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Roquinimex-related 3-quinolinecarboxamide derivatives were prepared and evaluated for treatment of autoimmune disorders. The compounds were tested in mice for their inhibitory effects on disease development in the acute experimental autoimmune encephalomyelitis model and selected compounds in the beagle dog for induction of proinflammatory reaction. Structure-activity relationships are discussed. Compound 8c, laquinimod, showed improved potency and superior toxicological profile compared to the lead compound roquinimex (1b, Linomide) and was selected for clinical studies (currently in phase II).

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The bacterial superantigen staphylococcal enterotoxin A (SEA) is an extremely potent activator of T lymphocytes when presented on major histocompatibility complex (MHC) The therapeutic use of naked monoclonal antibodies (mAbs) in human epithelial cancer has met with limited success (1). The amount of mAb found to accumulate in the tumor is generally low, tumor cells display extensive heterogeneity in antigen expression, and the effector mechanisms responsible for tumor-cell destruction are insufficient (1, 2). Recent progress in the molecular understanding of T-cell recognition has provided insight into the role of T cells in the response against allogeneic and neoplastic tissues. The vigorous and destructive response against an allograft involves a high frequency of T lymphocytes that, via the T-cell receptor (TCR), recognizes peptide antigens presented in the context of major histocompatibility complex (MHC) molecules. In contrast, the frequency of T cells responding to a tumor is generally low and insufficient to interfere with tumor growth. This suggests that an attractive approach for immunotherapy would be to target a high frequency of T cells to the tumor area. We have therefore developed an antibody-based therapy that provides tumor cells with superantigenicity. Superantigens (SAgs) are a family of bacterial and viral proteins that activate a high frequency of T cells to cytokine release and cell-mediated cytotoxicity (3)(4)(5). Bacterial SAgs bind with high affinity to MHC class II molecules and subsequently interact with T cells expressing particular sequences in the variable (V) region of the TCR , / chain (TCR V(3) (3)(4)(5) MATERIALS AND METHODSProtein Reagents. Recombinant SEA was expressed in E. coli and purified to homogeneity. The hybridomas secreting the C215 (IgG2a) and C242 (IgGl) mAbs, reacting with human colon cancer, were produced at Pharmacia (8, 9). E. coli HB101 was used as host during the DNA construction work (10).

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