Pharmacokinetics and biodistribution of 177Lu-labeled multivalent single-chain Fv construct of the pancarcinoma monoclonal antibody CC49

Subhash Chauhan, Maneesh Jain, Erik D. Moore, Uwe A. Wittel, Jing Li, Peter R. Gwilt, David Colcher, Surinder K. Batra

Research output: Contribution to journalArticle

29 Citations (Scopus)

Abstract

Purpose: Lutetium-177 (177Lu) is a radionuclide of interest for radioimmunoimaging (RII) and radioimmunotherapy (RIT) on account of its short half-life (161 h) and the ability to emit both β and γ radiation. Single-chain Fv (scFv) constructs have shown advancement in cancer diagnosis and therapy due to the pharmacokinetics advantage and seem to be intriguing tools in oncology. The objective of this study was to evaluate the pharmacokinetics and biodistribution characteristics of the 177Lu-labeled tetravalent scFv of CC49 MAb and intact CC49 IgG in vivo. Methods: Conjugation and labeling conditions of multivalent scFv with 177Lu were optimized without affecting integrity and immunoreactivity. For this purpose, multivalent scFv constructs {dimer, sc(Fv)2; tetramer, [sc(Fv)2] 2} of the MAb CC49 were expressed as secretory proteins in Pichia pastoris. The purified scFv constructs and IgG form of CC49 were conjugated with a bifunctional chelating agent, ITCB-DTPA, and labeled with 177Lu. The comparative biodistribution, blood clearance, and tumor-targeting characteristics of 177Lu-labeled tetravalent [sc(Fv) 2]2 construct of CC49 MAb and intact CC49 IgG were investigated in the athymic mice bearing LS-174T xenografts. Results: Approximately, 90% of 177Lu incorporation was achieved using ITCB-DTPA chelator, and the labeled immunoconjugates maintained integrity and immunoreactivity. Blood clearance studies demonstrated an alpha half-life (t 1/2α) of 177Lu-labeled [sc(Fv)2] 2 and IgG of CC49 at 4.40 and 9.50 min and a beta half-life (t 1/2β) at 375 and 2,193 min, respectively. At 8 h post administration, the percent of the injected dose accumulated/gram (%ID/g) of the LS-174T tumor was 6.4±1.3 and 8.9±0.6 for 177Lu- labeled [sc(Fv)2]2 and IgG of CC49, respectively, in the absence of l-lysine. The corresponding values were 8.0±0.6 and 8.4±1.2 in the presence of l-lysine. Renal accumulation of [sc(Fv) 2]2 was significantly (p<0.005) reduced in the presence of L-lysine. Conclusion: The results of this study demonstrate that the ITCB-DTPA conjugation and 177Lu-labeling of scFvs are feasible without influencing the antibody characteristics. 177Lu-labeled [sc(Fv)2]2 showed faster clearance and equivalent tumor uptake at 8 h compared with its IgG form, with a markedly reduced renal uptake in the presence of l-lysine. Therefore, 177Lu-labeled [sc(Fv) 2]2 may be a potential radiopharmaceutical for the treatment of cancer.

Original languageEnglish (US)
Pages (from-to)264-273
Number of pages10
JournalEuropean Journal of Nuclear Medicine and Molecular Imaging
Volume32
Issue number3
DOIs
StatePublished - Mar 1 2005
Externally publishedYes

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Single-Chain Antibodies
Pharmacokinetics
Immunoglobulin G
Monoclonal Antibodies
Pentetic Acid
Lysine
Half-Life
Neoplasms
Chelating Agents
Lutetium
Radioimmunodetection
Immunoconjugates
Radioimmunotherapy
Kidney
Pichia
Radiopharmaceuticals
Heterografts
Nude Mice
Radioisotopes
Radiation

All Science Journal Classification (ASJC) codes

  • Radiology Nuclear Medicine and imaging

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Pharmacokinetics and biodistribution of 177Lu-labeled multivalent single-chain Fv construct of the pancarcinoma monoclonal antibody CC49. / Chauhan, Subhash; Jain, Maneesh; Moore, Erik D.; Wittel, Uwe A.; Li, Jing; Gwilt, Peter R.; Colcher, David; Batra, Surinder K.

In: European Journal of Nuclear Medicine and Molecular Imaging, Vol. 32, No. 3, 01.03.2005, p. 264-273.

