Localization of an antibody to CD74 (MHC class II invariant chain) to human B cell lymphoma xenografts in nude mice.
The tumor-specific localization of an anti-CD74 Ab, LL1, was demonstrated in nude mice bearing xenografts of human B-cell lymphoma. This Ab, conjugated to radionuclides emitting Auger electrons, including 125I and 111In, was previously reported to kill tumor cells in vitro effectively and specifically. The cytotoxic potency of this Ab is due to its uptake and catabolism at a very high level, which also affected the Ab biodistribution experiments. Thus, Ab localization to the tumor was only detected if a "residualizing" radiolabel was used, meaning a label that is trapped within cells, usually within lysosomes, after catabolism of the Ab to which it was conjugated. Similar results were obtained with three different residualizing labels: 111In conjugated via the chelators benzyl diethylenetriaminepentaacetic acid (DTPA) or 1.4,7,10-tetra-azacyclododecane-N, N', N", N"'-tetraacetic acid (DOTA), or 131I-dilactitol-tyramine, a residualizing form of iodine. The Ab protein dose could be high, 0.5 mg/mouse, without causing a decrease in specific tumor uptake, probably reflecting the high capacity for uptake. Moreover, tumors of moderate size were found to cause rapid, specific removal of the Ab from the blood, also a result of catabolic processes. This induced blood clearance naturally affected the Ab localization experiments, but this factor could be circumvented by increasing the Ab protein dose. Using a different Ab, anti-(mature MHC class II), the ability of Ab to penetrate relatively large solid tumors was investigated. Complete saturation of antigenic sites was observed in tumors up to 0.3 g in size, but quite high Ab protein doses were required, 5.0 mg/ mouse. These results provide a rationale for attempting therapy with radiolabeled LL1.
Shih
L
L
Garden State Cancer Center, Belleville, NJ 07109, USA.
Ong
G L
GL
Burton
J
J
Mishina
D
D
Goldenberg
D M
DM
Mattes
M J
MJ
D000818:Animals; D000906:Antibodies / Q000276:immunology*; D015703:Antigens, CD / Q000276:immunology; D000944:Antigens, Differentiation, B-Lymphocyte / Q000096:biosynthesis* / Q000276:immunology*; D015815:Cell Adhesion Molecules; D002469:Cell Separation; D004305:Dose-Response Relationship, Drug; D005434:Flow Cytometry; D000949:Histocompatibility Antigens Class II / Q000096:biosynthesis* / Q000276:immunology*; D006801:Humans; D018796:Immunoconjugates; D007205:Indium Radioisotopes; D007457:Iodine Radioisotopes; D037102:Lectins; D016393:Lymphoma, B-Cell / Q000276:immunology*; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D011845:Radio; D051918:Sialic Acid Binding Ig-like Lectin 2; D013997:Time Factors; D014018:Tissue Distribution; D014407:Tumor Cells, Cultured
D000906:Antibodies; D015703:Antigens, CD; D000944:Antigens, Differentiation, B-Lymphocyte; C497867:CD22 protein, human; C497868:Cd22 protein, mouse; D015815:Cell Adhesion Molecules; D000949:Histocompatibility Antigens Class II; D018796:Immunoconjugates; D007205:Indium Radioisotopes; D007457:Iodine Radioisotopes; D037102:Lectins; D051918:Sialic Acid Binding Ig-like Lectin 2; C045084:invariant chain