67Cu-2IT-BAT-Lym-1 pharmacokinetics, radiation dosimetry, toxicity and tumor regression in patients with lymphoma

Sally J. DeNardo, Gerald L. DeNardo, David L. Kukis, Sui Shen, Linda A. Kroger, Diane A. Denardo, Desiree S. Goldstein, Gary R. Mirick, Qansy Salako, Leonard F. Mausner, Suresh C. Srivastava, Claude F. Meares

    Research output: Contribution to journalArticle

    70 Citations (Scopus)

    Abstract

    Lym-1, a monoclonal antibody that preferentially targets malignant lymphocytes, has induced therapeutic responses and prolonged survival in patients with non-Hodgkin's lymphoma when labeled with 131I. Radiometal- labeled antibodies provide higher tumor radiation doses than corresponding 131I antibodies. 67Cu has an exceptional combination of properties desirable for radioimmunotherapy, including gamma and beta emissions for imaging and therapy, respectively, a biocompatible half-time and absence of pathways contributing to myelotoxicity. The radioimmunoconjugate, 67Cu- 2IT-BAT-Lym-1, has been shown to be efficacious in nude mice bearing human Burkitt's lymphoma (Raji) xenografts. Based on these results, a clinical study of the pharmacokinetics and dosimetry of 67Cu-2IT-BAT-Lym-1 in patients with lymphoma was initiated. Methods: Eleven patients with advanced stage 3 or 4 lymphoma were given a preload dose of unmodified Lym-1, then an imaging dose of 126-533 MBq (3.4-14.4 mCi) 67Cu-2IT-BAT-Lym-1. Total Lym-1 ranged from 25 to 70 mg dependent on the specific activity of the radioimmunoconjugate and was infused at a rate of 0.5-1 mg/min. Imaging, physical examination, including caliper measurement of superficial tumors, and analysis of blood urine and fecal samples were performed for a period of 6-13 d after infusion to assess pharmacokinetics, radiation dosimetry, toxicity and tumor regression. Results: In 7 patients, in whom superficial tumors had been accurately measured, tumors regressed from 18% to 75% (mean 48%) within several days of 67Cu-2IT-BAT-Lym-1 infusion. The uptake and biological half-time of 67Cu-2IT-BAT-Lym-1 in tumors were greater than those of normal tissues, except the mean liver half-time exceeded the mean tumor half-time. The mean tumor-to-marrow radiation ratio was 32:1, tumor- to-total body was 24:1 and tumor-to-liver was 1.5:1. Images were of very good quality; tumors and normal organs were readily identified. Mild and transient Lym-1 toxicity occurred in 6 patients; 1 patient developed a human antimouse antibody. There were no significant changes in blood counts or serum chemistries indicative of radiation toxicity. Conclusion: Because of the long residence time of 67Cu-2IT-BAT-Lym-1 in tumors, high therapeutic ratios were achieved and, remarkably, numerous tumor regressions were observed after imaging doses. The results indicate considerable therapeutic potential for 67Cu-2IT-BAT-Lym-1.

    Original languageEnglish (US)
    Pages (from-to)302-310
    Number of pages9
    JournalJournal of Nuclear Medicine
    Volume40
    Issue number2
    StatePublished - Feb 1999

    Fingerprint

    Radiometry
    Lymphoma
    Pharmacokinetics
    Neoplasms
    Immunoconjugates
    Radiation
    copper-67-2IT-BAT-Lym-1
    Antibodies
    Radioimmunotherapy
    Burkitt Lymphoma
    Liver
    Therapeutics
    Heterografts
    Nude Mice
    Non-Hodgkin's Lymphoma
    Physical Examination

    Keywords

    • Cu
    • Lymphoma
    • Pharmacokinetics
    • Radiation dosimetry
    • Radioimmunotherapy

    ASJC Scopus subject areas

    • Radiological and Ultrasound Technology

    Cite this

    DeNardo, S. J., DeNardo, G. L., Kukis, D. L., Shen, S., Kroger, L. A., Denardo, D. A., ... Meares, C. F. (1999). 67Cu-2IT-BAT-Lym-1 pharmacokinetics, radiation dosimetry, toxicity and tumor regression in patients with lymphoma. Journal of Nuclear Medicine, 40(2), 302-310.

    67Cu-2IT-BAT-Lym-1 pharmacokinetics, radiation dosimetry, toxicity and tumor regression in patients with lymphoma. / DeNardo, Sally J.; DeNardo, Gerald L.; Kukis, David L.; Shen, Sui; Kroger, Linda A.; Denardo, Diane A.; Goldstein, Desiree S.; Mirick, Gary R.; Salako, Qansy; Mausner, Leonard F.; Srivastava, Suresh C.; Meares, Claude F.

    In: Journal of Nuclear Medicine, Vol. 40, No. 2, 02.1999, p. 302-310.

