The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform
Leatrice Vogel - One of the best experts on this subject based on the ideXlab platform.
-
prophylaxis with a middle east respiratory syndrome coronavirus mers cov specific Human Monoclonal Antibody protects rabbits from mers cov infection
The Journal of Infectious Diseases, 2016Co-Authors: Katherine V Houser, Dimiter S. Dimitrov, Lisa M Gretebeck, Tianlei Ying, Yanping Wang, Leatrice Vogel, Elaine W Lamirande, Kevin W Bock, Ian N Moore, Kanta SubbaraoAbstract:With >1600 documented Human infections with Middle East respiratory syndrome coronavirus (MERS-CoV) and a case fatality rate of approximately 36%, medical countermeasures are needed to prevent and limit the disease. We examined the in vivo efficacy of the Human Monoclonal Antibody m336, which has high neutralizing activity against MERS-CoV in vitro. m336 was administered to rabbits intravenously or intranasally before infection with MERS-CoV. Prophylaxis with m336 resulted in a reduction of pulmonary viral RNA titers by 40-9000-fold, compared with an irrelevant control Antibody with little to no inflammation or viral antigen detected. This protection in rabbits supports further clinical development of m336.
-
Antibody pressure by a Human Monoclonal Antibody targeting the 2009 pandemic h1n1 virus hemagglutinin drives the emergence of a virus with increased virulence in mice
Mbio, 2012Co-Authors: Christopher D Odonnell, Leatrice Vogel, Amber Wright, Jens Wrammert, Guimei Li, Megan Mccausland, Naiying Zheng, Jonathan W Yewdell, Rafi Ahmed, Patrick C WilsonAbstract:ABSTRACT In 2009, a novel H1N1 influenza A virus (2009 pH1N1) emerged and caused a pandemic. A Human Monoclonal Antibody (hMAb; EM4C04), highly specific for the 2009 pH1N1 virus hemagglutinin (HA), was isolated from a severely ill 2009 pH1N1 virus-infected patient. We postulated that under immune pressure with EM4C04, the 2009 pH1N1 virus would undergo antigenic drift and mutate at sites that would identify the Antibody binding site. To do so, we infected MDCK cells in the presence of EM4C04 and generated 11 escape mutants, displaying 7 distinct amino acid substitutions in the HA. Six substitutions greatly reduced MAb binding (K123N, D131E, K133T, G134S, K157N, and G158E). Residues 131, 133, and 134 are contiguous with residues 157 and 158 in the globular domain structure and contribute to a novel pH1N1 Antibody epitope. One mutation near the receptor binding site, S186P, increased the binding affinity of the HA to the receptor. 186P and 131E are present in the highly virulent 1918 virus HA and were recently identified as virulence determinants in a mouse-passaged pH1N1 virus. We found that pH1N1 escape variants expressing these substitutions enhanced replication and lethality in mice compared to wild-type 2009 pH1N1 virus. The increased virulence of these viruses was associated with an increased affinity for α2,3 sialic acid receptors. Our study demonstrates that Antibody pressure by an hMAb targeting a novel epitope in the Sa region of 2009 pH1N1 HA is able to inadvertently drive the development of a more virulent virus with altered receptor binding properties. This broadens our understanding of antigenic drift. IMPORTANCE Influenza viruses accumulate amino acid substitutions to evade the Antibody response in a process known as antigenic drift, making it necessary to vaccinate against influenza annually. Mapping Human Monoclonal Antibody (hMAb) epitopes is a necessary step towards understanding antigenic drift in Humans. We defined the specificity of an hMAb that specifically targeted the 2009 pH1N1 virus and describe a novel epitope. In addition, we identified a previously unappreciated potential for Antibody escape to enhance the pathogenicity of a virus. The escape mutation that we identified with in vitro immune pressure was independently reported by other investigators using in vivo selection in nonimmune mice. Although in vitro generation of escape mutants is unlikely to recapitulate antigenic drift in its entirety, the data demonstrate that pressure by a Human Monoclonal Antibody targeting a novel epitope in the hemagglutinin of the 2009 pandemic H1N1 virus can inadvertently drive the development of escape mutants, of which a subset have increased virulence and altered receptor binding properties.
