Skip to main content
SpringerLink
Log in

Preclinical Therapy of Breast Cancer with a Radioiodinated Humanized Anti-EGP-1 Monoclonal Antibody: Advantage of a Residualizing Iodine Radiolabel

  • Published:
Breast Cancer Research and Treatment Aims and scope Submit manuscript

Abstract

Background. A humanized monoclonal antibody (MAb), hRS7, labeled with 131I-IMP-R4, was evaluated for the preclinical radioimmunotherapy (RAIT) of breast cancer. 131I-IMP-R4 is an improved residualizing form of 131I that overcomes the short tumor residence time associated with conventionally radioiodinated MAbs. RS7, an internalizing MAb, recognizes epithelial glycoprotein-1, which is highly expressed in the carcinomas of breast, lung, ovary, and prostate.

Methods. A humanized version of RS7 was generated by CDR-grafting and transfection. In vivo experiments were carried out in nude mice bearing subcutaneous MDA-MB-468 human breast cancer xenografts. Therapy experiments were performed using established tumors with mean tumor volume (MTV) of 0.3 cm3, and single administrations, at ∼70% of the estimated maximum tolerated doses (MTD), of the residualizing 131I-IMP-R4-hRS7 and 131I-hRS7 prepared by the conventional chloramine-T method [131I-hRS7 (CT)]. Therapeutic specificity was determined by comparison with untreated and non-specific MAb controls.

Results. hRS7 was functionally very similar to murine and chimeric RS7. A biodistribution study using 125I-IMP-R4-hRS7 and 131I-hRS7 (CT) indicated a dosimetric advantage for the former. The MTVs 8 weeks post-treatment were 20, 163, and 280% of the starting MTVs of 131I-IMP-R4-hRS7-treated, 131I-hRS7 (CT)-treated, and untreated groups, respectively. Complete remissions were seen in 5 of 11 [and 6 of 8] mice treated with 131I-IMP-R4-hRS7, and in 1 of 11 mice treated with 131I-hRS7(CT). 131I-IMP-R4-hRS7 was significantly more efficacious than 131I-hRS7 (CT) [P = 0.01 for AUC] and the control 131I-IMP-R4-MAb.

Conclusion. 131I-IMP-R4-hRS7 is a promising new agent for RAIT, providing significant therapeutic advantage in comparison to the conventionally 131I-labeled antibody.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Cancer Facts and Figures. American Cancer Society, Atlanta, GA, 2003

  2. Hortobagi GN: Multidisciplinary management of advanced primary and metastatic breast cancer. Cancer 74(Suppl): 416–423, 1994

    Google Scholar 

  3. Ayash LJ: High dose chemotherapy with autologous stem cell support for the treatment of metastatic breast cancer. Cancer 74(Suppl): 532–535, 1994

    Google Scholar 

  4. Pegram MD, Lipton A, Hayes DF, Weber BL, Baselga JM, Tripathy D, Baly D, Baughman SA, Twaddell T, Glaspy JA, Slamon DJ: Phase II study of receptor-enhanced chemosensitivity using recombinant humanized anti-p185HER2/neu monoclonal antibody plus cisplatin in patients with HER2/ neu-overexpressing metastatic breast cancer refractory to chemotherapy treatment. J Clin Oncol 16: 2659–2671, 1998

    Google Scholar 

  5. Goldenberg DM: Targeted therapy of cancer with radiolabeled antibodies. J Nucl Med 43: 693–713, 2002

    Google Scholar 

  6. Kramer EL, Liebes L, Wasserheit C, Noz ME, Blank EW, Zabalegui A, Melamed J, Furmanski P, Peterson JA, Ceriani RL: Initial clinical evaluation of radiolabeled MX-DTPA humanized BrE-3 antibody in patients with advanced breast cancer. Clin Cancer Res 4: 1679–1688, 1998

    Google Scholar 

  7. Richman CM, DeNardo SJ, O'Donnell RT, Goldstein DS, Shen S, Kukis DL, Kroger LA, Yuan A, Boniface GR, Griffith IJ, DeNardo GL: Dosimetry-based therapy in metastatic breast cancer patients using 90Y monoclonal antibody 170H.82 with autologous stem cell support and cyclosporin A. Clin Cancer Res 5(Suppl): 3243s–3248s, 1999

