Value through Innovation24 January 2015

Scientific Publications

Boehringer Ingelheim offers an overview of scientific publications on the following pages. This overview represents all publications of the last three years (YTD) where employees of Boehringer Ingelheim worldwide were involved.

18 publications regarding Immunology
  • Author:
    Qian J; Wang Q; Dose M; Pruett N; Kieffer-Kwon K-R; Resch W; Liang G; Tang Z; Mathé E; Benner C; Dubois W; Nelson S; Vian L; Oliveira TY; Jankovic M; Hakim O; Gazumyan A; Pavri R; Awasthi P; Song B; Liu G; Chen L; Zhu S; Feigenbaum L; Staudt L; Murre C; Ruan Y; Robbiani DF; Pan-Hammarström Q; Nussenzweig MC; Casellas R
    Title:
    B cell super-enhancers and regulatory clusters recruit AID tumorigenic activity
    Source:
    Cell 159 (7), 1524-1537 (2014)
    Abstract:
    The antibody gene mutator activation-induced cytidine deaminase (AID) promiscuously damages oncogenes, leading to chromosomal translocations and tumorigenesis. Why nonimmunoglobulin loci are susceptible to AID activity is unknown. Here, we study AID-mediated lesions in the context of nuclear architecture and the B cell regulome. We show that AID targets are not randomly distributed across the genome but are predominantly grouped within super-enhancers and regulatory clusters. Unexpectedly, in these domains, AID deaminates active promoters and eRNA+ enhancers interconnected in some instances over megabases of linear chromatin. Using genome editing, we demonstrate that 3D-linked targets cooperate to recruit AID-mediated breaks. Furthermore, a comparison of hypermutation in mouse B cells, AID-induced kataegis in human lymphomas, and translocations in MEFs reveals that AID damages different genes in different cell types. Yet, in all cases, the targets are predominantly associated with topological complex, highly transcribed super-enhancers, demonstrating that these compartments are key mediators of AID recruitment
  • Author:
    Wu TY-H; Singh M; Miller AT; De Gregorio E; Doro F; D'Oro U; Skibinski DAG; Mbow ML; Bufali S; Herman AE; Cortez A; Li Y; Nayak BP; Tritto E; Filippi CM; Otten GR; Brito LA; Monaci E; Li C; Aprea S; Valentini S; Calabro S; Laera D; Brunelli B; Caproni E; Malyala P; Panchal RG; Warren TK; Bavari S; O'Hagan DT; Cooke MP; Valiante NM
    Title:
    Rational design of small molecules as vaccine adjuvants
    Source:
    Scie Transl Med 6 (263) art.no. 263ra160 (2014)
    Abstract:
    Adjuvants increase vaccine potency largely by activating innate immunity and promoting inflammation. Limiting the side effects of this inflammation is a major hurdle for adjuvant use in vaccines for humans. It has been difficult to improve on adjuvant safety because of a poor understanding of adjuvant mechanism and the empirical nature of adjuvant discovery and development historically.We describe new principles for the rational optimization of small-molecule immune potentiators (SMIPs) targeting Toll-like receptor 7 as adjuvants with a predicted increase in their therapeutic indices. Unlike traditional drugs, SMIP-based adjuvants need to have limited bioavailability and remain localized for optimal efficacy. These features also lead to temporally and spatially restricted inflammation that should decrease side effects. Throughmedicinal and formulation chemistry and extensive immunopharmacology, we show that in vivo potency can be increasedwith little to no systemic exposure, localized innate immune activation and short in vivo residence times of SMIP-based adjuvants. This work provides a systematic and generalizable approach to engineering small molecules for use as vaccine adjuvants.
