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Molecular Imaging and Contrast Agent Database (MICAD) [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2004-2013.

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Molecular Imaging and Contrast Agent Database (MICAD) [Internet].

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111In-Ibritumomab tiuxetan

111In-2B8 MAb

Created: ; Last Update: September 26, 2007.

Chemical name:111In-Ibritumomab tiuxetan
Abbreviated name:111In-2B8 MAb
Synonym:111In-Zevalin®, 111In-anti-CD20 antibody, 111In-IDEC-2B8 MAb
Agent Category:Antibody
Target:CD20 antigen on B-cell non-Hodgkin’s lymphoma
Target Category:Antibody-antigen binding
Method of detection:Single-photon emission computed tomography (SPECT), planar gamma imaging
Source of signal:111In
Activation:No
Studies:
  • Checkbox In vitro
  • Checkbox Rodents
  • Checkbox Non-human primates
  • Checkbox Humans
Click on protein, nucleotide (RefSeq), and gene for more information about CD20.

Background

[PubMed]

111In-Ibritumomab tiuxetan (111In-2B8) is an immunoconjugate of a murine anti-CD20 monoclonal antibody (MAb) that is chelated to 111In for imaging of lymphoid malignancies (1-3). It was approved in the United States in 2002 as a required imaging component of the 90Y-ibritumomab tiuxetan therapeutic regimen for the treatment of patients with relapsed or refractory low-grade, follicular, or transformed B-cell non-Hodgkin’s lymphoma (NHL), including patients with rituximab-refractory follicular NHL (4). 111In is a gamma emitter with a physical half-life (t½) of 2.8 days.

The CD20 antigen (Bp35) is a 35-kDa, cell-surface nonglycosylated, hydrophobic phosphoprotein expressed on normal and malignant B-cells, and it does not shed, modulate, or internalize (5-8). It is a transmembrane protein that acts as a calcium channel and plays an important role in cell cycle progression and differentiation of B cells. CD20 is present on approximately 9% of the peripheral blood mononuclear cell fraction and >90% of B-cells from blood and lymphoid organs. Lymphoma cells from >90% of patients with B-cell NHL express this antigen. CD20 is not expressed on uncommitted hematopoietic precursor stem cells. When antibodies bind to this antigen, they induce apoptosis, antibody-dependent cellular cytotoxicity, and complement-dependent cytotoxicity of lymphoma cells. Despite the presence of CD20 on normal B cells, it appears to be a good tumor target for molecular targeting with antibodies for the management of NHL.

Radiolabeled MAbs have been developed for both diagnosis and therapy of tumors (5, 9, 10). Ibritumomab was developed as an anti-CD20 MAb and was characterized by Reff et al. (11). A chimeric 2B8 MAb was constructed and later developed as an United States Food and Drug Administration-approved drug, rituximab (unlabeled MAb), for NHL therapy. Developed from the same 2B8 mouse hybridoma, ibritumomab is an intact murine IgG1a kappa MAb composed of two murine gamma 1 heavy chains (445 amino acids each) and two kappa light chains (213 amino acids each). With the use of tiuxetan (MX-DTPA) as the linker-chelator, 111In can be stably linked to ibritumomab for imaging (4, 11, 12). Alternatively, 90Y, a pure beta emitter, can be similarly linked to ibritumomab for therapy. MX-DTPA forms a stable covalent urea-type bond with the antibody and chelates the radionuclide via five carboxyl groups and three amino groups (13). Ibritumomab tiuxetan has an approximate molecular mass of 148 kDa. In the Food and Drug Administration approved protocol for the 90Y-ibritumomab tiuxetan therapeutic regimen, 250 mg/m2 rituximab is given to the patient before the radioactive dose of 185 MBq (5 mCi)/1.6 mg to minimize uptake of 111In-2B8 by normal tissue and blood mononuclear cells. An 111In-2B8 MAb scan is performed 48-72 h after administration to detect altered biodistribution of the radiolabeled MAb.

The commercial kit for the preparation of 111In-ibritumomab tiuxetan contains 3.2 mg/2 ml ibritumomab tiuxetan in 0.9% sodium chloride solution (4).

