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Broberg K.E.,Lund University | Warholm M.,Karolinska Institutet | Tinnerberg H.,Lund University | Axmon A.,Lund University | And 4 more authors.
Pharmacogenetics and Genomics | Year: 2010

BACKGROUND: Toluene di-isocyanate (TDI) is widely used in the production of polyurethane foams and paints. As TDI causes respiratory disease in only a fraction of exposed workers, genetic factors may play a key role in disease susceptibility. Polymorphisms in TDI metabolising genes may affect elimination kinetics, resulting in differences in body retention, and in its turn differences in adverse effects. OBJECTIVES: To analyze how genotype modifies the associations between (i) TDI in air (2,4-TDI and 2,6-TDI) and its metabolites toluene diamine (TDA; 2,4-TDA and 2,6-TDA) in hydrolyzed urine; and (ii) 2,4-TDA and 2,6-TDA in hydrolyzed plasma and 2,4-TDA and 2,6-TDA in urine. METHODS: Workers exposed to TDI were analyzed for 2,4-TDI and 2,6-TDI in air (N=70), 2,4-TDA and 2,6-TDA in hydrolyzed urine (N=124) and in plasma (N=128), and genotype: CYP1A1*2A, CYP1A1*2B, GSTA1-52, GSTM1O, GSTM3B, GSTP1 I105V, GSTP1 A114V, GSTT1O, MPO-463, NAT1*3, *4, *10, *11, *14, *15, NAT2*5, *6, *7, and SULT1A1 R213H. RESULTS: GSTP1 105 strongly modified the relationship between 2,4-TDA in plasma and in urine: ValVal carriers had about twice as steep regression slope than IleIle carriers. A similar pattern was found for 2,6-TDA. CYP1A1*2A, GSTM1, GSTP1, GSTT1, and MPO possibly influenced the relationship between TDA in plasma and urine. CONCLUSION: Our results show, for the first time, genetic modification on the human TDI metabolism. The findings suggest that GSTP1 genotype should be considered when evaluating biomarkers of TDI exposure in urine and plasma. Moreover, the results support earlier findings of GSTP1 105 Val as protective against TDI-related asthma. © 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins.


Fritzson I.,Active Biotech Research AB | Svensson B.,SARomics AB | Al-Karadaghi S.,Lund University | Walse B.,SARomics AB | And 4 more authors.
ChemMedChem | Year: 2010

A strategy that combines virtual screening and structureguided selection of fragments was used to identify three unexplored classes of human DHODH inhibitor compounds: 4-hydroxycoumarins, fenamic acids, and N-(alkylcarbonyl) anthranilic acids. Structure-guided selection of fragments targeting the inner subsite of the DHODH ubiquinone binding site made these findings possible with screening of fewer than 300 fragments in a DHODH assay. Fragments from the three inhibitor classes identified were subsequently chemically expanded to target an additional subsite of hydrophobic character. All three classes were found to exhibit distinct structure-activity relationships upon expansion. The novel N-(alkylcarbonyl)anthranilic acid class shows the most promising potency against human DHODH, with IC50 values in the low nanomolar range. The structure of human DHODH in complex with an inhibitor of this class is presented. © 2010 Wiley-VCH Verlag GmbHand Co. KGaA, Weinheim.


Forsberg G.,Active Biotech Research AB | Skartved N.-J.,Symphogen | Wallen-Ohman M.,Active Biotech Research AB | Nyhlen H.C.,Active Biotech Research AB | And 3 more authors.
Journal of Immunotherapy | Year: 2010

Antibody-targeted superantigens have a potential to become useful drugs for tumor therapy. However, clinical practice has identified several issues that need to be addressed to optimize such molecules. On the basis of the experience from superantigen products in clinical trials, a novel tumor-targeted superantigen, naptumomab estafenatox (5T4FabV18-SEA/E-120 or ABR-217620) has been designed. Critical properties, such as tumor reactivity, therapeutic window, and seroreactivity were all improved. The engineered 5T4Fab moiety recognizes the 5T4 antigen expressed on a large number of solid tumor forms with an affinity in the order of 1nM. The fusion protein induces T-cell mediated killing of tumor cells at concentrations around 10pM. Compared with a construct with a wild-type superantigen, it is more potent in mediating killing of tumor cells but a 10,000-fold less active in mediating killing of MHC class II positive cells. The target epitopes for naturally occurring antibodies toward bacterial superantigens are reduced. Only large excesses of human anti-SEA antibodies neutralize the antitumor effects of the antibody-targeted superantigen. Naptumomab estafenatox induces dramatic reduction of established human tumors in Severe Combined Immunodeficient mice grafted with human lymphocytes. Thus, naptumomab estafenatox is a novel optimized tumor-targeted superantigen currently investigated in clinical trials. Copyright © 2010 by Lippincott Williams & Wilkins.