-
evaluation of Human Monoclonal Antibody 80r for immunoprophylaxis of severe acute respiratory syndrome by an animal study epitope mapping and analysis of spike variants
Journal of Virology, 2005Co-Authors: Wenhui Li, Leatrice Vogel, Kanta Subbarao, Anjeanette Roberts, Leslie J Matthews, Akikazu Murakami, Swee Kee Wong, Michael Farzan, Wayne A MarascoAbstract:In this report, the antiviral activity of 80R immunoglobulin G1 (IgG1), a Human Monoclonal Antibody against severe acute respiratory syndrome coronavirus (SARS-CoV) spike (S) protein that acts as a viral entry inhibitor in vitro, was investigated in vivo in a mouse model. When 80R IgG1 was given prophylactically to mice at doses therapeutically achievable in Humans, viral replication was reduced by more than 4 orders of magnitude to below assay limits. The essential core region of S protein required for 80R binding was identified as a conformationally sensitive fragment (residues 324 to 503) that overlaps the receptor ACE2-binding domain. Amino acids critical for 80R binding were identified. In addition, the effects of various 80R-binding domain amino acid substitutions which occur in SARS-like-CoV from civet cats, and which evolved during the 2002/2003 outbreak and in a 2003/2004 Guangdong index patient, were analyzed. The results demonstrated that the vast majority of SARS-CoVs are sensitive to 80R. We propose that by establishing the susceptibility and resistance profiles of newly emerging SARS-CoVs through early S1 genotyping of the core 180-amino-acid neutralizing epitope of 80R, an effective immunoprophylaxis strategy with 80R should be possible in an outbreak setting. Our study also cautions that for any prophylaxis strategy based on neutralizing Antibody responses, whether by passive or active immunization, a genotyping monitor will be necessary for effective use.
Dimiter S. Dimitrov - One of the best experts on this subject based on the ideXlab platform.
-
prophylaxis with a middle east respiratory syndrome coronavirus mers cov specific Human Monoclonal Antibody protects rabbits from mers cov infection
The Journal of Infectious Diseases, 2016Co-Authors: Katherine V Houser, Dimiter S. Dimitrov, Lisa M Gretebeck, Tianlei Ying, Yanping Wang, Leatrice Vogel, Elaine W Lamirande, Kevin W Bock, Ian N Moore, Kanta SubbaraoAbstract:With >1600 documented Human infections with Middle East respiratory syndrome coronavirus (MERS-CoV) and a case fatality rate of approximately 36%, medical countermeasures are needed to prevent and limit the disease. We examined the in vivo efficacy of the Human Monoclonal Antibody m336, which has high neutralizing activity against MERS-CoV in vitro. m336 was administered to rabbits intravenously or intranasally before infection with MERS-CoV. Prophylaxis with m336 resulted in a reduction of pulmonary viral RNA titers by 40-9000-fold, compared with an irrelevant control Antibody with little to no inflammation or viral antigen detected. This protection in rabbits supports further clinical development of m336.
-
a dual specific anti igf 1 igf 2 Human Monoclonal Antibody alone and in combination with temsirolimus for therapy of neuroblastoma
International Journal of Cancer, 2015Co-Authors: Dimiter S. Dimitrov, Qi Zhao, Hoa Tran, Naikong V CheungAbstract:The insulin-like growth factors (IGFs), IGF-1 and IGF-2, have been implicated in the growth, survival and metastasis of a broad range of malignancies including pediatric tumors. They bind to the IGF receptor type 1 (IGF-1R) and the insulin receptor (IR) which are overexpressed in many types of solid malignancies. Activation of the IR by IGF-2 results in increased survival of tumor cells. We have previously identified a novel Human Monoclonal Antibody, m708.5, which binds with high (pM) affinity to both Human IGF-1 and IGF-2, and potently inhibits phosphorylation of the IGF-1R and the IR in tumor cells. m708.5 exhibited strong antitumor activity as a single agent against most cell lines derived from neuroblastoma, Ewing family of tumor, rhabdomyosarcoma and osteosarcoma. When tested in neuroblastoma cell lines, it showed strong synergy with temsirolimus and synergy with chemotherapeutic agents in vitro. In xenograft models, the combination of m708.5 and temsirolimus significantly inhibited neuroblastoma growth and prolonged mouse survival. Taken together, these results support the clinical development of m708.5 for pediatric solid tumors with potential for synergy with chemotherapy and mTOR inhibitors.
