tresperimus and Graft-vs-Host-Disease

Acute and chronic graft versus host disease (GVHD) remain the major barriers to successful hematopoietic cell transplantation. The induction of GVHD may be divided into three phases: recipient conditioning;donor T-cell activation; andeffector cells mediating GVHD. This review examines GVHD prevention and treatment using this conceptual model as framework. The various pharmacological agents discussed impact on different phases of the GVHD cascade. For example, keratinocyte growth factor and interleukin (IL)-11 are cytokines that may be useful in disrupting phase I of the GVHD cascade by blocking gastrointestinal tract damage, and lowering serum levels of lipopolysaccharide and tumour necrosis factor (TNF)-alpha. Cyclosporin, tacrolimus (FK-506) and sirolimus (rapamycin) are some of the main agents that disrupt phase II (donor T-cell activation). Mycophenolate mofetil and tresperimus probably act on this phase as well. Other novel drugs that affect phase II are tolerance-induction agents such as CTLA-4 and anti-CD40-ligand monoclonal antibodies, and preliminary results using CTLA-4 monoclonal antibody in GVHD prevention are encouraging. Examples of agents that disrupt phase III are the IL-2 receptor antagonist daclizumab and the anti-TNFalpha monoclonal antibody infliximab. These anti-cytokine antibodies have shown promising results in early studies. The most effective approach to GVHD prevention will probably be a combination regimen where the three phases of the GVHD cascade are disrupted. Once GVHD has occurred, all three phases of the cascade are activated. Developments of combination therapy for treatment of both acute and chronic GVHD are likely to yield better results than monotherapy. The numerous new treatment modalities presented should improve the outlook for patients with acute and chronic GVHD.

Topics: Acute Disease; Animals; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Carbamates; Chronic Disease; Combined Modality Therapy; Cyclosporine; Daclizumab; Fibroblast Growth Factor 7; Fibroblast Growth Factors; Graft vs Host Disease; Humans; Immunoglobulin G; Immunosuppressive Agents; Infliximab; Interleukin-11; Mycophenolic Acid; Receptors, Interleukin-2; Sirolimus; T-Lymphocytes; Tacrolimus

Tresperimus is a novel agent that induces allogeneic transplant tolerance. It is structurally related to deoxyspergualin (DSG) but has been modified to resist rapid hydrolysis in aqueous solution, which simplifies administration. Despite this modification, tresperimus's actions in experimental models seem almost identical to DSG. Initially, DSG was developed as an antitumour agent. Its antitumour efficacy appears limited but DSG and tresperimus have favourable effects on transplant rejection. A short course of tresperimus has been shown to have similar or greater quantitative effects to cyclosporin in bone marrow, cardiac and skin transplant models. However, qualitatively the effects are different. Prevention of rejection is due to induction of donor-specific tolerance without affecting immunity to third party antigens. In addition, CD4+ T-cells from tresperimus-treated animals can transfer donor specific tolerance to naïve animals, an effect not seen with cyclosporin or other traditional immunosuppressive drugs. The mechanism by which tolerance is induced is not clear. Tresperimus (like DSG) binds to Hsc70, which among other effects inhibits nuclear localisation of NF-kappa B. NF-kappa B nuclear localisation is induced by CD40 ligation in antigen-presenting cells, an important early step in T-cell co-stimulation. NF-kappa B is also required for CD28 ligation signalling, important in late co-stimulation. It also is involved in B-cell activation, via CD40 ligation and kappa light chain production. Hsc70 is also required for efficient cytosolic peptide chaperoning to MHC class I molecules. Presumably, it is disruption of T-cell/dendritic cell interaction that leads to induction of T-cell anergy. Tresperimus is well-tolerated. The main dose limiting side effects are orthostatic hypotension and peri-oral numbness. These effects are dependant on blood drug levels and, due to its short half-life, correspond to the rate of infusion. Phase II/III clinical studies are accruing patients and results have not yet been reported. Tresperimus shows promise in the move from immunosuppression to tolerance induction as the way to prevent transplant rejection and graft versus host disease (G v HD). However, its role in tolerance induction and effect in combination with other tolerance inducing agents e.g., CTLA-4-Ig and anti-CD40L antibodies remains unclear.

