Therapeutic applications of aptamers

Kaur, Gurjot; Roy, Ipsita

doi:10.1517/13543784.17.1.43

Cited by 85 publications

(40 citation statements)

References 106 publications

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“…Bi-specific aptamers optimized in such ways could mimic most eligible features of comparable therapeutic antibody approaches but exceed them, for example, with uniform and cost-effective synthesis as well as a proposed absence of immunogenicity (13,73).…”

Section: Discussionmentioning

confidence: 99%

Bi-specific Aptamers Mediating Tumor Cell Lysis

Boltz

Piater

Toleikis

et al. 2011

Journal of Biological Chemistry

134

127

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Antibody-dependent cellular cytotoxicity plays a pivotal role in antibody-based tumor therapies and is based on the recruitment of natural killer cells to antibody-bound tumor cells via binding of the Fc␥ receptor III (CD16). Here we describe the generation of chimeric DNA aptamers that simultaneously bind to CD16␣ and c-Met, a receptor that is overexpressed in many tumors. By application of the systematic evolution of ligands by exponential enrichment (SELEX) method, CD16␣ specific DNA aptamers were isolated that bound with high specificity and affinity (91 pM-195 nM) to their respective recombinant and cellularly expressed target proteins. Two optimized CD16␣ specific aptamers were coupled to each of two c-Met specific aptamers using different linkers. Bi-specific aptamers retained suitable binding properties and displayed simultaneous binding to both antigens. Moreover, they mediated cellular cytotoxicity dependent on aptamer and effector cell concentration. Displacement of a bi-specific aptamer from CD16␣ by competing antibody 3G8 reduced cytotoxicity and confirmed the proposed mode of action. These results represent the first gain of a tumoreffective function of two distinct oligonucleotides by linkage into a bi-specific aptamer mediating cellular cytotoxicity.Aptamers are structured single-stranded oligonucleotides that can bind to a large variety of targets with high affinity and specificity (1, 2). Aptamers can be isolated by an in vitro selection and an evolution process referred to as systematic evolution of ligands by exponential enrichment (SELEX) 2 (3, 4). Because aptamers have the capacity to inhibit protein-protein interactions with potencies similar to those observed with antibodies, aptamers can also trigger inhibition signals, e.g. by blocking receptor multimerization, and consequently act as therapeutic antagonists. Reversely, bi-and multivalent aptamers can activate co-stimulatory receptors, e.g. to enhance T cell reactivity (5, 6). Finally, aptamers can be applied in ligand-based targeted therapies to specifically deliver cytotoxic payloads (7,8) or siRNA (9) to tumor cells. Monoclonal antibodies serve as established and successful tumor therapeutics. However, naturally bivalent antibody formats comprise the risks of immunogenicity (10) and undesired activation by receptor dimerization (11). Development of monovalent therapeutic antibodies is elaborate and time-intensive (MetMAb (12)). Although antibodies exceed aptamers with proof as therapeutic molecules, high stability, and good pharmacokinetics, the potential advantages of aptamers are a rapid optimization, cost-effective and uniform synthesis, and a high probability of an absence of immunogenicity (5, 13). Approval of Macugen (pegaptanib sodium (14)) as the first therapeutic aptamer in 2007 as well as promising approaches in preclinical development and clinical trials (15, 16) only a few years after inception of the technology indicate aptamers as a promising new class of targeted therapeutics.Antibody-dependent cellular cytotoxicity (A...

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Section: Discussionmentioning

confidence: 99%

Bi-specific Aptamers Mediating Tumor Cell Lysis

Boltz

Piater

Toleikis

et al. 2011

Journal of Biological Chemistry

134

127

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“…The first aptamer to be approved by the US Food and Drug Administration (FDA) in 2004, Pegaptanib sodium (Macugen), for the treatment of age-related macular degeneration, contains not only 2'-Omethylated purines, and 2'-fluorine-pyrimidines to protect against endonucleases, but also a PEG moiety and a 3'-dT to enhance its pharmacokinetic properties and protect it against exonuclease attack [19]. These modifications led to Macugen having an initial half-life of 1.4h, which was extended to 131h following all these modifications [20]. In this way, it is possible to tailor the various chemical modifications to achieve a desired pharmacokinetic and biodistribution profile of a specific aptamer for a specific clinical application.…”

Section: Aptamers As Therapeutics and Therano-sticsmentioning

confidence: 99%

“…Vaccination and immunomodulation has proven immensely beneficial to human health, as evidenced by the great success of the smallpox, measles, polio and rabies vaccines, though there are several inherent problems associated with vaccine production, including both the genetic instability and heat sensitivity of the vaccines [28]. Aptamers can at least overcome the heat sensitivity, being highly stable at room temperature, and given the ease of selection and production, these nucleic acids can be quickly selected against new emerging strains [20,29]. Nucleic acids can elicit a broad spectrum activity against a wide range of viruses, or be designed against a specific viral strain.…”

