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Immuno-Therapy

Radioimmunotherapy for model B cell malignancies using 90Y-labeled anti-CD19 and anti-CD20 monoclonal antibodies

Abstract

In recent years, radioimmunotherapy (RIT) with β particle emitting radionuclides targeting the CD20 antigen on B cells in the treatment of non-Hodgkin's lymphoma has provided the most compelling human clinical data for the success of RIT. CD19, like CD20, is an antigen expressed on the surface of cells of the B lineage, and CD19 may provide an alternative target for radioimmunotherapy of B cell neoplasms. CD19 has been largely overlooked as a target for conventional 131I RIT, because the antigen rapidly internalizes upon binding of antibody, resulting in catabolism and significant release of 131I. Such modulation may be an advantage to RIT with radiometals such as 90Y, 177Lu, 213Bi and 225Ac. Herein, we have compared β particle RIT with antibodies targeting either CD19 or CD20. The anti-CD19 and anti-CD20 antibodies, B4 or C2B8, respectively, were appended with the SCN-CHX-A”-DTPA bifunctional chelating agent and labeled with 90Y. In the tumor model used, there were three times as many CD20 target sites on lymphoma cells as compared to CD19 sites (62000 vs 20000 binding sites, respectively). We compared the efficacy of the 90Y-labeled antibodies to reduce lymphoma in a nude mouse xenograft solid tumor model, after measurable lymphoma appeared. Reduction in tumor size began at day 3 in all three 90Y-treated groups, but tumor began to recur in many animals 9 days after the treatments. There was one cure in each specific treatment group. In contrast, the tumor in the two control groups showed no regression. There was a significant prolongation of median survival time from xenograft (P < 0.0001) in all the 90Y-labeled antibody construct-treated groups (32 days for 0.15 mCi 90Y-B4; 26 days for 0.20 mCi 90Y-C2B8, and 23 days for 0.15 mCi 90Y-C2B8) in comparison to the two control groups (11 days for 0.02 mg of C2B8 and 9 days for untreated growth controls). Specificity of the radioimmunotherapy was also shown. In conclusion, 90Y-labeled anti-CD19 antibody has efficacy comparable to 90Y-labeled anti-CD20 antibody in the treatment of mice bearing human lymphoma xenografts. These data suggest that CD19-targeted RIT merits further study.

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References

  1. Press OW . Emerging immunotherapies for non-Hodgkin lymphoma: the tortoise approaches the finish line Ann Intern Med 2000 132: 916–918

    Article  CAS  Google Scholar 

  2. Denardo SJ, Kroger LA, Denardo GL . A new era for radiolabeled antibodies in cancer Curr Opin Immunol, 1999 11: 563–569

    Article  CAS  Google Scholar 

  3. Kaminski MS, Gribbin T, Estes J, Ross CW, Regan D, Zasadny K, Tamminen J, Kison P, Tuck M, Fisher S . I-131 anti-B1 antibody for previously untreated follicular lymphoma (FL): clinical and molecular remissions Proc Am Soc Clin Oncol 1998 17: 2

    Google Scholar 

  4. Knox SJ, Goris ML, Trisler K, Negrin R, Davis T, Liles TM, Grillo-Lopez A, Chinn P, Varns C, Ning SC, Fowler S, Deb N, Becker M, Marquez C, Levy R . Yttrium-90-labeled anti-CD20 monoclonal antibody therapy of recurrent B-cell lymphoma Clin Cancer Res 1996 2: 457–470

    CAS  PubMed  Google Scholar 

  5. DeNardo SJ, Denardo GI, Goldstein DS, Kroger LA, Lamborn KR, Levey NB, McGahan JP, Salako Q, Shen S, Lewis JP . Maximum tolerated dose, toxicity, and efficacy of I-131-Lym-1 antibody for fractionated radioimmunotherapy of non-Hodgkin's lymphoma J Clin Oncol 1998 16: 3246–3256

    Article  CAS  Google Scholar 

  6. White CA, Halpern SE, Parker BA, Miller RA, Hupf HB, Shawler DL, Collins HA, Royston I . Radioimmunotherapy of relapsed B-cell lymphoma with yttrium-90 anti-idiotype monoclonal antibodies Blood 1996 87: 3640–3649

    CAS  PubMed  Google Scholar 

  7. Press OW, Eary JF, Appelbaum FR, Martin PJ, Badger CC, Nelp WB, Glenn S, Butchko G, Fisher DR, Porter B, Matthews DC, Fisher LD, Berstein ID . Radiolabeled antibody therapy of B cell lymphoma with autologous bone marrow support N Engl J Med 1993 329: 1219–1224