Research output: Contribution to journalArticle

Chauhan, Subhash ; Jain, Maneesh ; Moore, Erik D. ; Wittel, Uwe A. ; Li, Jing ; Gwilt, Peter R. ; Colcher, David ; Batra, Surinder K. / Pharmacokinetics and biodistribution of 177Lu-labeled multivalent single-chain Fv construct of the pancarcinoma monoclonal antibody CC49. In: European Journal of Nuclear Medicine and Molecular Imaging. 2005 ; Vol. 32, No. 3. pp. 264-273.
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title = "Pharmacokinetics and biodistribution of 177Lu-labeled multivalent single-chain Fv construct of the pancarcinoma monoclonal antibody CC49",
abstract = "Purpose: Lutetium-177 (177Lu) is a radionuclide of interest for radioimmunoimaging (RII) and radioimmunotherapy (RIT) on account of its short half-life (161 h) and the ability to emit both β and γ radiation. Single-chain Fv (scFv) constructs have shown advancement in cancer diagnosis and therapy due to the pharmacokinetics advantage and seem to be intriguing tools in oncology. The objective of this study was to evaluate the pharmacokinetics and biodistribution characteristics of the 177Lu-labeled tetravalent scFv of CC49 MAb and intact CC49 IgG in vivo. Methods: Conjugation and labeling conditions of multivalent scFv with 177Lu were optimized without affecting integrity and immunoreactivity. For this purpose, multivalent scFv constructs {dimer, sc(Fv)2; tetramer, [sc(Fv)2] 2} of the MAb CC49 were expressed as secretory proteins in Pichia pastoris. The purified scFv constructs and IgG form of CC49 were conjugated with a bifunctional chelating agent, ITCB-DTPA, and labeled with 177Lu. The comparative biodistribution, blood clearance, and tumor-targeting characteristics of 177Lu-labeled tetravalent [sc(Fv) 2]2 construct of CC49 MAb and intact CC49 IgG were investigated in the athymic mice bearing LS-174T xenografts. Results: Approximately, 90{\%} of 177Lu incorporation was achieved using ITCB-DTPA chelator, and the labeled immunoconjugates maintained integrity and immunoreactivity. Blood clearance studies demonstrated an alpha half-life (t 1/2α) of 177Lu-labeled [sc(Fv)2] 2 and IgG of CC49 at 4.40 and 9.50 min and a beta half-life (t 1/2β) at 375 and 2,193 min, respectively. At 8 h post administration, the percent of the injected dose accumulated/gram ({\%}ID/g) of the LS-174T tumor was 6.4±1.3 and 8.9±0.6 for 177Lu- labeled [sc(Fv)2]2 and IgG of CC49, respectively, in the absence of l-lysine. The corresponding values were 8.0±0.6 and 8.4±1.2 in the presence of l-lysine. Renal accumulation of [sc(Fv) 2]2 was significantly (p<0.005) reduced in the presence of L-lysine. Conclusion: The results of this study demonstrate that the ITCB-DTPA conjugation and 177Lu-labeling of scFvs are feasible without influencing the antibody characteristics. 177Lu-labeled [sc(Fv)2]2 showed faster clearance and equivalent tumor uptake at 8 h compared with its IgG form, with a markedly reduced renal uptake in the presence of l-lysine. Therefore, 177Lu-labeled [sc(Fv) 2]2 may be a potential radiopharmaceutical for the treatment of cancer.",
author = "Subhash Chauhan and Maneesh Jain and Moore, {Erik D.} and Wittel, {Uwe A.} and Jing Li and Gwilt, {Peter R.} and David Colcher and Batra, {Surinder K.}",
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language = "English (US)",
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pages = "264--273",
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TY - JOUR

T1 - Pharmacokinetics and biodistribution of 177Lu-labeled multivalent single-chain Fv construct of the pancarcinoma monoclonal antibody CC49

AU - Chauhan, Subhash

AU - Jain, Maneesh

AU - Moore, Erik D.

AU - Wittel, Uwe A.

AU - Li, Jing

AU - Gwilt, Peter R.

AU - Colcher, David

AU - Batra, Surinder K.

