Selective targeting and photocoagulation of ocular angiogenesis mediated by a phage-derived human antibody fragment

10.1038/13679 ◽  
1999 ◽  
Vol 17 (10) ◽  
pp. 984-988 ◽  
Author(s):  
Manfred Birchler ◽  
Francesca Viti ◽  
Luciano Zardi ◽  
Bernhard Spiess ◽  
Dario Neri
Keyword(s):  
Antibody Fragment ◽  
Human Antibody ◽  
Ocular Angiogenesis ◽  
Selective Targeting

Selective targeting of tumour neovasculature by a radiohalogenated human antibody fragment specific for the ED-B domain of fibronectin

2001 ◽  
Vol 28 (4) ◽  
pp. 534-539 ◽  
Author(s):  
Salvatore Demartis ◽  
Lorenzo Tarli ◽  
Laura Borsi ◽  
Luciano Zardi ◽  
Dario Neri
Keyword(s):  
Antibody Fragment ◽  
Human Antibody ◽  
Selective Targeting

A High-Affinity Human Antibody That Targets Tumoral Blood Vessels

Blood ◽  
1999 ◽  
Vol 94 (1) ◽  
pp. 192-198 ◽  
Author(s):  
Lorenzo Tarli ◽  
Enrica Balza ◽  
Francesca Viti ◽  
Laura Borsi ◽  
Patrizia Castellani ◽  
...  
Keyword(s):  
Blood Vessels ◽  
Small Cell Lung Carcinoma ◽  
Antibody Fragment ◽  
Human Colon ◽  
Experimental Models ◽  
Human Antibody ◽  
Cell Lung Carcinoma ◽  
High Affinity ◽  
Biodistribution Studies

Angiogenesis is a characteristic feature of many aggressive tumors and of other relevant disorders. Molecules capable of specifically binding to new-forming blood vessels, but not to mature vessels, could be used as selective vehicles and would, therefore, open diagnostic and therapeutic opportunities. We have studied the distribution of the ED-B oncofetal domain of fibronectin, a marker of angiogenesis, in four different tumor animal models: the F9 murine teratocarcinoma, SKMEL-28 human melanoma, N592 human small cell lung carcinoma, and C51 human colon carcinoma. In all of these experimental models we observed accumulation of the fibronectin isoform containing the ED-B domain around neovascular structures when the tumors were in the exponentially growing phase, but not in the slow-growing phase. Then we performed biodistribution studies in mice bearing a subcutaneously implanted F9 murine teratocarcinoma, using a high-affinity human antibody fragment (L19) directed against the ED-B domain of fibronectin. Radiolabeled L19, but not an irrelevant anti-lysozyme antibody fragment (D1.3), efficiently localizes in the tumoral vessels. The maximal dose of L19 accumulated in the tumor was observed 3 hours after injection (8.2% injected dose per gram). By virtue of the rapid clearance of the antibody fragment from the circulation, tumor-to-blood ratios of 1.9, 3.7, and 11.8 were obtained at 3, 5, and 24 hours, respectively. The tumor-targeting performance of L19 was not dose-dependent in the 0.7 to 10 μg range of injected antibody. The integral of the radioactivity localized in tumoral vessels over 24 hours was greater than 70-fold higher than the integral of the radioactivity in blood over the same time period, normalized per gram of tissue or fluid. These findings quantitatively show that new-forming blood vessels can selectively be targeted in vivo using specific antibodies, and suggest that L19 may be of clinical utility for the immunoscintigraphic detection of angiogenesis in patients.

scholarly journals Structure-Based Modification of an Anti-neuraminidase Human Antibody Restores Protection Efficacy against the Drifted Influenza Virus

mBio ◽  
2020 ◽  
Vol 11 (5) ◽  
Author(s):  
Haihai Jiang ◽  
Weiyu Peng ◽  
Jianxun Qi ◽  
Yan Chai ◽  
Hao Song ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Influenza Virus ◽  
Antibody Fragment ◽  
Salt Bridge ◽  
Cross Reactivity ◽  
Human Antibody ◽  
Influenza Strain ◽  
Group 2 ◽  
Fragment Antigen Binding ◽  
Group 1