    Google Scholar 

  8. Wong JYC, Somlo G, Odom-Maryon T, Williams LE, Liu A, Yamauchi D, Wu AM, Yazaki P, Wilczynski S, Shively JE, Forman S, Doroshow JH, Raubitschek AA: Initial clinical experience evaluating yttrium-90-chimeric T84.66 anticarcinoembryonic antigen antibody and autologous hematopoietic stem cell support in patients with carcinoembryonic antigen-producing metastatic breast cancer. Clin Cancer Res 5(Suppl): 3224s–3231s, 1999

    Google Scholar 

  9. DeNardo SJ, Mirick GR, Kroger LA, O'Grady LF, Erickson KL, Yuan A, Lamborn KR, Hellstrom I, Hellstrom KE, DeNardo GL: The biologic window for ChL6 radioimmunotherapy. Cancer 73(Suppl): 1023–1032, 1994

    Google Scholar 

  10. Sgouros G: Radioimmunotherapy of micrometastases: sidestepping the solid-tumor hurdle. J Nucl Med 36: 1910–1912, 1995

    Google Scholar 

  11. Geissler F, Anderson S, Press O: Intracellular catabolism of radiolabeled anti-CD3 antibodies by leukemic T cells. Cell Immunol 137: 96–110, 1991

    Google Scholar 

  12. Shih LB, Thorpe SR, Griffiths GL, Diril H, Ong GL, Hansen HJ, Goldenberg DM, Mattes MJ: The processing and fate of antibodies and their radiolabels bound to the surface of tumor cells in vitro: a comparison of nine radiolabels. J Nucl Med 35: 899–908, 1994

    Google Scholar 

  13. Mattes MJ, Griffiths GL, Diril H, Goldenberg DM, Ong GL, Shih LB: Processing of antibody-radioisotope conjugates after binding to the surface of tumor cells. Cancer 73: 787–793, 1994

    Google Scholar 

  14. Stein R, Govindan SV, Mattes MJ, Chen S, Reed L, Newsome G, McBride BJ, Griffiths GL, Hansen HJ, Goldenberg DM: Improved iodine radiolabels for monoclonal antibody therapy. Cancer Res 63: 111–118, 2003

    Google Scholar 

  15. Stein R, Basu A, Chen S, Shih LB, Goldenberg DM: Specificity and properties of MAb RS7-3G11 and the antigen defined by this pancarcinoma antibody. Int J Cancer 55: 938–946, 1993

    Google Scholar 

  16. Stein R, Basu A, Goldenberg DM, Lloyd KO, Mattes MJ: Characterization of cluster 13: the epithelial/carcinoma antigen recognized by MAb RS7. Int J Cancer 8(Suppl): 60–63, 1994

    Google Scholar 

  17. Shih LB, Xuan H, Aninipot R, Stein R, Goldenberg DM: In vitro and in vivo reactivity of an internalizing antibody, RS7, with human breast cancer. Cancer Res 55(Suppl): 5857s–5863s, 1995

    Google Scholar 

  18. Stein R, Goldenberg DM, Thorpe S, Basu A, Mattes MJ: Effects of radiolabeling monoclonal antibodies with a residualizing iodine radiolabel on the accretion of radioisotope in tumor. Cancer Res 55: 3132–3139, 1995

    Google Scholar 

  19. Stein R, Goldenberg DM, Thorpe S, Mattes MJ: Advantage of a residualizing iodine radiolabel for radioimmunotherapy of xenografts of human non-small-cell carcinoma of the lung. Cancer Res 38: 391–395, 1997

    Google Scholar 

  20. Stein R, Govindan SV, Mattes MJ, Shih LB, Griffiths GL, Hansen HJ, Goldenberg DM: targeting human cancer xenografts with MAbs labeled using radioiodinated, DTPAappended, peptides. Clin Cancer Res 5(Suppl): 3079s–3087s, 1999

    Google Scholar 

  21. Stein R, Govindan SV, Chen S, Reed L, Spiegelman H, Griffiths GL, Hansen HJ, Goldenberg DM: Successful therapy of a human lung cancer xenograft using MAb RS7 labeled with residualizing radioiodine. Crit Rev Oncol Hematol 39(Suppl): 173–180, 2001