  • Author:
    El-Far M; Pellerin C; Pilote L; Fortin J-F; Lessard IA D; Peretz Y; Wardrop E; Salois P; Bethell RC; Cordingley MG; Kukolj G
    Title:
    CD160 isoforms and regulation of CD4 and CD8 T-cell responses
    Source:
    J Transl Med 12 (1) art. no. 217 (2014)
    Abstract:
    Background: Coexpression of CD160 and PD-1 on HIV-specific CD8+ T-cells defines a highly exhausted T-cell subset. CD160 binds to Herpes Virus Entry Mediator (HVEM) and blocking this interaction with HVEM antibodies reverses T-cell exhaustion. As HVEM binds both inhibitory and activatory receptors, our aim in the current study was to assess the impact of CD160-specific antibodies on the enhancement of T-cell activation.Methods: Expression of the two CD160 isoforms; glycosylphosphatidylinositol-anchored (CD160-GPI) and the transmembrane isoforms (CD160-TM) was assessed in CD4 and CD8 primary T-cells by quantitative RT-PCR and Flow-cytometry. Binding of these isoforms to HVEM ligand and the differential capacities of CD160 and HVEM specific antibodies to inhibit this binding were further evaluated using a Time-Resolved Fluorescence assay (TRF). The impact of both CD160 and HVEM specific antibodies on enhancing T-cell functionality upon antigenic stimulation was performed in comparative ex vivo studies using primary cells from HIV-infected subjects stimulated with HIV antigens in the presence or absence of blocking antibodies to the key inhibitory receptor PD-1.Results: We first show that both CD160 isoforms, CD160-GPI and CD160-TM, were expressed in human primary CD4+ and CD8+ T-cells. The two isoforms were also recognized by the HVEM ligand, although this binding was less pronounced with the CD160-TM isoform. Mechanistic studies revealed that although HVEM specific antibodies blocked its binding to CD160-GPI, surprisingly, these antibodies enhanced HVEM binding to CD160-TM, suggesting that potential antibody-mediated HVEM multimerization and/or induced conformational changes may be required for optimal CD160-TM binding. Triggering of CD160-GPI over-expressed on Jurkat cells with either bead-bound HVEM-Fc or anti-CD160 monoclonal antibodies enhanced cell activation, consistent with a positive co-stimulatory role for CD160-GPI. However, CD160-TM did not respond to this stimulation, likely due to the lack of optimal HVEM binding. Finally, ex vivo assays using PBMCs from HIV viremic subjects showed that the use of CD160-GPI-specific antibodies combined with blockade of PD-1 synergistically enhanced the proliferation of HIV-1 specific CD8+ T-cells upon antigenic stimulation.Conclusions: Antibodies targeting CD160-GPI complement the blockade of PD-1 to enhance HIV-specific T-cell responses and warrant further investigation in the development of novel immunotherapeutic approaches.
  • Author:
    .krnjug I; Rueckert C; Libanova R; Lienenklaus S; Weiss S; Guzmán CA
    Title:
    The mucosal adjuvant cyclic di-AMP exerts immune stimulatory effects on dendritic cells and macrophages
    Source:
    PLoS ONE 9 (4) art.no.e95728 (2014)
    Abstract:
    The cyclic di-nucleotide bis-(3.,5.)-cyclic dimeric adenosine monophosphate (c-di-AMP) is a candidate mucosal adjuvant with proven efficacy in preclinical models. It was shown to promote specific humoral and cellular immune responses following mucosal administration. To date, there is only fragmentary knowledge on the cellular and molecular mode of action of c-di-AMP. Here, we report on the identification of dendritic cells and macrophages as target cells of c-di-AMP. We show that c-di-AMP induces the cell surface up-regulation of T cell co-stimulatory molecules as well as the production of interferon-.. Those responses were characterized by in vitro experiments with murine and human immune cells and in vivo studies in mice. Analyses of dendritic cell subsets revealed conventional dendritic cells as principal responders to stimulation by c-di-AMP. We discuss the impact of the reported antigen presenting cell activation on the previously observed adjuvant effects of c-di-AMP in mouse immunization studies. © 2014 .krnjug et al.
