title: Characterization of binding mode of action of a blocking anti-platelet-derived growth factor (PDGF)-B monoclonal antibody, MOR8457, reveals conformational flexibility and avidity needed for PDGF-BB to bind PDGF receptor-β.
abstract: Platelet derived growth factor-BB (PDGF-BB) is an important mitogen and cell survival factor during development. PDGF-BB binds PDGF receptor-β (PDGFRβ) to trigger receptor dimerization and tyrosine kinase activation. We present the pharmacological and biophysical characterization of a blocking PDGF-BB monoclonal antibody, MOR8457, and contrast this to PDGFRβ. MOR8457 binds to PDGF-BB with high affinity and selectivity, and prevents PDGF-BB induced cell proliferation competitively and with high potency. The structural characterization of the MOR8457-PDGF-BB complex indicates that MOR8457 binds with a 2:1 stoichiometry, but that binding of a single MOR8457 moiety is sufficient to prevent binding to PDGFRβ. Comparison of the MOR8457-PDGF-BB structure with that of the PDGFRβ-PDGF-BB complex suggested the potential reason for this was a substantial bending and twisting of PDGF-BB in the MOR8457 structure, relative to the structures of PDGF-BB alone, bound to a PDGF-BB aptamer or PDGFRβ, which makes it nonpermissive for PDGFRβ binding. These biochemical and structural data offer insights into the permissive structure of PDGF-BB needed for agonism as well as strategies for developing specific PDGF ligand antagonists.
authors.forename: Jun
authors.initials: J
authors.lastname: Kuai
authors.forename: Lidia
authors.initials: L
authors.lastname: Mosyak
authors.forename: Jon
authors.initials: J
authors.lastname: Brooks
authors.forename: Michael
authors.initials: M
authors.lastname: Cain
authors.affiliation: ‡Scholar Rock LLC, 300 Technology Square, Cambridge, Massachusetts 02142, United States.
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Carven
authors.affiliation: §Pfizer Japan Inc., 3-22-7 Yoyogi, Shibuya, Tokyo 151-8589, Japan.
authors.forename: Shinji
authors.initials: S
authors.lastname: Ogawa
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Ishino
authors.forename: May
authors.initials: M
authors.lastname: Tam
authors.forename: Edward R
authors.initials: ER
authors.lastname: Lavallie
authors.forename: Zhiyong
authors.initials: Z
authors.lastname: Yang
authors.affiliation: ∥Roche Diagnostics GmbH, Nonnenwald 2, 82377 Penzberg, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Ponsel
authors.affiliation: ⊥MorphoSys AG, Lena-Christ Strasse 48, 82152 Martinsried, Germany.
authors.forename: Robert
authors.initials: R
authors.lastname: Rauchenberger
authors.affiliation: ¶Takeda Pharmaceuticals International Inc., One Takeda Parkway, Deerfield, Illinois 60015, United States.
authors.forename: Robert
authors.initials: R
authors.lastname: Arch
authors.forename: Nick
authors.initials: N
authors.lastname: Pullen
mesh_terms: D000911:Antibodies, Monoclonal / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D057134:Antibodies, Neutralizing / Q000737:chemistry* / Q000235:genetics / Q000494:pharmacology; D052158:Aptamers, Peptide / Q000737:chemistry / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D000077214:Becaplermin; D001666:Binding Sites, Antibody; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D006801:Humans; D020574:Proto-Oncogene Proteins c-sis / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D020797:Receptor, Platelet-Derived Growth Factor beta
chemical_list: D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; D052158:Aptamers, Peptide; D020574:Proto-Oncogene Proteins c-sis; D000077214:Becaplermin; D020797:Receptor, Platelet-Derived Growth Factor beta