Preclinical and Phase 1a Clinical Evaluation of an Anti-Vegf Pegylated Aptamer (Eye001) for the Treatment of Exudative Age-Related Macular Degeneration

Martín, Daniel; Klein, Michael L.; Haller, Julia A.; Adamis, Anthony P.; Gragoudas, Evangelos S.; Miller, Joan W.; Blumenkrantz, Mark; Goldberg, Morton F.; Yannuzzi, Lawrence A.; Henninger, Dwight; Wiegand, Laurie B.; Chen, Long Shiuh; Drolet, Daniel; Gill, Stanley C.; Bill, Jerry; Tomkinson, Blake; Bendele, Raymond A.; O’Shaughnessy, Denis; Guyer, David R.; Patel, Sudi

doi:10.1097/00006982-200204000-00002

Cited by 363 publications

(57 citation statements)

References 19 publications

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“…A number of excellent recent reviews have summarized the developments in this field over the past two decades. 6,47,107,108,109 The scorecard at this time includes one approved drug (Macugen or pegaptanib), 44,110,111,112 two compounds in phase 3 clinical trials (Revolixys™ or pegnivacogin and Fovista™ or E10030) 45,113,114,115,116,117 and many candidates in earlier stages of development. 6,47,107 To place this track record in a proper context, we should recall that it took 11 years from the invention of hybridoma technology 118 to the first monoclonal antibody therapeutic, a murine monoclonal to CD3, 119 and more than two decades of major improvements for true blossoming of the technology and full acceptance of antibodies as drugs.…”

Section: Therapeuticsmentioning

confidence: 99%

Nucleic Acid Ligands With Protein-like Side Chains: Modified Aptamers and Their Use as Diagnostic and Therapeutic Agents

Rohloff

Gelinas

Jarvis

et al. 2014

Molecular Therapy - Nucleic Acids

431

391

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Limited chemical diversity of nucleic acid libraries has long been suspected to be a major constraining factor in the overall success of SELEX (Systematic Evolution of Ligands by EXponential enrichment). Despite this constraint, SELEX has enjoyed considerable success over the past quarter of a century as a result of the enormous size of starting libraries and conformational richness of nucleic acids. With judicious introduction of functional groups absent in natural nucleic acids, the “diversity gap” between nucleic acid–based ligands and protein-based ligands can be substantially bridged, to generate a new class of ligands that represent the best of both worlds. We have explored the effect of various functional groups at the 5-position of uracil and found that hydrophobic aromatic side chains have the most profound influence on the success rate of SELEX and allow the identification of ligands with very low dissociation rate constants (named Slow Off-rate Modified Aptamers or SOMAmers). Such modified nucleotides create unique intramolecular motifs and make direct contacts with proteins. Importantly, SOMAmers engage their protein targets with surfaces that have significantly more hydrophobic character compared with conventional aptamers, thereby increasing the range of epitopes that are available for binding. These improvements have enabled us to build a collection of SOMAmers to over 3,000 human proteins encompassing major families such as growth factors, cytokines, enzymes, hormones, and receptors, with additional SOMAmers aimed at pathogen and rodent proteins. Such a large and growing collection of exquisite affinity reagents expands the scope of possible applications in diagnostics and therapeutics.

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Section: Therapeuticsmentioning

confidence: 99%

Nucleic Acid Ligands With Protein-like Side Chains: Modified Aptamers and Their Use as Diagnostic and Therapeutic Agents

Rohloff

Gelinas

Jarvis

et al. 2014

Molecular Therapy - Nucleic Acids

431

391

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“…Furthermore, administration of DNA aptamers have not been associated with the generation of T and B cell responses. 44,45 These features are especially relevant to chronic or long-term administration of aptamers aimed at treating patients with allergies, arthritis, and autoimmune responses including rejection of tissues following transplantations. In contrast, most protein-based agents including humanized monoclonal antibodies do engender an immune response when administered chronically to patients.…”

Section: Discussionmentioning

confidence: 99%

Agonistic CD200R1 DNA Aptamers Are Potent Immunosuppressants That Prolong Allogeneic Skin Graft Survival

Prodeus

Cydzik

Abdul-Wahid

et al. 2014

Molecular Therapy - Nucleic Acids

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CD200R1 expressed on the surface of myeloid and lymphoid cells delivers immune inhibitory signals to modulate inflammation when engaged with its ligand CD200. Signalling through CD200/CD200R1 has been implicated in a number of immune-related diseases including allergy, infection, cancer and transplantation, as well as several autoimmune disorders including arthritis, systemic lupus erythematosus, and multiple sclerosis. We report the development and characterization of DNA aptamers, which bind to murine CD200R1 and act as potent signalling molecules in the absence of exogenous CD200. These agonistic aptamers suppress cytotoxic T-lymphocyte induction in 5-day allogeneic mixed leukocyte culture and induce rapid phosphorylation of the CD200R1 cytoplasmic tail thereby initiating immune inhibitory signalling. PEGylated conjugates of these aptamers show significant in vivo immunosuppression and enhance survival of allogeneic skin grafts as effectively as soluble CD200Fc. As DNA aptamers exhibit inherent advantages over conventional protein-based therapeutics including low immunogenicity, ease of synthesis, low cost, and long shelf life, such CD200R1 agonistic aptamers may emerge as useful and safe nonsteroidal anti-inflammatory therapeutic agents.

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“…It selectively binds to the VEGF-A 165 , which is the most potent and prevalent isoform expressed during pathologic neovascularization [8]. Macugen was approved by the Food and Drug Administration (FDA) in December 2004 for the treatment of wet AMD [9], becoming the first pharmacological agent approved for ocular angiogenesis.…”

Section: Against Vegfmentioning

confidence: 99%

Emerging Pharmacologic Therapies for Wet Age-Related Macular Degeneration

Hui

2009

Ophthalmologica

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As researchers and clinicians are beginning to understand that wet age-related macular degeneration (AMD) is more than simply a vascular disease that includes angiogenic, vascular and inflammatory components, they are exploring new agents with different mechanisms of action addressing multiple targets in this complex pathophysiology. Some of them are already available in human trials or even approved vascular epithelial growth factor (VEGF) blockers such as Macugen, Lucentis, Avastin, VEGF Trap-Eye and Cand5; VEGF receptor blockers such as TG100801, vatalanib, pazopanib, Sirna-027 and a vaccine approach; inflammation inhibitors and immunosuppressants such as Retaane, Kenalog, ARC1905, POT-4, OT-551. The last group is mixed, containing agents such as Zybrestat, AdPEGF, Sirolimus, JSM6427, ATG003, E10030. This article reviews these currently emerging agents and briefly discusses the next step for the treatment of wet AMD.

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Preclinical and Phase 1a Clinical Evaluation of an Anti-Vegf Pegylated Aptamer (Eye001) for the Treatment of Exudative Age-Related Macular Degeneration

Cited by 363 publications

References 19 publications

Nucleic Acid Ligands With Protein-like Side Chains: Modified Aptamers and Their Use as Diagnostic and Therapeutic Agents

Nucleic Acid Ligands With Protein-like Side Chains: Modified Aptamers and Their Use as Diagnostic and Therapeutic Agents

Agonistic CD200R1 DNA Aptamers Are Potent Immunosuppressants That Prolong Allogeneic Skin Graft Survival

Emerging Pharmacologic Therapies for Wet Age-Related Macular Degeneration

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