Imaging and Pharmacokinetics of 64Cu-DOTA-HB22.7 Administered by Intravenous, Intraperitoneal, or Subcutaneous Injection to Mice Bearing Non-Hodgkin’s Lymphoma Xenografts

  • Shiloh M. Martin
  • Robert T. O’Donnell
  • David L. Kukis
  • Craig K. Abbey
  • Hayes McKnight
  • Julie L. Sutcliffe
  • Joseph M. Tuscano
Research Article

Abstract

Purpose

The aim of the study is to compare the tumor-specific targeting, pharmacokinetics, and biodistribution of 64Cu-DOTA-HB22.7 when administered to xenograft-bearing mice intravenously (IV), intraperitoneally (IP), and subcutaneously (SQ).

Procedures

Mice bearing human non-Hodgkin’s lymphoma (NHL) xenografts were injected IV, IP, or SQ with 64Cu-DOTA-HB22.7. Xenograft targeting was evaluated by micro positron emission tomography (microPET) and confirmed by organ biodistribution studies. Blood measurements of 64Cu were performed to determine the pharmacokinetics and clearance of 64Cu-DOTA-HB22.7.

Results

64Cu-DOTA-HB22.7 demonstrated equivalent tumor targeting within 24–48 h, regardless of the route of administration. Organ biodistribution confirmed tumor-specific targeting. Blood pharmacokinetics demonstrated that 64Cu-DOTA-HB22.7 accessed the bloodstream after IP and SQ administration to a similar degree as IV administration, albeit at a slower rate.

Conclusions

These findings establish 64Cu-DOTA-HB22.7 as a potential radioimmunotherapeutic and/or NHL-specific imaging agent. These findings provide evidence that IP and SQ administration can achieve results equivalent to IV administration and may lead to more efficient, reproducible treatment plans for antibody-based therapeutics.

Key words

HB22.7 CD22 Non-Hodgkin’s lymphoma PET 64Cu 

Abbreviations

64Cu

Copper-64

DOTA-NHS-ester

1,4,7,10-tetraazacyclododecane-N,N′,N′′,N′′′-tetraacetic acid mono(N-hydroxysuccinimidyl ester)

