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European Journal of Nuclear Medicine and Molecular Imaging

Published in:

01-07-2008 | Original Article

Therapy of human carcinoma xenografts with antibodies to EGFr and HER-2 conjugated to radionuclides emitting low-energy electrons

Authors: M. Jules Mattes, David M. Goldenberg

Published in: European Journal of Nuclear Medicine and Molecular Imaging | Issue 7/2008

Abstract

Purpose

Low-energy electrons (10–50 keV) can be effective and specific cytotoxic agents when delivered to the cell surface by antibodies, because their path length in tissue is comparable to a cell diameter. In this study, we have begun to evaluate the therapeutic potential of antibodies (Abs) conjugated to ¹¹¹In against carcinoma xenografts in nude mice.

Methods

Abs to EGFr or HER-2 were labeled with ¹¹¹In to a high specific activity of approximately 1.48 GBq/mg (40 mCi/mg). They were injected into nude mice 5–6 days after inoculation of human carcinoma cells, either A431 or SK-OV-3, and tumor growth was monitored. In preliminary in vitro experiments, we calculated the cumulative decays per cell, estimated the centigray dose delivered to the nucleus, and related this to the fraction surviving.

Results

Abs to both antigens provided significant protection in nude mouse xenograft models (p values ranging from <0.05 to <0.001). Some mice appeared to be cured, but most had delayed tumor growth. The specificity of the effect was demonstrated by testing non-reactive Abs labeled in the same way. The radioactivity was required, because unconjugated Abs had no therapeutic effect. The maximum tolerated dose was required in order for therapy to be effective, but most of the treated mice had no significant weight loss or other overt signs of toxicity.

Conclusion

Abs labeled with nuclides emitting low-energy electrons, such as ¹¹¹In, can be effective therapeutic agents against microscopic s.c. tumors. This strategy should be considered for clinical applications.

Ong GL, Elsamra SE, Goldenberg DM, Mattes MJ. Single-cell cytotoxicity with radiolabeled antibodies. Clin Cancer Res 2001;7:192–201.PubMed

Michel RB, Castillo ME, Andrews PM, Mattes MJ. In vitro toxicity of A-431 carcinoma cells with antibodies to EGFr and EGP-1 conjugated to radionuclides emitting low-energy electrons. Clin Cancer Res 2004;10:5957–66.PubMedCrossRef

Michel RB, Andrews PM, Castillo ME, Mattes MJ. In vitro cytotoxicity of carcinoma cells with ¹¹¹In-labeled antibodies to HER-2. Mol Cancer Ther 2005;4:927–37.PubMedCrossRef

Michel RB, Rosario AV, Andrews PM, Goldenberg DM, Mattes MJ. Therapy of small s.c. B-lymphoma xenografts with antibodies conjugated to radionuclides emitting low-energy electrons. Clin Cancer Res 2005;11:777–86.PubMed

Goddu SM, Howell RW, Bouchet LG, Bolch WE, Rao DV. MIRD cellular S values. Reston, VA: Society of Nuclear Medicine; 1997.

Michel RB, Brechbiel MW, Mattes MJ. A comparison of four radionuclides conjugated to antibodies for single-cell kill. J Nucl Med 2003;44:632–40.PubMed

Behr TM, Béhé M, Löhr M, Sgouros G, Angerstein C, Wehrmann E, et al. Therapeutic advantage of Auger electron- over β-emitting radiometals or radioiodine when conjugated to internalizing antibodies. Eur J Nucl Med 2000;27:753–65.PubMedCrossRef

Bender H, Takahashi H, Adachi K, Belser P, Liang S, Prewett M, et al. Immunotherapy of human glioma xenografts with unlabeled, ¹³¹I-, or ¹²⁵I-labeled monoclonal antibody 425 to epidermal growth factor receptor. Cancer Res 1992;52:121–6.PubMed

Ochakovskaya R, Osorio L, Goldenberg D, Mattes M. Therapy of disseminated B-cell lymphoma xenografts in SCID mice with an anti-CD74 antibody conjugated with ¹¹¹In, ⁶⁷Ga, or ⁹⁰Y. Clin Cancer Res 2001;7:1505–10.PubMed

10.

Brady L, Miyamoto C, Woo DV, Rackover M, Emrich J, Bender H, et al. Malignant astrocytomas treated with iodine-125 labeled monoclonal antibody 425 against epidermal growth factor receptor: a phase II trial. Int J Radiat Oncol Biol Phys 1992;22:225–30.PubMed

11.

