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      Adnectins: engineered target-binding protein therapeutics

      review-article
      1
      Protein Engineering, Design and Selection
      Oxford University Press
      10Fn3, Adnectin, Engineered therapeutic proteins, mRNA display, PROfusion

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          Abstract

          Adnectins TM are a new family of therapeutic proteins based on the 10th fibronectin type III domain, and designed to bind with high affinity and specificity to therapeutically relevant targets. Adnectins share with antibody variable domains a beta-sheet sandwich fold with diversified loops, but differ from antibodies in primary sequence and have a simpler, single-domain structure without disulfide bonds. As a consequence, Adnectins bind targets with affinity and specificity as high as those of antibodies, but are easier to manipulate genetically and compatible with bacterial expression systems. Adnectins that bind macromolecular targets with nanomolar and picomolar affinity have been selected using in vitro evolution methods, including mRNA display, phage display and yeast display. CT-322, a PEGylated, anti-angiogenic Adnectin that binds vascular endothelial growth factor (VEGF) receptor 2 and blocks its interaction with VEGF A, C and D, is being evaluated in Phase II clinical trials for efficacy in several oncology indications.

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          Most cited references50

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          Strategies and challenges for the next generation of therapeutic antibodies.

          Antibodies and related products are the fastest growing class of therapeutic agents. By analysing the regulatory approvals of IgG-based biotherapeutic agents in the past 10 years, we can gain insights into the successful strategies used by pharmaceutical companies so far to bring innovative drugs to the market. Many challenges will have to be faced in the next decade to bring more efficient and affordable antibody-based drugs to the clinic. Here, we discuss strategies to select the best therapeutic antigen targets, to optimize the structure of IgG antibodies and to design related or new structures with additional functions.
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            The fibronectin type III domain as a scaffold for novel binding proteins.

            The fibronectin type III domain (FN3) is a small autonomous folding unit which occurs in many animal proteins involving in ligand binding. The beta-sandwich structure of FN3 closely resembles that of immunoglobulin domains. We have prepared a phage display library of FN3 in which residues in two surface loops were randomized. We have selected mutant FN3s which bind to a test ligand, ubiquitin, with significant affinities, while the wild-type FN3 shows no measurable affinity. A dominant clone was expressed as a soluble protein and its properties were investigated in detail. Heteronuclear NMR characterization revealed that the selected mutant protein retains the global fold of FN3. It also has a modest conformational stability despite mutations at 12 out of 94 residues. These results clearly show the potential of FN3 as a scaffold for engineering novel binding proteins. Copyright 1998 Academic Press.
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              Domain antibodies: proteins for therapy.

              Occurring naturally in "heavy chain" immunoglobulins from camels, and now produced in fully human form, domain antibodies (dAbs) are the smallest known antigen-binding fragments of antibodies, ranging from 11 kDa to 15 kDa. dAbs are the robust variable regions of the heavy and light chains of immunoglobulins (VH and VL respectively). They are highly expressed in microbial cell culture, show favourable biophysical properties including solubility and temperature stability, and are well suited to selection and affinity maturation by in vitro selection systems such as phage display. dAbs are bioactive as monomers and, owing to their small size and inherent stability, can be formatted into larger molecules to create drugs with prolonged serum half-lives or other pharmacological activities.
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                Author and article information

                Journal
                Protein Eng Des Sel
                proeng
                proeng
                Protein Engineering, Design and Selection
                Oxford University Press
                1741-0126
                1741-0134
                Jan-Feb 2011
                10 November 2010
                10 November 2010
                : 24
                : 1-2 , Special Issue: Three Decades of Protein Engineering: Impact on Structural Biology and Therapy
                : 3-9
                Affiliations
                Department of Protein Design, simpleAdnexus, A Bristol-Myers Squibb R&D Company , Waltham, MA 02453, USA
                Author notes
                [1 ]To whom correspondence should be addressed. E-mail: dlipovsek@ 123456adnexustx.com

                Edited by Liz Meiering

                Article
                gzq097
                10.1093/protein/gzq097
                3003446
                21068165
                f43092b9-c9cc-4804-8b3f-c1e785197051
                © The Author 2010. Published by Oxford University Press.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/2.5), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited

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                Biomedical engineering
                mrna display,engineered therapeutic proteins,adnectin,profusion,10fn3
                Biomedical engineering
                mrna display, engineered therapeutic proteins, adnectin, profusion, 10fn3

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