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Key Points Although immunosuppressive therapy is effective at present, toxicity remains an important problem. Many of the existing immunosuppressive agents are directed against ubiquitous targets and therefore have side effects that are unrelated to immunosuppression. Consequently, generating drugs against molecules with restricted expression and/or function might be advantageous. The Janus kinase JAK3 is crucial for signalling by key immunoregulatory cytokines, but has restricted expression and function. This is best illustrated by patients with mutations of the gene encoding this kinase: such children have severe combined immunodeficiency but do not have abnormalities outside of the immune system. This phenotype suggests that JAK3 might be an ideal target. A selective JAK3 inhibitor, CP-690,550, has now been generated to effectively block immune responses both in vitro and in vivo . Other JAK3 inhibitors have been previously described, but none are as potent or selective as CP-690,550. This drug is effective in models of transplant rejection and is not associated with the toxicities that are seen with other immunosuppressive agents. A JAK3 inhibitor is likely to have uses in many settings beyond transplantation, including autoimmune disease and possibly haematopoietic malignancy. Targeting other JAKS and other elements in the JAK/STAT pathway is also conceptually appealing. On the basis of the phenotype that is associated with TYK2 deficiency, a TYK2 antagonist might be useful in inhibiting diseases that are characterized by the activation of T H 1 cells. Given their importance in malignant transformation and immunoregulation, STAT proteins have received considerable attention as therapeutic targets and STAT inhibitors are being studied at present. SOCs proteins are cytokine-induced feedback inhibitors of signalling, which can also be considered as potential targets. Thousands of organs are transplanted each year and millions of people suffer from autoimmune diseases, which creates a need for an armamentarium of immunosuppressive drugs. Unfortunately, immunosuppressants have unwanted side effects owing, in part, to the fact that they have ubiquitous molecular targets. Cytokines have emerged as important controllers of the immune response, and work during the past decade has identified Janus kinases (JAKs) and signal transducers, and activators of transcription (STATs), as crucial intracellular elements in cytokine signalling. Here, we discuss the potential of the JAK/STAT pathway as a target for new immunosuppressants. In particular, the inhibition of JAK3 seems to be an excellent strategy, because of the selective expression and precise functions of this kinase.

The purpose of this study was to predict a safe starting dose of AMG 181, a human anti‐α4β7 antibody for treating inflammatory bowel diseases, based on cynomolgus monkey pharmacokinetic (PK) and pharmacodynamic (PD) data. A two‐compartment model with parallel linear and target‐mediated drug disposition for AMG 181 PK in cynomolgus monkey was developed. The estimated parameters were allometrically scaled to predict human PK. An Emax PD model was used to relate AMG 181 concentration and free α4β7 receptor data in cynomolgus monkey. AMG 181 clinical doses were selected based on observed exposures at the no adverse effect level of 80 mg·kg−1 in monkeys, the predicted human exposures, and AMG 181 concentration expected to produce greater than 50% α4β7 receptor occupancy in humans. The predicted human AMG 181 clearance and central volume of distribution were 144 mL·day−1 and 2900 mL, respectively. The estimated EC50 for free α4β7 receptor was 14 ng·mL−1. At the 0.7 mg starting dose in humans, the predicted exposure margins were greater than 490,000 and AMG 181 concentrations were predicted to only briefly cover the free α4β7 receptor EC10. Predictions for both Cmax and AUC matched with those observed in the first‐in‐human study within the 7 mg subcutaneous to 420 mg intravenous dose range. The developed model aided in selection of a safe starting dose and a pharmacological relevant dose escalation strategy for testing of AMG 181 in humans. The clinically observed human AMG 181 PK data validated the modeling approach based on cynomolgus monkey data alone. e00098

