DOCSLIB.ORG

Recent Advances in Inflammatory Bowel Disease: Mucosal Immune

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Recent Advances in Inflammatory Bowel Disease: Mucosal Immune Recent advances in basic science Recent advances in inflammatory bowel disease: Gut: first published as 10.1136/gutjnl-2012-303955 on 8 October 2013. Downloaded from mucosal immune cells in intestinal inflammation M Zaeem Cader,1,2 Arthur Kaser1 1Department of Medicine, ABSTRACT Recent years have seen a rapid and exciting Division of Gastroenterology & The intestine and its immune system have evolved to expansion in our understanding of the mucosal Hepatology, University of Cambridge, Addenbrooke’s meet the extraordinary task of maintaining tolerance to immune system with novel insights into environ- Hospital, Cambridge, UK the largest, most complex and diverse microbial mental influences of diet and the microbiota; the 2Wellcome Trust PhD commensal habitat, while meticulously attacking and convergence and integration of fundamental cellu- Programme for Clinicians, containing even minute numbers of occasionally lar processes such as autophagy, microbial sensing Cambridge Institute for incoming pathogens. While our understanding is still far and endoplasmic reticulum (ER) stress; as well as Medical Research, School of Clinical Medicine, University of from complete, recent studies have provided exciting the discovery of new cell types, for example innate Cambridge, Cambridge, UK novel insights into the complex interplay of the many lymphoid cells (ILCs). distinct intestinal immune cell types as well as the The gut is unlike the systemic immune system in Correspondence to discovery of entirely new cell subsets. These studies have several respects and much of the extensive reper- Dr Arthur Kaser, Department of Medicine, Division of also revealed how proper development and function of toire of immune cells and their characteristics are Gastroenterology and the intestinal immune system is dependent on its specific indeed unique to the intestine. For example, the Hepatology, University of microbiota, which appears to have evolutionarily co- majority of intestinal effector T cells are antigen Cambridge, Addenbrooke’s evolved. Here we review key immune cells that maintain experienced and less dependent on co-stimulation, Hospital, Level 5 Box 157, intestinal homeostasis and, conversely, describe how and many intestinal T cells do not express Cambridge CB2 0QQ, UK; 45 [email protected] altered function and imbalances may lead to CD28. Such differences might have immediate inflammatory bowel disease (IBD). We highlight the clinical aspects attached to them; for example, this Received 25 January 2013 latest developments within this field, covering the major might help explain why abatacept (CTLA4-Ig), Revised 13 March 2013 players in IBD including intestinal epithelial cells, which blocks co-stimulation, might have failed in Accepted 14 March 2013 macrophages, dendritic cells, adaptive immune cells, and CD and UC, while being highly effective in mech- the newly discovered innate lymphoid cells, which anistically seemingly related conditions such as – appear of characteristic importance for immune function rheumatoid arthritis.6 8 at mucosal surfaces. We set these mucosal immune This review aims to highlight some key recent pathways in the functional context of IBD risk genes developments, and discusses how perturbations where such insight is available. Moreover, we frame our within the many various components of the http://gut.bmj.com/ discussion of fundamental biological pathways that have mucosal immune system can lead to inflammation. been elucidated in model systems in the context of We put these fundamental biological principles in results from clinical trials in IBD that targeted key the context of IBD, whenever possible by reviewing mediators secreted by these cells, as an attempt of results from clinical trials (table 1) that targeted ‘functional’ appraisal of these pathways in human specific molecules within these pathways since disease. these allow functional appraisal of these biological pathways in patients. Needless to say, the essentially on September 28, 2021 by guest. Protected copyright. binary clinical outcomes measures of these trials with barely any immunological assessments usually INTRODUCTION being performed and reported, set limitations to The gastrointestinal tract represents perhaps the this approach. In the same context, we also discuss most sophisticated and complicated immune organ the cellular mechanisms of some IBD risk genes for of the entire body.1 The intestinal epithelium, the which functional insight has indeed been experi- inner single cell lining of the intestine, and evolu- mentally gained, but refrain from inclusion of the tionarily the most ancient part of the innate overwhelming majority that still awaits experimen- immune system,2 separates the essentially sterile tal interrogation. host from the intestinal microbiota, which is among the most intensely populated microbial habitats on MUCOSAL IMMUNE DEVELOPMENT earth.3 The intestinal immune system is tasked to INSTRUCTED BY ENVIRONMENT AND prevent the invasion of harmful pathogens while MICROBIOTA remaining tolerant of innocuous food substances The human intestine covers a huge surface area of and commensal microorganisms. This carefully approximately 200–400 m2. Residing within the regulated immune balance has been shaped by lumen are an estimated 100 trillion microbial several million years’ co-evolution between the host cells.9 Whilst these commensal bacteria perform and gut microbiota and is essential for the healthy numerous metabolic functions essential to the development and integrity of the intestine. By con- host,3 pathogens that gain access and manage to trast, breakdown of immune homeostasis can lead expand within this complex ecosystem pose a con- to inflammatory bowel disease (IBD) and its two stant threat of invasive disease. The mucosal To cite: Cader MZ, Kaser A. main forms: Crohn’s disease (CD) and ulcerative immune system has evolved several layers to regu- – Gut 2013;62:1653 1664. colitis (UC).1 late the delicate and dynamic balance between Cader MZ, et al. Gut 2013;62:1653–1664. doi:10.1136/gutjnl-2012-303955 1653 Recent advances in basic science Table 1 Current and emerging biological inflammatory bowel disease (IBD) treatments targeting the mucosal immune cells and pathways Gut: first published as 10.1136/gutjnl-2012-303955 on 8 October 2013. Downloaded from described in this review Biological target Drugs Description Innate immune cell signalling TNFα Infliximab, adalimumab, The most well established biological treatment for IBD likely acts by neutralisation of certolizumab pegol inflammatory macrophage derived TNF. However there is also evidence that these agents also promote T cell apoptosis and may induce regulatory macrophages. TLR TLR9 DIMS0150 (Kappaproct), BL-7040 TLR activation in response to bacterial recognition such as TLR9 binding to unmethylated CpG MyD88 RDP58 motifs activate downstream inflammatory cascades that may contribute to disease and perpetuate inflammation in response to commensals. TLR signalling is also required for maintenance of a healthy epithelium, and MyD88 deficient mice have increased susceptibility to experimental colitis. T cell activity T cell CD3 Visilizumab An exaggerated T cell response is a fundamental hallmark of IBD, and these treatments are proliferation CD25 Basiliximab, daclizumab therefore aimed at limiting T cell proliferation and expansion, but will also inhibit protective Protein kinase C Sotrastaurin and regulatory T cell functions. inhibitor Chemotaxis CCR9 CCX-025, CCX282-B Inhibits the CCR9 chemokine receptor and intestinal homing of T cells in response to CCL25 chemokine ligand. α4β7 integrin Vedolizumab, natalizumab, Blocks the α4β7 integrin, which interacts with MAdCAM-1 on intestinal endothelial cells and ELND-004, AJM-300, etrolizumab mediates gut T cell homing. MAdCAM-1 PF-547659 IP-10 MDX-1100 Blocks interferon inducible protein-10 (IP-10), also known as CXCL10 (high levels seen in UC), which binds to CXCR3 and recruits activated T cells, NK cells and eosinophils. Regulatory T cells OvaSave Injection of autologous, OVA-expanded regulatory T cells. Pro-inflammatory cytokines— These have traditionally been considered in the context of T cells; many of the following cytokines are also produced and/or act on other immune cells such as innate lymphoid cells (ILCs) JAK Tafocitinib Inhibits JAK-STAT signalling pathway and thereby blocks subsequent inflammatory cytokine production; including IL-2, 4, 7, 9, 15, and 21. IL-12/23 Ustekinumab, SCH900222, Produced by myeloid cells, IL-12 and IL-23 share their p40 subunit and promote briakinumab pro-inflammatory Th1 and Th17 differentiation; but more recently have been also been shown to act on ILCs. IL-17 Secukinumab, brodalumab, Produced by Th17 and ILCs, IL-17 is considered pro-inflammatory but also has important vidofludimus homeostatic function. Notably secukinumab (anti-IL-17A) appears to worsen CD. γ γ IFN Fontolizumab IFN is a classical Th1 cytokine; also produced by inflammatory ILCs. http://gut.bmj.com/ IL-13 QAX576, anrukinzumab, IL-13 is a cytokine associated with UC, whose production by NKT cells appears essential in tralokinumab murine oxazolone colitis. IL-6 and IL-6R Tocilizumab, PF04236921, C326 IL-6 produced by myeloid cells upregulates anti-apoptotic genes in T cells and promotes inflammatory for example, Th17 cell expansion. CD, Crohn’s disease; NKT, natural killer T cells; TLR, toll-like receptor; TNF, tumour necrosis factor; UC, ulcerative colitis. tolerance and vigilance (figures 1A,B and 2). The development
