In vitro and in vivo characterization of 177Lu-huA33: A radioimmunoconjugate against colorectal cancer

Almqvist, Ylva; Steffen, Ann-Charlott; Tolmachev, Vladimir; Divgi, Chaitanya R.; Sundin, Anders

doi:10.1016/j.nucmedbio.2006.09.003

« Previous Next »Nuclear Medicine and Biology
Volume 33, Issue 8 , Pages 991-998, November 2006

In vitro and in vivo characterization of ¹⁷⁷Lu-huA33:

A radioimmunoconjugate against colorectal cancer

Ylva Almqvist
- Division of Radiology, Department of Oncology, Radiology, and Clinical Immunology, Uppsala University, Uppsala, Sweden
- Corresponding author. Division of Biomedical Radiation Sciences, Rudbeck Laboratory, 751 85 Uppsala, Sweden. Tel.: +46 18 471 38 68; fax: +46 18 471 34 32.
Ann-Charlott Steffen
- Division of Biomedical Radiation Sciences, Department of Oncology, Radiology, and Clinical Immunology, Uppsala University, Uppsala, Sweden
Vladimir Tolmachev
- Division of Biomedical Radiation Sciences, Department of Oncology, Radiology, and Clinical Immunology, Uppsala University, Uppsala, Sweden
Chaitanya R. Divgi
- Nuclear Medicine and Clinical Molecular Imaging, Hospital of the University of Pennsylvania, Philadelphia, PA, USA
Anders Sundin
- Division of Radiology, Department of Oncology, Radiology, and Clinical Immunology, Uppsala University, Uppsala, Sweden

Received 18 May 2006; received in revised form 30 August 2006; accepted 18 September 2006.

Abstract

Introduction

The humanized monoclonal antibody A33 (huA33) is a potential targeting agent against colorectal carcinoma since the A33 antigen is highly and homogenously expressed in >95% of all colorectal cancers, both primary tumors and metastases. The aim of this study was to determine the biodistribution and tumor-targeting ability of ¹⁷⁷Lu-labeled huA33.

Methods

huA33 was labeled with the β-emitting therapeutic nuclide ¹⁷⁷Lu using the chelator CHX-Aʺ-DTPA, and the properties of the ¹⁷⁷Lu-CHX-Aʺ-huA33 (¹⁷⁷Lu-huA33) conjugate was determined both in vitro and in vivo in a biodistribution study in nude mice xenografted with colorectal SW1222 tumor cells.

Results

The ¹⁷⁷Lu-huA33 conjugate bound specifically to colorectal cancer cells in vitro (with a K_D value of 2.3±0.3 nM, determined by a saturation assay) and in vivo. The tumor uptake of ¹⁷⁷Lu-huA33 was very high, peaking at 134±21%ID/g 72 h postinjection (pi). Normal tissue uptake was low; radioactivity concentration in blood (which had the second highest radioactivity concentration) was lower than in tumor at all time points studied (8 h to 10 days). The tumor-to-blood ratio increased with time, reaching 70±30, 10 days pi. Throughout the study, the uptake of ¹⁷⁷Lu in bone (known to accumulate free ¹⁷⁷Lu) was low, and the fraction of protein-bound ¹⁷⁷Lu in plasma samples was high (95% to 99%). This indicates high stability of the ¹⁷⁷Lu-huA33 conjugate in vivo.

Conclusion

The ¹⁷⁷Lu-huA33 conjugate shows a very favorable biodistribution, with an impressively high tumor uptake and high tumor-to-organ ratios, indicating that the conjugate may be suitable for radioimmunotherapy of colorectal cancer.

Keywords: Antibody, A33 antigen, ¹⁷⁷Lu, Colorectal cancer