title: Function blocking antibodies to neuropilin-1 generated from a designed human synthetic antibody phage library.
abstract: Non-immune (naïve) antibody phage libraries have become an important source of human antibodies. The synthetic phage antibody library described here utilizes a single human framework with a template containing human consensus complementarity-determining regions (CDRs). Diversity of the libraries was introduced at select CDR positions using tailored degenerate and trinucleotide codons that mimic natural human antibodies. Neuropilin-1 (NRP1), a cell-surface receptor for both vascular endothelial growth factor (VEGF) and class 3 semaphorins, is expressed on endothelial cells and neurons. NRP1 is required for vascular development and is expressed widely in the developing vasculature. To investigate the possibility of function blocking antibodies to NRP1 as potential therapeutics, and study the consequence of targeting NRP1 in murine tumor models, panels of antibodies that cross-react with human and murine NRP1 were generated from a designed antibody phage library. Antibody (YW64.3) binds to the CUB domains (a1a2) of NRP1 and completely blocks Sema3A induced neuron collapse; antibody (YW107.4.87) binds to the coagulation factor V/VIII domains (b1b2) of NRP1 and blocks VEGF binding and VEGF induced cell migration. YW107.4.87 inhibits tumor growth in animal xenograft models. These antibodies have provided valuable tools to study the roles of NRP1 in vascular and tumor biology.
authors.affiliation: Antibody Engineering, Genentech Inc, South San Francisco, CA 94080, USA.
authors.forename: Wei-Ching
authors.initials: WC
authors.lastname: Liang
authors.forename: Mark S
authors.initials: MS
authors.lastname: Dennis
authors.forename: Scott
authors.initials: S
authors.lastname: Stawicki
authors.forename: Yvan
authors.initials: Y
authors.lastname: Chanthery
authors.forename: Qi
authors.initials: Q
authors.lastname: Pan
authors.forename: Yongmei
authors.initials: Y
authors.lastname: Chen
authors.forename: Charles
authors.initials: C
authors.lastname: Eigenbrot
authors.forename: JianPing
authors.initials: J
authors.lastname: Yin
authors.forename: Alexander W
authors.initials: AW
authors.lastname: Koch
authors.forename: Xiumin
authors.initials: X
authors.lastname: Wu
authors.forename: Napoleone
authors.initials: N
authors.lastname: Ferrara
authors.forename: Anil
authors.initials: A
authors.lastname: Bagri
authors.forename: Marc
authors.initials: M
authors.lastname: Tessier-Lavigne
authors.forename: Ryan J
authors.initials: RJ
authors.lastname: Watts
authors.forename: Yan
authors.initials: Y
authors.lastname: Wu
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D019138:Antibodies, Blocking / Q000737:chemistry / Q000276:immunology*; D000915:Antibody Affinity / Q000187:drug effects; D016466:CHO Cells; D002465:Cell Movement / Q000187:drug effects; D022801:Complementarity Determining Regions / Q000737:chemistry / Q000276:immunology; D006224:Cricetinae; D003412:Cricetulus; D020439:Growth Cones / Q000187:drug effects; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology; D007700:Kinetics; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D009369:Neoplasms / Q000473:pathology; D039942:Neuropilin-1 / Q000276:immunology*; D019151:Peptide Library; D017434:Protein Structure, Tertiary / Q000187:drug effects; D040121:Semaphorin-3A / Q000494:pharmacology
chemical_list: D019138:Antibodies, Blocking; D022801:Complementarity Determining Regions; D007074:Immunoglobulin G; D019151:Peptide Library; D040121:Semaphorin-3A; D039942:Neuropilin-1