Phase II Trial of Carcinoembryonic Antigen Radioimmunotherapy With <sup>131</sup>I-Labetuzumab After Salvage Resection of Colorectal Metastases in the Liver: Five-Year Safety and Efficacy Results

Liersch, Torsten; Meller, J.; Kulle, Bettina; Behr, Thomas M.; Markus, Peter M.; Langer, Claus; Ghadimi, B. Michael; Wegener, William A.; Kovacs, Jacqueline; Horak, Ivan D.; Becker, H.; Goldenberg, David M.

doi:10.1200/jco.2005.18.622

Cited by 118 publications

(93 citation statements)

References 26 publications

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“…CEA is present on a high proportion of colorectal cancers, in which it is accessible to intravenously administered antibody, whereas in normal colorectal epithelium, due to the apical localisation of the antigen, it is not (Granowska, 1993). Radioconjugates targeting CEA have been used in early phase clinical trials in CRC (Wong et al, 2004;Liersch et al, 2005), but there is so far no unconjugated anti-CEA antibody licensed for treatment (Blumenthal et al, 2008). The pre-clinical studies reported here are directed at optimising PR1A3 for use in the treatment of colorectal cancer.…”

mentioning

confidence: 99%

Humanised IgG1 antibody variants targeting membrane-bound carcinoembryonic antigen by antibody-dependent cellular cytotoxicity and phagocytosis

Ashraf

Umaña²,

Mössner³

et al. 2009

Br J Cancer

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BACKGROUND: The effect of glycoengineering a membrane specific anti-carcinoembryonic antigen (CEA) (this paper uses the original term CEA for the formally designated CEACAM5) antibody (PR1A3) on its ability to enhance killing of colorectal cancer (CRC) cell lines by human immune effector cells was assessed. In vivo efficacy of the antibody was also tested. METHODS: The antibody was modified using EBNA cells cotransfected with b-1,4-N-acetylglucosaminyltransferase III and the humanised hPR1A3 antibody genes. RESULTS: The resulting alteration of the Fc segment glycosylation pattern enhances the antibody's binding affinity to the FcgRIIIa receptor on human immune effector cells but does not alter the antibody's binding capacity. Antibody-dependent cellular cytotoxicity (ADCC) is inhibited in the presence of anti-FcgRIII blocking antibodies. This glycovariant of hPR1A3 enhances ADCC 10-fold relative to the parent unmodified antibody using either unfractionated peripheral blood mononuclear or natural killer (NK) cells and CEA-positive CRC cells as targets. NK cells are far more potent in eliciting ADCC than either freshly isolated monocytes or granulocytes. Flow cytometry and automated fluorescent microscopy have been used to show that both versions of hPR1A3 can induce antibody-dependent cellular phagocytosis (ADCP) by monocyte-derived macrophages. However, the glycovariant antibody did not mediate enhanced ADCP. This may be explained by the relatively low expression of FcgRIIIa on cultured macrophages. In vivo studies show the efficacy of glycoengineered humanised IgG1 PR1A3 in significantly improving survival in a CRC metastatic murine model. CONCLUSION: The greatly enhanced in vitro ADCC activity of the glycoengineered version of hPR1A3 is likely to be clinically beneficial.

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mentioning

confidence: 99%

Humanised IgG1 antibody variants targeting membrane-bound carcinoembryonic antigen by antibody-dependent cellular cytotoxicity and phagocytosis

Ashraf

Umaña²,

Mössner³

et al. 2009

Br J Cancer

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“…In a Phase II clinical trial, 23 patients underwent Labetuzumab treatment after salvage resection of liver metastasis of colorectal cancer. The median overall survival rate was 68 months, median disease-free survival was 18 months, and five-year survival rate was 51.3% (Liersch et al, 2005). Both the median overall survival and five-year survival rates were improved compared to historical and contemporaneous controls of not receiving the labetuzumab treatment.…”

Section: Labetuzumab (Cea-cide)mentioning

confidence: 69%

Therapeutic radionuclides in nuclear medicine: current and future prospects

Yeong

Cheng

2014

J. Zhejiang Univ. Sci. B

156

115

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Abstract:The potential use of radionuclides in therapy has been recognized for many decades. A number of radionuclides, such as iodine-131 ( 131 I), phosphorous-32 ( 32 P), strontium-90 ( 90 Sr), and yttrium-90 ( 90 Y), have been used successfully for the treatment of many benign and malignant disorders. Recently, the rapid growth of this branch of nuclear medicine has been stimulated by the introduction of a number of new radionuclides and radiopharmaceuticals for the treatment of metastatic bone pain and neuroendocrine and other malignant or non-malignant tumours. Today, the field of radionuclide therapy is enjoying an exciting phase and is poised for greater growth and development in the coming years. For example, in Asia, the high prevalence of thyroid and liver diseases has prompted many novel developments and clinical trials using targeted radionuclide therapy. This paper reviews the characteristics and clinical applications of the commonly available therapeutic radionuclides, as well as the problems and issues involved in translating novel radionuclides into clinical therapies.

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“…In the 1980s, radiolabelled murine PR1A3 was also demonstrated to be highly specific for human colorectal lesions (Granowska et al, 1989). The other two papers present data relating to the use of a radioconjugate form of MN-14 (Hajjar et al, 2002;Liersch et al, 2005). In the letter from Blumenthal et al, there is reference to unpublished results with unconjugated MN-14 being used in patients.…”

Section: Sirmentioning

confidence: 97%

Reply: In vitro and in vivo anticancer efficacy of unconjugated humanised anti-CEA monoclonal antibodies

et al. 2008

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Phase II Trial of Carcinoembryonic Antigen Radioimmunotherapy With ¹³¹I-Labetuzumab After Salvage Resection of Colorectal Metastases in the Liver: Five-Year Safety and Efficacy Results

Cited by 118 publications

References 26 publications

Humanised IgG1 antibody variants targeting membrane-bound carcinoembryonic antigen by antibody-dependent cellular cytotoxicity and phagocytosis

Humanised IgG1 antibody variants targeting membrane-bound carcinoembryonic antigen by antibody-dependent cellular cytotoxicity and phagocytosis

Therapeutic radionuclides in nuclear medicine: current and future prospects

Reply: In vitro and in vivo anticancer efficacy of unconjugated humanised anti-CEA monoclonal antibodies

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Phase II Trial of Carcinoembryonic Antigen Radioimmunotherapy With 131I-Labetuzumab After Salvage Resection of Colorectal Metastases in the Liver: Five-Year Safety and Efficacy Results

Cited by 118 publications

References 26 publications

Humanised IgG1 antibody variants targeting membrane-bound carcinoembryonic antigen by antibody-dependent cellular cytotoxicity and phagocytosis

Humanised IgG1 antibody variants targeting membrane-bound carcinoembryonic antigen by antibody-dependent cellular cytotoxicity and phagocytosis

Therapeutic radionuclides in nuclear medicine: current and future prospects

Reply: In vitro and in vivo anticancer efficacy of unconjugated humanised anti-CEA monoclonal antibodies

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Phase II Trial of Carcinoembryonic Antigen Radioimmunotherapy With ¹³¹I-Labetuzumab After Salvage Resection of Colorectal Metastases in the Liver: Five-Year Safety and Efficacy Results