[PubMed]

The transforming growth factor-β (TGF-β) belongs to a superfamily of cytokines that mediate their activity through serine/threonine kinase receptors and are involved in a variety of cellular processes such as proliferation, differentiation, and migration (1, 2). The TGF-β is a tumor suppressor, but under certain cellular conditions it can promote tumor progression and cancer metastasis as discussed by Meulmeester and ten Dijke (2) and Inman (3). Although TGF-β and its receptors are considered to be important targets for the treatment of highly invasive tumors such as glioblastomas and those of breast cancer, no drug or antibody is available to inhibit the activity of this cytokine or its receptor signaling pathway to treat these malignancies (4). A subset of breast cancer patients exhibited overexpression or suppression of genes related to the TGF-β signaling pathway, and these individuals also showed a shorter metastasis-free or relapse-free survival (5). Therefore, noninvasive imaging of TGF-β will not only help in understanding the functioning of this receptor–ligand system and assist in the development of novel agents that can target the TGF-β or its receptor, but it will also assist in the selection of patients who would benefit most from such an anti-cancer treatment (5).

Fresolimumab, a human anti-TGF-β monoclonal antibody (mAb) that neutralizes all active isoforms of TGF-β, was developed and used in a phase I study for the treatment of 22 patients with advanced melanoma and renal cell carcinoma (5). After the treatment, one patient showed stable disease, one patient had a partial response, and three patients showed a mixed response. In addition, no dose-limiting toxicity with the Ab was apparent in the patients. To further improve the likelihood of a positive outcome after the treatment with fresolimumab, it would be helpful to know if the TGF-β or its receptor are overexpressed and activated in the tumor, and also whether the mAb is able to detect such tumors. For this, Oude Munnink et al. evaluated ⁸⁹Zr-labeled fresolimumab ([⁸⁹Zr]-fresolimumab) for the detection and quantification of tumors that overexpress TGF-β with positron emission tomography (PET) in a nude mouse model (5). The investigators chose to label the mAb with ⁸⁹Zr because it has a long half-life (~78 h), and is also suitable to study binding of the labeled antibody to the tumor and to monitor its organ distribution in animal models. The biodistribution of [⁸⁹Zr]-fresolimumab was also studied in mice bearing xenograft tumors that express varying levels of TGF-β.

[PubMed]

Fresolimumab was obtained from a commercial source and conjugated with N-succinyldesferrioxamine-B-tetrafluorphenol (N-sucDf-TFP) as detailed by Oude Munnink et al. (5). Fresolimumab and N-sucDf-TFP had an effective conjugation of 62.0 ± 9.0%. N-sucDf-fresolimumab was stored at −20°C until required and was labeled with clinical grade ⁸⁹Zr-oxalate on the day of use. The radiochemical purity (RCP) of [⁸⁹Zr]-fresolimumab was 97.0 ± 1.2% as determined with high-performance liquid chromatography (HPLC), and it was used without further purification. The specific activity of the labeled mAb was reported to be up to 1,000 MBq/6.6 nmol (2.7 mCi/6.6 nmol).

[⁸⁹Zr]-Fresolimumab was stable in 0.9% NaCl at 4°C and in human serum at 37°C for >168 h as determined with HPLC (5).

Human IgG was conjugated to 2-(4-isothiocyanatobenzyl)-diethylenetriaminepentaacetic acid and then labeled with ¹¹¹In ([¹¹¹In]-IgG) on the required day for use as a control in the biodistribution study (5). The radiochemical yield, RCP, specific activity, and stability of the labeled IgG were not reported.

[PubMed]

In a competitive TGF-β binding assay with [⁸⁹Zr]-fresolimumab in the presence of increasing concentrations of unlabeled fresolimumab, the 50% inhibition of the maximum binding of labeled fresolimumab was determined to be 14 nM compared with 18 nM for the unlabeled mAb (5). This indicated that conjugating the mAb with N-sucDf-TFP and labeling it with ⁸⁹Zr did not alter the affinity of [⁸⁹Zr]-fresolimumab for the ligand.

[PubMed]

No publication is currently available.

[Disclaimers]

No information is currently available.

1.

Hawinkels L.J., Ten Dijke P. Exploring anti-TGF-beta therapies in cancer and fibrosis. Growth Factors. 2011;29(4):140–52. [PubMed: 21718111]

2.

Meulmeester E., Ten Dijke P. The dynamic roles of TGF-beta in cancer. J Pathol. 2011;223(2):205–18. [PubMed: 20957627]

3.

Inman G.J. Switching TGFbeta from a tumor suppressor to a tumor promoter. Curr Opin Genet Dev. 2011;21(1):93–9. [PubMed: 21251810]

4.

Garber K. Companies waver in efforts to target transforming growth factor beta in cancer. J Natl Cancer Inst. 2009;101(24):1664–7. [PubMed: 19933941]

5.

Oude Munnink T.H., Arjaans M.E., Timmer-Bosscha H., Schroder C.P., Hesselink J.W., Vedelaar S.R., Walenkamp A.M., Reiss M., Gregory R.C., Lub-de Hooge M.N., de Vries E.G. PET with the 89Zr-Labeled Transforming Growth Factor-beta Antibody Fresolimumab in Tumor Models. J Nucl Med. 2011;52(12):2001–8. [PubMed: 22072706]

6.

Minn A.J., Kang Y., Serganova I., Gupta G.P., Giri D.D., Doubrovin M., Ponomarev V., Gerald W.L., Blasberg R., Massague J. Distinct organ-specific metastatic potential of individual breast cancer cells and primary tumors. J Clin Invest. 2005;115(1):44–55. [PMC free article: PMC539194] [PubMed: 15630443]