  • Author:
    Profita M; Albano GD; Riccobono L; Di Sano C; Montalbano AM; Gagliardo R; Anzalone G; Bonanno A; Pieper MP; Gjomarkaj M
    Title:
    Increased levels of Th17 cells are associated with non-neuronal acetylcholine in COPD patients
    Source:
    Immunobiology 219 (5), 392-401 (2014)
    Abstract:
    T-lymphocytes, including Th17-cells and T-cells expressing acetylcholine (ACh), are key components of systemic inflammation in chronic obstructive pulmonary disease (COPD). We investigated whether ACh promotes Th17 cells in COPD.ACh, IL-17A, IL-22, ROR.t, FOXP3 expression and AChIL-17A, AChIL-22, AChROR.t coexpression was evaluated in peripheral blood mononuclear cells (PBMC) from COPD patients (n=16), healthy smokers (HS) (n=12) and healthy control subjects (HC) (n=13) (cultured for 48h with PMA) by flow cytometry. Furthermore, we studied the effect of Tiotropium (Spiriva®) (100nM) and Olodaterol (1nM) alone or in combination, and of hemicholinium-3 (50.M) on AChIL-17A, AChIL-22, AChROR.t, and FOXP3 expression in CD3+PBT-cells of PBMC from COPD patients (n=6) cultured for 48h with PMA.CD3+PBT-cells expressing ACh, IL-17A, IL-22 and ROR.t together with CD3+PBT-cells co-expressing AChIL-17A, AChIL-22 and AChROR.t were significantly increased in COPD patients compared to HC and HS subjects with higher levels in HS than in HC without a significant difference. CD3+FOXP3+PBT-cells were increased in HS than in HC and COPD. Tiotropium and Olodaterol reduced the percentage of CD3+PBT-cells co-expressing AChIL-17A, AChIL-22, and AChROR.t while increased the CD3+FOXP3+PBT-cells in PBMC from COPD patients, cultured in vitro for 48h, with an additive effect when used in combination. Hemicholnium-3 reduced the percentage of ACh+IL-17A+, ACh+IL-22+, and ACh+ROR.t+ while it did not affect FOXP3+ expression in CD3+PBT-cells from cultured PBMC from COPD patients.We concluded that ACh might promote the increased levels of Th17-cells in systemic inflammation of COPD. Long-acting .2-agonists and anticholinergic drugs might contribute to control this event. © 2014 Elsevier GmbH.
  • Author:
    Krug N; Gupta A; Badorrek P; Koenen R; Mueller M; Pivovarova A; Hilbert J; Wetzel K; Hohlfeld JM; Wood C
    Title:
    Efficacy of the oral chemoattractant receptor homologous molecule on T H2 cells antagonist BI 671800 in patients with seasonal allergic rhinitis
    Source:
    J Allergy Clin Immunol 133 (2), 414-419 e8 (2014)
    Abstract:
    Background The inflammatory response in patients with seasonal allergic rhinitis (SAR) is partly mediated by the prostaglandin D2 receptor chemoattractant receptor homologous molecule on TH2 cells (CRTH2). Objective We sought to investigate the efficacy and safety of the oral CRTH2 antagonist BI 671800 (50, 200, and 400 mg twice daily), fluticasone propionate nasal spray (200 .g once daily), or oral montelukast (10 mg once daily) administered for 2 weeks in patients with SAR. Methods In this randomized, double-blind, placebo-controlled, partial-crossover study, participants aged 18 to 65 years with a positive skin prick test to Dactylis glomerata pollen were exposed to out-of-season allergen in the environmental challenge chamber for 6 hours. The