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.

Platelet derived growth factor-BB (PDGF-BB) is an important mitogen and cell survival factor during development. PDGF-BB binds PDGF receptor-beta (PDGFR beta) 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 PDGFR beta. 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 PDGFR beta. Comparison of the MOR8457-PDGF-BB structure with that of the PDGFR beta-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 PDGFR,6, which makes it nonpermissive for PDGFR beta 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.