DOCSLIB.ORG

Modeling and Simulation of Anti-Sclerostin Therapy for the Treatment of Osteoporosis

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Modeling and Simulation of Anti-Sclerostin Therapy for the Treatment of Osteoporosis MODELING AND SIMULATION OF ANTI-SCLEROSTIN THERAPY FOR THE TREATMENT OF OSTEOPOROSIS TANG CHENG CAI (B.Sc. (Hons), NUS) A THESIS SUBMITTED FOR THE DEGREE OF DOCTOR OF PHILOSOPHY DEPARTMENT OF PHARMACY NATIONAL UNIVERSITY OF SINGAPORE 2016 DECLARATION I hereby declare that the thesis is my original work and it has been written by me in its entirety. I have duly acknowledged all the sources of information that have been used in the thesis This thesis has also not been submitted for any degree in any university previously. Tang Cheng Cai May 2016 I Acknowledgement Part of the project includes the pharmacokinetic and pharmacodynamics (PK- PD) modeling of the investigational drug, blosozumab, an anti-sclerostin antibody for the treatment of osteoporosis that was done in my capacity as an employee of Eli Lilly and Company (Eli Lilly). Eli Lilly is the copyright owner of the data, figures and tables included in sections 3 and 4 of this thesis and permission was sought and obtained to use and reproduce the data, figures and tables here. Results of the PK-PD models were previously presented at the 6th Annual Meeting of the American Conference of Pharmacometrics 2015 (ACoP6, Crystal City, VA). I would like to thank the blosozumab and functional teams within Eli Lilly, special thanks to Dr. Thomas Raub, Dr. Bruce Mitlak and Gregory Cox, J.D, for their support, time and effort to review and comment on this thesis. I would like to thank my company supervisor for this project Dr. Hu Leijun within Eli Lilly for the useful discussion on the blosozumab clinical data. He supported, mentored and advised me on the project as well as gave me career guidance outside of his working hours. I would also like to express appreciation for my NUS supervisors Prof. Paul Ho Chi Lui and Dr. Yau Wai Ping for the numerous useful discussion and insights throughout this period of project work I would like to thank my company supervisor Dr. Tham Lai San within Eli Lilly for supporting and administering the PhD program with EDB to make this project possible as well as giving me one-to-one mentoring on career planning and progression. Lastly, I would like express my love and appreciations to my wife, Pei Wen, for her understanding and tremendous support during this period of time. She worked tirelessly to care for the household, our two young, energetic and lovely children Benjamin and Grace; and allowed time for me to meet the demands of this project. II Publications and Posters Related to the Project Poster Presentations: Tang CC, Benson C, McColm J, Sipos A, Mitlak B, Hu L. Population pharmacokinetics and pharmacodynamics of Blosozumab. 6th Annual Meeting of American Conference on Pharmacometrics; 2015 Oct 4-7. Crystal City, VA Publications: McColm J, Hu L, Womack T, Tang CC, Chiang AY. Single- and multiple- dose randomized studies of blosozumab, a monoclonal antibody against sclerostin, in healthy postmenopausal women. J bone Miner Res. 2014;29(4):935-943. III Table of Content Sections Page Acknowledgement ....................................................................................................... II Publications and Posters Related to the Project .......................................................... III Table of Content ........................................................................................................ IV Summary ................................................................................................................... VII List of Tables ............................................................................................................. IX List of Figures ............................................................................................................ XI List of Abbreviations ................................................................................................ XV 1. Introduction .............................................................................................................. 1 1.1. Bone Morphology and Functions .................................................................. 1 1.2. Bone Cells ..................................................................................................... 2 1.3. Osteoporosis .................................................................................................. 5 1.4. Targeting the Wnt Pathway .......................................................................... 9 1.5. Development of Anti-Sclerostin Therapy for Osteoporosis Treatment ...... 11 1.6. Development of Blosozumab ...................................................................... 13 2. Objectives .............................................................................................................. 16 3. Population PK-PD Models of Blosozumab Materials and Methods ...................... 19 3.1. Blosozumab Clinical Studies Background .................................................. 