primary efficacy variable was the total nasal symptom score assessed as the area under the curve (AUC)0-6h. Results In total, 146 patients (63.7% male; mean age, 36.1 years) were randomized. The adjusted mean total nasal symptom score AUC0-6h was significantly reduced versus placebo with 200 mg of BI 671800 (absolute difference, -0.85; percentage difference, -17%; P =.0026), montelukast (absolute difference, -0.74; percentage difference, -15%; P =.0115), and fluticasone propionate (absolute difference, -1.64; percentage difference, -33%; P <.0001). Compared with placebo, BI 671800 significantly reduced nasal eosinophil values (P <.05 for all doses), significantly inhibited nasal inflammatory cytokine levels (IL-4 and eotaxin, P <.05; 200 mg twice daily), and induced a dose-related reduction in ex vivo prostaglandin D2-mediated eosinophil shape change. Conclusion Two hundred milligrams of BI 671800 twice daily demonstrated efficacy in treating SAR symptoms induced by environmental challenge chamber allergen exposure and had a favorable safety profile. © 2013 American Academy of Allergy, Asthma & Immunology
  • Author:
    Profita M; Albano GD; Riccobono L; Di Sano C; Montalbano AM; Gagliardo R; Anzalone G; Bonanno A; Pieper MP; Gjomarkaj M
    Title:
    Increased levels of Th17 cells are associated with non-neuronal acetylcholine in COPD patients
    Source:
    Immunobiology Article in press (2014)
    Abstract:
    T-lymphocytes, including Th17-cells and T-cells expressing acetylcholine (ACh), are key components of systemic inflammation in chronic obstructive pulmonary disease (COPD). We investigated whether ACh promotes Th17 cells in COPD. ACh, IL-17A, IL-22, ROR.t, FOXP3 expression and AChIL-17A, AChIL-22, AChROR.t coexpression was evaluated in peripheral blood mononuclear cells (PBMC) from COPD patients (n = 16), healthy smokers (HS) (n = 12) and healthy control subjects (HC) (n = 13) (cultured for 48 h with PMA) by flow cytometry. Furthermore, we studied the effect of Tiotropium (Spiriva®) (100 nM) and Olodaterol (1 nM) alone or in combination, and of hemicholinium-3 (50 .M) on AChIL-17A, AChIL-22, AChROR.t, and FOXP3 expression in CD3+PBT-cells of PBMC from COPD patients (n = 6) cultured for 48 h with PMA. CD3+PBT-cells expressing ACh, IL-17A, IL-22 and ROR.t together with CD3+PBT-cells co-expressing AChIL-17A, AChIL-22 and AChROR.t were significantly increased in COPD patients compared to HC and HS subjects with higher levels in HS than in HC without a significant difference. CD3+FOXP3+PBT-cells were increased in HS than in HC and COPD. Tiotropium and Olodaterol reduced the percentage of CD3+PBT-cells co-expressing AChIL-17A, AChIL-22, and AChROR.t while increased the CD3+FOXP3+PBT-cells in PBMC from COPD patients, cultured in vitro for 48 h, with an additive effect when used in combination. Hemicholnium-3 reduced the percentage of ACh+IL-17A+, ACh+IL-22+, and ACh+ROR.t+ while it did not affect FOXP3+ expression in CD3+PBT-cells from cultured PBMC from COPD patients. We concluded that ACh might promote the increased levels of Th17-cells in systemic inflammation of COPD. Long-acting .2-agonists and anticholinergic drugs might contribute to control this event. © 2014.
