CD30-antigen-specific targeting and activation of T cells via murine bispecific monoclonal antibodies against CD3 and CD28: potential use for the treatment of Hodgkin's lymphoma

Cross-linking of specific tumor antigens with the T-cell-associated CD3 and CD28 antigens can increase IL-2 secretion, proliferation and antigen-specific cytotoxicity in resting T cells. This cross-linking can be achieved effectively by bispecific monoclonal antibodies (BiMAb) with specificity for both the tumor antigen and CD3 or CD28 antigen, respectively. To take advantage of the enhanced activation of CD3 pre-activated T cells by additional activation via the CD28 antigen, BiMAb OKT3/HRS-3 with reactivity to both CD3 and the Hodgkin's-lymphoma-associated CD30 antigen and the BiMAb 15E8/HRS-3 with reactivity to both CD28 and CD30 antigen were generated by hybridoma fusion. Resting T cells, represented by Jurkat cells (CD3+/CD28+) were specifically activated to produce IL-2 by co-cultivation with an EBV-transformed B-cell line (LAZ509, CD30+/CD19+) only in the presence of the CD30/CD28 cross-linking BiMAb and an additional cross-linking anti-CD3/CD19 BiMAb (OKT3/6A4). Neither the cross-linking BiMAbs alone nor any combination of the monospecific parental MAbs induced a comparable IL-2 production by Jurkat cells in the presence of LAZ509. In addition, using a combination of these BiMAbs, an antigen-dependent cytotoxicity was induced by targeting APC-depleted peripheral blood lymphocytes to CD30+ L540 cells. T cells, previously specifically activated by CD3/CD30 in the presence of CD30 antigen, were cytotoxic to CD30+ cell lines only after incubation with BiMAb anti-CD28/CD30. Neither of the BiMAbs nor any of the parental antibodies induced a comparable effect. Our results indicate that such BiMAbs may offer a new approach for specific immunotherapy of Hodgkin's lymphoma, which takes advantage of cytokine secretion and cytotoxicity of activated T cells