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https://www.readbyqxmd.com/read/28533435/enzymatic-inactivation-of-endogenous-igg-by-ides-enhances%C3%A2-therapeutic-antibody-efficacy
#1
Sofia Järnum, Anna Runström, Robert Bockermann, Lena Winstedt, Max Crispin, Christian Kjellman
Endogenous plasma IgG sets an immunological threshold that dictates the activity of tumor-directed therapeutic antibodies. Saturation of cellular antibody receptors by endogenous antibody limits antibody-dependent cell-mediated cytotoxicity (ADCC) and antibody dependent cellular phagocytosis (ADCP). Here we show how enzymatic cleavage of IgG using the bacterial enzyme IdeS can be utilized to empty both high and low affinity Fcγ-receptors and clear the entire endogenous antibody pool. Using in vitro models, tumor animal models as well as ex vivo analysis of sera collected during a previous clinical trial with IdeS, we show how clearing of competing plasma antibody levels with IdeS unblocks cellular antibody receptors...
May 22, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28526406/trastuzumab-emtansine-suppresses-the-growth-of-her2-positive-small-cell-lung-cancer-in-preclinical-models
#2
Osamu Morimura, Toshiyuki Minami, Takashi Kijima, Shohei Koyama, Tomoyuki Otsuka, Yuhei Kinehara, Akio Osa, Masayoshi Higashiguchi, Kotaro Miyake, Izumi Nagatomo, Haruhiko Hirata, Kota Iwahori, Takayuki Takimoto, Yoshito Takeda, Hiroshi Kida, Atsushi Kumanogoh
Overcoming chemoresistance is essential for achieving better prognoses in SCLC. Previously, we reported that HER2 is upregulated when HER2-positive SCLC cells acquire chemoresistance. HER2-upregulated cisplatin- or etoposide-resistant SCLC cells were sensitive to trastuzumab-mediated ADCC. However, irinotecan-resistant SCLC cells, such as SBC-3/SN-38, were refractory to trastuzumab despite high HER2 expression. To address this issue, we examined the antitumor efficacy of trastuzumab emtansine (T-DM1) on trastuzumab-resistant HER2-positive SCLC...
May 16, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28526063/targeting-the-cxcr4-pathway-using-a-novel-anti-cxcr4-igg1-antibody-pf-06747143-in-chronic-lymphocytic-leukemia
#3
Manoj K Kashyap, Carlos I Amaya-Chanaga, Deepak Kumar, Brett Simmons, Nanni Huser, Yin Gu, Max Hallin, Kevin Lindquist, Rolla Yafawi, Michael Y Choi, Ale-Ali Amine, Laura Z Rassenti, Cathy Zhang, Shu-Hui Liu, Tod Smeal, Valeria R Fantin, Thomas J Kipps, Flavia Pernasetti, Januario E Castro
BACKGROUND: The CXCR4-CXCL12 axis plays an important role in the chronic lymphocytic leukemia (CLL)-microenvironment interaction. Overexpression of CXCR4 has been reported in different hematological malignancies including CLL. Binding of the pro-survival chemokine CXCL12 with its cognate receptor CXCR4 induces cell migration. CXCL12/CXCR4 signaling axis promotes cell survival and proliferation and may contribute to the tropism of leukemia cells towards lymphoid tissues and bone marrow...
May 19, 2017: Journal of Hematology & Oncology
https://www.readbyqxmd.com/read/28515346/the-novel-complex-combination-of-alum-cpg-odn-and-hh2-as-adjuvant-in-cancer-vaccine-effectively-suppresses-tumor-growth-in-vivo
#4
Yaomei Tian, Meng Li, Chaoheng Yu, Rui Zhang, Xueyan Zhang, Rong Huang, Lian Lu, Fengjiao Yuan, Yingzi Fan, Bailing Zhou, Ke Men, Heng Xu, Li Yang
Single-component adjuvant is prone to eliciting a specific type of Th1 or Th2 response. So, the development of combinatorial adjuvants inducing a robust mixed Th1/Th2 response is a promising vaccination strategy against cancer. Here, we describe a novel combination of aluminum salts (alum), CpG oligodeoxynucleotide (CpG) and innate defense regulator peptide HH2 for improving anti-tumor immune responses. The CpG-HH2 complex significantly enhanced the production of IFN-γ, TNF-α and IL-1β, promoted the uptake of antigen and strengthened the activation of p38, Erk1/2 and NF-κB in vitro, compared to CpG or HH2 alone...
