Biomedical subjects
Publications and source records attributed to Francis J Dumont.
Mitsubishi Pharma Corp and Novartis AG are developing fingolimod, an orally active immunosuppressant affecting lymphocyte re-circulation, for the potential prevention of transplant rejection and the treatment of autoimmune diseases, including multiple sclerosis. Fingolimodis a synthetic sphingosine analog that becomes phosphorylated in vivo and acts as a sphingosine-1-phosphate receptor agonist.
Protein Design Labs is developing fontolizumab, a humanized anti-interferon gamma monoclonal antibody, for the potential treatment of autoimmune diseases. By February 2003, the company was actively seeking to outlicense the development and commercialization rights to fontolizumab outside of the US and Canada.
ISAtx-247 is a ciclosporin A analog under development by Isotechnika and Roche as an immunosuppressant for the potential prevention of organ rejection after transplantation, and for the potential treatment of autoimmune diseases such as rheumatoid arthritis, psoriasis and type 1 diabetes. A phase II renal transplantation study had been completed by June 2003.
Bristol-Myers Squibb is developing the fusion protein abatacept for the potential treatment of various immunological disorders, including rheumatoid arthritis, multiple sclerosis and systemic lupus erythematosus. Abatacept is undergoing phase III clinical trials.
CXCR6, the receptor for the membrane-anchored chemokine, CXCL16, is expressed on a subset of CCR5-bearing memory T cells, and may play a role in recruiting these cells to sites of inflammation. Here, we set out to determine the effect of T cell activation on CXCR6 expression. Highly purified human peripheral blood T cells were cultured for 7-8 days in presence of IL-2 (400 U/ml) to enhance CXCR6 expression. Overnight stimulation with anti-CD3 mAb+anti-CD28 mAb, which resulted in CD69 induction and cytokine (IL-2 and IFN-gamma) production, reduced cell surface expression of CXCR6 by 85% and that of CCR5 by 76%. The Ca(2+) ionophore, ionomycin (125-500 ng/ml), also markedly diminished CXCR6 expression (85%), but without inducing CD69 expression or cytokine production, and reduced CCR5 expression by only 40%. In contrast, the phorbol esters, PdBu or PMA had little effect on CXCR6 expression (23% reduction) but induced CD69 expression and caused a profound down-regulation (92%) of CCR5 expression. Moreover, CCR7, whose expression was low on CXCR6(+) T cells, was little affected by any of these modes of activation. The down-regulation of CXCR6 expression induced by CD3/CD28 activation was blocked by the broad kinase inhibitor, staurosporine, and by the src kinase inhibitor, PP2, but not by the MEK1 inhibitor, U0106. Most interestingly, the calcineurin inhibitor, FK506, consistently inhibited CD3/CD28-induced CXCR6 down-regulation. FK506 also blocked the decrease of CXCR6 expression caused by ionomycin, whereas staurosporine or PP2 had no effect on this decrease. Altogether, these data indicate that CXCR6 expression is down-regulated, independent of CCR5 or CD69 expression and of cytokine induction, by T cell activation signals that involve predominantly the Ca(2+)-dependent calcineurin pathway.
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CAMPATH (CAMPATH-1H, alemtuzumab, MabCAMPATH), is a lymphocyte-depleting humanized monoclonal antibody that was recently approved in the USA and Europe for the treatment of chronic lymphocytic leukemia (CLL). It targets CD52--a small glycosylphosphatidylinositol-anchored glycoprotein that is highly expressed on normal T- and B-lymphocytes and on a large proportion of lymphoid cell malignancies--but not on hematopoietic progenitor cells. CAMPATH was shown to be effective against CLL refractory to chemotherapy with an acceptable toxicity profile. CAMPATH is also active against T-cell prolymphocytic leukemia and has been extensively used to prevent graft-versus-host disease associated with bone marrow transplantation. CAMPATH is owned by ILEX Pharmaceuticals LP and distributed by Schering AG and its US affiliate Berlex Laboratories.
IDEC, in collaboration with Eisai, is developing IDEC-131 (E6040), a humanized monoclonal antibody (mAb) against CD154, the ligand for CD40 also called CD40L or gp39, for the potential treatment of several autoimmune diseases. IDEC-131 is based on technology that IDEC licensed from Dartmouth Medical School where researchers demonstrated the biological effects of the anti-CD154 antibody in animal models of autoimmunity. In January 2001, phase II trials in psoriasis and idiopathic thrombocytopenic purpura (ITP) were initiated. By january 2002, a phase II trial in Crohn's disease was also ongoing. A pilot, multicenter, multiple-dose phase I trial in moderate-to-severe psoriasis was initiated in January 2001. This trial was ongoing in January 2002. IDEC, in collaboration with Dartmouth Medical School had also initiated a phase I trial in multiple sclerosis by March 1999. IDEC-131 was also previously being developed for systemic lupus ezythematosus (SLE), although no further development for this indication has been reported since the disclosure of disappointing phase II results in April 2000. Analysts at Morgan Stanley predicted in February 2002, that the product would be launched in 2005, with sales of US $25 million, rising to US $75 million in 2006.
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