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Analysis of a Therapeutic Antibody Cocktail Reveals Determinants for Cooperative and Broad Ebolavirus Neutralization.
Gilchuk P, Murin CD, Milligan JC, Cross RW, Mire CE, Ilinykh PA, Huang K, Kuzmina N, Altman PX, Hui S, Gunn BM, Bryan AL, Davidson E, Doranz BJ, Turner HL, Alkutkar T, Flinko R, Orlandi C, Carnahan R, Nargi R, Bombardi RG, Vodzak ME, Li S, Okoli A, Ibeawuchi M, Ohiaeri B, Lewis GK, Alter G, Bukreyev A, Saphire EO, Geisbert TW, Ward AB, Crowe JE
(2020) Immunity 52: 388-403.e12
MeSH Terms: Animals, Antibodies, Monoclonal, Antibodies, Neutralizing, Antibodies, Viral, Cell Line, Disease Models, Animal, Drug Therapy, Combination, Ebolavirus, Epitopes, Female, Glycoproteins, Hemorrhagic Fever, Ebola, Humans, Immunoglobulin Fab Fragments, Macaca mulatta, Male, Mice, Mice, Inbred BALB C, Molecular Mimicry, Protein Conformation
Show Abstract · Added March 31, 2020
Structural principles underlying the composition of protective antiviral monoclonal antibody (mAb) cocktails are poorly defined. Here, we exploited antibody cooperativity to develop a therapeutic mAb cocktail against Ebola virus. We systematically analyzed the antibody repertoire in human survivors and identified a pair of potently neutralizing mAbs that cooperatively bound to the ebolavirus glycoprotein (GP). High-resolution structures revealed that in a two-antibody cocktail, molecular mimicry was a major feature of mAb-GP interactions. Broadly neutralizing mAb rEBOV-520 targeted a conserved epitope on the GP base region. mAb rEBOV-548 bound to a glycan cap epitope, possessed neutralizing and Fc-mediated effector function activities, and potentiated neutralization by rEBOV-520. Remodeling of the glycan cap structures by the cocktail enabled enhanced GP binding and virus neutralization. The cocktail demonstrated resistance to virus escape and protected non-human primates (NHPs) against Ebola virus disease. These data illuminate structural principles of antibody cooperativity with implications for development of antiviral immunotherapeutics.
Copyright © 2020 Elsevier Inc. All rights reserved.
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20 MeSH Terms
An autoimmune-based, paraneoplastic neurologic syndrome following checkpoint inhibition and concurrent radiotherapy for merkel cell carcinoma: case report.
Sherry AD, Bezzerides M, Khattab MH, Luo G, Ancell KK, Kirschner AN
(2020) Strahlenther Onkol 196: 664-670
MeSH Terms: Aged, Antibodies, Monoclonal, Humanized, Antineoplastic Agents, Immunological, Antineoplastic Combined Chemotherapy Protocols, Autoimmune Diseases of the Nervous System, Axilla, Carboplatin, Carcinoma, Merkel Cell, Combined Modality Therapy, Deglutition Disorders, Etoposide, Fatal Outcome, Fingers, Hallucinations, Humans, Lymphatic Metastasis, Male, Neuralgia, Palliative Care, Paraneoplastic Syndromes, Nervous System, Parenteral Nutrition, Total, Pneumonia, Aspiration, Positron Emission Tomography Computed Tomography, Radioimmunotherapy, Radiotherapy, High-Energy, Radiotherapy, Intensity-Modulated, Skin Neoplasms
Show Abstract · Added March 3, 2020
PURPOSE - Merkel cell carcinoma is highly sensitive to both radiation and immunotherapy. Moreover, concurrent radioimmunotherapy may capitalize on anti-tumor immune activity and improve Merkel cell treatment response, although an enhanced immune system may cross-react with native tissues and lead to significant sequelae.
METHODS - Here we present a case study of a patient with metastatic Merkel cell carcinoma treated with radiotherapy concurrent with pembrolizumab.
RESULTS - After radioimmunotherapy, the patient developed sensory neuropathy, visual hallucinations, and mixed motor neuron findings. Neurologic dysfunction progressed to profound gastrointestinal dysmotility necessitating parenteral nutrition and intubation with eventual expiration.