Ig

immunoglobulin

IV

intravenous

IP

intraperitoneal

mAb

monoclonal antibody

NHL

non-Hodgkin’s lymphoma

RIT

radioimmunotherapy

SQ

subcutaneous

TLC

thin layer chromatography

References

  1. 1.
    Schumer ST, Joyce RM (2003) Radioimmunotherapy for Non-Hodgkin’s Lymphoma. Progress in Oncology 46–72Google Scholar
  2. 2.
    Lindley C (1991) The lymphomas: Hodgkin’s disease and non-Hodgkin’s lymphomas. Am Pharm NS31 46–51Google Scholar
  3. 3.
    DeNardo GL (2005) Treatment of non-Hodgkin’s lymphoma (NHL) with radiolabeled antibodies (mAbs). Semin Nucl Med 35:202–211PubMedCrossRefGoogle Scholar
  4. 4.
    DeNardo GL, O'Donnell RT, DeNardo SJ (2001) Radiolabeled anti-lymphoma antibodies. Cancer Chemother Biol Response Modif 19:297–308PubMedGoogle Scholar
  5. 5.
    Kukis DL, DeNardo GL, DeNardo SJ et al (1995) Effect of the extent of chelate substitution on the immunoreactivity and biodistribution of 2IT-BAT-Lym-1 immunoconjugates. Cancer Res 55:878–884PubMedGoogle Scholar
  6. 6.
    Juweid ME (2002) Radioimmunotherapy of B-cell non-Hodgkin’s lymphoma: from clinical trials to clinical practice. J Nucl Med 43:1507–1529PubMedGoogle Scholar
  7. 7.
    Riley MB, Gordon LI (2004) Efficacy and safety of radioimmunotherapy with yttrium 90 ibritumomab tiuxetan (Zevalin). Semin Oncol Nurs 20:8–13PubMedCrossRefGoogle Scholar
  8. 8.
    Hjortland GO, Garman-Vik SS, Juell S (2004) Immunotoxin treatment targeted to the high-molecular-weight melanoma-associated antigen prolonging the survival of immunodeficient rats with invasive intracranial human glioblastoma multiforme. J Neurosurg 100:320–327PubMedGoogle Scholar
  9. 9.
    Kawakami K, Nakajima O, Morishita R, Nagai R (2006) Targeted anticancer immunotoxins and cytotoxic agents with direct killing moieties. Scientific World Journal 6:781–790PubMedGoogle Scholar
  10. 10.
    Tedder TF, Tuscano J, Sato S, Kehrl JH (1997) CD22, a B lymphocyte-specific adhesion molecule that regulates antigen receptor signaling. Annu Rev Immunol 15:481–504PubMedCrossRefGoogle Scholar
  11. 11.
    Sato S, Tuscano JM, Inaoki M, Tedder TF (1998) CD22 negatively and positively regulates signal transduction through the B lymphocyte antigen receptor. Semin Immunol 10:287–297PubMedCrossRefGoogle Scholar
  12. 12.
    Tuscano JM, Riva A, Toscano SN, Tedder TF, Kehrl JH (1999) CD22 cross-linking generates B-cell antigen receptor-independent signals that activate the JNK/SAPK signaling cascade. Blood 94:1382–1392PubMedGoogle Scholar
  13. 13.
    Tuscano JM, O'Donnell RT, Miers LA et al (2003) Anti-CD22 ligand-blocking antibody HB22.7 has independent lymphomacidal properties and augments the efficacy of 90Y-DOTA-peptide-Lym-1 in lymphoma xenografts. Blood 101:3641–3647PubMedCrossRefGoogle Scholar
  14. 14.
    Koppe MJ, Postema EJ, Aarts F, Oyen WJ, Bleichrodt RP, Boerman OC (2005) Antibody-guided radiation therapy of cancer. Cancer Metastasis Rev 24:539–567PubMedCrossRefGoogle Scholar
  15. 15.
    Postema EJ, Boerman OC, Oyen WJ, Raemaekers JM, Corstens FH (2001) Radioimmunotherapy of B-cell non-Hodgkin’s lymphoma. Eur J Nucl Med 28:1725–1735PubMedCrossRefGoogle Scholar
  16. 16.
    O'Grady LF, DeNardo G, DeNardo S (1986) Radiolabelled monoclonal antibodies for the detection of cancer. Am J Physiol Imaging 1:44–53PubMedGoogle Scholar
  17. 17.
    Rao AV, Akabani G, Rizzieri DA (2005) Radioimmunotherapy for Non-Hodgkin’s Lymphoma. Clin Med Res 3:157–165PubMedCrossRefGoogle Scholar
  18. 18.
    Smith SV (2004) Molecular imaging with copper-64. J Inorg Biochem 98:1874–1901PubMedCrossRefGoogle Scholar
