title: Evolution of potent and stable placental-growth-factor-1-targeting CovX-bodies from phage display peptide discovery.
abstract: Novel phage-derived peptides are the first reported molecules specifically targeting human placental growth factor 1 (PlGF-1). Phage data enabled peptide modifications that decreased IC(50) values in PlGF-1/VEGFR-1 competition ELISA from 100 to 1 μM. Peptides exhibiting enhanced potency were bioconjugated to the CovX antibody scaffold 1 (CVX-2000), generating bivalent CovX-Bodies with 2 nM K(D) against PlGF-1. In vitro and in vivo peptide cleavage mapping studies enabled the identification of proteolytic hotspots that were subsequently chemically modified. These changes decreased IC(50) to 0.4 nM and increased compound stability from 5% remaining at 6 h after injection to 35% remaining at 24 h with a β phase half-life of 75 h in mice. In cynomolgus monkey, a 78 h β half-life was observed for lead compound 2. The pharmacological properties of 2 are currently being explored.
authors.affiliation: CovX Research, Pfizer, Inc, 9381 Judicial Drive, Suite 200, San Diego, California 92121, United States. kristen.e.bower@pfizer.com
authors.forename: Kristen E
authors.initials: KE
authors.lastname: Bower
authors.forename: Son N
authors.initials: SN
authors.lastname: Lam
authors.forename: Bryan D
authors.initials: BD
authors.lastname: Oates
authors.forename: Joselyn R
authors.initials: JR
authors.lastname: Del Rosario
authors.forename: Emily
authors.initials: E
authors.lastname: Corner
authors.forename: Trina F
authors.initials: TF
authors.lastname: Osothprarop
authors.forename: Arvind G
authors.initials: AG
authors.lastname: Kinhikar
authors.forename: Julie A
authors.initials: JA
authors.lastname: Hoye
authors.forename: R Ryan
authors.initials: RR
authors.lastname: Preston
authors.forename: Robert E
authors.initials: RE
authors.lastname: Murphy
authors.forename: Lioudmila A
authors.initials: LA
authors.lastname: Campbell
authors.forename: Hanhua
authors.initials: H
authors.lastname: Huang
authors.forename: Judith
authors.initials: J
authors.lastname: Jimenez
authors.forename: Xia
authors.initials: X
authors.lastname: Cao
authors.forename: Gang
authors.initials: G
authors.lastname: Chen
authors.forename: Zemeda W
authors.initials: ZW
authors.lastname: Ainekulu
authors.forename: Aakash B
authors.initials: AB
authors.lastname: Datt
authors.forename: Nancy J
authors.initials: NJ
authors.lastname: Levin
authors.forename: Venkata R
authors.initials: VR
authors.lastname: Doppalapudi
authors.forename: Steven R
authors.initials: SR
authors.lastname: Pirie-Shepherd
authors.forename: Curt
authors.initials: C
authors.lastname: Bradshaw
authors.forename: Gary
authors.initials: G
authors.lastname: Woodnutt
authors.forename: Rodney W
authors.initials: RW
authors.lastname: Lappe
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D000906:Antibodies / Q000737:chemistry*; D001667:Binding, Competitive; D003429:Cross Reactions; D004355:Drug Stability; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D019151:Peptide Library; D010455:Peptides / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D000072483:Placenta Growth Factor; D011257:Pregnancy Proteins / Q000378:metabolism*; D011485:Protein Binding; D013329:Structure-Activity Relationship; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000037:antagonists & inhibitors
chemical_list: D000906:Antibodies; C000608036:PGF protein, human; D019151:Peptide Library; D010455:Peptides; C000608037:Pgf protein, mouse; D011257:Pregnancy Proteins; D000072483:Placenta Growth Factor; D040281:Vascular Endothelial Growth Factor Receptor-1