-
Therapeutic treatment of Nipah virus infection in nonHuman primates with a neutralizing Human Monoclonal Antibody.
Science translational medicine, 2014Co-Authors: Thomas W Geisbert, Friederike Feldmann, Joan B Geisbert, Yeepeng Chan, Zhongyu Zhu, Dimiter S. Dimitrov, Krystle N. Agans, Chad E. Mire, Karla A. Fenton, Dana P. ScottAbstract:Nipah virus (NiV) is an emerging zoonotic paramyxovirus that causes severe and often fatal disease in pigs and Humans. There are currently no vaccines or treatments approved for Human use. Studies in small-animal models of NiV infection suggest that Antibody therapy may be a promising treatment. However, most studies have assessed treatment at times shortly after virus exposure before animals show signs of disease. We assessed the efficacy of a fully Human Monoclonal Antibody, m102.4, at several time points after virus exposure including at the onset of clinical illness in a uniformly lethal nonHuman primate model of NiV disease. Sixteen African green monkeys (AGMs) were challenged intratracheally with a lethal dose of NiV, and 12 animals were infused twice with m102.4 (15 mg/kg) beginning at either 1, 3, or 5 days after virus challenge and again about 2 days later. The presence of viral RNA, infectious virus, and/or NiV-specific immune responses demonstrated that all subjects were infected after challenge. All 12 AGMs that received m102.4 survived infection, whereas the untreated control subjects succumbed to disease between days 8 and 10 after infection. AGMs in the day 5 treatment group exhibited clinical signs of disease, but all animals recovered by day 16. These results represent the successful therapeutic in vivo efficacy by an investigational drug against NiV in a nonHuman primate and highlight the potential impact that a Monoclonal Antibody can have on a highly pathogenic zoonotic Human disease.
-
Human Monoclonal Antibody fragments binding to insulin like growth factors i and ii with picomolar affinity
Molecular Cancer Therapeutics, 2011Co-Authors: Qi Zhao, Zhongyu Zhu, Yang Feng, Dimiter S. DimitrovAbstract:The type 1 insulin-like growth factor receptor (IGF1R) and its ligands (IGF1 and IGF2) have been implicated in a variety of physiological processes and in diseases such as cancer. In addition to IGF1R, IGF2 also activates the insulin receptor (IR) isoform A and therefore antibodies against IGF2 can inhibit cell proliferation mediated by the signaling through both IGF1R and IR triggered by IGF2. We identified a new Human Monoclonal Antibody (mAb), m708.2, which bound to IGF1 and IGF2 but not to insulin. m708.2 potently inhibited signal transduction mediated by the interaction of IGF1 or IGF2 with the IGF1R and IGF2 with the IR. It also inhibited the growth of the breast cancer cell line MCF-7. An affinity-matured derivative of m708.2, m708.5, bound to IGF1 with equilibrium dissociation constant, KD = 200 pM and to IGF2 with KD = 60 pM. m708.5 inhibited signal transduction mediated by IGF1 and IGF2 and cancer cell growth more potently than m708.2. These results suggest that m708.5 could have potential as a candidate therapeutic for cancers driven by the IGF1,2 interactions with IGF1R and IR.