Load more

Recommended publications
  • Predictive QSAR Tools to Aid in Early Process Development of Monoclonal Antibodies
    Predictive QSAR tools to aid in early process development of monoclonal antibodies John Micael Andreas Karlberg Published work submitted to Newcastle University for the degree of Doctor of Philosophy in the School of Engineering November 2019 Abstract Monoclonal antibodies (mAbs) have become one of the fastest growing markets for diagnostic and therapeutic treatments over the last 30 years with a global sales revenue around $89 billion reported in 2017. A popular framework widely used in pharmaceutical industries for designing manufacturing processes for mAbs is Quality by Design (QbD) due to providing a structured and systematic approach in investigation and screening process parameters that might influence the product quality. However, due to the large number of product quality attributes (CQAs) and process parameters that exist in an mAb process platform, extensive investigation is needed to characterise their impact on the product quality which makes the process development costly and time consuming. There is thus an urgent need for methods and tools that can be used for early risk-based selection of critical product properties and process factors to reduce the number of potential factors that have to be investigated, thereby aiding in speeding up the process development and reduce costs. In this study, a framework for predictive model development based on Quantitative Structure- Activity Relationship (QSAR) modelling was developed to link structural features and properties of mAbs to Hydrophobic Interaction Chromatography (HIC) retention times and expressed mAb yield from HEK cells. Model development was based on a structured approach for incremental model refinement and evaluation that aided in increasing model performance until becoming acceptable in accordance to the OECD guidelines for QSAR models.
    [Show full text]
  • Biologic Armamentarium in Psoriasis
    Vol 9, Issue 1, 2016 ISSN - 0974-2441 Review Article BIOLOGIC ARMAMENTARIUM IN PSORIASIS GANESH PAI1*, NITHIN SASHIDHARAN2 1Medical Director, Derma-Care ‘The Trade Centre’, Mangalore - 575 003, Karnataka, India. 2Consultant Clinical Pharmacologist, Derma-Care ‘The Trade Centre’, Mangalore - 575 003, Karnataka, India. Email: [email protected] Received: 14 July 2015, Revised and Accepted: 24 August 2015 ABSTRACT Psoriasis is an autoimmune disease and further classed as a chronic inflammatory skin condition serving as a global burden. A moderate to severe psoriasis can be treated with conventional therapies. Less efficacy, poor patient compliance, and toxicity issues were the major problems associated with conventional therapies. The introduction of biologic therapy has a great impression on psoriatic treatment duration and enhanced quality of life in psoriasis patients. The new biologic therapies are tailor-made medications with the goal of more specific and effective treatment; less toxicity. The biologic therapy is aimed to target antigen presentation and co-stimulation, T-cell activation, and leukocyte adhesion; and pro-inflammatory cascade. They act as effective and safer substitute to traditional therapy. Secukinumab, certolizumab, itolizumab, golimumab, ustekinumab, adalimumab, infliximab etanercept, alefacept, etc. are the approved biologic with the global market. This review briefs about psoriasis pathogenesis, traditional treatments, and biologic therapies potential. Keywords: Psoriasis, Biologic, Non-biologic treatment. INTRODUCTION migration, potentiation of Th1 type of response, angiogenesis, and epidermal hyperplasia [7]. Psoriasis is an autoimmune disease and further classed as a chronic inflammatory skin condition with prevalence ranging 1-3% in the TNF- is plays vital role in the pathogenesis of psoriasis. It acts by world [1].
