Springer Online Journal Archives 1860-2000
Conclusions The data discussed in this review demonstrates that genetically engineered superantigens are highly effective anti-tumor agents in an experimental murine tumor model. The tumor-suppressive activity of Fab-SEA fusion proteins has been shown against established B16 lung metastases and recently also demonstrated against disseminated human colon carcinomas in SCID mice engrafted with human lymphocytes [9, 24]. The local response involves a pronounced infiltration and activation of CD4+ and CD8+ T lymphocytes. Fab-SEA proteins direct CTL against antigen-positive tumor cells and induce local release of tumor-suppressive cytokines. In situ expression of cytokines in the tumor may be particularly important in elimination of antigen-negative tumor cells inevitably present in any tumor. We have also shown that it is feasible to reduce the systemic toxicity and simultaneously retain the therapeutic efficacy of Fab-SEA fusion proteins by means of site-directed mutageneses of amino acids critical for MHC class II binding. The C215Fab-SEAD227A mutant had an estimated K d of 10-9 M for the tumor antigen compared to K d of less than 10-5 for the interaction with MHC class II molecules, giving the fusion protein a 10000-fold preference for the tumor antigen versus MHC class II molecules compared to a 100-fold difference for the wild-type C215Fab-SEA for the tumor antigen. It is likely, however, that the optimal MHC class II binding of SEA may vary in different clinical indications. If the targeted tumors such as lymphomas and leukemias, express MHC class II, it may be favorable to retain the affinity for MHC class II at a moderate level, since SEA induced cross-linking of MHC class II on the tumor cell might increase expression of co-stimulatory signals (Fig. 7). Similarly, during therapy of certain solid tumors, release of inflammatory cytokines by tumor-infiltrating MHC class II+ monocytes, may be influenced by MHC class II cross-linking, and thereby facilitate tumor uptake of the Fab-SEA protein.
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