title: Multivalent avimer proteins evolved by exon shuffling of a family of human receptor domains.
abstract: We have developed a class of binding proteins, called avimers, to overcome the limitations of antibodies and other immunoglobulin-based therapeutic proteins. Avimers are evolved from a large family of human extracellular receptor domains by in vitro exon shuffling and phage display, generating multidomain proteins with binding and inhibitory properties. Linking multiple independent binding domains creates avidity and results in improved affinity and specificity compared with conventional single-epitope binding proteins. Other potential advantages over immunoglobulin domains include simple and efficient production of multitarget-specific molecules in Escherichia coli, improved thermostability and resistance to proteases. Avimers with sub-nM affinities were obtained against five targets. An avimer that inhibits interleukin 6 with 0.8 pM IC50 in cell-based assays is biologically active in two animal models.
authors.affiliation: Avidia, Inc., 2450 Bayshore Parkway, Mountain View, California 94043, USA. josh.silverman@avidia.com
authors.forename: Joshua
authors.initials: J
authors.lastname: Silverman
authors.forename: Qiang
authors.initials: Q
authors.lastname: Liu
authors.forename: Qiang
authors.initials: Q
authors.lastname: Lu
authors.forename: Alice
authors.initials: A
authors.lastname: Bakker
authors.forename: Wayne
authors.initials: W
authors.lastname: To
authors.forename: Amy
authors.initials: A
authors.lastname: Duguay
authors.forename: Ben M
authors.initials: BM
authors.lastname: Alba
authors.forename: Richard
authors.initials: R
authors.lastname: Smith
authors.forename: Alberto
authors.initials: A
authors.lastname: Rivas
authors.forename: Peng
authors.initials: P
authors.lastname: Li
authors.forename: Hon
authors.initials: H
authors.lastname: Le
authors.forename: Erik
authors.initials: E
authors.lastname: Whitehorn
authors.forename: Kevin W
authors.initials: KW
authors.lastname: Moore
authors.forename: Candace
authors.initials: C
authors.lastname: Swimmer
authors.forename: Victor
authors.initials: V
authors.lastname: Perlroth
authors.forename: Martin
authors.initials: M
authors.lastname: Vogt
authors.forename: Joost
authors.initials: J
authors.lastname: Kolkman
authors.forename: Willem Pim C
authors.initials: WP
authors.lastname: Stemmer
mesh_terms: D000818:Animals; D032621:DNA Shuffling / Q000379:methods*; D019143:Evolution, Molecular; D005091:Exons / Q000235:genetics*; D005260:Female; D006801:Humans; D051379:Mice; D015202:Protein Engineering / Q000379:methods*; D017434:Protein Structure, Tertiary; D011956:Receptors, Cell Surface / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*
chemical_list: D011956:Receptors, Cell Surface