Targeted alpha therapy using a novel CD70 targeted thorium-227 conjugate in in vitro and in vivo models of renal cell carcinoma
The cell surface receptor CD70 has been previously reported as a promising target for B-cell lymphomas and several solid cancers including renal cell carcinoma. We describe herein the characterization and efficacy of a novel CD70 targeted thorium-227 conjugate (CD70-TTC) comprising the combination o...
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| Published in: | Oncotarget Vol. 8; no. 34; pp. 56311 - 56326 |
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| Main Authors: | , , , , , , , |
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| Abstract | The cell surface receptor CD70 has been previously reported as a promising target for B-cell lymphomas and several solid cancers including renal cell carcinoma. We describe herein the characterization and efficacy of a novel CD70 targeted thorium-227 conjugate (CD70-TTC) comprising the combination of the three components, a CD70 targeting antibody, a chelator moiety and the short-range, high-energy alpha-emitting radionuclide thorium-227 (
Th).
analysis demonstrated that the CD70-TTC retained binding affinity to its target and displayed potent and specific cytotoxicity compared to an isotype control-TTC. A biodistribution study in subcutaneous tumor-bearing nude mice using the human renal cell carcinoma cell line 786-O demonstrated significant uptake and retention with 122 ± 42% of the injected dose of
Th per gram (% ID/g) remaining in the tumor seven days post dose administration compared to only 3% ID/g for the isotype control-TTC. Tumor accumulation correlated with a dose dependent and statistically significant inhibition in tumor growth compared to vehicle and isotype control-TTC groups at radioactivity doses as low as 50 kBq/kg. The CD70-TTC was well tolerated as evidenced by only modest changes in hematology and normal gain in body weight of the mice. To our knowledge, this is the first report describing molecular targeting of CD70 expressing tumors using a targeted alpha-therapy (TAT). |
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| AbstractList | The cell surface receptor CD70 has been previously reported as a promising target for B-cell lymphomas and several solid cancers including renal cell carcinoma. We describe herein the characterization and efficacy of a novel CD70 targeted thorium-227 conjugate (CD70-TTC) comprising the combination of the three components, a CD70 targeting antibody, a chelator moiety and the short-range, high-energy alpha-emitting radionuclide thorium-227 (
227
Th).
In vitro
analysis demonstrated that the CD70-TTC retained binding affinity to its target and displayed potent and specific cytotoxicity compared to an isotype control-TTC. A biodistribution study in subcutaneous tumor-bearing nude mice using the human renal cell carcinoma cell line 786-O demonstrated significant uptake and retention with 122 ± 42% of the injected dose of
227
Th per gram (% ID/g) remaining in the tumor seven days post dose administration compared to only 3% ID/g for the isotype control-TTC. Tumor accumulation correlated with a dose dependent and statistically significant inhibition in tumor growth compared to vehicle and isotype control-TTC groups at radioactivity doses as low as 50 kBq/kg. The CD70-TTC was well tolerated as evidenced by only modest changes in hematology and normal gain in body weight of the mice. To our knowledge, this is the first report describing molecular targeting of CD70 expressing tumors using a targeted alpha-therapy (TAT). The cell surface receptor CD70 has been previously reported as a promising target for B-cell lymphomas and several solid cancers including renal cell carcinoma. We describe herein the characterization and efficacy of a novel CD70 targeted thorium-227 conjugate (CD70-TTC) comprising the combination of the three components, a CD70 targeting antibody, a chelator moiety and the short-range, high-energy alpha-emitting radionuclide thorium-227 ( Th). analysis demonstrated that the CD70-TTC retained binding affinity to its