Radioimmunotherapy in the pi-BCL1 B cell lymphoma model: efficacy depends on more than targeted irradiation alone.
We report the in vivo radioimmunotherapy (RIT) of a new variant of the BCL1 syngeneic mouse B-cell lymphoma model, pi-BCL1, using a panel of monoclonal antibodies (MoAb) reactive with B cell-associated antigens (CD19, CD22, CD40, MHC II, and idiotype). MoAb were radiolabeled with 131I or used in conjunction with external beam irradiation. When administered early in disease (day 4) 131I-anti-MHC II MoAb produced long term disease free survivors as a result of targeted irradiation alone; the equivalent unlabelled MoAb was non-therapeutic. In contrast, 131I-anti-CD40, and 131I-anti-Idiotype (Id) MoAb administered at day 4 despite targeting irradiation and having intrinsic therapeutic activity as unconjugated antibodies, protected mice for approximately 30 days. The 131I-anti-CD19 and anti-CD22 were therapeutically inactive. Treating later in the disease (day 14, after tumor inoculation) permitted study of the efficacy in the presence of an increased tumor load. An increased tumor burden brought about an expected reduction in therapeutic activity with 131I-anti-MHC II, but surprisingly, 131I anti-CD40 and 131I-anti-Id were able to produce prolonged disease free survival in most mice. This unexpected potency of 131I-anti-CD40 and 131I-anti-Id late in disease appeared to result from the direct cytotoxic action induced by these MoAb. Mechanisms by which these two MoAb operate, in producing long-term disease free survival in animals with advanced disease appear different. Our therapeutic results have important implications for the selection of reagents for RIT and demonstrate that successful treatment with such agents may involve more than simple targeting of irradiation.
Illidge
T
T
Cancer Sciences Division, School of Medicine, Southampton University, Southampton, United Kingdom. tmi@soton.ac.uk
Honeychurch
J
J
Vandersteen
A
A
Cragg
M
M
D000818:Animals; D000888:Antibodies, Anti-Idiotypic / Q000276:immunology; D000911:Antibodies, Monoclonal / Q000276:immunology; D015703:Antigens, CD / Q000032:analysis; D018941:Antigens, CD19 / Q000032:analysis; D000944:Antigens, Differentiation, B-Lymphocyte / Q000032:analysis; D017209:Apoptosis / Q000528:radiation effects; D019013:CD40 Antigens / Q000032:analysis; D015815:Cell Adhesion Molecules; D004273:DNA, Neoplasm / Q000032:analysis; D004195:Disease Models, Animal; D005260:Female; D005455:Fluorescent Antibody Technique; D005805:Genes, MHC Class I / Q000235:genetics; D005802:Genes, MHC Class II / Q000235:genetics; D066298:In Vitro Techniques; D007457:Iodine Radioisotopes / Q000627:therapeutic use; D037102:Lectins; D016393:Lymphoma, B-Cell / Q000532:radiotherapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D016499:Radioimmunotherapy; D051918:Sialic Acid Binding Ig-like Lectin 2; D016019:Survival Analysis; D013997:Time Factors; D014407:Tumor Cells, Cultured / Q000166:cytology
D000888:Antibodies, Anti-Idiotypic; D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D018941:Antigens, CD19; D000944:Antigens, Differentiation, B-Lymphocyte; D019013:CD40 Antigens; C497868:Cd22 protein, mouse; D015815:Cell Adhesion Molecules; D004273:DNA, Neoplasm; D007457:Iodine Radioisotopes; D037102:Lectins; D051918:Sialic Acid Binding Ig-like Lectin 2