    [Show full text]
  • Australian Public Assessment Report for Ixekizumab
    Australian Public Assessment Report for Ixekizumab Proprietary Product Name: Taltz Sponsor: Eli Lilly Australia May 2017 Therapeutic Goods Administration About the Therapeutic Goods Administration (TGA) • The Therapeutic Goods Administration (TGA) is part of the Australian Government Department of Health and is responsible for regulating medicines and medical devices. • The TGA administers the Therapeutic Goods Act 1989 (the Act), applying a risk management approach designed to ensure therapeutic goods supplied in Australia meet acceptable standards of quality, safety and efficacy (performance) when necessary. • The work of the TGA is based on applying scientific and clinical expertise to decision- making, to ensure that the benefits to consumers outweigh any risks associated with the use of medicines and medical devices. • The TGA relies on the public, healthcare professionals and industry to report problems with medicines or medical devices. TGA investigates reports received by it to determine any necessary regulatory action. • To report a problem with a medicine or medical device, please see the information on the TGA website <https://www.tga.gov.au>. About AusPARs • An Australian Public Assessment Report (AusPAR) provides information about the evaluation of a prescription medicine and the considerations that led the TGA to approve or not approve a prescription medicine submission. • AusPARs are prepared and published by the TGA. • An AusPAR is prepared for submissions that relate to new chemical entities, generic medicines, major variations and extensions of indications. • An AusPAR is a static document; it provides information that relates to a submission at a particular point in time. • A new AusPAR will be developed to reflect changes to indications and/or major variations to a prescription medicine subject to evaluation by the TGA.
    [Show full text]
  • HY 2021 Results
    Roche HY 2021 results Basel, 22 July 2021 This presentation contains certain forward-looking statements. These forward-looking statements may be identified by words such as ‘believes’, ‘expects’, ‘anticipates’, ‘projects’, ‘intends’, ‘should’, ‘seeks’, ‘estimates’, ‘future’ or similar expressions or by discussion of, among other things, strategy, goals, plans or intentions. Various factors may cause actual results to differ materially in the future from those reflected in forward-looking statements contained in this presentation, among others: 1 pricing and product initiatives of competitors; 2 legislative and regulatory developments and economic conditions; 3 delay or inability in obtaining regulatory approvals or bringing products to market; 4 fluctuations in currency exchange rates and general financial market conditions; 5 uncertainties in the discovery, development or marketing of new products or new uses of existing products, including without limitation negative results of clinical trials or research projects, unexpected side-effects of pipeline or marketed products; 6 increased government pricing pressures; 7 interruptions in production; 8 loss of or inability to obtain adequate protection for intellectual property rights; 9 litigation; 10 loss of key executives or other employees; and 11 adverse publicity and news coverage. Any statements regarding earnings per share growth is not a profit forecast and should not be interpreted to mean that Roche’s earnings or earnings per share for this year or any subsequent period will necessarily match or exceed the historical published earnings or earnings per share of Roche. For marketed products discussed in this presentation, please see full prescribing information on our website www.roche.com All mentioned trademarks are legally protected.