    Research output: Contribution to journalArticle

    DeNardo, SJ, DeNardo, GL, Kukis, DL, Shen, S, Kroger, LA, Denardo, DA, Goldstein, DS, Mirick, GR, Salako, Q, Mausner, LF, Srivastava, SC & Meares, CF 1999, '67Cu-2IT-BAT-Lym-1 pharmacokinetics, radiation dosimetry, toxicity and tumor regression in patients with lymphoma', Journal of Nuclear Medicine, vol. 40, no. 2, pp. 302-310.
    DeNardo, Sally J. ; DeNardo, Gerald L. ; Kukis, David L. ; Shen, Sui ; Kroger, Linda A. ; Denardo, Diane A. ; Goldstein, Desiree S. ; Mirick, Gary R. ; Salako, Qansy ; Mausner, Leonard F. ; Srivastava, Suresh C. ; Meares, Claude F. / 67Cu-2IT-BAT-Lym-1 pharmacokinetics, radiation dosimetry, toxicity and tumor regression in patients with lymphoma. In: Journal of Nuclear Medicine. 1999 ; Vol. 40, No. 2. pp. 302-310.
    @article{f55ed26b83f64214814ef214373c6fcf,
    title = "67Cu-2IT-BAT-Lym-1 pharmacokinetics, radiation dosimetry, toxicity and tumor regression in patients with lymphoma",
    abstract = "Lym-1, a monoclonal antibody that preferentially targets malignant lymphocytes, has induced therapeutic responses and prolonged survival in patients with non-Hodgkin's lymphoma when labeled with 131I. Radiometal- labeled antibodies provide higher tumor radiation doses than corresponding 131I antibodies. 67Cu has an exceptional combination of properties desirable for radioimmunotherapy, including gamma and beta emissions for imaging and therapy, respectively, a biocompatible half-time and absence of pathways contributing to myelotoxicity. The radioimmunoconjugate, 67Cu- 2IT-BAT-Lym-1, has been shown to be efficacious in nude mice bearing human Burkitt's lymphoma (Raji) xenografts. Based on these results, a clinical study of the pharmacokinetics and dosimetry of 67Cu-2IT-BAT-Lym-1 in patients with lymphoma was initiated. Methods: Eleven patients with advanced stage 3 or 4 lymphoma were given a preload dose of unmodified Lym-1, then an imaging dose of 126-533 MBq (3.4-14.4 mCi) 67Cu-2IT-BAT-Lym-1. Total Lym-1 ranged from 25 to 70 mg dependent on the specific activity of the radioimmunoconjugate and was infused at a rate of 0.5-1 mg/min. Imaging, physical examination, including caliper measurement of superficial tumors, and analysis of blood urine and fecal samples were performed for a period of 6-13 d after infusion to assess pharmacokinetics, radiation dosimetry, toxicity and tumor regression. Results: In 7 patients, in whom superficial tumors had been accurately measured, tumors regressed from 18{\%} to 75{\%} (mean 48{\%}) within several days of 67Cu-2IT-BAT-Lym-1 infusion. The uptake and biological half-time of 67Cu-2IT-BAT-Lym-1 in tumors were greater than those of normal tissues, except the mean liver half-time exceeded the mean tumor half-time. The mean tumor-to-marrow radiation ratio was 32:1, tumor- to-total body was 24:1 and tumor-to-liver was 1.5:1. Images were of very good quality; tumors and normal organs were readily identified. Mild and transient Lym-1 toxicity occurred in 6 patients; 1 patient developed a human antimouse antibody. There were no significant changes in blood counts or serum chemistries indicative of radiation toxicity. Conclusion: Because of the long residence time of 67Cu-2IT-BAT-Lym-1 in tumors, high therapeutic ratios were achieved and, remarkably, numerous tumor regressions were observed after imaging doses. The results indicate considerable therapeutic potential for 67Cu-2IT-BAT-Lym-1.",
    keywords = "Cu, Lymphoma, Pharmacokinetics, Radiation dosimetry, Radioimmunotherapy",
    author = "DeNardo, {Sally J.} and DeNardo, {Gerald L.} and Kukis, {David L.} and Sui Shen and Kroger, {Linda A.} and Denardo, {Diane A.} and Goldstein, {Desiree S.} and Mirick, {Gary R.} and Qansy Salako and Mausner, {Leonard F.} and Srivastava, {Suresh C.} and Meares, {Claude F.}",
    year = "1999",
    month = "2",
    language = "English (US)",
    volume = "40",
    pages = "302--310",
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    TY - JOUR

    T1 - 67Cu-2IT-BAT-Lym-1 pharmacokinetics, radiation dosimetry, toxicity and tumor regression in patients with lymphoma

    AU - DeNardo, Sally J.

    AU - DeNardo, Gerald L.

    AU - Kukis, David L.

    AU - Shen, Sui

    AU - Kroger, Linda A.

    AU - Denardo, Diane A.

    AU - Goldstein, Desiree S.

    AU - Mirick, Gary R.

    AU - Salako, Qansy

    AU - Mausner, Leonard F.

    AU - Srivastava, Suresh C.

    AU - Meares, Claude F.