  • Author:
    Teixeira LH; Tararam CA; Lasaro MO; Camacho AGA; Ersching J; Leal MT; Herrera S; Bruna-Romero O; Soares IS; Nussenzweig RS; Ertl HCJ; Nussenzweig V; Rodrigues MM
    Title:
    Immunogenicity of a prime-boost vaccine containing the circumsporozoite proteins of plasmodium vivax in rodents
    Source:
    Infect Immun 82 (2), 793-807 (2014)
    Abstract:
    Plasmodium vivax is the most widespread and the second most prevalent malaria-causing species in the world. Current measures used to control the transmission of this disease would benefit from the development of an efficacious vaccine.In the case of the deadly parasite P. falciparum, the recombinant RTS,S vaccine containing the circumsporozoite antigen (CSP) consistently protects 30 to 50% of human volunteers against infection and is undergoing phase III clinical trials in Africa with similar efficacy. These findings encouraged us to develop a P. vivax vaccine containing the three circulating allelic forms of P. vivax CSP. Toward this goal, we generated three recombinant bacterial proteins representing the CSP alleles, as well as a hybrid polypeptide called PvCSP-All-CSP-epitopes. This hybrid contains the conserved N and C termini of P. vivax CSP and the three variant repeat domains in tandem. We also generated simian and human recombinant replication-defective adenovirus vectors expressing PvCSP-All-CSP-epitopes. Mice immunized with the mixture of recombinantproteins in a formulation containing the adjuvant poly(I.C) developed high and long-lasting serum IgG titers comparable to those elicited by proteins emulsified in complete Freund's adjuvant. Antibody titers were similar in mice immunized with homologous (protein-protein) and heterologous (adenovirus-protein) vaccine regimens. The antibodies recognized the three allelic forms of CSP, reacted to the repeated and nonrepeated regions of CSP, and recognized sporozoites expressing the alleles VK210 and VK247. The vaccine formulations described in this work should be useful for the further development of an anti-P. vivax vaccine. © 2014, American Society for Microbiology.
  • Author:
    Krug N; Gupta A; Badorrek P; Koenen R; Mueller M; Pivovarova A; Hilbert J; Wetzel K; Hohlfeld JM; Wood C
    Title:
    Efficacy of the oral chemoattractant receptor homologous molecule on TH2 cells antagonist BI 671800 in patients with seasonal allergic rhinitis
    Source:
    J Allergy Clin Immunol Article in press (2013)
    Abstract:
    Background: The inflammatory response in patients with seasonal allergic rhinitis (SAR) is partly mediated by the prostaglandin D2 receptor chemoattractant receptor homologous molecule on TH2 cells (CRTH2). Objective: We sought to investigate the efficacy and safety of the oral CRTH2 antagonist BI 671800 (50, 200, and 400 mg twice daily), fluticasone propionate nasal spray (200 .g once daily), or oral montelukast (10 mg once daily) administered for 2 weeks in patients with SAR. Methods: In this randomized, double-blind, placebo-controlled, partial-crossover study, participants aged 18 to 65 years with a positive skin prick test to Dactylis glomerata pollen were exposed to out-of-season allergen in the environmental challenge chamber for 6 hours. The primary efficacy variable was the total nasal symptom score assessed as the area under the curve (AUC)0-6h. Results: In total, 146 patients (63.7% male; mean age, 36.1 years) were randomized. The adjusted mean total nasal symptom score AUC0-6h was significantly reduced versus placebo with 200 mg of BI 671800 (absolute difference, -0.85; percentage difference, -17%; P = .0026), montelukast (absolute difference, -0.74; percentage difference, -15%; P = .0115), and fluticasone propionate (absolute difference, -1.64; percentage difference, -33%; P < .0001). Compared with placebo, BI 671800 significantly reduced nasal eosinophil values (P < .05 for all doses), significantly inhibited nasal inflammatory cytokine levels (IL-4 and eotaxin, P < .05; 200 mg twice daily), and induced a dose-related reduction in ex vivo prostaglandin D2-mediated eosinophil shape change. Conclusion: Two hundred milligrams of BI 671800 twice daily demonstrated efficacy in treating SAR symptoms induced by environmental challenge chamber allergen exposure and had a favorable safety profile. © 2013 American Academy of Allergy, Asthma & Immunology
  • Author:
    Noyes A; Boesch A; Godavarti R; Titchener-Hooker N; Coffman J; Mukhopadhyay T
    Title:
    High throughput quantification of capsular polysaccharides for multivalent vaccines using precipitation with a cationic surfactant
    Source:
    Vaccine 31 (48), 5659-5665 (2013)
    Abstract:
    The increasing requirement for multivalent vaccines containing diverse capsular polysaccharides has created an unmet need for a fast and straightforward assay for polysaccharide titer. We describe a novel and robust assay for the quantitation of anionic capsular polysaccharides. The binding of hexadecyltrimethyammonium bromide (Hb) to anionic capsular polysaccharides results in a precipitation reaction wherein the suspension turbidity is proportional to polysaccharide titer. The turbidity can be quickly measured as absorbance across a range of wavelengths that resolve scattering light. Carbohydrates comprised of repeating units of one to seven monosaccharides with phosphodiester groups, uronic acids, and sialic acids all reacted strongly and there does not appear to be specificity with respect to the particular anionic moiety. The assay is compatible with an array of common buffers across a pH range of 3.0-8.75 and with NaCl concentration exceeding 400. mM. Interference from DNA can be eliminated with a short incubation step with DNase. With these treatments, the assay has been employed in samples as complex as fermentation broth. A two-log dynamic range has been established with a mean relative standard deviation less than 10% across this range although inferior performance has been observed in fermentation broth.The precipitation assay enables the rapid quantitation of anionic polysaccharides. The resulting procedure can robustly measure the titer of myriad anionic capsular polysaccharides (CPS) in 96 samples in less than 30. min using low toxicity reagents and routine laboratory equipment. This development will greatly reduce the effort required to measure polysaccharide titer and yield during process development of polysaccharide vaccines. © 2013 The Authors.