    Article  CAS  Google Scholar 

  8. Kaminski MS, Zasadny KR, Francis IR, Milik AW, Ross CW, Moon SD, Crawford SM, Burgess JM, Petry NA, Butchko GM, Glenn SD, Wahl RL . Radioimmunotherapy of B-cell lymphoma with I-131 anti-B1 (anti-CD20) antibody N Engl J Med 1993 329: 459–465

    Article  CAS  Google Scholar 

  9. Vose JM . Colcher D. Gobar L. Bierman PJ. Augustine S. Tempero M. Leichner P. Lynch JC. Goldenberg D. Armitage JO. Phase I/II trial of multiple dose Iodine-131-MAb LL2 (CD22) in patients with recurrent non-Hodgkin's lymphoma Leuk Lymphoma 2000 38: 91–101

    Article  CAS  Google Scholar 

  10. Scheurmann RH, Racila E . CD19 antigen in leukemia and lymphoma diagnosis and immunotherapy Leuk Lymphoma 1995 18: 385–397

    Article  Google Scholar 

  11. Scheinberg DA, Strand M . Kinetic and catabolic considerations of monoclonal antibody targeting in erythroleukemic mice Cancer Res 1983 43: 265–272

    CAS  PubMed  Google Scholar 

  12. Press OW, Shan D, Howell-Clark J, Eary J, Appelbaum FR, Matthews D, King DJ, Haines AMR, Hamann P, Hinman L, Shochat D, Bernstein ID . Comparative metabolism and retention of Iodine-125, Yttrium-90, and Indium-111 radioimmunoconjugates by cancer cells Cancer Res 1996 56: 2123–2129

    CAS  PubMed  Google Scholar 

  13. Juweid ME, Stadtmauer E, Hajjar G, Sharkey RM, Suleiman S, Luger S, Swayne LC, Alavi A, Goldenberg DM . Pharmacokinetics, dosimetry, and initial therapeutic results with I-131 and In-111/Y-90 labeled humanized LL2 anti-CD22 monoclonal antibody in patients with relapsed, refractory non-Hodgkin's lymphoma Clin Cancer Res 1999 5: 3292s–3303s

    CAS  PubMed  Google Scholar 

  14. Hooijberg E, Sein JJ, van den Berk PCM, Hart AAM, van der Valk MA, Kast WM, Melief CJM, Kekman A . Eradication of large human B cell tumors in nude mice with unconjugated CD20 monoclonal antibodies and interleukin 2 Cancer Res 1995 55: 2627–2634

    CAS  PubMed  Google Scholar 

  15. Davis TA, Czerwinski DK, Levy R . Therapy of B-cell lymphoma with anti-CD20 antibodies can result in the loss of CD20 antigen expression Clin Cancer Res 1999 5: 611–615

    CAS  PubMed  Google Scholar 

  16. Buchsbaum DJ, Wahl RL, Normolle DP, Kaminski MS . Therapy with unlabeled and I-131 labeled Pan-B-cell monoclonal antibodies in nude mice bearing Raji Burkitt's lymphoma xenografts Cancer Res 1992 52: 6476–6481

    CAS  PubMed  Google Scholar 

  17. Wei BR, Ghetie MA, Vitetta ES . The combined use of an immunotoxin and a radioimmunoconjugate to treat disseminated human B-cell lymphoma in immunodeficient mice Clin Cancer Res 2000 6: 631–642

    CAS  PubMed  Google Scholar 

  18. Caron PC, Sung Co M, Bull MK, Avdalovic NM, Queen C, Scheinberg DA . Biological and immunological features of humanized M195 (anti-CD33) monoclonal antibodies Cancer Res 1992 52: 6761–6767

    CAS  PubMed  Google Scholar 

  19. Brechbiel MW, Gansow OA . Synthesis of C-functionalised transcyclohexyldiethylenetriaminepentaacetic acids for labeling of monoclonal antibodies with the bismuth-212 a-particle emitter J Chem Soc Perkin Trans I 1992 1173–1178

  20. Nikula TK, Curcio MJ, Brechbiel MW, Gansow OA, Finn RD, Scheinberg DA . A rapid, single vessel method for preparation of clinical grade ligand conjugated monoclonal antibodies Nucl Med Bio 1995 22: 387–390

    Article  CAS  Google Scholar 

  21. Pippin CG, Parker TA, McMurry TJ, Brechbiel MW . Spectrophotometric method for the determination of a bifuctional DTPA ligand in DTPA-monoclonal antibody conjugates Bioconjugate Chem 1992 3: 342–345