    [Show full text]
  • Looking for Therapeutic Antibodies in Next Generation Sequencing Repositories
    bioRxiv preprint doi: https://doi.org/10.1101/572958; this version posted March 10, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. Title: Looking for Therapeutic Antibodies in Next Generation Sequencing Repositories. Authors: Konrad Krawczyk1*, Matthew Raybould2, Aleksandr Kovaltsuk2, Charlotte M. Deane2 1 NaturalAntibody, Hamburg, Germany 2 Oxford University Department of Statistics, Oxford, UK *Correspondence to [email protected] Abstract: Recently it has become possible to query the great diversity of natural antibody repertoires using Next Generation Sequencing (NGS). These methods are capable of producing millions of sequences in a single experiment. Here we compare Clinical Stage Therapeutic antibodies to the ~1b sequences from 60 independent sequencing studies in the Observed Antibody Space Database. Of the 242 post Phase I antibodies, we find 16 with sequence identity matches of 95% or better for both heavy and light chains. There are also 54 perfect matches to therapeutic CDR-H3 regions in the NGS outputs, suggesting a nontrivial amount of convergence between naturally observed sequences and those developed artificially. This has potential implications for both the discovery of antibody therapeutics and the legal protection of commercial antibodies. Introduction Antibodies are proteins in jawed vertebrates that recognize noxious molecules (antigens) for elimination. An organism expresses millions of diverse antibodies to increase the chances that some of them will be able to bind the foreign antigen, initiating the adaptive immune response.
    [Show full text]
  • USTEKINUMAB and BRIAKINUMAB (ABT-874) TARGET P40, the SUBUNIT SHARED by IL-23 and IL-12
    USTEKINUMABUSTEKINUMAB aanndd BRIAKINUMABBRIAKINUMAB Andrew Blauvelt, M.D. Professor, Dept. of Dermatology and Dept. of Molecular Microbiology & Immunology Oregon Health & Science University Chief, Dermatology Service Veteran’s Affairs Medical Center Portland, Oregon CONFLICTSCONFLICTS OFOF INTERESTINTEREST • Centocor: scientific advisor, principal investigator for clinical studies, received lab research funds • Abbott: scientific advisor, principal investigator for clinical studies • Lilly: principal investigator for clinical studies PROMINENT T CELL INFILTRATION ADJACENT TO HYPERPROLIFERATIVE KERATINOCYTES IN PSORIASIS REF: Jim Krueger, Rockefeller Univ. DC ACTIVATION ⇒ TC ACTIVATION ⇒ KC ACTIVATION IL-12 ⇑Antimicrobial pep- Mature Naïve IFN-γ tides (LL-37, HBD-2) DC TC Th1 KC DC TNF-α ⇑Proinflammatory T-bet cytokines (TNF-α) IL-12 Immature DC IL-23 ⇑Antimicrobial pep- IL-17A tides (LL-37, HBD-2) ⇑Proinflammatory Mature Naïve IL-17F IL-17F cytokines (TNF- ) DC TC Th17 KC α IL-22 ⇑CCL20 (CCR6 ligand) CCR6+ TNF-α ⇑Proliferation IL-1β RORγt + IL-6/IL-23 Positive feedback loops Triggers in genetically Activation/proliferation of TC predisposed persons Activation of TNF-α+ dermal DC - Trauma (“inflammatory DC”) - Candida albicans Recruitment of CCR6+ Th17 cells via CCL20 Recruitment of CCR6+ blood DC via CCL20 - Streptococcus Recruitment of CCR6+ blood DC via CCL20 DC ACTIVATION ⇒ TC ACTIVATION ⇒ KC ACTIVATION IL-12 ⇑Antimicrobial pep- Mature Naïve IFN-γ tides (LL-37, HBD-2) DC TC Th1 KC DC TNF-α ⇑Proinflammatory T-bet cytokines (TNF-α)
    [Show full text]
