Indirect targeting of IGF receptor signaling in vivo by substrate-selective inhibition of PAPP-A proteolytic activity

Jakob H. Mikkelsen, Zachary T. Resch, Bhanu Kalra, Gopal Savjani, Ajay Kumar, Cheryl A Conover, Claus Oxvig

Research output: Contribution to journalArticle

30 Citations (Scopus)

Abstract

The insulin-like growth factor (IGF) signaling pathway is involved in certain human cancers, and the feasibility of directly targeting the IGF receptor has been actively investigated. However, recent evidence from clinical trials suggests that this approach can be problematic. We have developed an alternative strategy to indirectly inhibit the IGF signaling by targeting the metalloproteinase, pregnancy-associated plasma protein-A (PAPP-A). PAPP-A associated with the cell surface cleaves IGF binding protein-4 (IGFBP-4), when IGF is bound to IGFBP-4, and thereby increases IGF bioavailability for receptor activation in an autocrine/paracrine manner. We hypothesized that inhibition of PAPP-A would suppress excessive local IGF signaling in tissues where this is caused by increased PAPP-A proteolytic activity. To test this hypothesis, we developed an inhibitory monoclonal antibody, mAb 1/41, which targets a unique substrate-binding exosite of PAPP-A. This inhibitor selectively and specifically inhibits proteolytic cleavage of IGFBP-4 with an inhibitory constant (Ki) of 135 pM. In addition, it inhibited intracellular signaling of the IGF receptor (AKT phosphorylation) in monolayers of A549 cells, an IGF-responsive lung cancer-derived cell line found to express high levels of PAPP-A. We further showed that mAb 1/41 is effective towards PAPP-A bound to cell surfaces, and that it is capable of inhibiting PAPP-A activity in vivo. Using a murine xenograft model of A549 cells, we demonstrated that mAb 1/41 administered intraperitoneally significantly inhibited tumor growth. Analysis of xenograft tumor tissue recovered from treated mice showed penetration of mAb 1/41, reduced IGFBP-4 proteolysis, and reduced AKT phosphorylation. Our study provides proof of concept that IGF signaling can be selectively reduced by targeting a regulatory proteinase that functions extracellularly, upstream of the IGF receptor. PAPP-A targeting thus represents an alternative therapeutic strategy for inhibiting IGF receptor signaling.

Original languageEnglish (US)
Pages (from-to)1014-1025
Number of pages12
JournalOncotarget
Volume5
Issue number4
StatePublished - 2014

Fingerprint

Pregnancy-Associated Plasma Protein-A
Somatomedin Receptors
Somatomedins
Insulin-Like Growth Factor Binding Protein 4
Heterografts
Phosphorylation
Neoplasms
Metalloproteases
Protein Transport
Biological Availability
Proteolysis
Lung Neoplasms
Peptide Hydrolases
Monoclonal Antibodies
Clinical Trials
Cell Line

Keywords

  • Insulin-like growth factor receptor
  • Pregnancy-associated plasma protein-A
  • Proteolytic inhibition
  • Therapeutic antibody
  • Xenograft mouse model

ASJC Scopus subject areas

  • Oncology
  • Medicine(all)

Cite this

Mikkelsen, J. H., Resch, Z. T., Kalra, B., Savjani, G., Kumar, A., Conover, C. A., & Oxvig, C. (2014). Indirect targeting of IGF receptor signaling in vivo by substrate-selective inhibition of PAPP-A proteolytic activity. Oncotarget, 5(4), 1014-1025.

Indirect targeting of IGF receptor signaling in vivo by substrate-selective inhibition of PAPP-A proteolytic activity. / Mikkelsen, Jakob H.; Resch, Zachary T.; Kalra, Bhanu; Savjani, Gopal; Kumar, Ajay; Conover, Cheryl A; Oxvig, Claus.

In: Oncotarget, Vol. 5, No. 4, 2014, p. 1014-1025.

Research output: Contribution to journalArticle

Mikkelsen, JH, Resch, ZT, Kalra, B, Savjani, G, Kumar, A, Conover, CA & Oxvig, C 2014, 'Indirect targeting of IGF receptor signaling in vivo by substrate-selective inhibition of PAPP-A proteolytic activity', Oncotarget, vol. 5, no. 4, pp. 1014-1025.
Mikkelsen, Jakob H. ; Resch, Zachary T. ; Kalra, Bhanu ; Savjani, Gopal ; Kumar, Ajay ; Conover, Cheryl A ; Oxvig, Claus. / Indirect targeting of IGF receptor signaling in vivo by substrate-selective inhibition of PAPP-A proteolytic activity. In: Oncotarget. 2014 ; Vol. 5, No. 4. pp. 1014-1025.
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