ABSTRACT Here, we investigate a monoclonal antibody, Z2B3, isolated from an H7N9-infected patient, that exhibited cross-reactivity to both N9 (group 2) and a broad range of seasonal and avian N1 (group 1) proteins but lost activity to the N1 with the substitution K432E. This substitution exists in 99.25% of seasonal influenza strains after 2013. The NA-Z2B3 complex structures indicated that Z2B3 binds within the conserved active site of the neuraminidase (NA) protein. A salt bridge between D102 in Z2B3 and K432 in NA plays an important role in binding. Structure-based modification of Z2B3 with D102R in heavy chain reversed the salt bridge and restored the binding and inhibition of N1 with E432. Furthermore, Z2B3-D102R can protect mice from A/Serbia/NS-601/2014 H1N1 virus (NA contains E432) infection while the wild-type Z2B3 antibody shows no protection. This study demonstrates that a broadly reactive and protective antibody to NA can be in principle edited to restore binding and inhibition to recently drifted N1 NA and regain protection against the variant influenza strain. IMPORTANCE The immune system produces antibodies to protect the human body from harmful invaders. The monoclonal antibody (MAb) is one kind of effective antivirals. In this study, we isolated an antibody (Z2B3) from an H7N9 influenza virus-infected child. It shows cross-reactivity to both group 1 (N1) and group 2 (N9) neuraminidases (NAs) but is sensitive to N1 NA with a K432E substitution. Structural analysis of the NA-antibody fragment antigen-binding (Fab) complex provides a clue for antibody modification, and the modified antibody restored binding and inhibition to recently drifted N1 NA and regained protection against the variant influenza strain. This finding suggests that antibodies to NA may be a useful therapy and can be in principle edited to defeat drifted influenza virus.

scholarly journals Nonspecific Effect of Mycograb on Amphotericin B MIC

2012 ◽  
Vol 56 (7) ◽  
pp. 3963-3964 ◽  
Author(s):  
D. L. Richie ◽  
M. A. Ghannoum ◽  
N. Isham ◽  
K. V. Thompson ◽  
N. S. Ryder
Keyword(s):  
Human Serum ◽  
Amphotericin B ◽  
Antibody Fragment ◽  
Human Antibody ◽  
Nonspecific Effect ◽  
Hsp 90

ABSTRACTMycograb C28Y is a recombinant human antibody fragment thought to target HSP-90 and potentiate amphotericin B (AMB). Absence ofin vivoefficacy led us to reevaluate itsin vitroactivity. Interactions between AMB and Mycograb were investigated using a checkerboard design. Addition of Mycograb or various unrelated proteins, including human serum, resulted in similar decreases in the MIC of AMB. Potentiation of AMB by Mycograb appears to be a nonspecific protein effect.

scholarly journals Structure of a patient-derived antibody in complex with allergen reveals simultaneous conventional and superantigen-like recognition

2018 ◽  
Vol 115 (37) ◽  
pp. E8707-E8716 ◽  
Author(s):  
Alkistis N. Mitropoulou ◽  
Holly Bowen ◽  
Tihomir S. Dodev ◽  
Anna M. Davies ◽  
Heather J. Bax ◽  
...  
Keyword(s):  
B Cell ◽  
Antibody Fragment ◽  
Cell Receptor ◽  
Size Exclusion ◽  
Cross Linking ◽  
Human Antibody ◽  
Alternative Mode ◽  
Dual Reactivity ◽  
Effector Cells ◽  
Allergen Molecule

Antibodies classically bind antigens via their complementarity-determining regions, but an alternative mode of interaction involving V-domain framework regions has been observed for some B cell “superantigens.” We report the crystal structure of an antibody employing both modes of interaction simultaneously and binding two antigen molecules. This human antibody from an allergic individual binds to the grass pollen allergen Phl p 7. Not only are two allergen molecules bound to each antibody fragment (Fab) but also each allergen molecule is bound by two Fabs: One epitope is recognized classically, the other in a superantigen-like manner. A single allergen molecule thus cross-links two identical Fabs, contrary to the one-antibody–one-epitope dogma, which dictates that a dimeric allergen at least is required for this to occur. Allergens trigger immediate hypersensitivity reactions by cross-linking receptor-bound IgE molecules on effector cells. We found that monomeric Phl p 7 induced degranulation of basophils sensitized solely with this monoclonal antibody expressed as an IgE, demonstrating that the dual specificity has functional consequences. The monomeric state of Phl p 7 and two structurally related allergens was confirmed by size-exclusion chromatography and multiangle laser light scattering, and the results were supported by degranulation studies with the related allergens, a second patient-derived allergen-specific antibody lacking the nonclassical binding site, and mutagenesis of the nonclassically recognized allergen epitope. The antibody dual reactivity and cross-linking mechanism not only have implications for understanding allergenicity and allergen potency but, importantly, also have broader relevance to antigen recognition by membrane Ig and cross-linking of the B cell receptor.

scholarly journals Towards a transcriptome-based theranostic platform for unfavorable breast cancer phenotypes

2016 ◽  
Vol 113 (45) ◽  
pp. 12780-12785 ◽  
Author(s):  
Andrey S. Dobroff ◽  
Sara D’Angelo ◽  
Bedrich L. Eckhardt ◽  
Fortunato Ferrara ◽  
Daniela I. Staquicini ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Surface ◽  
Antibody Fragment ◽  
Surface Expression ◽  
Cell Surface Expression ◽  
Binding Motif ◽  
Human Antibody ◽  
Surface Receptors ◽  
Cancer Phenotypes

