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Targeted Therapy of Colorectal Cancer: Preclinical Evaluation of a Radiolabelled Antibody
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Radiology.
2008 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Targeted radiotherapy (TRT) of cancer is a promising approach that enables selective treatment of tumour cells, while sparing normal tissue. The humanized monoclonal antibody A33 (huA33) is a potential targeting agent for TRT of colorectal cancer, since its antigen is expressed in more than 95 % of all colorectal carcinomas. The aim of this thesis was to evaluate the therapeutic potential of the two huA33-based TRT-conjugates, 177Lu-huA33, and 211At-huA33.

The conjugates 177Lu-huA33, and 211At-huA33, bound specifically to colorectal cancer cells, both in vitro and in vivo. A dose dependent cytotoxic effect of 211At-huA33 was also demonstrated in vitro. From a therapeutic perspective, both conjugates had a favourable biodistribution in tumour-bearing nude mice, with high tumour uptake and a low uptake in normal organs (with the exception of an expected thyroid uptake of 211At). After injection of 211At-huA33, the blood absorbed a slightly higher dose than the tumour, but for 177Lu-huA33, the tumour received a 12 times higher dose than blood. Two days after intravenous injection of 177Lu-huA33 in tumour-bearing mice, the tumours could be clearly visualised by gamma camera imaging, with very low interference from normal tissue radioactivity. In an experimental therapy study, also performed in tumour-bearing mice, there was an excellent therapeutic effect of 177Lu-huA33. About 50 % of the treated animals were tumour free 140 days after injection of 177Lu-huA33, while none of the non-radioactive controls survived beyond 20 days after injection of treatment substances.

In conclusion, this thesis demonstrates that the therapeutic conjugates 177Lu-huA33, and 211At-huA33, are promising targeting agents that might help improve therapy of colorectal cancer.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis , 2008. , p. 54
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 336
Keywords [en]
Molecular medicine, tumour targeting, antibody, A33, radionuclide, colorectal cancer, therapy
Keywords [sv]
Molekylärmedicin
Identifiers
URN: urn:nbn:se:uu:diva-8657ISBN: 978-91-554-7171-2 (print)OAI: oai:DiVA.org:uu-8657DiVA, id: diva2:171877
Public defence
2008-05-17, Rudbecksalen, Rudbecklaboratoriet, Dag Hammarskjölds väg 20, Uppsala, 09:15
Opponent
Supervisors
Available from: 2008-04-23 Created: 2008-04-23 Last updated: 2011-01-25Bibliographically approved
List of papers
1.
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2. Biodistribution of At-211-Labeled humanized monoclonal antibody A33
Open this publication in new window or tab >>Biodistribution of At-211-Labeled humanized monoclonal antibody A33
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2007 (English)In: Cancer Biotherapy and Radiopharmaceuticals, ISSN 1084-9785, E-ISSN 1557-8852, Vol. 22, no 4, p. 480-487Article in journal (Refereed) Published
Abstract [en]

Radioimmunotherapy (RIT) could be a possible adjuvant treatment method for patients with colorectal carcinoma. The A33 antigen is a promising RIT target, as it is highly and homogenously expressed in 95% of all colorectal carcinomas. In this study, the humanized monoclonal antibody A33 (huA33), targeting the A33 antigen, was labeled with the therapeutic nuclide 211At, and the biodistribution and in vivo targeting ability of the conjugate was investigated in an athymic mouse xenograft model. There was an accumulation of 211At in tumor tissue over time, but no substantial accumulation was seen in any organ apart from the skin and thyroid, indicating no major release of free 211At in vivo. At all time points, the uptake of 211At-huA33 was higher in tumor tissue than in most organs, and at 8 hours postinjection (p.i.), no organ had a higher uptake than tumor tissue. The tumor-to-blood ratio of 211At-huA33 increased with time, reaching 2.5 after 21 hours p.i. The highest absorbed dose was found in the blood, but the tumor received a higher dose than any organ other than the thyroid. An in vivo blocking experiment showed that 211At-huA33 binds specifically to human tumor xenografts in athymic mice. In conclusion, the favorable biodistribution and specific in vivo targeting ability of 211At-huA33 makes it a potential therapeutic agent for the RIT of metastatic colorectal carcinoma.

Keywords
A33, monoclonal antibody, At-211, radioimmunotherapy, biodistribution
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-17038 (URN)10.1089/cbr.2007.349 (DOI)000249320800003 ()17803442 (PubMedID)
Available from: 2008-06-16 Created: 2008-06-16 Last updated: 2017-12-08Bibliographically approved
3. In vitro and in vivo characterization of 177Lu‑huA33: A radioimmunoconjugate against colorectal cancer
Open this publication in new window or tab >>In vitro and in vivo characterization of 177Lu‑huA33: A radioimmunoconjugate against colorectal cancer
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2006 (English)In: Nuclear Medicine and Biology, ISSN 0969-8051, E-ISSN 1872-9614, Vol. 33, no 8, p. 991-998Article in journal (Refereed) Published
Abstract [en]

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 (177)Lu-labeled huA33. METHODS: huA33 was labeled with the beta-emitting therapeutic nuclide (177)Lu using the chelator CHX-A"-DTPA, and the properties of the (177)Lu-CHX-A"-huA33 ((177)Lu-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 (177)Lu-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 (177)Lu-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 (177)Lu in bone (known to accumulate free (177)Lu) was low, and the fraction of protein-bound (177)Lu in plasma samples was high (95% to 99%). This indicates high stability of the (177)Lu-huA33 conjugate in vivo. CONCLUSION: The (177)Lu-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
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-97087 (URN)10.1016/j.nucmedbio.2006.09.003 (DOI)000242840500007 ()17127172 (PubMedID)
Available from: 2008-04-23 Created: 2008-04-23 Last updated: 2017-12-14Bibliographically approved
4. Therapy of colorectal cancer xenografts in nude mice using 177Lu labelled humanized antibody A33
Open this publication in new window or tab >>Therapy of colorectal cancer xenografts in nude mice using 177Lu labelled humanized antibody A33
Manuscript (Other academic)
Identifiers
urn:nbn:se:uu:diva-97088 (URN)
Available from: 2008-04-23 Created: 2008-04-23 Last updated: 2010-01-13Bibliographically approved

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