Treatment of human B cell lymphoma xenografts with a CD3 x CD19 diabody and T cells.
The use of anti-CD3 x antitumor bispecific Abs is an attractive and highly specific approach in cancer therapy. Recombinant Ab technology now provides powerful tools to enhance the potency of such immunotherapeutic constructs. We designed a heterodimeric diabody specific for human CD19 on B cells and CD3epsilon chain of the TCR complex. After production in Escherichia coli and purification, we analyzed its affinity, stability, and pharmacokinetics, and tested its capacity to stimulate T cell proliferation and mediate in vitro lysis of CD19+ tumor cells. The effect of the diabody on tumor growth was investigated in an in vivo model using immunodeficient mice bearing a human B cell lymphoma. The CD3 x CD19 diabody specifically interacted with both CD3- and CD19-positive cells, was able to stimulate T cell proliferation in the presence of tumor cells, and induced the lysis of CD19+ cells in the presence of activated human PBL. The lytic potential of the diabody was enhanced in the presence of an anti-CD28 mAb. In vivo experiments indicated a higher stability and longer blood retention of diabodies compared with single chain Fv fragments. Treatment of immunodeficient mice bearing B lymphoma xenografts with the diabody and preactivated human PBL efficiently inhibited tumor growth. The survival time was further prolonged by including the anti-CD28 mAb. The CD3 x CD19 diabody is a powerful tool that should facilitate the immunotherapy of minimal residual disease in patients with B cell leukemias and malignant lymphomas.
Cochlovius
B
B
Recombinant Antibody Research Group, Department of Tumor Progression and Immune Defense, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Kipriyanov
S M
SM
Stassar
M J
MJ
Christ
O
O
Schuhmacher
J
J
Strauss
G
G
Moldenhauer
G
G
Little
M
M
D000818:Animals; D018033:Antibodies, Bispecific / Q000235:genetics / Q000302:isolation & purification / Q000493:pharmacokinetics / Q000494:pharmacology*; D018941:Antigens, CD19 / Q000235:genetics / Q000276:immunology*; D000970:Antineoplastic Agents / Q000302:isolation & purification / Q000493:pharmacokinetics / Q000494:pharmacology; D001666:Binding Sites, Antibody; D015870:Gene Expression / Q000276:immunology; D006801:Humans; D019169:Jurkat Cells; D016393:Lymphoma, B-Cell / Q000276:immunology* / Q000628:therapy*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009368:Neoplasm Transplantation; D017260:Receptor-CD3 Complex, Antigen, T-Cell / Q000235:genetics / Q000276:immunology*; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000302:isolation & purification / Q000493:pharmacokinetics / Q000494:pharmacology; D013601:T-Lymphocytes / Q000637:transplantation*; D014183:Transplantation, Heterologous / Q000276:immunology*; D014407:Tumor Cells, Cultured
D018033:Antibodies, Bispecific; D018941:Antigens, CD19; D000970:Antineoplastic Agents; D017260:Receptor-CD3 Complex, Antigen, T-Cell; D011994:Recombinant Proteins