Development of monoclonal anti-PDGF-CC antibodies as tools for investigating human tissue expression and for blocking PDGF-CC induced PDGFRα signalling in vivo

PLoS One. 2018 Jul 27;13(7):e0201089. doi: 10.1371/journal.pone.0201089. eCollection 2018.

Abstract

PDGF-CC is a member of the platelet-derived growth factor (PDGF) family that stimulates PDGFRα phosphorylation and thereby activates intracellular signalling events essential for development but also in cancer, fibrosis and neuropathologies involving blood-brain barrier (BBB) disruption. In order to elucidate the biological and pathological role(s) of PDGF-CC signalling, we have generated high affinity neutralizing monoclonal antibodies (mAbs) recognizing human PDGF-CC. We determined the complementarity determining regions (CDRs) of the selected clones, and mapped the binding epitope for clone 6B3. Using the monoclonal 6B3, we determined the expression pattern for PDGF-CC in different human primary tumours and control tissues, and explored its ability to neutralize PDGF-CC-induced phosphorylation of PDGFRα. In addition, we showed that PDGF-CC induced disruption of the blood-retinal barrier (BRB) was significantly reduced upon intraperitoneal administration of a chimeric anti-PDGF-CC antibody. In summary, we report on high affinity monoclonal antibodies against PDGF-CC that have therapeutic efficacy in vivo.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • A549 Cells
  • Animals
  • Antibodies, Monoclonal / immunology*
  • Blood-Retinal Barrier / drug effects
  • Blood-Retinal Barrier / metabolism
  • Blood-Retinal Barrier / pathology
  • Capillary Permeability
  • Gene Expression / drug effects
  • Humans
  • Immunohistochemistry
  • Lymphokines / antagonists & inhibitors*
  • Lymphokines / immunology*
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Neoplasms / metabolism
  • Neoplasms / pathology
  • Platelet-Derived Growth Factor / antagonists & inhibitors*
  • Platelet-Derived Growth Factor / immunology*
  • Receptor, Platelet-Derived Growth Factor alpha / metabolism*
  • Recombinant Proteins / immunology
  • Signal Transduction / drug effects

Substances

  • Antibodies, Monoclonal
  • Lymphokines
  • Platelet-Derived Growth Factor
  • Recombinant Proteins
  • platelet-derived growth factor C
  • Receptor, Platelet-Derived Growth Factor alpha

Grants and funding

This study was supported by the Swedish Heart and Lung Foundation (20110451 and 20120077, U.E.), the Swedish Research Council (2011-03861, U.E.), the Swedish Cancer Foundation (CAN 2011/792 and CAN 2014/630, U.E.), and the Karolinska Institutet. This work was supported in part by the Australian National Health and Medical Research Council (NHMRC) Development Grants 1038334 and 1075898 and Practitioner Fellowship to A.M.S. and funds from the Operational Infrastructure Support Program provided by the Victorian Government, Australia. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The funders provided support in the form of salaries for authors [HL, MZ, IN, XL, LA, BG, AP, CM, BC, AMN, FES, AMS and UE], but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.