April 28, 2017: Oncotarget
https://www.readbyqxmd.com/read/28507812/a-barf1-specific-mab-as-a-new-immunotherapeutic-tool-for-the-management-of-ebv-related-tumors
#5
Riccardo Turrini, Anna Merlo, Debora Martorelli, Damiana Antonia Faè, Roberta Sommaggio, Isabella Monia Montagner, Vito Barbieri, Oriano Marin, Paola Zanovello, Riccardo Dolcetti, Antonio Rosato
The use of monoclonal antibodies (mAb) for the diagnosis and treatment of malignancies is acquiring an increasing clinical importance, thanks to their specificity, efficacy and relative easiness of use. However, in the context of Epstein-Barr virus (EBV)-related malignancies, only cancers of B-cell origin can benefit from therapeutic mAb targeting specific B-cell lineage antigens. To overcome this limitation, we generated a new mAb specific for BARF1, an EBV-encoded protein with transforming and immune-modulating properties...
2017: Oncoimmunology
https://www.readbyqxmd.com/read/28507799/characterization-of-a-human-anti-tumoral-nk-cell-population-expanded-after-bcg-treatment-of-leukocytes
#6
Eva M García-Cuesta, Gloria Esteso, Omodele Ashiru, Sheila López-Cobo, Mario Álvarez-Maestro, Ana Linares, Mei M Ho, Luis Martínez-Piñeiro, Hugh T Reyburn, Mar Valés-Gómez
Immunotherapy, via intra-vesical instillations of BCG, is the therapy of choice for patients with high-risk non-muscle invasive bladder cancer. The subsequent recruitment of lymphocytes and myeloid cells, as well as the release of cytokines and chemokines, is believed to induce a local immune response that eliminates these tumors, but the detailed mechanisms of action of this therapy are not well understood. Here, we have studied the phenotype and function of the responding lymphocyte populations as well as the spectrum of cytokines and chemokines produced in an in vitro model of human peripheral blood mononuclear cells (PBMCs) co-cultured with BCG...
2017: Oncoimmunology
https://www.readbyqxmd.com/read/28504613/chlpmab-23-cancer-specific-human-mouse-chimeric-anti-podoplanin-antibody-exhibits-antitumor-activity-via-antibody-dependent-cellular-cytotoxicity
#7
Mika K Kaneko, Takuro Nakamura, Akiko Kunita, Masashi Fukayama, Shinji Abe, Yasuhiko Nishioka, Shinji Yamada, Miyuki Yanaka, Noriko Saidoh, Kanae Yoshida, Yuki Fujii, Satoshi Ogasawara, Yukinari Kato
Podoplanin is expressed in many cancers, including oral cancers and brain tumors. The interaction between podoplanin and its receptor C-type lectin-like receptor 2 (CLEC-2) has been reported to be involved in cancer metastasis and tumor malignancy. We previously established many monoclonal antibodies (mAbs) against human podoplanin using the cancer-specific mAb (CasMab) technology. LpMab-23 (IgG1, kappa), one of the mouse anti-podoplanin mAbs, was shown to be a CasMab. However, we have not shown the usefulness of LpMab-23 for antibody therapy against podoplanin-expressing cancers...
May 15, 2017: Monoclonal Antibodies in Immunodiagnosis and Immunotherapy
https://www.readbyqxmd.com/read/28498953/pathological-role-of-anti-cd4-antibodies-in-hiv-infected-immunologic-non-responders-under-viral-suppressive-antiretroviral-therapy
#8
Zhenwu Luo, Zhen Li, Lisa Martin, Zhuang Wan, Eric G Meissner, Enrique Espinosa, Hao Wu, Xiaocong Yu, Pingfu Fu, Maria Anna Julia Westerink, J Michael Kilby, Jennifer Wu, Lei Huang, Sonya L Heath, Zihai Li, Wei Jiang
Increased mortality and morbidity occurs in human immunodeficiency virus (HIV)-infected patients who fail to increase CD4+ T cell counts despite achieving viral suppression with antiretroviral therapy (ART). Here we identified an underlying mechanism. Significantly elevated plasma levels of anti-CD4 IgGs were found in HIV+ immunologic non-responders (CD4+ T cell counts ≤ 350 cells/μl) compared to HIV+ immunologic responders (CD4+ T cell counts ≥ 500 cells/μl) and healthy controls. Higher plasma level of anti-CD4 IgG correlated with blunted CD4+ T cell recovery...