Synthesis

[PubMed]

2B8 MAb was synthesized based on the hybridoma technique developed by Kohler and Milstein (14, 15). BALB/c mice were immunized with the human lymphoblastoid cell line SB (4, 16). Spleens were isolated from mice with high serum titers of anti-CD20 antibodies, and the splenocytes were fused with the mouse myeloma SP2/0. Brechbiel and Gansow (12) synthesized the MX-DTPA [2-(p-isothiocyanatobenzyl)-6-methyldiethylenetriaminepentaacetic acid] chelator by substituting a 4-isothiocyanatobenzyl group onto the carbon backbone of DTPA. Methyl groups were strategically incorporated onto the backbone of the ligand via a peptide synthesis route. In the commercial preparation, 203.5 MBq (5.5 mCi) of 111In chloride buffered by 50 mM sodium acetate (1.5 times the volume of 111In chloride) is reacted with 1.6 mg/ml 2B8 MAb for 30 min. A formulation buffer containing human albumin is used to terminate the reaction and to protect the radiolabeled product from radiolysis (4).

In Vitro Studies: Testing in Cells and Tissues

[PubMed]

Chinn et al. (16) used flow cytometry to show that 2B8 MAb was specific for B cells and did not react with other T cells, monocytes, and macrophages. 111In-2B8 MAb was prepared with a specific activity (sa) of 111 MBq/mg (3 mCi/mg) and it exhibited no apparent loss of immunoreactivity compared with the unlabeled 2B8 MAb. An in vitro stability study indicated that the immunoreactivity was retained for incubation times up to 48 h at 4oC. The apparent affinity (Kd) of ibritumomab tiuxetan for CD20 was 14-18 nM (4).

Animal Studies

Rodents

[PubMed]

The biodistribution of 37 kBq (1 µCi) of 111In-2B8 MAb with a specific activity of 111 MBq/mg (3 mCi/mg) in mice was determined by Chinn et al. (16). The highest level of radioactivity was in the blood and decreased from 40.3 ± 5.3% injected dose (ID)/g (n = 5) at 1 h to 19% ID/g at 72 h. The lungs and liver had the next highest levels with 14.2 ± 1.4% ID/g and 10.3 ± 1.6% ID/g at 1 h, respectively, which decreased to 7.6 ± 0.3% ID/g and 9.9 ± 1.8% ID/g at 72 h, respectively. The localization of 617.9 kBq (16.7 µCi) of 111In-2B8 MAb in athymic mice (n = 3) bearing Ramos B cell tumors showed that the radioactivity in the tumor steadily increased from 0.5 ± 0.2% ID/g at 1 h to 13.4 ± 1.0% ID/g at 72 h, and the tumor/muscle ratio increased from 1.5 ± 0.6 at 1 h to 20.6 ± 7.2 at 72 h.

Other Non-Primate Mammals

[PubMed]

No publication is currently available.

Non-Human Primates

[PubMed]

No publication is currently available.

Human Studies

[PubMed]

In a Phase III trial of 90Y-2B8 MAb therapy, patients with histologically confirmed, relapsed or refractory low-grade, follicular, or transformed CD20+ B-cell NHL received an infusion of 250 mg/m2 rituximab and then an imaging dose of 185 MBq (5 mCi) of 111In-2B8 MAb (13). The median biological blood t½ of the antibody was 47 h and the median blood residence time was 26 h. The fraction of injected radioactivity excreted in urine over 7 days was estimated to be 8.3%. In another study, 111In-2B8 MAb detected 56% and 92% of known tumor sites when the patients were pretreated with unlabeled 2B8 MAb doses of 1.0 and 2.5 mg/kg, respectively (4). In comparison, only 18% of known sites of disease were detected when no unlabeled 2B8 MAb was administered.

The dosimetry of 111In-2B8 MAb has been estimated with use of sequential whole body images and the MIRDOSE 3 software program (13, 17). The distribution of 111In-2B8 MAb showed moderately high radioactivity in the liver and spleen, and relatively low radioactivity in the kidneys, urinary bladder and bowel. The spleen received the highest absorbed radiation dose, 0.9 mGy/MBq (3333 mrad/mCi), and the bone marrow received 0.2 mGy/MBq (741 mrad/mCi). The liver received the second highest dose, 0.7 mGy/MBq (2590 mrad/mCi), and both the lower large intestinal wall and the heart wall received 0.4 mGy/MBq (1481 mrad/mCi). The urinary bladder wall and the kidneys received only 0.2 mGy/MBq (741 mrad/mCi).

Conti et al. (18) reported the results of the 111In-2B8 MAb imaging registry as a component of the 90Y-2B8 MAb therapy for 953 patients who were treated between March 2002 and March 2003. Altered biodistribution was reported in <0.6% of cases and involved mostly prominent bone marrow uptake. In these cases, imaging appeared to help prevent the delivery of excessive radiation to the bone marrow.

