What's in the pipeline? New immunosuppressive drugs in transplantation.
In the pipeline, there are a number of novel immunosuppressive drugs in preclinical development or in early clinical trials. The major target of new agents are cell-surface molecules important in immune cell interactions (especially the costimulatory pathway), signaling pathways that activate T cells, T-cell proliferation and trafficking and recruitment of immune cells responsible for rejection. The most promising biologic agents include a humanized anti-CD11a (anti-LFA1), humanized anti-B7.1/B7.2, a second-generation CTLA4Ig (LEA29Y) and a humanized antibody to anti-CD45 RB. Inhibitors of T-cell activation and signaling are still in preclinical development. The most interesting inhibitors of T-cell proliferation include inhibitors of the Janus protein tyrosine kinase, JAK3, and FK778, a leflunomide analog. Chemokines play an important role in rejection by virtue of their critical role as regulator of trafficking and activation of lymphocytes. Early trials of FTY720, a synthetic small molecule with functional homology to sphingosine-1 phosphate leading to lymphocyte sequestration, appear very promising; however, enthusiasm for this drug is mitigated by its potential cardiac side-effects. Antagonists to several chemokine receptors, including CCR1, CXCR3 and CCR5, have been shown to be effective in experimental transplantation and are likely to be considered for clinical development.
Vincenti
Flavio
F
University of California, San Francisco, Kidney Transplant Service, 505 Parnassus Avenue, Room 884M, San Francisco, CA 94143-0116, USA. vincentif@surgery.ucsf.edu
D000069594:Abatacept; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D000938:Antigen-Presenting Cells / Q000276:immunology; D000954:Antigens, Surface / Q000276:immunology; D015195:Drug Design; D006801:Humans; D018796:Immunoconjugates / Q000627:therapeutic use*; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D008213:Lymphocyte Activation; D013601:T-Lymphocytes / Q000276:immunology; D014181:Transplantation Immunology
D000911:Antibodies, Monoclonal; D000954:Antigens, Surface; D018796:Immunoconjugates; D007166:Immunosuppressive Agents; C114320:anti-LFA-1 monoclonal antibody; D000069594:Abatacept