  19. 19.
    Phelps ME (2000) Inaugural article: positron emission tomography provides molecular imaging of biological processes. Proc Natl Acad Sci USA 97:9226–9233PubMedCrossRefGoogle Scholar
  20. 20.
    Winnard P Jr., Raman V (2003) Real time non-invasive imaging of receptor-ligand interactions in vivo. J Cell Biochem 90:454–463PubMedCrossRefGoogle Scholar
  21. 21.
    Hale G, Rebello P, Brettman LR et al (2004) Blood concentrations of alemtuzumab and antiglobin responses in patients with chronic lymphocytic leukemia following intravenous or subcutaneous routes of administration. Blood 104:948–955PubMedCrossRefGoogle Scholar
  22. 22.
    Meares CF, McCall MJ, Reardan DT, Goodwin DA, Diamanti CI, McTigue M (1984) Conjugation of antibodies with bifunctional chelating agents: isothiocyanate and bromoacetamide reagents, methods of analysis, and subsequent addition of metal ions. Anal Biochem 142:68–78PubMedCrossRefGoogle Scholar
  23. 23.
    McCarthy DW, Shefer RE, Klinkowstein RE et al (1997) Efficient production of high specific activity 64Cu using a biomedical cyclotron. Nucl Med Biol 24:35–43PubMedCrossRefGoogle Scholar
  24. 24.
    Tai YC, Chatziioannou AF, Yang Y et al (2003) MicroPET II: design, development and initial performance of an improved microPET scanner for small-animal imaging. Phys Med Biol 48:1519–1537PubMedCrossRefGoogle Scholar
  25. 25.
    Chatziioannou A, Tai YC, Doshi N, Cherry SR (2001) Detector development for microPET II: a 1 microl resolution PET scanner for small animal imaging. Phys Med Biol 46:2899–2910PubMedCrossRefGoogle Scholar
  26. 26.
    Qi J, Leahy RM, Cherry SR, Chatziioannou A, Farquhar TH (1998) High-resolution 3D Bayesian image reconstruction using the microPET small-animal scanner. Phys Med Biol 43:1001–1013PubMedCrossRefGoogle Scholar
  27. 27.
    Chatziioannou A, Qi J, Moore A et al (2000) Comparison of 3-D maximum a posteriori and filtered backprojection algorithms for high-resolution animal imaging with microPET. IEEE Trans Med Imaging 19:507–512PubMedCrossRefGoogle Scholar
  28. 28.
    Abbey CK, Borowsky AD, McGoldrick ET et al (2004) In vivo positron-emission tomography imaging of progression and transformation in a mouse model of mammary neoplasia. Proc Natl Acad Sci USA 101:11438–11443PubMedCrossRefGoogle Scholar
  29. 29.
    Qi J, Leahy RM (1999) A theoretical study of the contrast recovery and variance of MAP reconstructions from PET data. IEEE Trans Med Imaging 18:293–305PubMedCrossRefGoogle Scholar
  30. 30.
    Love C, Tomas MB, Tronco GG, Palestro CJ (2005) FDG PET of infection and inflammation. Radiographics 25:1357–1368PubMedCrossRefGoogle Scholar
  31. 31.
    Rosenbaum SJ, Lind T, Antoch G, Bockisch A (2006) False-positive FDG PET uptake—the role of PET/CT. Eur Radiol 16:1054–1065PubMedCrossRefGoogle Scholar
  32. 32.
    Jacene HA, Stearns V, Wahl RL (2006) Lymphadenopathy resulting from acute hepatitis C infection mimicking metastatic breast carcinoma on FDG PET/CT. Clin Nucl Med 31:379–381PubMedCrossRefGoogle Scholar
  33. 33.
    Engel P, Wagner N, Miller AS, Tedder TF (1995) Identification of the ligand binding domains of CD22, a member of the immunoglobulin superfamily that uniquely binds a sialic acid-dependent ligand. J Exp Med 181:1581–1586PubMedCrossRefGoogle Scholar
  34. 34.
    Eischen A, Doclos B, Schmitt-Goguel M et al (1994) Human resident peritoneal macrophages: phenotype and biology. Br J Haematol 88:712–722PubMedCrossRefGoogle Scholar
  35. 35.