target and displayed potent and specific cytotoxicity compared to an isotype control-TTC. A biodistribution study in subcutaneous tumor-bearing nude mice using the human renal cell carcinoma cell line 786-O demonstrated significant uptake and retention with 122 ± 42% of the injected dose of Th per gram (% ID/g) remaining in the tumor seven days post dose administration compared to only 3% ID/g for the isotype control-TTC. Tumor accumulation correlated with a dose dependent and statistically significant inhibition in tumor growth compared to vehicle and isotype control-TTC groups at radioactivity doses as low as 50 kBq/kg. The CD70-TTC was well tolerated as evidenced by only modest changes in hematology and normal gain in body weight of the mice. To our knowledge, this is the first report describing molecular targeting of CD70 expressing tumors using a targeted alpha-therapy (TAT). The cell surface receptor CD70 has been previously reported as a promising target for B-cell lymphomas and several solid cancers including renal cell carcinoma. We describe herein the characterization and efficacy of a novel CD70 targeted thorium-227 conjugate (CD70-TTC) comprising the combination of the three components, a CD70 targeting antibody, a chelator moiety and the short-range, high-energy alpha-emitting radionuclide thorium-227 (227Th). In vitro analysis demonstrated that the CD70-TTC retained binding affinity to its target and displayed potent and specific cytotoxicity compared to an isotype control-TTC. A biodistribution study in subcutaneous tumor-bearing nude mice using the human renal cell carcinoma cell line 786-O demonstrated significant uptake and retention with 122 ± 42% of the injected dose of 227Th per gram (% ID/g) remaining in the tumor seven days post dose administration compared to only 3% ID/g for the isotype control-TTC. Tumor accumulation correlated with a dose dependent and statistically significant inhibition in tumor growth compared to vehicle and isotype control-TTC groups at radioactivity doses as low as 50 kBq/kg. The CD70-TTC was well tolerated as evidenced by only modest changes in hematology and normal gain in body weight of the mice. To our knowledge, this is the first report describing molecular targeting of CD70 expressing tumors using a targeted alpha-therapy (TAT). |
| Author | Bjerke, Roger M Mihaylova, Dessislava Cuthbertson, Alan S Hagemann, Urs B Uran, Steinar R Karlsson, Jenny Borrebaek, Joergen Grant, Derek |
| AuthorAffiliation | 1 Thorium Conjugate Research, Bayer AS, Oslo, Norway |
| AuthorAffiliation_xml | – name: 1 Thorium Conjugate Research, Bayer AS, Oslo, Norway |
| Author_xml | – sequence: 1 givenname: Urs B surname: Hagemann fullname: Hagemann, Urs B organization: Thorium Conjugate Research, Bayer AS, Oslo, Norway – sequence: 2 givenname: Dessislava surname: Mihaylova fullname: Mihaylova, Dessislava organization: Thorium Conjugate Research, Bayer AS, Oslo, Norway – sequence: 3 givenname: Steinar R surname: Uran fullname: Uran, Steinar R organization: Thorium Conjugate Research, Bayer AS, Oslo, Norway – sequence: 4 givenname: Joergen surname: Borrebaek fullname: Borrebaek, Joergen organization: Thorium Conjugate Research, Bayer AS, Oslo, Norway – sequence: 5 givenname: Derek surname: Grant fullname: Grant, Derek organization: Thorium Conjugate Research, Bayer AS, Oslo, Norway – sequence: 6 givenname: Roger M surname: Bjerke fullname: Bjerke, Roger M organization: Thorium Conjugate Research, Bayer AS, Oslo, Norway – sequence: 7 givenname: Jenny surname: Karlsson fullname: Karlsson, Jenny organization: Thorium Conjugate Research, Bayer AS, Oslo, Norway – sequence: 8 givenname: Alan S surname: Cuthbertson fullname: Cuthbertson, Alan S organization: Thorium Conjugate Research, Bayer AS, Oslo, Norway |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/28915592$$D View this record in MEDLINE/PubMed |
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| Keywords | alpha particles renal cell carcinoma radioimmunotherapy targeted alpha therapy (TAT) thorium-227 |
| Language | English |
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