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Biodistribution of At-211-Labeled humanized monoclonal antibody A33
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi, Enheten för radiologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi, Enheten för biomedicinsk strålningsvetenskap.
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi, Enheten för biomedicinsk strålningsvetenskap.
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi, Enheten för biomedicinsk strålningsvetenskap.
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2007 (Engelska)Ingår i: Cancer Biotherapy and Radiopharmaceuticals, ISSN 1084-9785, E-ISSN 1557-8852, Vol. 22, nr 4, s. 480-487Artikel i tidskrift (Refereegranskat) 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.

Ort, förlag, år, upplaga, sidor
2007. Vol. 22, nr 4, s. 480-487
Nyckelord [en]
A33, monoclonal antibody, At-211, radioimmunotherapy, biodistribution
Nationell ämneskategori
Medicin och hälsovetenskap
Identifikatorer
URN: urn:nbn:se:uu:diva-17038DOI: 10.1089/cbr.2007.349ISI: 000249320800003PubMedID: 17803442OAI: oai:DiVA.org:uu-17038DiVA, id: diva2:44809
Tillgänglig från: 2008-06-16 Skapad: 2008-06-16 Senast uppdaterad: 2017-12-08Bibliografiskt granskad
Ingår i avhandling
1. Targeted Therapy of Colorectal Cancer: Preclinical Evaluation of a Radiolabelled Antibody
Öppna denna publikation i ny flik eller fönster >>Targeted Therapy of Colorectal Cancer: Preclinical Evaluation of a Radiolabelled Antibody
2008 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
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.

Ort, förlag, år, upplaga, sidor
Uppsala: Acta Universitatis Upsaliensis, 2008. s. 54
Serie
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 336
Nyckelord
Molecular medicine, tumour targeting, antibody, A33, radionuclide, colorectal cancer, therapy, Molekylärmedicin
Identifikatorer
urn:nbn:se:uu:diva-8657 (URN)978-91-554-7171-2 (ISBN)
Disputation
2008-05-17, Rudbecksalen, Rudbecklaboratoriet, Dag Hammarskjölds väg 20, Uppsala, 09:15
Opponent
Handledare
Tillgänglig från: 2008-04-23 Skapad: 2008-04-23 Senast uppdaterad: 2011-01-25Bibliografiskt granskad

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