CONCLUSION - This case represents a unique autoimmune paraneoplastic neurologic syndrome, likely specific to neuroendocrine tumors and motivated by concurrent radioimmunotherapy. Recognition of the potential role of radioimmunotherapy may provide an advantage in anticipating these severe sequelae.
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Identification and Characterization of Unique Neutralizing Antibodies to Mouse EGF Receptor.
Jae Huh W, Niitsu H, Carney B, McKinley ET, Houghton JL, Coffey RJ
(2020) Gastroenterology 158: 1500-1502
MeSH Terms: Animals, Antibodies, Monoclonal, Humanized, Antibodies, Neutralizing, Azoxymethane, Carcinogens, Cells, Cultured, Colonic Neoplasms, Dextran Sulfate, Disease Models, Animal, ErbB Receptors, Gastritis, Hypertrophic, Genes, Reporter, Hepatocytes, Humans, Mice, Mice, Transgenic, Primary Cell Culture
Added January 31, 2020
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Mechanism of differential Zika and dengue virus neutralization by a public antibody lineage targeting the DIII lateral ridge.
Zhao H, Xu L, Bombardi R, Nargi R, Deng Z, Errico JM, Nelson CA, Dowd KA, Pierson TC, Crowe JE, Diamond MS, Fremont DH
(2020) J Exp Med 217:
MeSH Terms: Aedes, Animals, Antibodies, Monoclonal, Antibodies, Neutralizing, Antibodies, Viral, Cell Line, Tumor, Chlorocebus aethiops, Cross Reactions, Crystallography, X-Ray, Dengue, Dengue Virus, Epitopes, HEK293 Cells, Humans, Hydrogen Bonding, Immunoglobulin Fab Fragments, Protein Binding, Protein Conformation, Protein Domains, Vero Cells, Viral Envelope Proteins, Zika Virus, Zika Virus Infection
Show Abstract · Added March 31, 2020
We previously generated a panel of human monoclonal antibodies (mAbs) against Zika virus (ZIKV) and identified one, ZIKV-116, that shares germline usage with mAbs identified in multiple donors. Here we show that ZIKV-116 interferes with ZIKV infection at a post-cellular attachment step by blocking viral fusion with host membranes. ZIKV-116 recognizes the lateral ridge of envelope protein domain III, with one critical residue varying between the Asian and African strains responsible for differential binding affinity and neutralization potency (E393D). ZIKV-116 also binds to and cross-neutralizes some dengue virus serotype 1 (DENV1) strains, with genotype-dependent inhibition explained by variation in a domain II residue (R204K) that potentially modulates exposure of the distally located, partially cryptic epitope. The V-J reverted germline configuration of ZIKV-116 preferentially binds to and neutralizes an Asian ZIKV strain, suggesting that this epitope may optimally induce related B cell clonotypes. Overall, these studies provide a structural and molecular mechanism for a cross-reactive mAb that uniquely neutralizes ZIKV and DENV1.
© 2019 Zhao et al.
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23 MeSH Terms
Influenza H7N9 Virus Neuraminidase-Specific Human Monoclonal Antibodies Inhibit Viral Egress and Protect from Lethal Influenza Infection in Mice.
Gilchuk IM, Bangaru S, Gilchuk P, Irving RP, Kose N, Bombardi RG, Thornburg NJ, Creech CB, Edwards KM, Li S, Turner HL, Yu W, Zhu X, Wilson IA, Ward AB, Crowe JE
(2019) Cell Host Microbe 26: 715-728.e8
MeSH Terms: Animals, Antibodies, Heterophile, Antibodies, Monoclonal, Antibodies, Neutralizing, Antibodies, Viral, Birds, Epitopes, Humans, Influenza A Virus, H7N9 Subtype, Influenza Vaccines, Influenza in Birds, Influenza, Human, Mice, Neuraminidase, Orthomyxoviridae Infections, Pre-Exposure Prophylaxis, Vaccination, Vaccines, Inactivated, Viral Proteins, Virus Release
Show Abstract · Added March 31, 2020
H7N9 avian influenza virus causes severe infections and might have the potential to trigger a major pandemic. Molecular determinants of human humoral immune response to N9 neuraminidase (NA) proteins, which exhibit unusual features compared with seasonal influenza virus NA proteins, are ill-defined. We isolated 35 human monoclonal antibodies (mAbs) from two H7N9 survivors and two vaccinees. These mAbs react to NA in a subtype-specific manner and recognize diverse antigenic sites on the surface of N9 NA, including epitopes overlapping with, or distinct from, the enzyme active site. Despite recognizing multiple antigenic sites, the mAbs use a common mechanism of action by blocking egress of nascent virions from infected cells, thereby providing an antiviral prophylactic and therapeutic protection in vivo in mice. Studies of breadth, potency, and diversity of antigenic recognition from four subjects suggest that vaccination with inactivated adjuvanted vaccine induce NA-reactive responses comparable to that of H7N9 natural infection.
