Clinical & Experimental Metastasis

, Volume 27, Issue 4, pp 217–231

Targeting activated integrin αvβ3 with patient-derived antibodies impacts late-stage multiorgan metastasis

  • Karin Staflin
  • Joseph S. Krueger
  • Janna Hachmann
  • Jane S. Forsyth
  • Mihaela Lorger
  • Sebastian C. J. Steiniger
  • Jenny Mee
  • Cristina Pop
  • Guy S. Salvesen
  • Kim D. Janda
  • Brunhilde Felding-Habermann
Research Paper

DOI: 10.1007/s10585-010-9320-5

Cite this article as:
Staflin, K., Krueger, J.S., Hachmann, J. et al. Clin Exp Metastasis (2010) 27: 217. doi:10.1007/s10585-010-9320-5

Abstract

Advanced metastatic disease is difficult to manage and specific therapeutic targets are rare. We showed earlier that metastatic breast cancer cells use the activated conformer of adhesion receptor integrin αvβ3 for dissemination. We now investigated if targeting this form of the receptor can impact advanced metastatic disease, and we analyzed the mechanisms involved. Treatment of advanced multi-organ metastasis in SCID mice with patient-derived scFv antibodies specific for activated integrin αvβ3 caused stagnation and regression of metastatic growth. The antibodies specifically localized to tumor lesions in vivo and inhibited αvβ3 ligand binding at nanomolar levels in vitro. At the cellular level, the scFs associated rapidly with high affinity αvβ3 and dissociated extremely slowly. Thus, the scFvs occupy the receptor on metastatic tumor cells for prolonged periods of time, allowing for inhibition of established cell interaction with natural αvβ3 ligands. Potential apoptosis inducing effects of the antibodies through interaction with caspase-3 were studied as potential additional mechanism of treatment response. However, in contrast to a previous concept, neither the RGD-containing ligand mimetic scFvs nor RGD peptides bound or activated caspase-3 at the cellular or molecular level. This indicates that the treatment effects seen in the animal model are primarily due to antibody interference with αvβ3 ligation. Inhibition of advanced metastatic disease by treatment with cancer patient derived single chain antibodies against the activated conformer of integrin αvβ3 identifies this form of the receptor as a suitable target for therapy.

Keywords

Advanced metastasisTreatmentActivated integrinPatient antibodies

Copyright information

© Springer Science+Business Media B.V. 2010

Authors and Affiliations

  • Karin Staflin
    • 1
  • Joseph S. Krueger
    • 1
  • Janna Hachmann
    • 1
  • Jane S. Forsyth
    • 1
  • Mihaela Lorger
    • 1
  • Sebastian C. J. Steiniger
    • 2
  • Jenny Mee
    • 2
  • Cristina Pop
    • 3
  • Guy S. Salvesen
    • 3
  • Kim D. Janda
    • 2
  • Brunhilde Felding-Habermann
    • 1
  1. 1.Department of Molecular and Experimental MedicineThe Scripps Research InstituteLa JollaUSA
  2. 2.Department of ChemistryThe Scripps Research InstituteLa JollaUSA
  3. 3.Program in Cell Death and Apoptosis Research, The Burnham InstituteLa JollaUSA