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89Zr-N-Succinyldesferal-human anti-insulin-like growth factor 1 receptor monoclonal antibody R1507

89Zr-R1507
, PhD
National Center for Biotechnology Information, NLM, NIH, Bethesda, MD

Created: ; Last Update: February 3, 2011.

Chemical name:89Zr-N-Succinyldesferal-human anti-insulin-like growth factor 1 receptor monoclonal antibody R1507
Abbreviated name:89Zr-R1507, 89Zr-Df-R1507
Synonym:
Agent category:Antibody
Target:Insulin-like growth factor 1 receptor (IGF-1R)
Target category:Receptor
Method of detection:Positron emission tomography (PET)
Source of signal:89Zr
Activation:No
Studies:
  • Checkbox In vitro
  • Checkbox Rodents
Structure not available in PubChem.

Background

[PubMed]

Insulin-like growth factor 1 (IGF-1, 70 amino acids) is secreted by the liver and target tissues in response to growth hormone stimulation (1). IGF-1 plays an important role in cell growth and development. IGF-1 binds to IGF-1 receptor (IGF-1R) with ~1,000-fold higher affinity than to insulin receptor. IGF-1R is a transmembrane tyrosine kinase receptor and is also highly expressed in many human cancers (2). IGF-1R plays an important role in tumor proliferation, apoptosis, angiogenesis, and metastasis (3, 4). Triple negative breast tumors are negative for estrogen receptors, progesterone receptors, and HER2. Patients with triple negative breast tumors have a lower survival rate than patients with estrogen receptor- or HER2-positive breast tumors (5). IGF-1R is overexpressed in 36% of all triple negative breast carcinomas (6). Therefore, monitoring of IGF-1R expression in breast tumor lesions with a non-invasive imaging modality is important for development of therapeutic treatments of these patients with anti-IGF-1R monoclonal antibodies (7). The human anti-IGF-1R monoclonal antibody R1507 is directed against the extracellular domain of human IGF-1R (8). In this chapter, Heskamp et al. (9) radiolabeled the human anti-IGF-1R monoclonal antibody R1507 with 89Zr for in vivo imaging of IFG-1R expression with positron emission tomography (PET). 89Zr-N-Succinyldesferal-human anti-IGF-1R monoclonal antibody R1507 (89Zr-R1507) has been evaluated in a triple negative breast cancer model in mice.

Synthesis

[PubMed]

R1507 was coupled with N-succinyldesferal via an amide linkage and labeled with 89Zr. R1507 was conjugated with two-fold molar excess of N-succinyldesferal-iron-tetrafluorophenol in 0.1 M NaHCO3 (pH 9) for 30 min at room temperature (9). A solution of 500 MBq (13.5 mCi) 89Zr and 3.3 nmol R1507 conjugate was incubated in buffer (pH 7.2) for 90 min at 35°C. 89Zr-R1507 was purified with column chromatography. 89Zr-R1507 exhibited a radiochemical purity of >98% with a labeling efficiency of 54%. The immunoreactivity of 89Zr-R1507 was not reported, whereas the immunoreactivity of 111In-DTPA-R1507 was 87%. The number of N-succinyldesferal groups per antibody was not reported.

In Vitro Studies: Testing in Cells and Tissues

[PubMed]

Heskamp et al. (9) reported that the parent antibody R1507 exhibited 50% inhibitory concentration (IC50) values of 0.08–0.12 nM for IGF-1R on the triple negative human breast cancer cell line SUM149. 111In-DTPA-R1507 was mainly membrane-bound in the early hours of incubation and then was gradually internalized until 62% of the surface-bound radioactivity was internalized at 48 h after incubation. The in vitro internalization of 89Zr-R1507 in SUM149 cells was not reported

Animal Studies

Rodents

[PubMed]

Heskamp et al. (9) performed ex vivo biodistribution studies in nude mice (n = 6/group) bearing triple negative breast SUM149 xenografts with injection of 5.3 MBq (0.14 mCi, 66 pmol) 89Zr-R1507. Tumor accumulation was 22 ± 3% injected dose/gram (ID/g) at 7 d after injection. As a comparison, 111In-DTPA-R1507 showed tumor accumulation of 21 ± 3% ID/g at 7 d after injection. Blocking studies were performed only with 111In-DTPA-R1507, which showed >80% inhibition of IGF-1R binding.