Copyright © 2019 Elsevier Inc. All rights reserved.
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Structural Basis of Protection against H7N9 Influenza Virus by Human Anti-N9 Neuraminidase Antibodies.
Zhu X, Turner HL, Lang S, McBride R, Bangaru S, Gilchuk IM, Yu W, Paulson JC, Crowe JE, Ward AB, Wilson IA
(2019) Cell Host Microbe 26: 729-738.e4
MeSH Terms: Animals, Antibodies, Monoclonal, Antibodies, Neutralizing, Antibodies, Viral, Antiviral Agents, Cryoelectron Microscopy, Epitopes, Humans, Influenza A Virus, H7N9 Subtype, Influenza Vaccines, Neuraminidase, Orthomyxoviridae Infections, Viral Proteins
Show Abstract · Added March 31, 2020
Influenza virus neuraminidase (NA) is a major target for small-molecule antiviral drugs. Antibodies targeting the NA surface antigen could also inhibit virus entry and egress to provide host protection. However, our understanding of the nature and range of target epitopes is limited because of a lack of human antibody structures with influenza neuraminidase. Here, we describe crystal and cryogenic electron microscopy (cryo-EM) structures of NAs from human-infecting avian H7N9 viruses in complex with five human anti-N9 antibodies, systematically defining several antigenic sites and antibody epitope footprints. These antibodies either fully or partially block the NA active site or bind to epitopes distant from the active site while still showing neuraminidase inhibition. The inhibition of antibodies to NAs was further analyzed by glycan array and solution-based NA activity assays. Together, these structural studies provide insights into protection by anti-NA antibodies and templates for the development of NA-based influenza virus vaccines and therapeutics.
Copyright © 2019 Elsevier Inc. All rights reserved.
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13 MeSH Terms
Increased reporting of fatal hepatitis associated with immune checkpoint inhibitors.
Vozy A, De Martin E, Johnson DB, Lebrun-Vignes B, Moslehi JJ, Salem JE
(2019) Eur J Cancer 123: 112-115
MeSH Terms: Adolescent, Adult, Aged, Aged, 80 and over, Antibodies, Monoclonal, Humanized, Antineoplastic Agents, Immunological, B7-H1 Antigen, CTLA-4 Antigen, Chemical and Drug Induced Liver Injury, Child, Databases, Factual, Female, Hepatitis, Autoimmune, Humans, Ipilimumab, Male, Massive Hepatic Necrosis, Middle Aged, Neoplasms, Nivolumab, Programmed Cell Death 1 Receptor, World Health Organization, Young Adult
Added November 12, 2019
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23 MeSH Terms
Human Gene-Encoded Human Monoclonal Antibodies against Staphylococcus aureus IsdB Use at Least Three Distinct Modes of Binding To Inhibit Bacterial Growth and Pathogenesis.
Bennett MR, Dong J, Bombardi RG, Soto C, Parrington HM, Nargi RS, Schoeder CT, Nagel MB, Schey KL, Meiler J, Skaar EP, Crowe JE
(2019) mBio 10:
MeSH Terms: Adaptive Immunity, Antibodies, Monoclonal, Crystallography, X-Ray, Humans, Immunity, Humoral, Proteomics, Staphylococcus aureus
Show Abstract · Added March 21, 2020
is an important human pathogen that infects nearly every human tissue. Like most organisms, the acquisition of nutrient iron is necessary for its survival. One route by which it obtains this metal is through the iron-regulated surface determinant (Isd) system that scavenges iron from the hemoglobin of the host. We show that the heavy chain variable region gene commonly encodes human monoclonal antibodies (mAbs) targeting IsdB-NEAT2. Remarkably, these antibodies bind to multiple antigenic sites. One class of -encoded mAbs blocks heme acquisition by binding to the heme-binding site of NEAT2, while two additional classes reduce the bacterial burden by an alternative Fc receptor-mediated mechanism. We further identified clonal lineages of -encoded mAbs using donor samples, showing that each lineage diversifies during infection by somatic hypermutation. These studies reveal that encoded antibodies contribute to a protective immune response, furthering our understanding of the correlates of protection against infection. The human pathogen causes a wide range of infections, including skin abscesses and sepsis. There is currently no licensed vaccine to prevent infection, and its treatment has become increasingly difficult due to antibiotic resistance. One potential way to inhibit pathogenesis is to prevent iron acquisition. The iron-regulated surface determinant (Isd) system has evolved in to acquire hemoglobin from the human host as a source of heme-iron. In this study, we investigated the molecular and structural basis for antibody-mediated correlates against a member of the Isd system, IsdB. The association of immunoglobulin heavy chain variable region gene-encoded human monoclonal antibodies with the response against IsdB is described using structural and functional studies to define the importance of this antibody class. We also determine that somatic hypermutation in the development of these antibodies hinders rather than fine-tunes the immune response to IsdB.