Topics: Animals; Carbamates; Graft vs Host Disease; Half-Life; Humans; Immunosuppressive Agents; Maximum Tolerated Dose; Transplantation Tolerance

Tresperimus (LF-08-0299) is an immunosuppressant under development by Laboratoires Fournier for its potential use in organ transplant rejection. Fournier has commenced phase III trials in the US and Europe [304203]. Tresperimus began phase I/II trials in 1995 for graft versus host rejection in combination with cyclosporine and tacrolimus, but later as first-line therapy. It demonstrated efficient immunosuppressive activity in a rat model of cardiac rejection [182951]. The company is seeking licensees for the product

Topics: Animals; Carbamates; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Drug Evaluation, Preclinical; Drug Therapy, Combination; Drugs, Investigational; Forecasting; Graft vs Host Disease; Humans; Immunosuppressive Agents; Molecular Structure; Prednisolone

A series of new analogues of 15-deoxyspergualin (DSG), an immunosuppressive agent currently commercialized in Japan, was synthesized and tested in a graft-versus-host disease (GVHD) model in mice. Using the general concept of bioisosteric replacement, variations of the hydroxyglycine central "C" region were made in order to determine its optimum structure in terms of in vivo immunosuppressive activity. By this way, the malonic derivative 13a was discovered as the first example of a new series of potent immunosuppressive agents encompassing a retro-amide bond linked to the hexyl-guanidino moiety. Structure-activity relationships of this series were studied by synthesizing compounds 13g-i and 13k-s. Variation of the "right-amide" of 13a led to the urea 19a and the carbamates 23 and 27a which proved to be equally active as DSG in our GVHD model. Finally 27a was found to be the most potent derivative, being slightly more active than DSG in a heart allotransplantation model in rats. Due to the absence of chiral center in its structure and to its improved chemical stability compared to DSG, 27a was selected as a candidate for clinical evaluation.

Topics: Animals; Glycine; Graft vs Host Disease; Guanidines; Heart Transplantation; Immunosuppressive Agents; Magnetic Resonance Spectroscopy; Mice; Molecular Structure; Rats; Structure-Activity Relationship; Transplantation, Homologous

A series of new analogues of 15-deoxyspergualin (DSG), an immunosuppressive agent commercialized in Japan, was synthesized and tested in a graft-versus-host disease (GVHD) model in mice. Various substitutions of the spermidine "D" region were made in order to determine its optimum structure in terms of in vivo immunosuppressive activity. Various positions of methylation were first investigated leading to the discovery of the monomethylated malonic derivative 56h in which the pro-R hydrogen of the methylene alpha to the primary amine of the spermidine moiety has been replaced by a methyl group. Synthesis of the similarly methylated analogue of the previously reported glycolic derivative LF 08-0299 afforded 60e which demonstrated a powerful activity at a dose as low as 0.3 mg/kg in the GVHD model and was much more potent than DSG in the demanding heart allotransplantation model in rats. The improvement of in vivo activity was supposed to be related to an increase of the metabolic stability of the methylated analogues compared to the parent molecules. Due to its very low active dose, compatible with a subcutaneous administration in humans, and its favorable pharmacological and toxicological profile, 60e was selected as a candidate for clinical evaluation.

Topics: Animals; Carbamates; Drug Evaluation, Preclinical; Graft vs Host Disease; Guanidines; Heart Transplantation; Immunosuppressive Agents; Mice; Rats; Rats, Inbred Lew; Spermidine; Stereoisomerism; Structure-Activity Relationship; Transplantation, Homologous

LF08-0299 (Tresperimus) is a new immunosuppressive analogue of Gusperimus (15-deoxyspergualin or DSG). Despite the fact that its mechanism of action remains unknown, DSG has previously been demonstrated to bind specifically to Hsc70 protein, a constitutive or cognate member of heat shock protein 70 family. Herein we further explore whether immobilised LF08-0299 will selectively retain the heat shock protein Hsc70. We analysed the correlation between biological activity in vivo in the prevention of murine graft-vs-host disease (GVHD) and the ability in vitro in dissociating Hsc70 from LF08-0299 resin for LF08-0299 and structural analogues. The Hsc70 protein bound to the LF08-0299 immobilised specifically via the spermidine primary amino group and could be successfully eluted from the column by various analogues of LF08-0299. All immunosuppressants tested were able to competitively bind Hsc70 although some biological inactive compounds could as well. Our data suggests that LF08-0299 and its active analogue effects were not mediated directly through the interaction of molecules with Hsc70. The mechanism of action probably occurred by more than one step, the first being the binding of Hsc70.