Section: Immunomodulationmentioning

confidence: 99%

Aptamer Therapeutics: The 21st Century`s Magic Bullet of Nanomedicine

Shigdar¹,

Luczo²,

Wei³

et al. 2010

TOPROCJ

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Aptamers, also known as chemical antibodies, are short single-stranded DNA, RNA or peptide molecules. These molecules can fold into complex three-dimensional structures and bind to target molecules with high affinity and specificity. The nucleic acid aptamers are selected from combinatorial libraries by an iterative in vitro selection procedure known as systematic evolution of ligands by exponential enrichment (SELEX). As a new class of therapeutics and drug targeting entities, bivalent and multivalent aptamer-based molecules are emerging as highly attractive alternatives to monoclonal antibodies as targeted therapeutics.Aptamers have several advantages, offering the possibility of overcoming limitations of antibodies: 1) they can be selected against toxic or non-immunogenic targets; 2) aptamers can be chemically modified by using modified nucleotides to enhance their stability in biological fluids or via incorporating reporter molecules, radioisotopes and functional groups for their detection and immobilization; 3) they have very low immunogenicity; 4) they display high stability at room temperature, in extreme pH, or solvent; 5) once selected, they can be chemically synthesized free from cell-culturederived contaminants, and they can be manufactured at any time, in large amounts, at relatively low cost and reproducibly; 6) they are smaller and thus can diffuse more rapidly into tissues and organs, leading to faster targeting in drug delivery; 7) they have lower molecular weight that can lead to faster body clearance, resulting in a low background noise for imaging and minimizing the radiation dose to the patient in diagnostic imaging. Thus, the high selectivity and sensitivity, ease of screening and production, chemical versatility as well as stability make aptamers a class of highly attractive agents for the development of novel therapeutics, targeted drug delivery vehicles and molecular imaging.In the review, we will discuss the latest technological advances in developing aptamers, its application as a novel class of drug on its own, as well as in surface functionalization of both polymer nanoparticles or nanoliposomes in the treatment of cancer, viral and autoimmune diseases.

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“…However, the disadvantages of using protein-based C5a inhibitors include an increased risk of immunogenicity due to their chronic use, as well as the cost of production, resulting in expensive therapies for patients (13 targets. Aptamers exhibit a high affinity for their targets, as their dissociation constants, which are comparable to those of certain monoclonal antibodies, are typically between the µM and low pM range (14,15). Therefore, the present study aimed to investigate the effect of C5a in a mouse model of acute 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced experimental colitis.…”

Section: Introductionmentioning

confidence: 99%

Effectiveness of C5a aptamers in a TNBS‑induced colitis mouse model

Wang

Chen

et al. 2017

Exp Ther Med

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Abstract. The complement-activated product, complement component 5a (C5a), is a potent inflammatory peptide with a broad spectrum of functions. In vivo and in vitro studies have demonstrated that C5a serves an important role in inflammation; however, the role of C5a in the pathogenesis of inflammatory bowel disease (IBD) is not known. The purpose of the current study was to investigate the role of C5a in IBD using an experimental mouse model of colitis. Colitis was induced in mice using 2,4,6-trinitrobenzene sulfonic acid (TNBS), and C5a aptamers were subsequently administered via intraperitoneal injection. Clinical symptoms of the disease, histopathological analysis of the colon and the level of inflammatory components were examined. The symptoms of colitis, including changes in behavior, weight loss, colon damage and an increase in inflammatory cytokines, were attenuated following the treatment of mice with TNBS-induced colitis with C5a aptamers. The aptamer-treated mice exhibited a marked attenuation of colitis when compared with untreated mice, as demonstrated by the phenotypic observations, histological examinations and inflammatory cytokine levels. Colitis is characterized by an imbalance between pro-inflammatory and anti-inflammatory mediators. The results of the current study suggest that C5a may serve a critical role in inflammation in IBD. IntroductionCrohn disease (CD) and ulcerative colitis (UC) are chronic relapsing gastrointestinal disorders, two main components of inflammatory bowel disease (IBD) (1). To date, the etiology of IBD is unknown; however, various inflammatory reactions constantly stimulate the mucosal and systemic immune systems and are involved in the inflammatory cascade (2). Approximately 25% of IBD cases occur before the age of 20 years, and 4% occur in persons younger than 5 years of age (3). In the treatment of IBD, a variety of pharmacological agents that target the inflammatory process are effective in controlling disease in patients and in sustaining symptomatic remission for prolonged periods, including tumor necrosis factor blockers, probiotics and corticosteroids (4).The complement system is widely considered to function to protect the host against invading microorganisms (5). However, previous studies investigating complement system activation have demonstrated that it may serve an injurious role in the pathogenesis of a number of inflammatory and immunological diseases (6,7). Complement activation products include complement component (C) 3a, C4a, C5a and C5b-9 and the membrane attack complex. C5a is an anaphylatoxin that exhibits chemotactic activities and promotes oxidative bursts, phagocytosis and the release of granule enzymes from neutrophils, monocytes and macrophages (7).A study involving C5a knockout mice has demonstrated that C5a serves a critical role in inflammatory diseases (8). Several inflammatory diseases have been attributed to the ability of C5a to bind with high-affinity C5a receptors (9,10), including the C5a anaphylatoxin chemotactic receptor and C5L2,...

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Therapeutic applications of aptamers

Cited by 85 publications

References 106 publications

Bi-specific Aptamers Mediating Tumor Cell Lysis

Bi-specific Aptamers Mediating Tumor Cell Lysis

Aptamer Therapeutics: The 21st Century`s Magic Bullet of Nanomedicine

Effectiveness of C5a aptamers in a TNBS‑induced colitis mouse model

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