Welt S, Scott AM, Divgi CR, Kemeny NE, Finn RD, Daghighian F, et al. Phase I/II study of iodine 125-labeled monoclonal antibody A33 in patients with advanced colon cancer. J Clin Oncol 1996;14:1787–97.PubMed

12.

Shih LB, Thorpe SR, Griffiths GL, Diril H, Ong GL, Hansen HJ, et al. 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 1994;35:899–908.PubMed

13.

Mendelsohn J, Baselga J. The EGF receptor family as targets for cancer therapy. Oncogene 2000;19:6550–65.PubMedCrossRef

14.

Ross JS, Fletcher JA. HER-2/neu (c-erb-B2) gene and protein in breast cancer. Am J Clin Pathol 1999;112:S53–67.PubMed

15.

Stein R, Goldenberg DM, Thorpe SR, Basu A, Mattes MJ. Effects of radiolabeling monoclonal antibodies with a residualizing iodine radiolabel on the accretion of radioisotope in tumors. Cancer Res 1995;55:3132–9.PubMed

16.

Michel RB, Ochakovskaya R, Mattes MJ. Rapid blood clearance of injected mouse IgG2a in SCID mice. Cancer Immunol Immunother 2002;51:547–56.PubMedCrossRef

17.

Michel RB, Ochakovskaya R, Mattes MJ. Antibody localization to B-cell lymphoma xenografts in immunodeficient mice: importance of using residualizing radiolabels. Clin Cancer Res 2002;8:2632–9.PubMed

18.

Bleeker WK, van Bueren JJL, van Ojik HH, Gerritsen AF, Pluyter M, Houtkamp M, et al. Dual mode of action of a human anti-epidermal growth factor receptor monoclonal antibody for cancer therapy. J Immunol 2004;173:4699–707.PubMed

19.

Spiridon CI, Guinn S, Vitetta ES. A comparison of the in vitro and in vivo activities of IgG and F(ab’)₂ fragments of a mixture of three monoclonal anti-HER-2 antibodies. Clin Cancer Res 2004;10:3542–51.PubMedCrossRef

20.

Michel RB, Andrews PM, Rosario AV, Goldenberg DM, Mattes MJ. ¹⁷⁷Lu-antibody conjugates for single cell kill of B-lymphoma cells in vitro and for therapy of micrometastases in vivo. Nucl Med Biol 2005;32:269–78.PubMedCrossRef

21.

McDevitt MR, Ma D, Lai LT, Simon J, Borchardt P, Frank RK, et al. Tumor therapy with targeted atomic nanogenerators. Science 2001;294:1537–40.PubMedCrossRef

22.

Zalutsky MR, Zhao X-G, Alston KL, Bigner D. High-level production of a-particle-emitting ²¹¹At and preparation of ²¹¹At-labeled antibodies for clinical use. J Nucl Med 2001;42:1508–15.PubMed

23.

Kozak RW, Atcher RW, Gansow OA, Friedman AM, Hines JJ, Waldmann TA. Bismuth-212-labeled anti-TAC monoclonal antibody: α-particle-emitting radionuclides as modalities for radioimmunotherapy. Proc Natl Acad Sci U S A 1986;83:474–8.PubMedCrossRef

24.

Hall EJ. Radiation dose-rate: a factor of importance in radiobiology and radiotherapy. Br J Radiol 1972;45:81–97.PubMedCrossRef

25.

Hu M, Chen P, Wang J, Chan C, Scollard DA, Reilly RM. Site-specific conjugation of HIV-1 tat peptides to IgG: a potential route to construct radioimmunoconjugates for targeting intracellular and nuclear epitopes in cancer. Eur J Nucl Med Mol Imaging 2006;33:301–10.PubMedCrossRef

26.

Govindan SV, Goldenberg DM, Elsamra SE, Griffiths GL, Ong GL, Brechbiel MW, et al. Radionuclides linked to a CD74 antibody as therapeutic agents for B-cell lymphoma: comparison of Auger electron emitters with β-particle emitters. J Nucl Med 2000;41:2089–97.PubMed

27.

De Santes K, Slamon D, Anderson SK, Shepard M, Fendly B, Maneval D, et al. Radiolabeled antibody targeting of the HER-2/neu oncoprotein. Cancer Res 1992;52:1916–23.PubMed

28.