    PY - 1999/2

    Y1 - 1999/2

    N2 - Lym-1, a monoclonal antibody that preferentially targets malignant lymphocytes, has induced therapeutic responses and prolonged survival in patients with non-Hodgkin's lymphoma when labeled with 131I. Radiometal- labeled antibodies provide higher tumor radiation doses than corresponding 131I antibodies. 67Cu has an exceptional combination of properties desirable for radioimmunotherapy, including gamma and beta emissions for imaging and therapy, respectively, a biocompatible half-time and absence of pathways contributing to myelotoxicity. The radioimmunoconjugate, 67Cu- 2IT-BAT-Lym-1, has been shown to be efficacious in nude mice bearing human Burkitt's lymphoma (Raji) xenografts. Based on these results, a clinical study of the pharmacokinetics and dosimetry of 67Cu-2IT-BAT-Lym-1 in patients with lymphoma was initiated. Methods: Eleven patients with advanced stage 3 or 4 lymphoma were given a preload dose of unmodified Lym-1, then an imaging dose of 126-533 MBq (3.4-14.4 mCi) 67Cu-2IT-BAT-Lym-1. Total Lym-1 ranged from 25 to 70 mg dependent on the specific activity of the radioimmunoconjugate and was infused at a rate of 0.5-1 mg/min. Imaging, physical examination, including caliper measurement of superficial tumors, and analysis of blood urine and fecal samples were performed for a period of 6-13 d after infusion to assess pharmacokinetics, radiation dosimetry, toxicity and tumor regression. Results: In 7 patients, in whom superficial tumors had been accurately measured, tumors regressed from 18% to 75% (mean 48%) within several days of 67Cu-2IT-BAT-Lym-1 infusion. The uptake and biological half-time of 67Cu-2IT-BAT-Lym-1 in tumors were greater than those of normal tissues, except the mean liver half-time exceeded the mean tumor half-time. The mean tumor-to-marrow radiation ratio was 32:1, tumor- to-total body was 24:1 and tumor-to-liver was 1.5:1. Images were of very good quality; tumors and normal organs were readily identified. Mild and transient Lym-1 toxicity occurred in 6 patients; 1 patient developed a human antimouse antibody. There were no significant changes in blood counts or serum chemistries indicative of radiation toxicity. Conclusion: Because of the long residence time of 67Cu-2IT-BAT-Lym-1 in tumors, high therapeutic ratios were achieved and, remarkably, numerous tumor regressions were observed after imaging doses. The results indicate considerable therapeutic potential for 67Cu-2IT-BAT-Lym-1.

    AB - Lym-1, a monoclonal antibody that preferentially targets malignant lymphocytes, has induced therapeutic responses and prolonged survival in patients with non-Hodgkin's lymphoma when labeled with 131I. Radiometal- labeled antibodies provide higher tumor radiation doses than corresponding 131I antibodies. 67Cu has an exceptional combination of properties desirable for radioimmunotherapy, including gamma and beta emissions for imaging and therapy, respectively, a biocompatible half-time and absence of pathways contributing to myelotoxicity. The radioimmunoconjugate, 67Cu- 2IT-BAT-Lym-1, has been shown to be efficacious in nude mice bearing human Burkitt's lymphoma (Raji) xenografts. Based on these results, a clinical study of the pharmacokinetics and dosimetry of 67Cu-2IT-BAT-Lym-1 in patients with lymphoma was initiated. Methods: Eleven patients with advanced stage 3 or 4 lymphoma were given a preload dose of unmodified Lym-1, then an imaging dose of 126-533 MBq (3.4-14.4 mCi) 67Cu-2IT-BAT-Lym-1. Total Lym-1 ranged from 25 to 70 mg dependent on the specific activity of the radioimmunoconjugate and was infused at a rate of 0.5-1 mg/min. Imaging, physical examination, including caliper measurement of superficial tumors, and analysis of blood urine and fecal samples were performed for a period of 6-13 d after infusion to assess pharmacokinetics, radiation dosimetry, toxicity and tumor regression. Results: In 7 patients, in whom superficial tumors had been accurately measured, tumors regressed from 18% to 75% (mean 48%) within several days of 67Cu-2IT-BAT-Lym-1 infusion. The uptake and biological half-time of 67Cu-2IT-BAT-Lym-1 in tumors were greater than those of normal tissues, except the mean liver half-time exceeded the mean tumor half-time. The mean tumor-to-marrow radiation ratio was 32:1, tumor- to-total body was 24:1 and tumor-to-liver was 1.5:1. Images were of very good quality; tumors and normal organs were readily identified. Mild and transient Lym-1 toxicity occurred in 6 patients; 1 patient developed a human antimouse antibody. There were no significant changes in blood counts or serum chemistries indicative of radiation toxicity. Conclusion: Because of the long residence time of 67Cu-2IT-BAT-Lym-1 in tumors, high therapeutic ratios were achieved and, remarkably, numerous tumor regressions were observed after imaging doses. The results indicate considerable therapeutic potential for 67Cu-2IT-BAT-Lym-1.

    KW - Cu

    KW - Lymphoma

    KW - Pharmacokinetics

    KW - Radiation dosimetry

    KW - Radioimmunotherapy

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