May 11, 2017: Journal of Infectious Diseases
https://www.readbyqxmd.com/read/28490585/crosslinking-of-a-cd4-mimetic-miniprotein-with-hiv-1-env-gp140-alters-kinetics-and-specificities-of-antibody-responses-against-hiv-1-env-in-macaques
#9
Xiaoying Shen, Willy M Bogers, Nicole L Yates, Guido Ferrari, Antu K Dey, William T Williams, Frederick H Jaeger, Kevin Wiehe, Sheetal Sawant, S Munir Alam, Celia C LaBranche, David C Montefiori, Loic Martin, Indresh Srivastava, Jonathan Heeney, Susan W Barnett, Georgia D Tomaras
Evaluation of the epitope specificities, location (systemic, mucosal) and effector function of antibodies elicited by novel HIV-1 immunogens engineered to improve exposure of specific epitopes is critical for HIV-1 vaccine development. Utilizing an array of humoral assays, we evaluated the magnitude, epitope specificity, avidity and function of systemic and mucosal immune responses elicited by a vaccine regimen containing Env cross-linked to a CD4 mimetic miniprotein (gp140-M64U1) in rhesus macaques. Crosslinking of gp140 Env with M64U1 resulted in an earlier increase in both the magnitude and avidity of the IgG binding response compared to Env protein alone...
May 10, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28477372/adcc-employing-an-nk-cell-line-hank-expressing-the-high-affinity-cd16-allele-with-avelumab-an-anti-pd-l1-antibody
#10
Caroline Jochems, James W Hodge, Massimo Fantini, Kwong Y Tsang, Amanda J Vandeveer, James L Gulley, Jeffrey Schlom
NK-92 cells, and their derivative, designated aNK, were obtained from a patient with non-Hodgkin lymphoma. Prior clinical studies employing adoptively transferred irradiated aNK cells have provided evidence of clinical benefit and an acceptable safety. aNK cells have now been engineered to express IL-2 and the high affinity (ha) CD16 allele (designated haNK). Avelumab is a human IgG1 anti-PD-L1 monoclonal antibody, which has shown evidence of clinical activity in a range of human tumors. Prior in vitro studies have shown that avelumab has the ability to mediate antibody-dependent cell-mediated cytotoxicity (ADCC) of human tumor cells when combined with NK cells...
May 6, 2017: International Journal of Cancer. Journal International du Cancer
https://www.readbyqxmd.com/read/28473206/syd985-a-novel-duocarmycin-based-her2-targeting-antibody-drug-conjugate-shows-promising-antitumor-activity-in-epithelial-ovarian-carcinoma-with-her2-neu-expression
#11
Gulden Menderes, Elena Bonazzoli, Stefania Bellone, Jonathan Black, Gary Altwerger, Alice Masserdotti, Francesca Pettinella, Luca Zammataro, Natalia Buza, Pei Hui, Serena Wong, Babak Litkouhi, Elena Ratner, Dan-Arin Silasi, Gloria S Huang, Masoud Azodi, Peter E Schwartz, Alessandro D Santin
BACKGROUND: Epithelial ovarian cancer (EOC) is an aggressive and heterogeneous disease. <10% of EOC demonstrate HER2/neu 3+ receptor over-expression. However, moderate to low (i.e., 2+ and 1+) HER2/neu expression is reported in up to 50% of EOC. The objective of this study was to compare the anti-tumor activity of SYD985, a novel HER2-targeting antibody-drug conjugate (ADC), to trastuzumab emtansine (T-DM1) in EOC models with differential HER2/neu expression. METHODS: The cytotoxicity of SYD985 and T-DM1 was evaluated using ten primary EOC cell lines with 0/1+, 2+, and 3+ HER2/neu expression in antibody-dependent cellular cytotoxicity (ADCC), proliferation, viability and bystander killing experiments...
May 1, 2017: Gynecologic Oncology
https://www.readbyqxmd.com/read/28472768/engineering-a-high-affinity-humanized-anti-cd24-antibody-to-target-hepatocellular-carcinoma-by-a-novel-cdr-grafting-design
#12
Fumou Sun, Tong Wang, Jiahao Jiang, Yang Wang, Zhaoxiong Ma, Zhaoting Li, Yue Han, Mingzhu Pan, Jialing Cai, Min Wang, Juan Zhang
Cluster of differentiation 24 (CD24) is a specific surface marker involved in the tumorigenesis and progression of hepatocellular carcinoma (HCC). However, all reported anti-CD24 antibodies are murine ones with inevitable immunogenicity. To address this, a method using both molecular structure and docking-based complementarity determining region (CDR) grafting was employed for humanization. After xenogeneic CDR grafting into a human antibody, three types of canonical residues (in the VL/VH interface core, in the loop foundation, and interaction with loop residues) that support loop conformation and residues involved in the antigenbinding interface were back-mutated...