  • Immunfarmakológia Immunfarmakológia
    Gergely: Immunfarmakológia Immunfarmakológia Prof Gergely Péter Az immunpatológiai betegségek döntő többsége gyulladásos, és ennek következtében általában szövetpusztulással járó betegség, melyben – jelenleg – a terápia alapvetően a gyulladás csökkentésére és/vagy megszűntetésére irányul. Vannak kizárólag gyulladásgátló gyógyszereink és vannak olyanok, amelyek az immunreakció(k) bénításával (=immunszuppresszió révén) vagy emellett vezetnek a gyulladás mérsékléséhez. Mind szerkezetileg, mind hatástanilag igen sokféle csoportba oszthatók, az alábbi felosztás elsősorban didaktikus célokat szolgál. 1. Nem-szteroid gyulladásgátlók (‘nonsteroidal antiinflammatory drugs’ NSAID) 2. Kortikoszteroidok 3. Allergia-elleni szerek (antiallergikumok) 4. Sejtoszlás-gátlók (citosztatikumok) 5. Nem citosztatikus hatású immunszuppresszív szerek 6. Egyéb gyulladásgátlók és immunmoduláns szerek 7. Biológiai terápia 1. Nem-szteroid gyulladásgátlók (NSAID) Ezeket a vegyületeket, melyek őse a szalicilsav (jelenleg, mint acetilszalicilsav ‘aszpirin’ használatos), igen kiterjedten alkalmazzák a reumatológiában, az onkológiában és az orvostudomány szinte minden ágában, ahol fájdalom- és lázcsillapításra van szükség. Egyes felmérések szerint a betegek egy ötöde szed valamilyen NSAID készítményt. Szerkezetük alapján a készítményeket több csoportba sorolhatjuk: szalicilátok (pl. acetilszalicilsav) pyrazolidinek (pl. fenilbutazon) ecetsav származékok (pl. indometacin) fenoxiecetsav származékok (pl. diclofenac, aceclofenac)) oxicamok (pl. piroxicam, meloxicam) propionsav
    [Show full text]
  • Ehealth DSI [Ehdsi V2.2.2-OR] Ehealth DSI – Master Value Set
    MTC eHealth DSI [eHDSI v2.2.2-OR] eHealth DSI – Master Value Set Catalogue Responsible : eHDSI Solution Provider PublishDate : Wed Nov 08 16:16:10 CET 2017 © eHealth DSI eHDSI Solution Provider v2.2.2-OR Wed Nov 08 16:16:10 CET 2017 Page 1 of 490 MTC Table of Contents epSOSActiveIngredient 4 epSOSAdministrativeGender 148 epSOSAdverseEventType 149 epSOSAllergenNoDrugs 150 epSOSBloodGroup 155 epSOSBloodPressure 156 epSOSCodeNoMedication 157 epSOSCodeProb 158 epSOSConfidentiality 159 epSOSCountry 160 epSOSDisplayLabel 167 epSOSDocumentCode 170 epSOSDoseForm 171 epSOSHealthcareProfessionalRoles 184 epSOSIllnessesandDisorders 186 epSOSLanguage 448 epSOSMedicalDevices 458 epSOSNullFavor 461 epSOSPackage 462 © eHealth DSI eHDSI Solution Provider v2.2.2-OR Wed Nov 08 16:16:10 CET 2017 Page 2 of 490 MTC epSOSPersonalRelationship 464 epSOSPregnancyInformation 466 epSOSProcedures 467 epSOSReactionAllergy 470 epSOSResolutionOutcome 472 epSOSRoleClass 473 epSOSRouteofAdministration 474 epSOSSections 477 epSOSSeverity 478 epSOSSocialHistory 479 epSOSStatusCode 480 epSOSSubstitutionCode 481 epSOSTelecomAddress 482 epSOSTimingEvent 483 epSOSUnits 484 epSOSUnknownInformation 487 epSOSVaccine 488 © eHealth DSI eHDSI Solution Provider v2.2.2-OR Wed Nov 08 16:16:10 CET 2017 Page 3 of 490 MTC epSOSActiveIngredient epSOSActiveIngredient Value Set ID 1.3.6.1.4.1.12559.11.10.1.3.1.42.24 TRANSLATIONS Code System ID Code System Version Concept Code Description (FSN) 2.16.840.1.113883.6.73 2017-01 A ALIMENTARY TRACT AND METABOLISM 2.16.840.1.113883.6.73 2017-01
    [Show full text]
  • The Two Tontti Tudiul Lui Hi Ha Unit