  • Author:
    Engel Michael; Schmidt Hendrick; Moroni-Zentgraf Petra
    Title:
    Efficacy of tiotropium in patients with asthma in relation to allergic status.
    Source:
    J Allergy Clin Immunol 131 (2) (1), AB1 (2013)
    Abstract:
    RATIONALE: The response of patients with asthma to some medications may be influenced by their allergic status. Tiotropium, a long-acting anticholinergic, has demonstrated efficacy and safety in patients with asthma (Kerstjens et al. NEJM 2012), but the relationship between response and patient allergic status has not been published in detail. METHODS: Analysis of prespecified subgroups was performed using data from two replicate, 48-week, placebo-controlled trials (N5912) conducted in patients with asthma on at least ICS+LABA randomized to adding tiotropium 5.mu.g Respimat or placebo once daily. The subgroup of patients with potentially allergic asthma was identified using three criteria: total serum IgE, blood eosinophils, or clinician judgment (CJ). Allergic status was positive if serum IgE was >430 .mu.g/L, blood eosinophils were >0.6.times.10 /L, or CJ was .mchlt.yes..mchgt. RESULTS: Peak FEV1 improved with tiotropium irrespective of allergic status in Trial 1 (IgE [subgroup3treatment interaction, P=0.86] and eosinophils [P=0.46]) and in Trial 2 (IgE [P=0.98]; eosinophils P=0.18]; and CJ [P=0.29]). Predose (trough) FEV1improved with tiotropium compared with placebo, irrespective of allergic status, across all three criteria (Trial 1 [IgE, P=0.85; eosinophils, P=0.83; and CJ, P=0.15]; Trial 2 [IgE, P=0.58; eosinophils, P=0.38; and CJ, P=0.85]). Pooled data analyses revealed that time to first severe asthma exacerbation and time to first asthma worsening were both increased with tiotropium compared with placebo, regardless of allergic status, based on the three criteria. Overall, adverse events were balanced. CONCLUSIONS: Tiotropium improved lung function and asthma control in patients with poorly controlled asthma despite treatment with ICS+LABA, irrespective of their allergic status.