April 19, 2017: Oncotarget
https://www.readbyqxmd.com/read/28467975/adcc-responses-and-blocking-of-egfr-mediated-signaling-and-cell-growth-by-combining-the-anti-egfr-antibodies-imgatuzumab-and-cetuximab-in-nsclc-cells
#13
Arjan Kol, Anton Terwisscha van Scheltinga, Martin Pool, Christian Gerdes, Elisabeth de Vries, Steven de Jong
Imgatuzumab is a novel glycoengineered anti-epidermal growth factor receptor (EGFR) monoclonal antibody optimized to induce both antibody-dependent cellular cytotoxicity (ADCC) and EGFR signal transduction inhibition. We investigated anti-EGFR monoclonal antibodies imgatuzumab and cetuximab-induced internalization and membranous turnover of EGFR, and whether this affected imgatuzumab-mediated ADCC responses and growth inhibition of non-small cell lung cancer (NSCLC) cells.In a panel of wild-type EGFR expressing human NSCLC cell lines, membranous and total EGFR levels were downregulated more effectively by imgatuzumab when compared with cetuximab...
April 17, 2017: Oncotarget
https://www.readbyqxmd.com/read/28466278/improving-antibody-based-cancer-therapeutics-through-glycan-engineering
#14
REVIEW
Xiaojie Yu, Michael J E Marshall, Mark S Cragg, Max Crispin
Antibody-based therapeutics has emerged as a major tool in cancer treatment. Guided by the superb specificity of the antibody variable domain, it allows the precise targeting of tumour markers. Recently, eliciting cellular effector functions, mediated by the Fc domain, has gained traction as a means by which to generate more potent antibody therapeutics. Extensive mutagenesis studies of the Fc protein backbone has enabled the generation of Fc variants that more optimally engage the Fcγ receptors known to mediate cellular effector functions such as antibody-dependent cellular cytotoxicity (ADCC) and cellular phagocytosis...
May 2, 2017: BioDrugs: Clinical Immunotherapeutics, Biopharmaceuticals and Gene Therapy
https://www.readbyqxmd.com/read/28465443/phase-i-and-preliminary-phase-ii-study-of-trc105-in-combination-with-sorafenib-in-hepatocellular-carcinoma
#15
Austin Duffy, Chi Ma, Susanna Ulahannan, Osama E Rahma, Oxana Makarova-Rusher, Liang Cao, Yunkai Yu, David Kleiner, Jane Trepel, Min-Jung Lee, Yusuke Tomita, Seth M Steinberg, Theo Heller, Baris Turkbey, Peter L Choyke, Cody J Peer, William D Figg, Bradford J Wood, Tim F Greten
Endoglin (CD105) is an endothelial membrane receptor expressed on tumor vasculature. Endoglin expression is induced by VEGF pathway inhibition. TRC105 is a chimeric IgG1 CD105 monoclonal antibody that inhibits angiogenesis, causes antibody-dependent cellular cytotoxicity (ADCC) and apoptosis of proliferating endothelium. <br /><br />Experimental Design: Patients with HCC (Childs Pugh A/B7), ECOG 0/1, were enrolled in a phase I study of TRC105 at 3, 6, 10, 15mg/kg q 2wks given with sorafenib 400mg bid...
May 2, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28465212/cell-culture-media-supplemented-with-raffinose-reproducibly-enhances-high-mannose-glycan-formation
#16
David Brühlmann, Anais Muhr, Rebecca Parker, Thomas Vuillemin, Blanka Bucsella, Franka Kalman, Serena Torre, Fabio La Neve, Antonio Lembo, Tobias Haas, Markus Sauer, Jonathan Souquet, Hervé Broly, Jürgen Hemberger, Martin Jordan
Glycosylation plays a pivotal role in pharmacokinetics and protein physiochemical characteristics. In particular, effector functions including antibody-dependent cell-mediated cytotoxicity (ADCC) can be desired, and it has been described that high-mannose species exhibited enhanced ADCC. In this work we present the trisaccharide raffinose as a novel cell culture medium supplement to promote high mannose N-glycans in fed-batch cultures, which is sought after in the development of biosimilars to match the quality profile of the reference medicinal product (RMP) also...