    THETWO TONTTI USTUDIUL 20170267753A1 LUI HI HA UNIT ( 19) United States (12 ) Patent Application Publication (10 ) Pub. No. : US 2017 /0267753 A1 Ehrenpreis (43 ) Pub . Date : Sep . 21 , 2017 ( 54 ) COMBINATION THERAPY FOR (52 ) U .S . CI. CO - ADMINISTRATION OF MONOCLONAL CPC .. .. CO7K 16 / 241 ( 2013 .01 ) ; A61K 39 / 3955 ANTIBODIES ( 2013 .01 ) ; A61K 31 /4706 ( 2013 .01 ) ; A61K 31 / 165 ( 2013 .01 ) ; CO7K 2317 /21 (2013 . 01 ) ; (71 ) Applicant: Eli D Ehrenpreis , Skokie , IL (US ) CO7K 2317/ 24 ( 2013. 01 ) ; A61K 2039/ 505 ( 2013 .01 ) (72 ) Inventor : Eli D Ehrenpreis, Skokie , IL (US ) (57 ) ABSTRACT Disclosed are methods for enhancing the efficacy of mono (21 ) Appl. No. : 15 /605 ,212 clonal antibody therapy , which entails co - administering a therapeutic monoclonal antibody , or a functional fragment (22 ) Filed : May 25 , 2017 thereof, and an effective amount of colchicine or hydroxy chloroquine , or a combination thereof, to a patient in need Related U . S . Application Data thereof . Also disclosed are methods of prolonging or increasing the time a monoclonal antibody remains in the (63 ) Continuation - in - part of application No . 14 / 947 , 193 , circulation of a patient, which entails co - administering a filed on Nov. 20 , 2015 . therapeutic monoclonal antibody , or a functional fragment ( 60 ) Provisional application No . 62/ 082, 682 , filed on Nov . of the monoclonal antibody , and an effective amount of 21 , 2014 . colchicine or hydroxychloroquine , or a combination thereof, to a patient in need thereof, wherein the time themonoclonal antibody remains in the circulation ( e . g . , blood serum ) of the Publication Classification patient is increased relative to the same regimen of admin (51 ) Int .
    [Show full text]
  • (12) Patent Application Publication (10) Pub. No.: US 2017/0172932 A1 Peyman (43) Pub
    US 20170172932A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2017/0172932 A1 Peyman (43) Pub. Date: Jun. 22, 2017 (54) EARLY CANCER DETECTION AND A 6LX 39/395 (2006.01) ENHANCED IMMUNOTHERAPY A61R 4I/00 (2006.01) (52) U.S. Cl. (71) Applicant: Gholam A. Peyman, Sun City, AZ CPC .......... A61K 9/50 (2013.01); A61K 39/39558 (US) (2013.01); A61K 4I/0052 (2013.01); A61 K 48/00 (2013.01); A61K 35/17 (2013.01); A61 K (72) Inventor: sham A. Peyman, Sun City, AZ 35/15 (2013.01); A61K 2035/124 (2013.01) (21) Appl. No.: 15/143,981 (57) ABSTRACT (22) Filed: May 2, 2016 A method of therapy for a tumor or other pathology by administering a combination of thermotherapy and immu Related U.S. Application Data notherapy optionally combined with gene delivery. The combination therapy beneficially treats the tumor and pre (63) Continuation-in-part of application No. 14/976,321, vents tumor recurrence, either locally or at a different site, by filed on Dec. 21, 2015. boosting the patient’s immune response both at the time or original therapy and/or for later therapy. With respect to Publication Classification gene delivery, the inventive method may be used in cancer (51) Int. Cl. therapy, but is not limited to such use; it will be appreciated A 6LX 9/50 (2006.01) that the inventive method may be used for gene delivery in A6 IK 35/5 (2006.01) general. The controlled and precise application of thermal A6 IK 4.8/00 (2006.01) energy enhances gene transfer to any cell, whether the cell A 6LX 35/7 (2006.01) is a neoplastic cell, a pre-neoplastic cell, or a normal cell.
