Rapid and specific targeting of 125I-labeled B lymphocyte stimulator to lymphoid tissues and B cell tumors in mice.
B lymphocyte stimulator (BLyS) protein is a member of the tumor necrosis factor (TNF) superfamily of cytokines that binds to B lineage cells, but not T cells, monocytes, natural killer cells, or granulocytes. BLyS protein binding to B cells is restricted to immunoglobulin-positive cells and is not evident on pro- or pre-B cell populations. This unique binding profile suggests that a radiolabeled form of BLyS protein may be a useful treatment for B cell neoplasias such as B cell lymphoma and multiple myeloma. Here, we report the biodistribution of radiolabeled recombinant human BLyS after intravenous injection into normal mice and mice bearing BCL1 tumor in the spleen or J558 tumor in the subcutaneous space. We also report the use of these data to estimate human dosimetry.


METHODS
(125)I-Labeled BLyS protein (50 micro g/kg, 0.185-0.37 MBq per mouse) was injected intravenously into BALB/c mice, and biodistribution was measured by direct counting of radioactivity in dissected tissues and by quantitative whole-body autoradiography (QWBA).


RESULTS
The half-life of radiolabeled BLyS protein in blood was approximately 2.7 h in both normal and tumor-bearing mice. The spleen showed the highest uptake of BLyS protein in both normal and tumor-bearing mice, with a maximum concentration (C(max)) of 35-45 percentage injected dose per gram (%ID/g) occurring between 1 and 3 h after injection. In lymph nodes, C(max) was approximately 20 %ID/g in normal and J558 tumor-bearing mice and 8-15 %ID/g in BCL1 tumor-bearing mice. Limited biodistribution data from the J558 tumors showed a C(max) of approximately 15 %ID/g. By contrast, C(max) was only approximately 5 %ID/g for both kidney and liver. QWBA confirmed high radioactivity in spleen, lymph nodes, and stomach contents and low radioactivity in kidney and liver. After 24 h, spleen and lymph nodes were still positive in QWBA images, whereas liver and kidney no longer had observable levels.


CONCLUSIONS
Radiolabeled BLyS showed specific and rapid targeting to lymphoid tissues and B cell tumors in mice. Unlike monoclonal antibodies, which have long plasma half-lives and considerable liver uptake, BLyS has distinct pharmacokinetic and biodistribution properties that may offer advantages compared with antibody-based radioimmunotherapy.
Riccobene
Todd A
TA
Preclinical Development, Human Genome Sciences, Incorporated, Rockville, Maryland 20850, USA. todd_riccobene@hgsi.com
Miceli
Renée C
RC
Lincoln
Clint
C
Knight
Yvonne
Y
Meadows
Joseph
J
Stabin
Michael G
MG
Sung
Cynthia
C
D000818:Animals; D001345:Autoradiography; D053264:B-Cell Activating Factor; D053265:B-Cell Activation Factor Receptor; D005260:Female; D007275:Injections, Intravenous; D007457:Iodine Radioisotopes / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D008221:Lymphoid Tissue / Q000378:metabolism*; D016393:Lymphoma, B-Cell / Q000378:metabolism / Q000532:radiotherapy*; D008565:Membrane Proteins / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D051379:Mice; D008807:Mice, Inbred BALB C; D009368:Neoplasm Transplantation; D010954:Plasmacytoma / Q000378:metabolism / Q000532:radiotherapy; D016499:Radioimmunotherapy; D011879:Radiotherapy Dosage; D018124:Receptors, Tumor Necrosis Factor / Q000032:analysis; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use; D013154:Spleen / Q000737:chemistry; D014018:Tissue Distribution; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*
D053264:B-Cell Activating Factor; D053265:B-Cell Activation Factor Receptor; C120197:BLyS receptor; D007457:Iodine Radioisotopes; D008565:Membrane Proteins; D018124:Receptors, Tumor Necrosis Factor; D011994:Recombinant Proteins; C505719:TNFSF13B protein, human; C486662:Tnfrsf13c protein, mouse; C505720:Tnfsf13b protein, mouse; D014409:Tumor Necrosis Factor-alpha