  • Author:
    Miriyala S; Panchatcharam M; Ramanujam M; Puvanakrishnan R
    Title:
    A novel tetrapeptide derivative exhibits in vitro inhibition of neutrophil-derived reactive oxygen species and lysosomal enzymes release
    Source:
    Oxidative Med Cell Longevity art no 853210 (2013)
    Abstract:
    Neutrophil infiltration plays a major role in the pathogenesis of myocardial injury. Oxidative injury is suggested to be a central mechanism of the cellular damage after acute myocardial infarction. This study is pertained to the prognostic role of a tetrapeptide derivative PEP1261 (BOC-Lys(BOC)-Arg- Asp-Ser(tBu)-OtBU), a peptide sequence (39-42) of lactoferrin, studied in the modulation of neutrophil functions in vitro by measuring the reactive oxygen species (ROS) generation, lysosomal enzymes release, and enhanced expression of C proteins. The groundwork experimentation was concerned with the isolation of neutrophils from the normal and acute myocardial infarct rats to find out the efficacy of PEP1261 in the presence of a powerful neutrophil stimulant, phorbol 12-myristate 13 acetate (PMA). Stimulation of neutrophils with PMA resulted in an oxidative burst of superoxide anion and enhanced release of lysosomal enzymes and expression of complement proteins. The present study further demonstrated that the free radicals increase the complement factors in the neutrophils confirming the role of ROS. PEP1261 treatment significantly reduced the levels of superoxide anion and inhibited the release of lysosomal enzymes in the stimulated control and infarct rat neutrophils. This study demonstrated that PEP1261 significantly inhibited the effect on the ROS generation as well as the mRNA synthesis and expression of the complement factors in neutrophils isolated from infarct heart. © 2013 Sumitra Miriyala et al.
  • Author:
    Miriyala S; Panchatcharam M; Landar A; Ramanujam M; Chatterjee S; Muthuswamy A
    Title:
    The janus of oxidative stress signaling in different pathophysiological conditions
    Source:
    Oxidative Med Cell Longevity art no 708796 (2013)
    Abstract:
    no abstract available
  • Author:
    Wu H S; Lunter A-K; Spillner E; Schmitz N; Heider K-H; Zeis M
    Title:
    A Novel Anti-CD37 antibody shows superior antibody dependent cellualar cytotoxic activity (ADCC) compared to Rituximab against patient-derived Lymphoma cells
    Source:
    DGHO Jahrestagung, Wien 18-22.10. 2013
  • Author:
    Sathish JG; Sethu S; Bielsky M-C; De Haan L; French NS; Govindappa K; Green J; Griffiths CEM; Holgate S; Jones D; Kimber I; Moggs J; Naisbitt DJ; Pirmohamed M; Reichmann G; Sims J; Subramanyam M; Todd MD; Van Der Laan JW; Weaver RJ; Park BK
    Title:
    Challenges and approaches for the development of safer immunomodulatory biologics
    Source:
    Nat Rev Drug Discov 12 (4), 306-324 (2013)
    Abstract:
    Immunomodulatory biologics, which render their therapeutic effects by modulating or harnessing immune responses, have proven their therapeutic utility in several complex conditions including cancer and autoimmune diseases. However, unwanted adverse reactions-including serious infections, malignancy, cytokine release syndrome, anaphylaxis and hypersensitivity as well as immunogenicity-pose a challenge to the development of new (and safer) immunomodulatory biologics. In this article, we assess the safety issues associated with immunomodulatory biologics and discuss the current approaches for predicting and mitigating adverse reactions associated with their use. We also outline how these approaches can inform the development of safer immunomodulatory biologics.
  • Author:
    Freebern W J; Bigwarfe T J; Price K D; Haggerty H G
    Title:
    Methods: Implementation of in vitro and ex vivo phagocytosis and respiratory burst function assessments in safety testing
    Source:
    J Immunotoxicol 10 (1), 106-117 (2013)
    Abstract:
    Abstract Functional innate immune assessments, including phagocytosis and respiratory burst, are at the forefront of immunotoxicology evaluation in pre-clinical animal species. Although in the clinic and in academic science, phagocytosis, and respiratory burst assessments have been reported for over two decades, the implementation of phagocytosis and respiratory burst analyses in toxicology safety programs is just recently gaining publicity. Discussed herein are general methods, both microtiter plate-based and flow cytometric-based, for assessing phagocytosis and respiratory burst in pre-clinical species including mouse, rat, dog, and monkey. This methods-centric discussion includes a review of technologies and descriptions of method applications, with examples of results from analyses testing reported inhibitors (rottlerin, wortmannin, and SB203580) of phagocytosis and respiratory burst. Justification of implementation, strategic experimental design planning, and feasibility aspects of evaluating test article effects on phagocytosis and respiratory burst function are described within the context of a case study. The case study involves investigation of the effects of a small molecule p38 kinase inhibitor, BMS-582949, on phagocytosis and respiratory burst functions in rat and monkey neutrophils and monocytes in vitro, as well as ex vivo in these innate immune cells from monkeys administered BMS-582949 during a 1-week repeat dose investigative study. The results of the in vitro and ex vivo assessments demonstrated that BMS-582949 inhibited phagocytosis and respiratory burst. These findings correlated with incidences of opportunistic infections observed in rat and monkey toxicity studies. © 2013 Informa Healthcare USA, Inc.