    [Show full text]
  • Novel Therapies for Eosinophilic Disorders
    Novel Therapies for Eosinophilic Disorders Bruce S. Bochner, MD KEYWORDS Eosinophil Therapies Antibodies Targets Pharmacology Biomarkers KEY POINTS A sizable unmet need exists for new, safe, selective, and effective treatments for eosinophil-associated diseases, such as hypereosinophilic syndrome, eosinophilic gastrointestinal disorders, nasal polyposis, and severe asthma. An improved panel of biomarkers to help guide diagnosis, treatment, and assessment of disease activity is also needed. An impressive array of novel therapeutic agents, including small molecules and biologics, that directly or indirectly target eosinophils and eosinophilic inflammation are undergoing controlled clinical trials, with many already showing promising results. A large list of additional eosinophil-related potential therapeutic targets remains to be pursued, including cell surface structures, soluble proteins that influence eosinophil biology, and eosinophil-derived mediators that have the potential to contribute adversely to disease pathophysiology. INTRODUCTION Eosinophilic disorders, also referred to as eosinophil-associated diseases, consist of a range of infrequent conditions affecting virtually any body compartment and organ.1 The most commonly affected areas include the bone marrow, blood, mucosal sur- faces, and skin, often with immense disease- and treatment-related morbidity, Disclosure Statement: Dr Bochner’s research efforts are supported by grants AI072265, AI097073 and HL107151 from the National Institutes of Health. He has current or recent consul- ting or scientific advisory board arrangements with, or has received honoraria from, Sanofi-A- ventis, Pfizer, Svelte Medical Systems, Biogen Idec, TEVA, and Allakos, Inc. and owns stock in Allakos, Inc. and Glycomimetics, Inc. He receives publication-related royalty payments from Elsevier and UpToDate and is a coinventor on existing and pending Siglec-8-related patents and, thus, may be entitled to a share of future royalties received by Johns Hopkins University on the potential sales of such products.
    [Show full text]
  • Association of Ustekinumab and Briakinumab with Major Adverse
    REVIEW Dermato-Endocrinology 4:3, 320–323; July–December 2012; © 2012 Landes Bioscience Association of ustekinumab and briakinumab with major adverse cardiovascular events An appraisal of meta-analyses and industry sponsored pooled analyses to date Thrasivoulos Tzellos,1,2 Athanassios Kyrgidis,1 Anastasia Trigoni2 and Christos C. Zouboulis1,* 1Division of Evidence Based Dermatology; Departments of Dermatology, Venereology, Allergology and Immunology; Dessau Medical Center; Dessau, Germany; 2Hospital for Skin and Venereal Diseases; Thessaloniki, Greece Keywords: briakinumab, ustekinumab, chronic plaque psoriasis, major adverse cardiovascular events, meta-analysis Safety concerns have been raised regarding possible briakinumab) and five cardiovascular deaths (1 ustekinumab, 4 association of major adverse cardiovascular events (MACEs) briakinumab) across all phases of these studies.1,2 distribute. with use of anti-IL-12/23 biologic agents for the treatment of Two industry-independent meta-analyses of these 9 random- chronic plaque psoriasis (CPP). Ten MACEs have been recorded ized, double-blind, placebo-controlled, monotherapy trials3-11 in actively-treated patients during the placebo-controlled not have been recently conducted to examine the possible association phase of phase II and III studies compared with zero events 1,2 in placebo-treated patients, along with a total of 53 MACEs of MACEs with anti-IL-12/23 agents. Ryan et al. did not detect (26 ustekinumab, 27 briakinumab) and five cardiovascular a statistical significant increase using the Mantel-Haenszel fixed- Do deaths (1 ustekinumab, 4 briakinumab) across all phases of effects model with absolute risk differences as an effect measure, these studies. Two industry-independent meta-analyses of although their findings approached significance (p = 0.11).1 In randomized, double-blind, placebo-controlled, monotherapy contrast, Tzellos et al.
    [Show full text]