The purpose of this study was to predict a safe starting dose of AMG 181, a human anti‐ α 4 β 7 antibody for treating inflammatory bowel diseases, based on cynomolgus monkey pharmacokinetic ( PK ) and pharmacodynamic ( PD ) data. A two‐compartment model with parallel linear and target‐mediated drug disposition for AMG 181 PK in cynomolgus monkey was developed. The estimated parameters were allometrically scaled to predict human PK . An E max PD model was used to relate AMG 181 concentration and free α 4 β 7 receptor data in cynomolgus monkey. AMG 181 clinical doses were selected based on observed exposures at the no adverse effect level of 80 mg·kg −1 in monkeys, the predicted human exposures, and AMG 181 concentration expected to produce greater than 50% α 4 β 7 receptor occupancy in humans. The predicted human AMG 181 clearance and central volume of distribution were 144 mL·day −1 and 2900 mL, respectively. The estimated EC 50 for free α 4 β 7 receptor was 14 ng·mL −1 . At the 0.7 mg starting dose in humans, the predicted exposure margins were greater than 490,000 and AMG 181 concentrations were predicted to only briefly cover the free α 4 β 7 receptor EC 10 . Predictions for both C max and AUC matched with those observed in the first‐in‐human study within the 7 mg subcutaneous to 420 mg intravenous dose range. The developed model aided in selection of a safe starting dose and a pharmacological relevant dose escalation strategy for testing of AMG 181 in humans. The clinically observed human AMG 181 PK data validated the modeling approach based on cynomolgus monkey data alone. e00098

Prenylated Ras GTPases transduce signals from the T cell receptor, CD28 costimulatory receptor and IL-2 receptor. Since signals from these receptors mediate T cell activation, proliferation and survival, we hypothesized that the prenylation inhibitor L-778,123 would impart immunomodulation. The effect of L-778,123 on T cell activation (CD71 or CD25 surface expression) was determined by flow cytometry. Peripheral blood mononuclear cell (PBMC) proliferation in the presence of L-778,123 and/or cyclosporine (CsA) was determined by [3H]thymidine incorporation. The ability of L-778,123 to inhibit IL-2 receptor signaling was investigated by measuring IL-2 induced proliferation in CTLL-2 cells and IL-2 prevention of apoptosis in activated human PBMC. L-778,123 inhibited lectin induced expression of CD71 and CD25 with IC50's of 6.48 +/- 1.31 microM and 84.1 +/- 50.0 microM, respectively. PBMC proliferation was inhibited by L-778,123 with an IC50 of 0.92 +/- 0.23 microM, and addition of CsA did not increase the potency. L-778,123 did not inhibit IL-2 and IFN-gamma production by T cells. L-778,123 abrogated IL-2 induced proliferation of CTLL-2 cells with an IC50 of 0.81 +/- 0.44 microM. However, L-778,123 minimally reversed the prosurvival effect of IL-2 in activated lymphocytes. IL-2 ligand and receptor production during T cell activation are relatively unaffected by L-778,123. However, the activation and proliferative effects of IL-2 on T cells are potently blocked by L-778,123. These results reveal a selective blockade of the IL-2 cytokine axis distal to the IL-2 receptor by the L-778,123 and warrant evaluation of prenylation inhibitors in treating transplant rejection and autoimmune diseases.

Docetaxel is an antineoplastic taxoid that interferes with microtubule polymerization dynamics and is used clinically to treat advanced cancers. Because microtubules play significant roles in T lymphocyte activation and function we characterized the in vitro immunomodulatory properties of docetaxel. Effects of docetaxel on lectin-induced peripheral blood mononuclear cell (PBMC) proliferation were measured by the 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assay and proliferating cell nuclear antigen (PCNA) staining. In addition, apoptosis was measured by annexin V staining and cell activation by determination of CD25 and CD71 cell surface expression. Intracellular calcium kinetics in lectin-activated Jurkat T lymphocytes exposed to docetaxel were investigated. Th1 cytokine production was assessed in T lymphocytes by intracellular cytokine staining. Docetaxel significantly inhibited PBMC proliferation and promoted apoptosis of lectin-activated PBMCs. Docetaxel significantly decreased expression of CD71 but not that of CD25. Docetaxel altered intracellular calcium homeostasis but did not affect Th1 cytokine production in T lymphocytes. In conclusion we demonstrate that docetaxel, although exerting significant antiproliferative effects on lymphocytes and promoting activation-induced apoptosis does affect only partially lymphocyte activation and function and does not affect Th1 cytokine production. These results suggest maintenance of lymphocyte functions important for host tumor surveillance and suggest that this compound may have a role in the treatment of cancer arising organ transplant recipients.