labeled anti-CD38 mAb...
May 2009: American Journal of Reproductive Immunology: AJRI
Tamaki Sumi, Waka Ishida, Ayako Ojima, Minako Kajisako, Tamami Sakanishi, Hideo Yagita, Atsuki Fukushima
CD27, which belongs to the TNF receptor family, is a costimulatory molecule that participates in T-cell activation. Unlike costimulatory molecules such as OX40 and 4-1BB, little is known about the role CD27 plays a role in the development of experimental diseases. We asked whether CD27 and its ligand CD70 participate in the development of experimental allergic conjunctivitis (EC) in BALB/c mice, which is generated by immunization with ragweed (RW) in alum and challenged 10 days later with RW in eye drops. The roles of CD27 and CD70 were tested by intraperitoneally injecting the mice with anti-CD27, anti-CD70 or a control Ab during the induction or effector phase...
August 15, 2008: Immunology Letters
Ruth R French, Vadim Y Taraban, Graham R Crowther, Tania F Rowley, Juliet C Gray, Peter W Johnson, Alison L Tutt, Aymen Al-Shamkhani, Martin J Glennie
Growing evidence points to the potential of agonistic anti-CD40 mAbs as adjuvants for vaccination against cancer. These appear to act by maturing dendritic cells (DCs) and allowing them to prime CD8 cytotoxic T lymphocytes (CTLs). Although it is well established that optimal T-cell priming requires costimulation via B7:CD28, recent studies emphasize the contribution of TNF receptors to this process. To understand how anti-CD40 mAbs trigger effective antitumor immunity, we investigated the role of TNFR superfamily members CD27 and 4-1BB in the generation of this immunity and showed that, although partially dependent on 4-1BB:4-1BBL engagement, it is completely reliant on CD27:CD70 interactions...
June 1, 2007: Blood
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