    Google Scholar 

  22. Leung SO, Goldenberg DM, Dion AS, Pellegrini MC, Shevitz J, Shih LB, Hansen HJ: Construction and characterization of a humanized, internalizing, B-cell (CD22)-specific, leukemia/ lymphoma antibody, LL2. Mol Immunol 32: 1413–1427, 1995

    Google Scholar 

  23. Qu Z, Losman MJ, Eliassen KC, Hansen HJ, Goldenberg DM, Leung SO: Humanization of Immu31, an α-fetoproteinspecific antibody. Clin Cancer Res 5(Suppl): 3095s–3100s, 1999

    Google Scholar 

  24. Losman MJ, Hansen HJ, Dworak H, Krishnan IS, Qu Z, Shih LB, Zeng L, Goldenberg DM, Leung SO: Generation of a high-producing clone of a humanized anti-B-cell lymphoma monoclonal antibody (hLL2). Cancer 80(Suppl): 2660–2666, 1997

    Google Scholar 

  25. Govindan SV, Mattes MJ, Stein R, McBride BJ, Karacay H, Goldenberg DM, Hansen HJ, Griffiths GL: Labeling of monoclonal antibodies with diethylenetriaminepentaacetic acidappended radioiodinated peptides containing D-amino acids. Bioconjugate Chem 10: 231–240, 1999

    Google Scholar 

  26. Ellman GL: Tissue sulfhydryl groups. Arch Biochem Biophys 82: 70–77, 1959

    Google Scholar 

  27. Stein R, Chen S, Sharkey RM, Goldenberg DM: Murine monoclonal antibodies raised against human non-small cell carcinoma of the lung: specificity and tumor targeting. Cancer Res 50: 1330–1336, 1990

    Google Scholar 

  28. Lindmo T, Boven E, Cuttitta F, Fedorko J, Bunn Jr PA: Determination of the immunoreactive fraction of radiolabeled monoclonal antibodies by linear extrapolation to binding at infinite antigen excess. J Immunol Meth 72: 77–89, 1984

    Google Scholar 

  29. Siegel JA, Stabin MG: Absorbed fractions for electrons and beta particles in spheres of various sizes. J Nucl Med 35: 152–156, 1994

    Google Scholar 

  30. Sharkey RM, Blumenthal RD, Goldenberg DM: Development of cancer radioimmunotherapy and its potential as an adjuvant treatment. In: Goldenberg DM (ed) Cancer Therapy with Radiolabeled Antibodies. CRC Press, Florida, 1995, pp 101–114

    Google Scholar 

  31. DeNardo SJ, Kukis DL, Kroger LA, O'Donnell RT, Lamborn KR, Miers LA, DeNardo DG, Meares CF, DeNardo GL: Synergy of taxol and radioimmunotherapy with yttrium-90-labeled chimeric L6 antibody: efficacy and toxicity in breast cancer xenografts. Proc Natl Acad Sci USA 94: 4000–4004, 1997

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Immunomedics, Inc., Morris Plains, USA

    Serengulam V. Govindan, Zhengxing Qu, Hong Ma, Hans J. Hansen, Gary L. Griffiths & Ivan D. Horak

  2. Garden State Cancer Center, Center for Molecular Medicine and Immunology, Belleville, NJ, USA

    Rhona Stein, Susan Chen, Philip Andrews & David M. Goldenberg

Authors
  1. Serengulam V. Govindan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Rhona Stein
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Zhengxing Qu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Susan Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Philip Andrews
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Hong Ma
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Hans J. Hansen
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Gary L. Griffiths
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Ivan D. Horak
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. David M. Goldenberg
    View author publications

    You can also search for this author in PubMed Google Scholar

Additional information

These authors contributed equally

Rights and permissions

Reprints and permissions

About this article

Cite this article

Govindan, S.V., Stein, R., Qu, Z. et al. Preclinical Therapy of Breast Cancer with a Radioiodinated Humanized Anti-EGP-1 Monoclonal Antibody: Advantage of a Residualizing Iodine Radiolabel. Breast Cancer Res Treat 84, 173–182 (2004). https://doi.org/10.1023/B:BREA.0000018417.02580.ef

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/B:BREA.0000018417.02580.ef

Search

Navigation