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A fully human monoclonal antibody to the insulin-like growth factor I receptor blocks ligand-dependent signaling and inhibits human tumor growth in vivo.
Cancer Res. 2003 Dec 15; 63(24):8912-21.CR

Abstract

The insulin-like growth factor I receptor (IGF-IR) is overexpressed in many diverse tumor types and is a critical signaling molecule for tumor cell proliferation and survival. Therapeutic strategies targeting the IGF-IR may therefore be effective broad-spectrum anticancer agents. Through screening of a Fab phage display library, we have generated a fully human antibody (A12) that binds to the IGF-IR with high affinity (4.11 x 10(-11) M) and inhibits ligand binding with an IC(50) of 0.6-1 nM. Antibody-mediated blockade of ligand binding to the IGF-IR inhibited downstream signaling of the two major insulin-like growth factor (IGF) pathways, mitogen-activated protein kinase and phosphatidylinositol 3'-kinase/Akt, in MCF7 human breast cancer cells. As a result, the mitogenic and proliferative potential of IGF-I and IGF-II were significantly reduced. A12 did not block insulin binding to the insulin receptor but could block binding to atypical IGF-IR in MCF7 cells. In addition, A12 was shown to induce IGF-IR internalization and degradation on specific binding to tumor cells, resulting in a significant reduction in cell surface receptor density. In xenograft tumor models in vivo, IGF-IR blockade by A12 was shown to occur rapidly, resulting in significant growth inhibition of breast, renal, and pancreatic tumors. Histological analysis of tumor sections demonstrated a marked increase in apoptotic tumor cells in antibody-treated animals. These results demonstrate that A12 possesses strong antitumor activity in vitro and in vivo and may therefore be an effective therapeutic candidate for the treatment of cancers that are dependent on IGF-IR signaling for growth and survival.

Authors+Show Affiliations

ImClone Systems Incorporated, New York, New York 10014, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

14695208

Citation

Burtrum, Douglas, et al. "A Fully Human Monoclonal Antibody to the Insulin-like Growth Factor I Receptor Blocks Ligand-dependent Signaling and Inhibits Human Tumor Growth in Vivo." Cancer Research, vol. 63, no. 24, 2003, pp. 8912-21.
Burtrum D, Zhu Z, Lu D, et al. A fully human monoclonal antibody to the insulin-like growth factor I receptor blocks ligand-dependent signaling and inhibits human tumor growth in vivo. Cancer Res. 2003;63(24):8912-21.
Burtrum, D., Zhu, Z., Lu, D., Anderson, D. M., Prewett, M., Pereira, D. S., Bassi, R., Abdullah, R., Hooper, A. T., Koo, H., Jimenez, X., Johnson, D., Apblett, R., Kussie, P., Bohlen, P., Witte, L., Hicklin, D. J., & Ludwig, D. L. (2003). A fully human monoclonal antibody to the insulin-like growth factor I receptor blocks ligand-dependent signaling and inhibits human tumor growth in vivo. Cancer Research, 63(24), 8912-21.
Burtrum D, et al. A Fully Human Monoclonal Antibody to the Insulin-like Growth Factor I Receptor Blocks Ligand-dependent Signaling and Inhibits Human Tumor Growth in Vivo. Cancer Res. 2003 Dec 15;63(24):8912-21. PubMed PMID: 14695208.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - A fully human monoclonal antibody to the insulin-like growth factor I receptor blocks ligand-dependent signaling and inhibits human tumor growth in vivo. AU - Burtrum,Douglas, AU - Zhu,Zhenping, AU - Lu,Dan, AU - Anderson,Donna Marie, AU - Prewett,Marie, AU - Pereira,Daniel S, AU - Bassi,Rajiv, AU - Abdullah,Rashed, AU - Hooper,Andrea T, AU - Koo,Henry, AU - Jimenez,Xenia, AU - Johnson,Danielle, AU - Apblett,Robin, AU - Kussie,Paul, AU - Bohlen,Peter, AU - Witte,Larry, AU - Hicklin,Daniel J, AU - Ludwig,Dale L, PY - 2003/12/26/pubmed PY - 2004/3/12/medline PY - 2003/12/26/entrez SP - 8912 EP - 21 JF - Cancer research JO - Cancer Res VL - 63 IS - 24 N2 - The insulin-like growth factor I receptor (IGF-IR) is overexpressed in many diverse tumor types and is a critical signaling molecule for tumor cell proliferation and survival. Therapeutic strategies targeting the IGF-IR may therefore be effective broad-spectrum anticancer agents. Through screening of a Fab phage display library, we have generated a fully human antibody (A12) that binds to the IGF-IR with high affinity (4.11 x 10(-11) M) and inhibits ligand binding with an IC(50) of 0.6-1 nM. Antibody-mediated blockade of ligand binding to the IGF-IR inhibited downstream signaling of the two major insulin-like growth factor (IGF) pathways, mitogen-activated protein kinase and phosphatidylinositol 3'-kinase/Akt, in MCF7 human breast cancer cells. As a result, the mitogenic and proliferative potential of IGF-I and IGF-II were significantly reduced. A12 did not block insulin binding to the insulin receptor but could block binding to atypical IGF-IR in MCF7 cells. In addition, A12 was shown to induce IGF-IR internalization and degradation on specific binding to tumor cells, resulting in a significant reduction in cell surface receptor density. In xenograft tumor models in vivo, IGF-IR blockade by A12 was shown to occur rapidly, resulting in significant growth inhibition of breast, renal, and pancreatic tumors. Histological analysis of tumor sections demonstrated a marked increase in apoptotic tumor cells in antibody-treated animals. These results demonstrate that A12 possesses strong antitumor activity in vitro and in vivo and may therefore be an effective therapeutic candidate for the treatment of cancers that are dependent on IGF-IR signaling for growth and survival. SN - 0008-5472 UR - https://www.unboundmedicine.com/medline/citation/14695208/A_fully_human_monoclonal_antibody_to_the_insulin_like_growth_factor_I_receptor_blocks_ligand_dependent_signaling_and_inhibits_human_tumor_growth_in_vivo_ L2 - http://cancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=14695208 DB - PRIME DP - Unbound Medicine ER -