-
a folate receptor beta specific Human Monoclonal Antibody recognizes activated macrophage of rheumatoid patients and mediates Antibody dependent cell mediated cytotoxicity
Arthritis Research & Therapy, 2011Co-Authors: Yang Feng, Zhongyu Zhu, Philip S Low, Jiayin Shen, Emily Streaker, Michael B Lockwood, Dimiter S. DimitrovAbstract:Folate receptor beta (FRβ) is only detectable in placenta and limited to some hematopoietic cells of myeloid lineage in healthy people. Studies have indicated that FRβ is over-expressed in activated macrophages in autoimmune diseases and some cancer cells. In this study we aimed to develop an FRβ-specific Human Monoclonal Antibody (mAb) that could be used as a therapeutic agent to treat rheumatoid arthritis and other autoimmune diseases, as well as FRβ positive cancers. Functional recombinant FRβ protein was produced in insect cells and used as antigen to isolate a mAb, m909, from a Human naive Fab phage display library. Binding of Fab and IgG1 m909 to FRβ was measured by ELISA, surface plasmon resonance, immune fluorescence staining, and flow cytometry. Antibody-dependent cell-mediated cytotoxicity (ADCC) was evaluated with FRβ positive CHO cells as target cells and isolated peripheral blood monocytes as effector cells in an in vitro assay. Fab m909 bound with relatively high affinity (equilibrium dissociation constant 57 nM) to FRβ. The IgG1 m909 showed much higher (femtomolar) avidity as measured by ELISA, and it bound to FRβ positive cells in a dose-dependent manner, but not to parental FRβ negative cells. m909 did not compete with folate for the binding to FRβ on cells. m909 was not only able to select FRβ positive, activated macrophages from synovial fluid cells of arthritis patients as efficiently as folate, but also able to mediate ADCC in FRβ positive cells. Unlike folate-drug conjugates, m909 selectively binds to FRβ, does not recognize FRα, and has at least one effector function. m909 alone has potential to eliminate FRβ positive cells. Because m909 does not compete with folate for receptor binding, it can be used with folate-drug conjugates in a combination therapy. m909 can also be a valuable research reagent.
Kanta Subbarao - One of the best experts on this subject based on the ideXlab platform.
-
prophylaxis with a middle east respiratory syndrome coronavirus mers cov specific Human Monoclonal Antibody protects rabbits from mers cov infection
The Journal of Infectious Diseases, 2016Co-Authors: Katherine V Houser, Dimiter S. Dimitrov, Lisa M Gretebeck, Tianlei Ying, Yanping Wang, Leatrice Vogel, Elaine W Lamirande, Kevin W Bock, Ian N Moore, Kanta SubbaraoAbstract:With >1600 documented Human infections with Middle East respiratory syndrome coronavirus (MERS-CoV) and a case fatality rate of approximately 36%, medical countermeasures are needed to prevent and limit the disease. We examined the in vivo efficacy of the Human Monoclonal Antibody m336, which has high neutralizing activity against MERS-CoV in vitro. m336 was administered to rabbits intravenously or intranasally before infection with MERS-CoV. Prophylaxis with m336 resulted in a reduction of pulmonary viral RNA titers by 40-9000-fold, compared with an irrelevant control Antibody with little to no inflammation or viral antigen detected. This protection in rabbits supports further clinical development of m336.
-
evaluation of Human Monoclonal Antibody 80r for immunoprophylaxis of severe acute respiratory syndrome by an animal study epitope mapping and analysis of spike variants
Journal of Virology, 2005Co-Authors: Wenhui Li, Leatrice Vogel, Kanta Subbarao, Anjeanette Roberts, Leslie J Matthews, Akikazu Murakami, Swee Kee Wong, Michael Farzan, Wayne A MarascoAbstract:In this report, the antiviral activity of 80R immunoglobulin G1 (IgG1), a Human Monoclonal Antibody against severe acute respiratory syndrome coronavirus (SARS-CoV) spike (S) protein that acts as a viral entry inhibitor in vitro, was investigated in vivo in a mouse model. When 80R IgG1 was given prophylactically to mice at doses therapeutically achievable in Humans, viral replication was reduced by more than 4 orders of magnitude to below assay limits. The essential core region of S protein required for 80R binding was identified as a conformationally sensitive fragment (residues 324 to 503) that overlaps the receptor ACE2-binding domain. Amino acids critical for 80R binding were identified. In addition, the effects of various 80R-binding domain amino acid substitutions which occur in SARS-like-CoV from civet cats, and which evolved during the 2002/2003 outbreak and in a 2003/2004 Guangdong index patient, were analyzed. The results demonstrated that the vast majority of SARS-CoVs are sensitive to 80R. We propose that by establishing the susceptibility and resistance profiles of newly emerging SARS-CoVs through early S1 genotyping of the core 180-amino-acid neutralizing epitope of 80R, an effective immunoprophylaxis strategy with 80R should be possible in an outbreak setting. Our study also cautions that for any prophylaxis strategy based on neutralizing Antibody responses, whether by passive or active immunization, a genotyping monitor will be necessary for effective use.
