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

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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.

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Acknowledgments

We thank Dr. J. Koziol of The Scripps Research Institute for statistical analyses. All animal work was performed in accordance with NIH guidelines and approved by the Institutional Animal Care and Use Committee of The Scripps Research Institute Animal Resources (AAALAC accredited). Grant support: NIH grants CA095458, CA112287 to BFH, CBCRP grants 12NB0176 and 13NB0180 to BFH and DOD grant W81XWH-08-1-0468 to BFH, and fellowships from the Swedish Research Council to KS, and from SG Komen to JSK and ML.

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Authors and Affiliations

  1. Department of Molecular and Experimental Medicine, The Scripps Research Institute, MEM 150, 10550 North Torrey Pines Road, La Jolla, CA, 92037, USA

    Karin Staflin, Joseph S. Krueger, Janna Hachmann, Jane S. Forsyth, Mihaela Lorger & Brunhilde Felding-Habermann

  2. Department of Chemistry, The Scripps Research Institute, La Jolla, CA, 92037, USA

    Sebastian C. J. Steiniger, Jenny Mee & Kim D. Janda

  3. Program in Cell Death and Apoptosis Research, The Burnham Institute, La Jolla, CA, 92037, USA

    Cristina Pop & Guy S. Salvesen

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  1. Karin Staflin
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  2. Joseph S. Krueger
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  11. Brunhilde Felding-Habermann
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Correspondence to Brunhilde Felding-Habermann.

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Staflin, K., Krueger, J.S., Hachmann, J. et al. Targeting activated integrin αvβ3 with patient-derived antibodies impacts late-stage multiorgan metastasis. Clin Exp Metastasis 27, 217–231 (2010). https://doi.org/10.1007/s10585-010-9320-5

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