title: Rational design of antibody protease inhibitors.
abstract: The bovine antibody BLV1H12, which has an ultralong CDR3H, provides a novel scaffold for engineering new functions into the antibody's variable region. By modifying the β-strand "stalk" of BLV1H12 with sequences derived from natural or synthetic protease inhibitors, we have generated antibodies that inhibit bovine trypsin and human neutrophil elastase (HNE) with low nanomolar affinities. We were also able to generate a humanized variant using a human immunoglobulin scaffold that shares a high degree of homology with BLV1H12. Further optimization yielded a highly selective humanized anti-HNE antibody with sub-nanomolar affinity. This work demonstrates a novel strategy for generating antibodies with potent and selective inhibitory activities against extracellular proteases involved in human disease.
authors.affiliation: †Department of Chemistry and the Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, California 92037, United States.
authors.forename: Tao
authors.initials: T
authors.lastname: Liu
authors.affiliation: ‡California Institute for Biomedical Research (Calibr), La Jolla, California 92037, United States.
authors.forename: Guangsen
authors.initials: G
authors.lastname: Fu
authors.affiliation: †Department of Chemistry and the Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, California 92037, United States.
authors.forename: Xiaozhou
authors.initials: X
authors.lastname: Luo
authors.affiliation: ‡California Institute for Biomedical Research (Calibr), La Jolla, California 92037, United States.
authors.forename: Yan
authors.initials: Y
authors.lastname: Liu
authors.affiliation: ‡California Institute for Biomedical Research (Calibr), La Jolla, California 92037, United States.
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.affiliation: †Department of Chemistry and the Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, California 92037, United States.
authors.forename: Rongsheng E
authors.initials: RE
authors.lastname: Wang
authors.affiliation: †Department of Chemistry and the Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, California 92037, United States.|‡California Institute for Biomedical Research (Calibr), La Jolla, California 92037, United States.
authors.forename: Peter G
authors.initials: PG
authors.lastname: Schultz
authors.affiliation: ‡California Institute for Biomedical Research (Calibr), La Jolla, California 92037, United States.
authors.forename: Feng
authors.initials: F
authors.lastname: Wang
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000906:Antibodies / Q000737:chemistry* / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized / Q000737:chemistry / Q000494:pharmacology; D000915:Antibody Affinity; D002417:Cattle; D006801:Humans; D007135:Immunoglobulin Variable Region / Q000737:chemistry / Q000494:pharmacology; D019272:Leukocyte Elastase / Q000037:antagonists & inhibitors / Q000276:immunology; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011480:Protease Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D011487:Protein Conformation; D015202:Protein Engineering; D014357:Trypsin / Q000276:immunology; D014361:Trypsin Inhibitors / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000906:Antibodies; D061067:Antibodies, Monoclonal, Humanized; D007135:Immunoglobulin Variable Region; D011480:Protease Inhibitors; D014361:Trypsin Inhibitors; D019272:Leukocyte Elastase; D014357:Trypsin