Aki Morisawa - One of the best experts on this subject based on the ideXlab platform.
-
fully Human Monoclonal Antibody directed to proteolytic cleavage site in severe acute respiratory syndrome sars coronavirus s protein neutralizes the virus in a rhesus macaque sars model
The Journal of Infectious Diseases, 2011Co-Authors: Tohru Miyoshiakiyama, Isao Ishida, Masaya Fukushi, Keina Yamaguchi, Yusuke Matsuoka, Takashi Ishihara, Masayoshi Tsukahara, Seisuke Hatakeyama, Norikazu Itoh, Aki MorisawaAbstract:Background There is still no effective method to prevent or treat severe acute respiratory syndrome (SARS), which is caused by SARS coronavirus (CoV). In the present study, we evaluated the efficacy of a fully Human Monoclonal Antibody capable of neutralizing SARS-CoV in vitro in a Rhesus macaque model of SARS. Methods The Antibody 5H10 was obtained by vaccination of KM mice bearing Human immunoglobulin genes with Escherichia coli-producing recombinant peptide containing the dominant epitope of the viral spike protein found in convalescent serum samples from patients with SARS. Results 5H10, which recognized the same epitope that is also a cleavage site critical for the entry of SARS-CoV into host cells, inhibited propagation of the virus and pathological changes found in Rhesus macaques infected with the virus through the nasal route. In addition, we analyzed the mode of action of 5H10, and the results suggested that 5H10 inhibited fusion between the virus envelope and host cell membrane. 5H10 has potential for use in prevention and treatment of SARS if it reemerges. Conclusions This study represents a platform to produce fully Human antibodies against emerging infectious diseases in a timely and safe manner.
Berend Jan Bosch - One of the best experts on this subject based on the ideXlab platform.
-
a Human Monoclonal Antibody blocking sars cov 2 infection
Nature Communications, 2020Co-Authors: Chunyan Wang, Dubravka Drabek, Nisreen M A Okba, Rien Van Haperen, Albert D M E Osterhaus, Frank J M Van Kuppeveld, Bart L Haagmans, Frank Grosveld, Berend Jan BoschAbstract:The emergence of the novel Human coronavirus SARS-CoV-2 in Wuhan, China has caused a worldwide epidemic of respiratory disease (COVID-19). Vaccines and targeted therapeutics for treatment of this disease are currently lacking. Here we report a Human Monoclonal Antibody that neutralizes SARS-CoV-2 (and SARS-CoV) in cell culture. This cross-neutralizing Antibody targets a communal epitope on these viruses and may offer potential for prevention and treatment of COVID-19.
-
a Human Monoclonal Antibody blocking sars cov 2 infection
bioRxiv, 2020Co-Authors: Chunyan Wang, Dubravka Drabek, Nisreen M A Okba, Rien Van Haperen, Albert D M E Osterhaus, Frank J M Van Kuppeveld, Bart L Haagmans, Frank Grosveld, Berend Jan BoschAbstract:The emergence of the novel Human coronavirus SARS-CoV-2 in Wuhan, China has caused a worldwide epidemic of respiratory disease (COVID-19). Vaccines and targeted therapeutics for treatment of this disease are currently lacking. Here we report a Human Monoclonal Antibody that neutralizes SARS-CoV-2 (and SARS-CoV). This cross-neutralizing Antibody targets a communal epitope on these viruses and offers potential for prevention and treatment of COVID-19.