  • Author:
    Tilp, C.; Kapur, V.; Loging, W.; Erb, K.J.
    Title:
    Prerequisites for the pharmaceutical industry to develop and commercialise helminths and helminth-derived product therapy
    Source:
    Int. J. Parasitol 43 (3-4), 319-325 (2013)
    Abstract:
    During the past 10. years, immunologists, epidemiologists and parasitologists have made many new exciting discoveries in the field of helminth-mediated immune regulation. In addition, many animal experiments have shown that certain helminths or products derived from helminths can protect mice from developing allergic or autoimmune disease. Some clinical trials utilising Trichuris suis or Necator americanus for the treatment of allergic disorders and inflammatory bowel disease have been conducted. The outcomes of these trials suggest that they may be used to treat these disorders. However, to date no helminth therapy is routinely being applied to patients and no helminth-derived product therapy has been developed. In order to bring new drugs to the market and shoulder the enormous costs involved in developing such therapies, pharmaceutical companies need to be involved. However, currently the resources from the pharmaceutical industry devoted to this concept are relatively small and there are good reasons why the industry may have been reluctant to invest in developing these types of therapies. In this review article, the hurdles that must be overcome before the pharmaceutical industry might invest in these novel therapies are outlined. © 2013 Australian Society for Parasitology Inc.
  • Author:
    Wagner C L; Visvanathan S; Elashoff M; Mcinnes I B; Mease P J; Krueger G G; Murphy F T; Papp K; Gomez-Reino JJ; Mack M; Beutler A; Gladman D; Kavanaugh A
    Title:
    Markers of inflammation and bone remodelling associated with improvement in clinical response measures in psoriatic arthritis patients treated with golimumab
    Source:
    Ann Rheum Dis 72 (1), 83-88 (2013)
    Abstract:
    Objective: To determine serum biomarker associations with clinical response to golimumab treatment in patients with psoriatic arthritis (PsA). Methods: GO-REVEAL was a randomised, placebo-controlled study of golimumab in patients with active PsA. Samples were collected from 100 patients at baseline, week 4 and week 14, and analysed for serum-based biomarkers and protein profiling (total 92 markers); data were correlated with clinical measures at week 14. Results: Serum levels of a subset of proteins (apolipoprotein C III, ENRAGE, IL-16, myeloperoxidase, vascular endothelial growth factor, pyridinoline, matrix metalloproteinase 3, C-reactive protein (CRP), carcinoembryonic antigen, intercellular adhesion molecule 1 and macrophage inflammatory protein 1?) at baseline or week 4 were strongly associated with American College of Rheumatology 20% improvement (ACR20) response and/or disease activity score in 28 joints (DAS28) at week 14. A smaller subset of proteins was significantly associated with a 75% improvement in the psoriasis area and severity index score (PASI75) at week 14, (adiponectin, apolipoprotein CIII, serum glutamic oxaloacetic transaminase, and tumour necrosis factor ?). Subsets of proteins were identified as potentially predictive of clinical response for each of the clinical measures, and the power of these biomarker panels to predict clinical response to golimumab treatment was stronger than for CRP alone. Conclusions: This analysis provides insight into several panels of markers that may have utility in identifying PsA patients likely to have ACR20, DAS28, or PASI75 responses following golimumab treatment. Copyright Article author (or their employer) 2012.