    Article  CAS  Google Scholar 

  22. Gates VL, Carey JE, Siegel JA, Kaminski MS ., Wahl RL. Nonmyeloabaltive Iodine-131 anti-B1 radioimmunotherapy as outpatient therapy J Nucl Med 1998 39: 1230–1236

    CAS  PubMed  Google Scholar 

  23. Liu SY, Eary JF, Petersdorf SH, Matin PJ, Maloney DG, Appelbaum FR, Matthews DC, Bush SA, Durack LD, Fisher DR, Gooley TA, Bernstein ID, Press OW . Follow-up of relapsed B-cell lymphoma patients treated with Iodine-131-labeled anti-CD20 antibody and autologous stem-cell rescue J Clin Oncol 1998 16: 3270–3278

    Article  CAS  Google Scholar 

  24. Vervoordeldonk SF, Heikens J, Goedemans WT, Merle PA, non dem Borne AE, van Royen EA, Slaper-Cortenbach IC, van Oers RH . 99mTc-CD19 monoclonal antibody is not useful for imaging of B cell non-Hodgkin's lymphoma Cancer Immunol Immunother 1996 42: 291–296

    Article  CAS  Google Scholar 

  25. Vervoordeldonk SF, Merle PA, van Leeuwen EF, van der Schoot CE, von dem Borne AE, Slaper-Cortenbach IC . Fc gamma receptor II (CD32) on malignant B cells influences modulation induced by anti-CD19 monoclonal antibody Blood 1994 83: 1632–1639

    CAS  PubMed  Google Scholar 

  26. Vervoordeldonk SF, Balkenende AY, van den Berg H, von dem Borne AE, van der Schoot CE, van Leeuwen EF, Slaper-Cortenbach IC . Degradation of radioiodinated B cell monoclonal antibodies: inhibition via a FC gamma receptor II mediated mechanism and by drugs Cancer Immunol Immunother 1996 42: 24–30

    Article  CAS  Google Scholar 

  27. Sharky RM, Behr TM, Mattes MJ, Stein R, Griffiths GL, Shih LB, Hansen HJ, Blumenthal RD, Dunn RM, Juweid ME, Goldenberg DM . Advantage of residualizing radiolabels for an internalizing antibody against the B-cell lymphoma antigen, CD22 Cancer Immunol Immunother 1997 44: 179–188

    Article  Google Scholar 

  28. Johnson TA, Press OW . Therapy of B-cell lymphomas with monoclonal antibodies and radioimmunoconjugates: the Seattle experience Ann Hematol 2000 79: 175–182

    Article  CAS  Google Scholar 

  29. Carrasquillo JA, White JD, Paik CH, Raubitschek A, Le N, Rotman M, Brechbiel MW, Gansow OA, Top LE, Perentesis P, Reynolds JC, Nelson DL, Waldmann TA . Similarities and differences in In-111 and Y-90-labeled 1B4M-DTPA anti-Tac monoclonal antibody distribution J Nucl Med 1999 40: 268–276

    CAS  PubMed  Google Scholar 

  30. Multani PS, O'Day S, Nadler LE, Grossbard ML . Phase II clinical trial of bolus infusion anti-B4 blocked ricin immunoconjugate in patients with relapsed B-cell non-Hodgkin's lymphoma Clin Cancer Res 1998 4: 2599–2604

    CAS  PubMed  Google Scholar 

  31. Herrera L, Farah RA, Pellegrini VA, Aquino DB, Sandler ES, Buchanan GR, Vitetta ES . Immunotoxins against CD19 and CD22 are effective in killing precursor-B acute lymphoblastic leukemia cells in vitro Leukemia 2000 14: 853–858

    Article  CAS  Google Scholar 

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Acknowledgements

We thank Immunogen, Inc. for making B4 available to us for use in this study and Dr Paul Borchardt for helpful discussions. This work was supported in part by grants from the Cure for Lymphoma Foundation, the Gabrielle Rich Foundation, the Lymphoma Foundation, and NIH PO1 CA33049. Dr Dangshe Ma is a King Hussein Memorial Fellow of the Cure for Lymphoma Foundation. Dr David Scheinberg is a Doris Duke Distinguished Clinical Science Professor.

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Ma, D., McDevitt, M., Barendswaard, E. et al. Radioimmunotherapy for model B cell malignancies using 90Y-labeled anti-CD19 and anti-CD20 monoclonal antibodies. Leukemia 16, 60–66 (2002). https://doi.org/10.1038/sj.leu.2402320

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