    Whitelaw DM (1966) The intravascular lifespan of monocytes. Blood 28:455–464PubMedGoogle Scholar
  36. 36.
    Garner B, van Reyk D, Dean RT, Jessup W (1997) Direct copper reduction by macrophagesIts role in low density lipoprotein oxidation. J Biol Chem 272:6927–6935PubMedCrossRefGoogle Scholar
  37. 37.
    Ehrenwald E, Chisolm GM, Fox PL (1994) Intact human ceruloplasmin oxidatively modifies low density lipoprotein. J Clin Invest 93:1493–1501PubMedCrossRefGoogle Scholar
  38. 38.
    Ehrenwald E, Fox PL (1996) Role of endogenous ceruloplasmin in low density lipoprotein oxidation by human U937 monocytic cells. J Clin Invest 97:884–890PubMedCrossRefGoogle Scholar
  39. 39.
    Chung J, Haile DJ, Wessling-Resnick M (2004) Copper-induced ferroportin-1 expression in J774 macrophages is associated with increased iron efflux. Proc Natl Acad Sci USA 101:2700–2705PubMedCrossRefGoogle Scholar
  40. 40.
    Rossi F (1986) The O2 -forming NADPH oxidase of the phagocytes: nature, mechanisms of activation and function. Biochim Biophys Acta 853:65–89PubMedGoogle Scholar
  41. 41.
    Babior BM, Kipnes RS, Curnutte JT (1973) Biological defense mechanisms. The production by leukocytes of superoxide, a potential bactericidal agent. J Clin Invest 52:741–744PubMedCrossRefGoogle Scholar
  42. 42.
    Pietarinen-Runtti P, Lakari E, Raivio KO, Kinnula VL (2000) Expression of antioxidant enzymes in human inflammatory cells. Am J Physiol Cell Physiol 278:C118–C125PubMedGoogle Scholar
  43. 43.
    Grunberg J, Novak-Hofer I, Honer M et al (2005) In-vivo evaluation of 177Lu- and 67/64Cu-labeled recombinant fragments of antibody chCE7 for radioimmunotherapy and PET imaging of L1-CAM positive tumors. Clin Cancer Res 11:5112–5120PubMedCrossRefGoogle Scholar
  44. 44.
    Lewis MR, Boswell CA, Laforest R et al (2001) Conjugation of monoclonal antibodies with TETA using activated esters: biological comparison of 64Cu-TETA-1A3 with 64Cu-BAT-2IT-1A3. Cancer Biother Radiopharm 16:483–494PubMedCrossRefGoogle Scholar
  45. 45.
    Cai W, Ebrahimnejad A, Chen K et al (2007) Quantitative radioimmunoPET imaging of EphA2 in tumor-bearing mice. Eur J Nucl Med Mol Imaging 34:2024–2036PubMedCrossRefGoogle Scholar
  46. 46.
    DeNardo GL, DeNardo SJ, Meares CF et al (1991) Pharmacokinetics of copper-67 conjugated Lym-1, a potential therapeutic radioimmunoconjugate, in mice and in patients with lymphoma. Antibody Immunoconj Radiopharm 4:777–785Google Scholar
  47. 47.
    Deshpande SV, DeNardo SJ, Meares CF et al (1988) Copper-67-labeled monoclonal antibody Lym-1, a potential radiopharmaceutical for cancer therapy: labeling and biodistribution in Raji tumored mice. J Nucl Med 29:217–225PubMedGoogle Scholar

Copyright information

© Academy of Molecular Imaging 2008

Authors and Affiliations

  • Shiloh M. Martin
    • 1
  • Robert T. O’Donnell
    • 1
    • 2
  • David L. Kukis
    • 3
  • Craig K. Abbey
    • 4
  • Hayes McKnight
    • 1
  • Julie L. Sutcliffe
    • 3
    • 5
  • Joseph M. Tuscano
    • 1
    • 2
    • 6
  1. 1.Division of Hematology and Oncology, Department of Internal MedicineUniversity of California, Davis Cancer CenterDavisUSA
  2. 2.Northern California Veterans Administration Healthcare SystemSacramentoUSA
  3. 3.Center for Molecular and Genomic ImagingUniversity of California DavisDavisUSA
  4. 4.Department of PsychologyUniversity of California Santa BarbaraSanta BarbaraUSA
  5. 5.Department of Biomedical EngineeringUniversity of California DavisDavisUSA
  6. 6.Department of Internal Medicine, Division of Hematology and OncologySacramentoUSA

Personalised recommendations