Copyright © 2019 Bennett et al.
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7 MeSH Terms
Immune checkpoint inhibitor-associated hypophysitis-World Health Organisation VigiBase report analysis.
Guerrero E, Johnson DB, Bachelot A, Lebrun-Vignes B, Moslehi JJ, Salem JE
(2019) Eur J Cancer 113: 10-13
MeSH Terms: Adult, Aged, Aged, 80 and over, Antibodies, Monoclonal, Antibodies, Monoclonal, Humanized, Antineoplastic Agents, Immunological, B7-H1 Antigen, CTLA-4 Antigen, Databases, Factual, Female, Humans, Hypophysitis, Ipilimumab, Male, Middle Aged, Nivolumab, Pharmacovigilance, Programmed Cell Death 1 Receptor, World Health Organization, Young Adult
Added November 12, 2019
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Hematologic Complications of Immune Checkpoint Inhibitors.
Davis EJ, Salem JE, Young A, Green JR, Ferrell PB, Ancell KK, Lebrun-Vignes B, Moslehi JJ, Johnson DB
(2019) Oncologist 24: 584-588
MeSH Terms: Adult, Adverse Drug Reaction Reporting Systems, Aged, Aged, 80 and over, Antibodies, Monoclonal, Humanized, Antineoplastic Agents, Immunological, B7-H1 Antigen, Databases, Factual, Female, Hematologic Diseases, Humans, Incidence, Ipilimumab, Male, Middle Aged, Neoplasms, Pharmacovigilance, Programmed Cell Death 1 Receptor, Risk Factors
Show Abstract · Added November 12, 2019
Immune checkpoint inhibitors have improved outcomes for patients with numerous hematological and solid cancers. Hematologic toxicities have been described, but the spectrum, timing, and clinical presentation of these complications are not well understood. We used the World Health Organization's pharmacovigilance database of individual-case-safety-reports (ICSRs) of adverse drug reactions, VigiBase, to identify cases of hematologic toxicities complicating immune checkpoint inhibitor therapy. We identified 168 ICSRs of immune thrombocytopenic purpura (ITP), hemolytic anemia (HA), hemophagocytic lymphohistiocytosis, aplastic anemia, and pure red cell aplasia in 164 ICSRs. ITP ( = 68) and HA ( = 57) were the most common of these toxicities and occurred concomitantly in four patients. These events occurred early on treatment (median 40 days) and were associated with fatal outcome in 12% of cases. Ipilimumab-based therapy (monotherapy or combination with anti-programmed death-1 [PD-1]) was associated with earlier onset (median 23 vs. 47.5 days,  = .006) than anti-PD-1/programmed death ligand-1 monotherapy. Reporting of hematologic toxicities has increased over the past 2 years (98 cases between January 2017 and March 2018 vs. 70 cases before 2017), possibly because of increased use of checkpoint inhibitors and improved recognition of toxicities. Future studies should evaluate incidence of hematologic toxicities, elucidate risk factors, and determine the most effective treatment algorithms. KEY POINTS: Immune-mediated hematologic toxicities are a potential side effect of immune checkpoint inhibitors (ICIs).Providers should monitor complete blood counts during treatment with ICIs.Corticosteroids are the mainstay of treatment for immune-mediated hematologic toxicities.Further research is needed to define patient-specific risk factors and optimal management strategies for hematologic toxicities.
© AlphaMed Press 2019.
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19 MeSH Terms