Adams GP, Shaller CC, Dadachova E, Simmons HH, Horak EM, Tesfaye A, et al. A single treatment of yttrium-90-labeled CHX-A"-C6.5 diabody inhibits the growth of established human tumor xenografts in immunodeficient mice. Cancer Res 2004;64:6200–06.PubMedCrossRef

29.

Persson M, Gedda L, Lundqvist H, Tolmachev V, Nordgren H, Malmström P-U, et al. [¹⁷⁷Lu]Pertuzumab: experimental therapy of HER-2-expressing xenografts. Cancer Res 2007;67:326–31.PubMedCrossRef

30.

Horak E, Hartmann F, Garmestani K, Wu C, Brechbiel M, Gansow OA, et al. Radioimmunotherapy targeting of HER2/neu oncoprotein on ovarian tumor using lead-212-DOTA-AE1. J Nucl Med 1997;38:1944–50.PubMed

31.

Adams GP, Shaller CC, Chappell LL, Wu C, Horak EM, Simmons HH, et al. Delivery of the α-emitting radioisotope bismuth-213 to solid tumors via single-chain Fv and diabody molecules. Nucl Med Biol 2000;27:339–46.PubMedCrossRef

32.

Borshardt PE, Yuan RR, Miederer M, McDevitt MR, Scheinberg DA. Targeted actinium-225 in vivo generators for therapy of ovarian cancer. Cancer Res 2003;63:5084–90.

33.

Valkema R, de Jong M, Bakker WH, Breeman WA, Kooij PP, Lugtenburg PJ, et al. Phase I study of peptide receptor radionuclide therapy with [In-DTPA]octreotide: the Rotterdam experience. Semin Nucl Med 2002;32:110–22.PubMedCrossRef

34.

Anthony LB, Woltering EA, Espenan GD, Cronin MD, Maloney TJ, McCarthy KE. Indium-111-pentetreotide prolongs survival in gastroenteropancreatic malignancies. Semin Nucl Med 2002;32:123–32.PubMedCrossRef

35.

Capello A, Krenning EP, Breeman WA, Bernard BF, de Jong M. Peptide receptor radionuclide therapy in vitro using [¹¹¹In-DTPA⁰]octreotide. J Nucl Med 2003;44:98–104.PubMed

36.

Xu F, Lupu R, Rodriguez GC, Whitaker RS, Boente MP, Berchuck A, et al. Antibody-induced growth inhibition is mediated through immunochemically and functionally distinct epitopes on the extracellular domain of the c-erbB-2 (HER-2/neu) gene product p185. Int J Cancer 1993;53:401–8.PubMedCrossRef

37.

Govindan SV, Michel RB, Griffiths GL, Goldenberg DM, Mattes MJ. Deferoxamine as a chelator for ⁶⁷Ga in the preparation of antibody conjugates. Nucl Med Biol 2005;32:513–9.PubMedCrossRef

38.

Steiner L, Blumberg PM. Mercury derivatives of the Fab and Fc fragments of a human myeloma protein. Biochemistry 1971;10:4725–39.PubMedCrossRef

39.

Goldenberg A, Masui H, Divgi C, Kamrath H, Pentlow K, Mendelsohn J. Imaging of human tumor xenografts with an indium-111-labeled anti-epidermal growth factor receptor monoclonal antibody. J Natl Cancer Inst 1989;81:1616–25.PubMedCrossRef

40.

Stein R, Goldenberg DM, Ong GL, Thorpe ST, Mattes MJ. Manipulation of blood clearance to optimize delivery of residualizing label-antibody conjugates to tumor cells in vivo. J Nuclear Med 1997;38:1392–400.

41.

Genentech. Herceptin prescription information. 2003

Title: Therapy of human carcinoma xenografts with antibodies to EGFr and HER-2 conjugated to radionuclides emitting low-energy electrons
Authors: M. Jules Mattes
David M. Goldenberg
Publication date: 01-07-2008
Publisher: Springer-Verlag
Published in: European Journal of Nuclear Medicine and Molecular Imaging / Issue 7/2008
Print ISSN: 1619-7070
Electronic ISSN: 1619-7089
DOI: https://doi.org/10.1007/s00259-008-0731-3

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Therapy of human carcinoma xenografts with antibodies to EGFr and HER-2 conjugated to radionuclides emitting low-energy electrons

Abstract

Purpose

Methods

Results

Conclusion

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Purpose

Methods

Results

Conclusion

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