Derivation of RNA aptamer inhibitors of human complement C5

Biesecker, Gregory; Dihel, Larry; Enney, K.; Bendele, Raymond A.

doi:10.1016/s0162-3109(99)00020-x

Cited by 132 publications

(86 citation statements)

References 26 publications

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“…78 ). Aptamers are single-stranded nucleotide stretches that have molecular recognition properties similar to those of antibodies, but offer better options for derivatization.…”

Section: Complement Component Inhibitorsmentioning

confidence: 99%

Complement-targeted therapeutics

2007

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The complement system is a central component of innate immunity and bridges the innate to the adaptive immune response. However, it can also turn its destructive capabilities against host cells and is involved in numerous diseases and pathological conditions. Modulation of the complement system has been recognized as a promising strategy in drug discovery, and a large number of therapeutic modalities have been developed. However, successful marketing of complement-targeted drugs has proved to be more difficult than initially expected, and many strategies have been discontinued. The US Food and Drug Administration's approval of the first complement-specific drug, an antibody against complement component C5 (eculizumab; Soliris), in March 2007, was a long-awaited breakthrough in the field. Approval of eculizumab validates the complement system as therapeutic target and might facilitate clinical development of other promising drug candidates.When the bactericidal properties of certain heat-labile blood components were initially described more than a century ago 1 , no one could have imagined the considerable impact the complement system would have on both immunology and our understanding of many disease processes. Even the name "complement," originally coined by Paul Ehrlich 2 , implied only a supplementary role of this system in the defense against microbial intruders. However, continued progress in research has led to a dramatic change in our knowledge about the complement system and moved it into the spotlight of basic and applied life sciences.Today it is clear that complement is a key player of the innate immune system. However, this integral position in the maintenance and regulation of immune and inflammation reactions also makes it a trigger point for a variety of pathologic conditions. Erroneous activation or insufficient regulation of the complement cascade may turn its destructive actions against the host's cells. As a consequence, many inflammatory and autoimmune diseases are thought to be caused, or at least supported, by unleashed complement. Inhibition or modulation of complement activity has therefore been recognized as a promising therapeutic strategy for many years.Although many creative attempts to design complement-specific drugs have been made in recent decades, their development from experimental concept to clinical product has faced many obstacles. In light of these complications, most of the major pharmaceutical companies seem to have abandoned their initial efforts to develop drugs that target complement. Despite its bitter taste, this decision has encouraged a series of small startup companies in the biotechnology field to take up the challenge. The first results of this commitment are now Correspondence should be addressed to J.D.L. (lambris@mail.med.upenn.edu). COMPETING INTERESTS STATEMENTThe authors declare competing financial interests: details accompany the full-text HTML version of the paper at http://www.nature.com/naturebiotechnology/.Reprints and permissions information i...

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“…78 ). Aptamers are single-stranded nucleotide stretches that have molecular recognition properties similar to those of antibodies, but offer better options for derivatization.…”

Section: Complement Component Inhibitorsmentioning

confidence: 99%

Complement-targeted therapeutics

2007

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“…126 Stemming from their initial enzymatic recognition studies, 2 0 -amino pyrimidines, 2 0 -fluoro pyrimidines and 2 0 -O-Methyl nucleotides have been successfully applied in aptamer development by conventional SELEX-based methodologies. [127][128][129][130][131][132][133][134] LNA is one of the successful nucleotide analogs extensively utilized in various fields because of their remarkable properties. 113,114 In LNA the sugar ring is conformationally locked by a O2 0 -C4 0 methylene linkage to adopt N-type sugar puckering.…”

Section: Chemically Modified Aptamer-oligonucleotide Chimeramentioning

confidence: 99%

Smart functional nucleic acid chimeras: Enabling tissue specific RNA targeting therapy

et al. 2015

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“…Both agents are intended for use together with a VEGF inhibitor. Illustrating the long time frame for development of therapeutics, especially when coupled with often discontinuous nature of drug development in biotechnology companies, both E10030 and ARC1905 in their current form were identi fi ed in the late 1990s ( Green et al 1996 ;Floege et al 1999 ;Biesecker et al 1999 ) . AMD and other ophthalmology indications remain an interesting area for aptamer-based therapeutics.…”

Section: And What About Complement (Or Any Other) Therapeutics?mentioning

confidence: 99%

Highly Multiplexed Proteomic Platform for Biomarker Discovery, Diagnostics, and Therapeutics

Mehan

Ostroff

Wilcox

et al. 2012

Complement Therapeutics

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Progression from health to disease is accompanied by complex changes in protein expression in both the circulation and affected tissues. Large-scale comparative interrogation of the human proteome can offer insights into disease biology as well as lead to the discovery of new biomarkers for diagnostics, new targets for therapeutics, and can identify patients most likely to benefit from treatment. Although genomic studies provide an increasingly sharper understanding of basic biological and pathobiological processes, they ultimately only offer a prediction of relative disease risk, whereas proteins offer an immediate assessment of "real-time" health and disease status. We have recently developed a new proteomic technology, based on modified aptamers, for biomarker discovery that is capable of simultaneously measuring more than a thousand proteins from small volumes of biological samples such as plasma, tissues, or cells. Our technology is enabled by SOMAmers (Slow Off-rate Modified Aptamers), a new class of protein binding reagents that contain chemically modified nucleotides that greatly expand the physicochemical diversity of nucleic acid-based ligands. Such modifications introduce functional groups that are absent in natural nucleic acids but are often found in protein-protein, small molecule-protein, and antibody-antigen interactions. The use of these modifications expands the range of possible targets for SELEX (Systematic Evolution of Ligands by EXponential Enrichment), results in improved binding properties, and facilitates selection of SOMAmers with slow dissociation rates. Our assay works by transforming protein concentrations in a mixture into a corresponding DNA signature, which is then quantified on current commercial DNA microarray platforms. In essence, we take advantage of the dual nature of SOMAmers as both folded binding entities with defined shapes and unique nucleic acid sequences recognizable by specific hybridization probes. Currently, our assay is capable of simultaneously measuring 1,030 proteins, extending to sub-pM detection limits, an average dynamic range of each analyte in the assay of > 3 logs, an overall dynamic range of at least 7 logs, and a throughput of one million analytes per week. Our collection includes SOMAmers that specifically recognize most of the complement cascade proteins. We have used this assay to identify potential biomarkers in a range of diseases such as malignancies, cardiovascular disorders, and inflammatory conditions. In this chapter, we describe the application of our technology to discovering large-scale protein expression changes associated with chronic kidney disease and non-small cell lung cancer. With this new proteomics technology-which is fast, economical, highly scalable, and flexible--we now have a powerful tool that enables whole-proteome proteomics, biomarker discovery, and advancing the next generation of evidence-based, "personalized" diagnostics and therapeutics.

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Derivation of RNA aptamer inhibitors of human complement C5

Cited by 132 publications

References 26 publications

Complement-targeted therapeutics

Complement-targeted therapeutics

Smart functional nucleic acid chimeras: Enabling tissue specific RNA targeting therapy

Highly Multiplexed Proteomic Platform for Biomarker Discovery, Diagnostics, and Therapeutics

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