Various other studies have been published on the dosimetry and efficacy of the therapeutic application of treating NHL with 90Y-2B8 MAb [PubMed].

References

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Ibritumomab tiuxetan (Zevalin) for non-Hodgkin's lymphoma. Med Lett Drugs Ther. 2002;44(1144):101–102. [PubMed: 12494494]
2.
Targeted treatment for non-Hodgkin's lymphoma. Health News. 2002;8(5):7. [PubMed: 12132412]
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First radiopharmaceutical for non-Hodgkin's lymphoma. FDA Consum. 2002;36(3):3. [PubMed: 12085807]
4.
Zevalin. Ibritumomab tiuxetan. Prescribing Information. biogen idec, 2005. 3-1074-247: p. 1-11.
5.
Hainsworth JD. Monoclonal antibody therapy in lymphoid malignancies. Oncologist. 2000;5(5):376–384. [PubMed: 11040273]
6.
Tobinai K. Rituximab and other emerging monoclonal antibody therapies for lymphoma. Expert Opin Emerg Drugs. 2002;7(2):289–302. [PubMed: 15989552]
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Tobinai K. Rituximab and other emerging antibodies as molecular target-based therapy of lymphoma. Int J Clin Oncol. 2003;8(4):212–223. [PubMed: 12955576]
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Zelenetz AD. A clinical and scientific overview of tositumomab and iodine I 131 tositumomab Semin Oncol 2003. 30(2) Suppl 4 22–30. [PubMed: 12728404]
9.
Kowalsky RJ, Falen SW. 2004.
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Wu AM, Senter PD. Arming antibodies: prospects and challenges for immunoconjugates. Nat Biotechnol. 2005;23(9):1137–1146. [PubMed: 16151407]
11.
Reff ME, Carner K, Chambers KS, Chinn PC, Leonard JE, Raab R, Newman RA, Hanna N, Anderson DR. Depletion of B cells in vivo by a chimeric mouse human monoclonal antibody to CD20. Blood. 1994;83(2):435–445. [PubMed: 7506951]
12.
Brechbiel MW, Gansow OA. Backbone-substituted DTPA ligands for 90Y radioimmunotherapy. Bioconjugate Chem. 1991;2:187–194. [PubMed: 1932218]
13.
Wiseman GA, White CA, Sparks RB, Erwin WD, Podoloff DA, Lamonica D, Bartlett NL, Parker JA, Dunn WL, Spies SM, Belanger R, Witzig TE, Leigh BR. Biodistribution and dosimetry results from a phase III prospectively randomized controlled trial of Zevalin radioimmunotherapy for low-grade, follicular, or transformed B-cell non-Hodgkin's lymphoma. Crit Rev Oncol Hematol. 2001;39(1-2):181–194. [PubMed: 11418315]
14.
Kohler G, Milstein C. Continuous cultures of fused cells secreting antibody of predefined specificity. Nature. 1975;256(5517):495–497. [PubMed: 1172191]
15.
Stashenko P, Nadler LM, Hardy R, Schlossman SF. Characterization of a human B lymphocyte-specific antigen. J Immunol. 1980;125(4):1678–1685. [PubMed: 6157744]
16.
Chinn PC, Leonard JE, Rosenberg J, Hanna N, Anderson DR. Preclinical evaluation of 90Y-labeled anti-CD20 monoclonal antibody for treatment of non-Hodgkin's lymphoma. Int J Oncol. 1999;15(5):1017–1025. [PubMed: 10536187]
17.
Wiseman GA, White CA, Stabin M, Dunn WL, Erwin W, Dahlbom M, Raubitschek A, Karvelis K, Schultheiss T, Witzig TE, Belanger R, Spies S, Silverman DH, Berlfein JR, Ding E, Grillo-Lopez AJ. Phase I/II 90Y-Zevalin (yttrium-90 ibritumomab tiuxetan, IDEC-Y2B8) radioimmunotherapy dosimetry results in relapsed or refractory non-Hodgkin's lymphoma. Eur J Nucl Med. 2000;27(7):766–777. [PubMed: 10952488]
18.
Conti PS. Radioimmunotherapy with yttrium 90 ibritumomab tiuxetan (Zevalin): the role of the nuclear medicine physician Semin Nucl Med 2004. 34(1) Suppl 1 2–3. [PubMed: 14762737]
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