Therapy of disseminated B-cell lymphoma xenografts in severe combined immunodeficient mice with an anti-CD74 antibody conjugated with (111)indium, (67)gallium, or (90)yttrium.
A radiolabeled antibody (Ab) to CD74 (the MHC class II invariant chain, Ii) was shown previously to effectively kill human B-lymphoma cells in vitro. Conjugates with both Auger electron and beta-particle emitters were able to kill cells, but the former displayed less nonspecific toxicity in the in vitro assay used. In this report, we have extended the studies to an in vivo model of tumor growth. The human B-cell lymphoma Raji was injected i.v. into severe combined immunodeficient mice, and radiolabeled Abs were injected at various times after tumor inoculation. The maximum tolerated dose (MTD), as well as lower doses, was tested. Tumor growth was monitored by hind-leg paralysis. With a 3-5-day interval before Ab injection, anti-CD74 conjugated to either (111)In or (67)Ga, at a dose of 240-350 microCi/mouse, produced a strong therapeutic effect, with greatly delayed tumor growth, and many of the treated mice were tumor free for >6 months. Control mice became paralyzed in 16-24 days, uniformly. Treatment at later time points (9-day interval) had little therapeutic effect. The MTD was required for optimal therapy. With the beta-particle emitter (90)Y, the MTD was much less, 25 microCi/mouse, and at this dose there was only a weak therapeutic effect. In conclusion, the data suggest that low-energy electrons are more effective than beta-particles in this model system. These results may be applicable to humans, particularly in the case of micrometastatic disease. This approach may also be effective with other Abs that accrete in large amounts.
Ochakovskaya
R
R
Garden State Cancer Center, Belleville, New Jersey 07109, USA.
Osorio
L
L
Goldenberg
D M
DM
Mattes
M J
MJ
D000818:Animals; D000906:Antibodies / Q000378:metabolism; D000944:Antigens, Differentiation, B-Lymphocyte / Q000276:immunology; D005260:Female; D005710:Gallium Radioisotopes / Q000378:metabolism; D000949:Histocompatibility Antigens Class II / Q000276:immunology; D006801:Humans; D007205:Indium Radioisotopes / Q000378:metabolism; D016393:Lymphoma, B-Cell / Q000473:pathology*; D020714:Maximum Tolerated Dose; D051379:Mice; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D011485:Protein Binding; D013997:Time Factors; D014407:Tumor Cells, Cultured; D015021:Yttrium Radioisotopes / Q000378:metabolism
D000906:Antibodies; D000944:Antigens, Differentiation, B-Lymphocyte; D005710:Gallium Radioisotopes; D000949:Histocompatibility Antigens Class II; D007205:Indium Radioisotopes; D015021:Yttrium Radioisotopes; C045084:invariant chain