PET imaging in nude mice showed that 89Zr-R1507 visualized the SUM149 tumor as early as 24 h after injection with a maximum contrast at 7 d. The tumor/liver ratios were 1.9 at 1 d, 2.9 at 3 d, and 4.7 at 7 d. Accumulation was observed in the liver, spleen, bone, and salivary glands. No blocking studies were performed.

Other Non-Primate Mammals

[PubMed]

No publication is currently available.

Non-Human Primates

[PubMed]

No publication is currently available.

Human Studies

[PubMed]

No publication is currently available.

References

1.
Hernandez-Sanchez C., Blakesley V., Kalebic T., Helman L., LeRoith D. The role of the tyrosine kinase domain of the insulin-like growth factor-I receptor in intracellular signaling, cellular proliferation, and tumorigenesis. J Biol Chem. 1995;270(49):29176–81. [PubMed: 7493944]
2.
LeRoith D., Werner H., Neuenschwander S., Kalebic T., Helman L.J. The role of the insulin-like growth factor-I receptor in cancer. Ann N Y Acad Sci. 1995;766:402–8. [PubMed: 7486685]
3.
Rosenzweig S.A., Atreya H.S. Defining the pathway to insulin-like growth factor system targeting in cancer. Biochem Pharmacol. 2010;80(8):1115–24. [PMC free article: PMC2934757] [PubMed: 20599789]
4.
Baserga R., Hongo A., Rubini M., Prisco M., Valentinis B. The IGF-I receptor in cell growth, transformation and apoptosis. Biochim Biophys Acta. 1997;1332(3):F105–26. [PubMed: 9196021]
5.
Carey L.A., Dees E.C., Sawyer L., Gatti L., Moore D.T., Collichio F., Ollila D.W., Sartor C.I., Graham M.L., Perou C.M. The triple negative paradox: primary tumor chemosensitivity of breast cancer subtypes. Clin Cancer Res. 2007;13(8):2329–34. [PubMed: 17438091]
6.
Lerma E., Peiro G., Ramon T., Fernandez S., Martinez D., Pons C., Munoz F., Sabate J.M., Alonso C., Ojeda B., Prat J., Barnadas A. Immunohistochemical heterogeneity of breast carcinomas negative for estrogen receptors, progesterone receptors and Her2/neu (basal-like breast carcinomas). Mod Pathol. 2007;20(11):1200–7. [PubMed: 17885672]
7.
Zha J., O'Brien C., Savage H., Huw L.Y., Zhong F., Berry L., Lewis Phillips G.D., Luis E., Cavet G., Hu X., Amler L.C., Lackner M.R. Molecular predictors of response to a humanized anti-insulin-like growth factor-I receptor monoclonal antibody in breast and colorectal cancer. Mol Cancer Ther. 2009;8(8):2110–21. [PubMed: 19671761]
8.
Gong Y., Yao E., Shen R., Goel A., Arcila M., Teruya-Feldstein J., Zakowski M.F., Frankel S., Peifer M., Thomas R.K., Ladanyi M., Pao W. High expression levels of total IGF-1R and sensitivity of NSCLC cells in vitro to an anti-IGF-1R antibody (R1507). PLoS One. 2009;4(10):e7273. [PMC free article: PMC2752171] [PubMed: 19806209]
9.
Heskamp S., van Laarhoven H.W., Molkenboer-Kuenen J.D., Franssen G.M., Versleijen-Jonkers Y.M., Oyen W.J., van der Graaf W.T., Boerman O.C. ImmunoSPECT and immunoPET of IGF-1R expression with the radiolabeled antibody R1507 in a triple-negative breast cancer model. J Nucl Med. 2010;51(10):1565–72. [PubMed: 20847162]
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