Topics: Animals; Binding Sites; Carbamates; Chromatography, Affinity; Graft vs Host Disease; HSP70 Heat-Shock Proteins; Humans; Immunosuppressive Agents; Jurkat Cells; Male; Mice; Mice, Inbred DBA; Mice, Inbred ICR; Protein Binding; Rabbits; Structure-Activity Relationship

Topics: Animals; Carbamates; Drugs, Investigational; Graft Rejection; Graft vs Host Disease; Humans; Immunosuppressive Agents; Mice; Rats

LF 08-0299 (Tresperimus), a novel immunosuppressive compound, has been previously shown to prevent graft-versus-host disease in murine models. In this study, we investigated the influence of LF 08-0299 on the TCR Vbeta repertoire of irradiated F1 recipient mice reconstituted with either syngeneic or parental bone marrow cells. We showed that a partial blockade of thymic differentiation occurred in normal mice under treatment at the transition CD4-/CD8- to CD4+/CD8+, and that this blockade was fully reversible. Despite the effect on the thymus, normal T cell repertoire negative selection was preserved following syngeneic bone marrow transplantation. We further assessed whether LF 08-0299 administration could modify Vbeta T cell expression in irradiated recipients reconstituted with parental bone marrow cells. In our murine parental to F1 transplant model, abnormal TCR Vbeta3, Vbeta5, Vbeta6 and Vbeta11 expression was demonstrated in peripheral lymph nodes of irradiated recipients. Moreover, Vbeta6 and Vbeta3 T cell populations were overexpressed. Administration of LF 08-0299 modified the pattern of Vbeta T cell expression. The expansion of Vbeta6 T cells was selectively inhibited under LF 08-0299 therapy and, in contrast, Vbeta5 T cells were overexpressed. Lymph node histological analysis showed that LF 08-0299 administration fully prevented the graft-versus-host reaction occurring in untreated recipient mice.

Topics: Animals; Bone Marrow Transplantation; Carbamates; Cell Differentiation; Graft vs Host Disease; Immunosuppressive Agents; Lymph Nodes; Male; Mice; Mice, Inbred C57BL; Mice, Inbred DBA; Receptors, Antigen, T-Cell, alpha-beta; T-Lymphocytes; Thymus Gland; Time Factors

We investigated the ability of LF 08--0299, a new immunosuppressive compound, to prevent murine graft-versus-host disease (GVHD) after allogeneic bone marrow transplantation (BMT). A short term LF 08--0299 treatment at optimal dosage protected more than 75% of recipient mice from lethal GVHD induced either across minor antigens alone or the full H2 barrier. Furthermore, LF 08--0299 still prevented lethal GVHD when treatment was delayed to 10 days post-BMT. Long-term LF 08--0299-treated survivors were free of clinical signs of GVHD, and histopathologic examination of liver, skin, and intestines was normal, demonstrating that recipient mice did not develop chronic GVHD. We assessed the immunocompetence of long-term surviving recipient mice. Results from MLR and CTL assays were weak whereas responses against unrelated H2 antigens were reduced but still preserved. Moreover, in vivo transfer experiments demonstrated that spleen cells from long-term survivors were unable to induce lethal GVHD in irradiated recipients of host origin, while spleen cells injected in irradiated recipients of a host-unrelated H2 were fully competent to induce a lethal GVHD. Together these results indicate that stable chimeric recipient mice were specifically tolerant to host antigens. We further showed that while LF 08--0299 can protect recipient mice from lethal GVHD, it also preserved a graft-versus-leukemia effect when mice were inoculated with P815 tumor cells. These data suggest that LF 08--0299 may be a novel pharmaceutical agent that would prevent GVHD in human unrelated bone marrow transplantation.

Topics: Adoptive Transfer; Animals; Bone Marrow Transplantation; Carbamates; Drug Administration Schedule; Drug Evaluation, Preclinical; Female; Graft Rejection; Graft vs Host Disease; H-2 Antigens; Immunocompetence; Immunosuppressive Agents; Lymphocyte Culture Test, Mixed; Male; Mast-Cell Sarcoma; Mice; Mice, Inbred Strains; Minor Histocompatibility Antigens; Neoplasm Transplantation; Radiation Chimera; T-Lymphocytes; T-Lymphocytes, Cytotoxic; Transplantation, Homologous

Topics: Animals; Bone Marrow Transplantation; Carbamates; Graft Survival; Graft vs Host Disease; Histocompatibility Testing; Immunosuppressive Agents; Leukemia, Experimental; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Inbred DBA; Mice, Inbred Strains; Minor Histocompatibility Antigens; Spleen; Whole-Body Irradiation

Topics: Animals; Bone Marrow Transplantation; Carbamates; Graft vs Host Disease; Immune Tolerance; Immunosuppressive Agents; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Inbred DBA; Minor Histocompatibility Antigens