PY - 2005/3/1

Y1 - 2005/3/1

N2 - Purpose: Lutetium-177 (177Lu) is a radionuclide of interest for radioimmunoimaging (RII) and radioimmunotherapy (RIT) on account of its short half-life (161 h) and the ability to emit both β and γ radiation. Single-chain Fv (scFv) constructs have shown advancement in cancer diagnosis and therapy due to the pharmacokinetics advantage and seem to be intriguing tools in oncology. The objective of this study was to evaluate the pharmacokinetics and biodistribution characteristics of the 177Lu-labeled tetravalent scFv of CC49 MAb and intact CC49 IgG in vivo. Methods: Conjugation and labeling conditions of multivalent scFv with 177Lu were optimized without affecting integrity and immunoreactivity. For this purpose, multivalent scFv constructs {dimer, sc(Fv)2; tetramer, [sc(Fv)2] 2} of the MAb CC49 were expressed as secretory proteins in Pichia pastoris. The purified scFv constructs and IgG form of CC49 were conjugated with a bifunctional chelating agent, ITCB-DTPA, and labeled with 177Lu. The comparative biodistribution, blood clearance, and tumor-targeting characteristics of 177Lu-labeled tetravalent [sc(Fv) 2]2 construct of CC49 MAb and intact CC49 IgG were investigated in the athymic mice bearing LS-174T xenografts. Results: Approximately, 90% of 177Lu incorporation was achieved using ITCB-DTPA chelator, and the labeled immunoconjugates maintained integrity and immunoreactivity. Blood clearance studies demonstrated an alpha half-life (t 1/2α) of 177Lu-labeled [sc(Fv)2] 2 and IgG of CC49 at 4.40 and 9.50 min and a beta half-life (t 1/2β) at 375 and 2,193 min, respectively. At 8 h post administration, the percent of the injected dose accumulated/gram (%ID/g) of the LS-174T tumor was 6.4±1.3 and 8.9±0.6 for 177Lu- labeled [sc(Fv)2]2 and IgG of CC49, respectively, in the absence of l-lysine. The corresponding values were 8.0±0.6 and 8.4±1.2 in the presence of l-lysine. Renal accumulation of [sc(Fv) 2]2 was significantly (p<0.005) reduced in the presence of L-lysine. Conclusion: The results of this study demonstrate that the ITCB-DTPA conjugation and 177Lu-labeling of scFvs are feasible without influencing the antibody characteristics. 177Lu-labeled [sc(Fv)2]2 showed faster clearance and equivalent tumor uptake at 8 h compared with its IgG form, with a markedly reduced renal uptake in the presence of l-lysine. Therefore, 177Lu-labeled [sc(Fv) 2]2 may be a potential radiopharmaceutical for the treatment of cancer.

AB - Purpose: Lutetium-177 (177Lu) is a radionuclide of interest for radioimmunoimaging (RII) and radioimmunotherapy (RIT) on account of its short half-life (161 h) and the ability to emit both β and γ radiation. Single-chain Fv (scFv) constructs have shown advancement in cancer diagnosis and therapy due to the pharmacokinetics advantage and seem to be intriguing tools in oncology. The objective of this study was to evaluate the pharmacokinetics and biodistribution characteristics of the 177Lu-labeled tetravalent scFv of CC49 MAb and intact CC49 IgG in vivo. Methods: Conjugation and labeling conditions of multivalent scFv with 177Lu were optimized without affecting integrity and immunoreactivity. For this purpose, multivalent scFv constructs {dimer, sc(Fv)2; tetramer, [sc(Fv)2] 2} of the MAb CC49 were expressed as secretory proteins in Pichia pastoris. The purified scFv constructs and IgG form of CC49 were conjugated with a bifunctional chelating agent, ITCB-DTPA, and labeled with 177Lu. The comparative biodistribution, blood clearance, and tumor-targeting characteristics of 177Lu-labeled tetravalent [sc(Fv) 2]2 construct of CC49 MAb and intact CC49 IgG were investigated in the athymic mice bearing LS-174T xenografts. Results: Approximately, 90% of 177Lu incorporation was achieved using ITCB-DTPA chelator, and the labeled immunoconjugates maintained integrity and immunoreactivity. Blood clearance studies demonstrated an alpha half-life (t 1/2α) of 177Lu-labeled [sc(Fv)2] 2 and IgG of CC49 at 4.40 and 9.50 min and a beta half-life (t 1/2β) at 375 and 2,193 min, respectively. At 8 h post administration, the percent of the injected dose accumulated/gram (%ID/g) of the LS-174T tumor was 6.4±1.3 and 8.9±0.6 for 177Lu- labeled [sc(Fv)2]2 and IgG of CC49, respectively, in the absence of l-lysine. The corresponding values were 8.0±0.6 and 8.4±1.2 in the presence of l-lysine. Renal accumulation of [sc(Fv) 2]2 was significantly (p<0.005) reduced in the presence of L-lysine. Conclusion: The results of this study demonstrate that the ITCB-DTPA conjugation and 177Lu-labeling of scFvs are feasible without influencing the antibody characteristics. 177Lu-labeled [sc(Fv)2]2 showed faster clearance and equivalent tumor uptake at 8 h compared with its IgG form, with a markedly reduced renal uptake in the presence of l-lysine. Therefore, 177Lu-labeled [sc(Fv) 2]2 may be a potential radiopharmaceutical for the treatment of cancer.

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