Inflammatory breast carcinoma (IBC) is one of the most lethal forms of human breast cancer, and effective treatment for IBC is an unmet clinical need in contemporary oncology. Tumor-targeted theranostic approaches are emerging in precision medicine, but only a few specific biomarkers are available. Here we report up-regulation of the 78-kDa glucose-regulated protein (GRP78) in two independent discovery and validation sets of specimens derived from IBC patients, suggesting translational promise for clinical applications. We show that a GRP78-binding motif displayed on either bacteriophage or adeno-associated virus/phage (AAVP) particles or loop-grafted onto a human antibody fragment specifically targets orthotopic IBC and other aggressive breast cancer models in vivo. To evaluate the theranostic value, we used GRP78-targeting AAVP particles to deliver the human Herpes simplex virus thymidine kinase type-1 (HSVtk) transgene, obtaining simultaneous in vivo diagnosis through PET imaging and tumor treatment by selective activation of the prodrug ganciclovir at tumor sites. Translation of this AAVP system is expected simultaneously to image, monitor, and treat the IBC phenotype and possibly other aggressive (e.g., invasive and/or metastatic) subtypes of breast cancer, based on the inducible cell-surface expression of the stress-response chaperone GRP78, and possibily other cell-surface receptors in human tumors.

Isolation and characterization of a human antibody fragment specific for Ts1 toxin from Tityus serrulatus scorpion

2011 ◽  
Vol 139 (1-2) ◽  
pp. 73-79 ◽  
Author(s):  
Itzel Amaro ◽  
Lidia Riaño-Umbarila ◽  
Baltazar Becerril ◽  
Lourival D. Possani
Keyword(s):  
Antibody Fragment ◽  
Human Antibody ◽  
Isolation And Characterization ◽  
Tityus Serrulatus

A Human Antibody Fragment with High Affinity for Biodegradable Polymer Film

2007 ◽  
Vol 18 (3) ◽  
pp. 645-651 ◽  
Author(s):  
Hideki Watanabe ◽  
Kouhei Tsumoto ◽  
Seiichi Taguchi ◽  
Koichi Yamashita ◽  
Yoshiharu Doi ◽  
...  
Keyword(s):  
Polymer Film ◽  
Biodegradable Polymer ◽  
Antibody Fragment ◽  
Human Antibody ◽  
High Affinity

scholarly journals Transcriptomics-Based Identification of Novel Factors Enhancing Heterologous Protein Secretion in Yeasts

2007 ◽  
Vol 73 (20) ◽  
pp. 6499-6507 ◽  
Author(s):  
Brigitte Gasser ◽  
Michael Sauer ◽  
Michael Maurer ◽  
Gerhard Stadlmayr ◽  
Diethard Mattanovich
Keyword(s):  
Protein Secretion ◽  
Rational Solution ◽  
Antibody Fragment ◽  
Efficient Production ◽  
Human Antibody ◽  
Scale Production ◽  
Heterologous Proteins ◽  
Fab Fragment ◽  
Folding Rate ◽  
Atpase Subunit

ABSTRACT Efficient production of heterologous proteins with yeasts and other eukaryotic hosts is often hampered by inefficient secretion of the product. Limitation of protein secretion has been attributed to a low folding rate, and a rational solution is the overexpression of proteins supporting folding, like protein disulfide isomerase (Pdi), or the unfolded protein response transcription factor Hac1. Assuming that other protein factors which are not directly involved in protein folding may also support secretion of heterologous proteins, we set out to analyze the differential transcriptome of a Pichia pastoris strain overexpressing human trypsinogen versus that of a nonexpressing strain. Five hundred twenty-four genes were identified to be significantly regulated. Excluding those genes with totally divergent functions (like, e.g., core metabolism), we reduced this number to 13 genes which were upregulated in the expression strain having potential function in the secretion machinery and in stress regulation. The respective Saccharomyces cerevisiae homologs of these genes, including the previously characterized secretion helpers PDI1, ERO1, SSO2, KAR2/BiP, and HAC1 as positive controls, were cloned and overexpressed in a P. pastoris strain expressing a human antibody Fab fragment. All genes except one showed a positive effect on Fab fragment secretion, as did the controls. Six out of these novel secretion helper factors, more precisely Bfr2 and Bmh2 (involved in protein transport), the chaperones Ssa4 and Sse1, the vacuolar ATPase subunit Cup5, and Kin2 (a protein kinase connected to exocytosis), proved their benefits for practical application in laboratory-scale production processes by increasing both specific production rates and the volumetric productivity of an antibody fragment up to 2.5-fold in fed-batch fermentations of P. pastoris.

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