Bispecific antibodies which simultaneously bind to effector cells and tumor cells can induce destruction of the tumor cells by the effector cells. By recruiting of an additional class of effector cells, such as T-cells, therapy with bispecific antibodies may be superior to treatment with monospecific anti-tumor antibodies. In the current proposal, bispecific antibody-directed immunotherapy will be studied in the 38C13 murine B-cell lymphoma model. Wild type and idiotype variant 38C13 lymphoma cells, which express different kappa light chains as part of their surface IgMs, are available that are indistinguishable with respect to other surface markers, in vitro behavior and in vivo growth. Two bispecific antibodies, secreted by hybrid-hybridomas, have been produced which simultaneously bind to the idiotype expressed by either wild type or variant 38C13 cells, and murine T cells via the CD3 receptor. In vitro, these bispecific antibodies can induce specific lysis of wild type or variant 38C13 cells by activated T cells. Preliminary in vivo studies indicate bispecific antibody-directed therapy in this system is superior to therapy with anti-idiotype antibody alone. The availability of two sets of tumor cell lines and bispecific antibodies supplies a system of controls that will aid in the further study of this form of therapy. Bispecific antibody preparations to be studied include those produced by hybrid-hybridomas (bispecific IgG) as well as those produced by chemical conjugation of intact antibodies and Fab fragments. F(ab')2 fragments of bispecific IgGs will also be analyzed. In vitro studies will compare the ability of the various antibody preparations to eliminate tumor target cells. In vivo studies will examine the development of tumor, tumor cell phenotype and survival of mice inoculated with wild type 38C13 and/or variant 38C13 cells, then treated with bispecific antibody. Co-therapy consisting of bispecific antibody plus IL- 2 and/or infusion of various subpopulations of T cells will also be analyzed. These studies will supply important information concerning the advantages and limitations of this potentially powerful therapeutic modality.
| Link, B K; Kostelny, S A; Cole, M S et al. (1998) Anti-CD3-based bispecific antibody designed for therapy of human B-cell malignancy can induce T-cell activation by antigen-dependent and antigen-independent mechanisms. Int J Cancer 77:251-6 |
| Link, B K; Weiner, G J (1998) Monoclonal antibodies in the treatment of human B-cell malignancies. Leuk Lymphoma 31:237-49 |
| Wooldridge, J E; Dahle, C E; Weiner, G J (1997) T-cell activation induced by anti-CD3 x anti-B-cell lymphoma monoclonal antibody is enhanced by pretreatment of lymphoma cells with soluble CD40 ligand. Cancer Immunol Immunother 45:174-9 |