April 29, 2017: Journal of Biotechnology
https://www.readbyqxmd.com/read/28454288/development-of-a-novel-anti-human-aspartyl-asparaginyl-%C3%AE-hydroxylase-monoclonal-antibody-with-diagnostic-and-therapeutic-potential
#17
Ting Huyan, Qi Li, Dan-Dan Dong, Hui Yang, Xiao-Ping Xue, Qing-Sheng Huang
Human aspartyl-(asparaginyl)-β-hydroxylase (HAAH) has recently been the subject of several studies, as it was previously observed to be overexpressed in numerous types of carcinoma cells and tissues in patient tumor samples. HAAH has been implicated in tumor invasion and metastasis, indicating that it may be an important target and biomarker for tumor diagnosis and treatment. However, the immunological tools currently available for the study of this protein, including monoclonal antibodies, are limited, as is the present knowledge regarding the role of HAAH in tumor therapy and diagnosis...
March 2017: Oncology Letters
https://www.readbyqxmd.com/read/28454118/simultaneous-exposure-to-fc%C3%AE-r-and-fc%C3%AE-r-on-monocytes-and-macrophages-enhances-antitumor-activity-in-vivo
#18
Bingyu Li, Lijun Xu, Fei Tao, Kun Xie, Zhiqiang Wu, You Li, Jie Li, Kaiming Chen, Chenyu Pi, Andrew Mendelsohn, James W Larrick, Hua Gu, Jianmin Fang
Therapeutic antibodies are effective for tumor immunotherapy and exhibit prominent clinical effects. All approved antibody therapeutics utilize IgG as the molecular format. Antibody-dependent cell-mediated cytotoxicity (ADCC) is a key mechanism for tumor cell killing by antibodies. For IgG antibodies, ADCC depends on FcγR-expressing cells, such as natural killer (NK) cells. However, in patients with a high tumor burden, antibody therapeutics may lose efficacy owing to exhaustion of FcγR-expressing effector cells as well as the inhibitory effects of certain FcγRs on effector cells...
April 10, 2017: Oncotarget
https://www.readbyqxmd.com/read/28453766/comparable-immune-function-inhibition-by-the-infliximab-biosimilar-ct-p13-implications-for-treatment-of-inflammatory-bowel-disease
#19
Ki Jung Lim, So Jung Lee, Sunghwan Kim, Su Yeon Lee, Min Seob Lee, Yoon A Park, Eun Jin Choi, Eun Beom Lee, Hwang Keun Jun, Jong Moon Cho, SooYoung Lee, Ki Sung Kwon, Byung Pil Lim, Myung-Shin Jeon, Eui Cheol Shin, Yong Sung Choi, Ella Fudim, Orit Picard, Miri Yavzori, Shomron Ben-Horin, Shin Jae Chang
Background and Aims: CT-P13 is the first biosimilar monoclonal antibody to infliximab, and was recently approved in the European Union, Japan, Korea, and USA for all six indications of infliximab. However, studies directly assessing the biologic activity of CT-P13 versus inflximab in the context of inflammatory bowel disease [IBD] are still scanty. In the present study, we aimed to compare the biological activities of CT-P13 and infliximab with specific focus on intestinal cells so as to gain insight into the potential biosimilarity of these two agents for treatment of IBD...
May 1, 2017: Journal of Crohn's & Colitis
https://www.readbyqxmd.com/read/28448604/non-invasive-imaging-assessment-of-the-biodistribution-of-gsk2849330-an-adcc-and-cdc-optimized-anti-her3-mab-and-its-role-in-tumor-macrophage-recruitment-in-human-tumor-bearing-mice
#20
Hasan Alsaid, Tinamarie Skedzielewski, Mary V Rambo, Kristen Hunsinger, Bao Hoang, William Fieles, Edward R Long, James Tunstead, Danielle J Vugts, Matthew Cleveland, Neil Clarke, Christopher Matheny, Beat M Jucker
The purpose of this work was to use various molecular imaging techniques to non-invasively assess GSK2849330 (anti HER3 ADCC and CDC enhanced 'AccretaMab' monoclonal antibody) pharmacokinetics and pharmacodynamics in human xenograft tumor-bearing mice. Immuno-PET biodistribution imaging of radiolabeled 89Zr-GSK2849330 was assessed in mice with HER3 negative (MIA-PaCa-2) and positive (CHL-1) human xenograft tumors. Dose dependency of GSK2849330 disposition was assessed using varying doses of unlabeled GSK2849330 co-injected with 89Zr-GSK2849330...
2017: PloS One
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