Helmersson S.,Lund University | Stenstrom M.,Active Biotech Research AB | Leanderson T.,Lund University | Ivars F.,Lund University
International Immunopharmacology | Year: 2011

Quinoline-3-carboxamides are currently in clinical development for treatment of both autoimmune disease and cancer. Carboxamides such as ABR-215757 (5757) have shown efficacy in several in vivo mouse models of human inflammatory autoimmune disease. Some microbial infections in mice cause GM-CSF dependent accumulation of dendritic cells expressing TNFα and inducible nitric oxide synthase (iNOS; Tip-DCs) in lymphoid organs. Functionally similar DCs develop in GM-CSF stimulated bone marrow (BM) cell cultures and offered an in vitro model that allowed us to study the impact of 5757 on cellular development of relevance for in vivo inflammatory conditions. We show in here that addition of 5757 to such cultures, in a dose-dependent way increased the frequency of DCs, while it reduced the frequency of Gr-1 + cells by inhibiting their proliferation. This effect was specific as the compound neither influenced DC development from myeloid progenitors, nor the development of granulocytes in G-CSF stimulated BM cell cultures. Importantly, we also show that 5757 treatment reduced the accumulation of Gr-1 + cells during inflammation in vivo. We therefore propose that this compound may ameliorate autoimmune disease by blocking proliferation of Gr-1 + cells during inflammation-induced mobilization of myeloid cells. © 2011 Elsevier B.V. All rights reserved.


Stenstrom M.,Lund University | Stenstrom M.,Active Biotech Research AB | Anderson P.,Lund University | Anderson P.,Institute Parasitologia y Biomedicina | And 3 more authors.
International Immunopharmacology | Year: 2010

The quinoline-3-carboxamide ABR-215757 (5757) is in clinical development for the treatment of human SLE and has shown efficacy in several mouse models of T cell-mediated inflammatory autoimmune disease. The goal of this study was to determine the impact of 5757 on steady state immune cells. We show that the number of splenic CD4 dendritic cells (DCs) was reduced in 5757-treated mice, while there was no effect on other splenic DC populations, on DCs in lymph nodes or on lymphocytes. This reduction was fully reversible and the kinetics of CD4 DC loss during exposure and recovery after withdrawal of treatment was identical. The loss of CD4 DCs was neither caused by reduced proliferation nor by increased apoptosis. CD4 DCs reside in the splenic marginal zone, but the loss of these cells did not influence other cell populations at this site. The similar kinetics of the decay and repopulation of the splenic CD4 DC compartment suggests that the reduced number of CD4 DC in 5757 treated mice may be a result of blockade of CD4 DC precursor development in the spleen and not of toxicity. Alternatively, induced emigration of CD4 DC to the periphery, or an interference with adherence of these cells in the spleen marginal zone, may also explain our data. © 2010 Elsevier B.V.


A strategy that combines virtual screening and structure-guided selection of fragments was used to identify three unexplored classes of human DHODH inhibitor compounds: 4-hydroxycoumarins, fenamic acids, and N-(alkylcarbonyl)anthranilic acids. Structure-guided selection of fragments targeting the inner subsite of the DHODH ubiquinone binding site made these findings possible with screening of fewer than 300 fragments in a DHODH assay. Fragments from the three inhibitor classes identified were subsequently chemically expanded to target an additional subsite of hydrophobic character. All three classes were found to exhibit distinct structure-activity relationships upon expansion. The novel N-(alkylcarbonyl)anthranilic acid class shows the most promising potency against human DHODH, with IC(50) values in the low nanomolar range. The structure of human DHODH in complex with an inhibitor of this class is presented.

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