Treatment of human B cell lymphoma xenografts with a CD3 x CD19 diabody and T cells

• Published in: The Journal of immunology (1950) Vol. 165; no. 2; pp. 888 - 895
• Main Authors: Cochlovius, B, Kipriyanov, S M, Stassar, M J, Christ, O, Schuhmacher, J, Strauss, G, Moldenhauer, G, Little, M
• Format: Journal Article
• Language: English
• Published: United States 15.07.2000
• Subjects: Animals; Antibodies, Bispecific - genetics; Antibodies, Bispecific - isolation & purification; Antibodies, Bispecific - pharmacokinetics; Antibodies, Bispecific - pharmacology; Antigens, CD19 - genetics; Antigens, CD19 - immunology; Antineoplastic Agents - isolation & purification; Antineoplastic Agents - pharmacokinetics; Antineoplastic Agents - pharmacology; Binding Sites, Antibody; CD19 antigen; CD3 antigen; Gene Expression - immunology; Humans; Jurkat Cells; Lymphoma, B-Cell - immunology; Lymphoma, B-Cell - therapy; Male; Mice; Mice, Knockout; Neoplasm Transplantation; Receptor-CD3 Complex, Antigen, T-Cell - genetics; Receptor-CD3 Complex, Antigen, T-Cell - immunology; Recombinant Proteins - biosynthesis; Recombinant Proteins - isolation & purification; Recombinant Proteins - pharmacokinetics; Recombinant Proteins - pharmacology; T-Lymphocytes - transplantation; Transplantation, Heterologous - immunology; Tumor Cells, Cultured
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.165.2.888

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.