Scripps VIVO scripps research logo

  • Index
  • Log in
  • Home
  • People
  • Organizations
  • Research
  • Events
Search form

Targeting activated integrin alpha v beta 3 with patient-derived antibodies impacts late-stage multiorgan metastasis

Academic Article
uri icon
  • Overview
  • Research
  • Identity
  • Additional Document Info
  • View All
scroll to property group menus

Overview

authors

  • Staflin, K.
  • Krueger, J. S.
  • Hachmann, J.
  • Forsyth, J. S.
  • Lorger, M.
  • Steiniger, S. C. J.
  • Mee, J.
  • Pop, C.
  • Salvesen, G. S.
  • Janda, Kim
  • Felding, Brunhilde

publication date

  • April 2010

journal

  • Clinical & Experimental Metastasis  Journal

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 alphavbeta3 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 alphavbeta3 caused stagnation and regression of metastatic growth. The antibodies specifically localized to tumor lesions in vivo and inhibited alphavbeta3 ligand binding at nanomolar levels in vitro. At the cellular level, the scFs associated rapidly with high affinity alphavbeta3 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 alphavbeta3 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 alphavbeta3 ligation. Inhibition of advanced metastatic disease by treatment with cancer patient derived single chain antibodies against the activated conformer of integrin alphavbeta3 identifies this form of the receptor as a suitable target for therapy.

subject areas

  • Animals
  • Caspase 3
  • Disease Models, Animal
  • Humans
  • Integrin alphaVbeta3
  • Mice
  • Mice, SCID
  • Neoplasm Metastasis
  • Single-Chain Antibodies
scroll to property group menus

Research

keywords

  • Activated integrin
  • Advanced metastasis
  • Patient antibodies
  • Treatment
scroll to property group menus

Identity

PubMed Central ID

  • PMC4830478

International Standard Serial Number (ISSN)

  • 0262-0898

Digital Object Identifier (DOI)

  • 10.1007/s10585-010-9320-5

PubMed ID

  • 20225083
scroll to property group menus

Additional Document Info

start page

  • 217

end page

  • 231

volume

  • 27

issue

  • 4

©2021 The Scripps Research Institute | Terms of Use | Powered by VIVO

  • About
  • Contact Us
  • Support