19 3.1.1. Sample Collections ......................................................................... 23 3.1.2. PK-PD Dataset Preparation ............................................................. 25 3.2. Population Pharmacokinetic/Pharmacodynamics Modeling Strategy ........ 27 3.2.1. General PK/PD Model Development Approach ............................. 27 3.2.2. Model Evaluation ............................................................................ 30 3.2.3. Pharmacokinetic Model .................................................................. 32 3.2.4. Pharmacodynamics Model .............................................................. 34 4. Population PK-PD Models of Blosozumab Results ............................................... 38 4.1. PK Data Disposition ................................................................................... 38 4.2. Final PK Model ........................................................................................... 40 4.3. PK Model Covariate Analysis .................................................................... 47 4.3.1. Effect of Body Weight on Blosozumab Clearance ......................... 47 4.3.2. Effect of Body Weight on Blosozumab Volumes of Distribution .. 48 4.4.3. Effect of Anti-Drug Antibody (ADA) on Blosozumab ................... 48 4.4. BMD Data Disposition ............................................................................... 48 4.5. Final BMD Model ....................................................................................... 51 IV 4.6. BMD Model Covariate Analysis................................................................. 58 5. System Pharmacology Model of Anti-Sclerostin Treatment Materials and Methods ............................................................................................................................... 60 5.1. Bone Remodeling Model Background ........................................................ 60 5.2. Dataset and Model Description ................................................................... 64 5.2.1. Mathematical Description of Target-Mediated Drug Disposition Kinetics ........................................................................................................ 66 5.2.2. Mathematical Description of the Bone Remodeling Model............ 72 5.2.3. Mathematical Description of the Bone Mineral Density Model ..... 79 6. System Pharmacology Model of Anti-Sclerostin Treatment Results..................... 81 6.1. Anti-Sclerostin mAb Target-Mediated Drug Disposition ........................... 81 6.1.1. Blosozumab TMDD model ............................................................. 81 6.1.1. Romosozumab TMDD model ......................................................... 82 6.2. Bone Biomarker Turnover Model ............................................................... 85 6.3. Bone Mineral Density Model ...................................................................... 91 6.4. Model Qualification .................................................................................... 93 6.4.1. Romosozumab TMDD Model ........................................................ 93 6.4.2. Bone biomarker and BMD prediction ............................................. 95 6.4.3. Defining the Boundary of Model Simulation.................................. 98 7. Simulation Experiments and Applications of the Models .................................... 101 7.1. Population PK-PD Model Simulations ..................................................... 101 7.1.1. Effect of Dosing Interval on Drug Exposure and BMD Responses .... ...................................................................................................... 102 7.1.2. Effect of Body Weight on Drug Exposure and BMD Responses . 107 7.2. Extended Bone Remodeling Model Simulations ...................................... 110 7.2.1. Effect of Dosing Interval on Drug Exposure and BMD Responses .... ...................................................................................................... 111 7.2.2. Duration of Precursor Osteoblast Suppression and Replenishment .... ...................................................................................................... 115 7.2.3. Long-Term Anti-Sclerostin Treatment ......................................... 116 7.2.4. Dose-Response Curve of BMD improvement .............................. 119 7.3. Comparison of Population PK-PD and Bone Remodeling Model ............ 124 7.3.1. Discussions, Strengths and Limitations of Population PK-PD Model .....................................................................................................
Load more

Recommended publications
  • Does Novartis Need a Big Immuno- Oncology Deal?
    Sandoz’s Biosimilar Rejection Ups Key Clinical Data And Drug Expert View Risks, But Won’t Kill Market Approvals Expected New data on growth in China’s FDA’s rejection of Sandoz’s version of In 2H 2016 Scrip takes a look at some turbulent pharma sector paint a Amgen’s Neulasta has revealed the truth clinical trial read-outs and drug approvals mixed and complex picture, indicating that chasing the biosimilar market may expected, clinical trials due to report in both challenges and opportunities be riskier & more costly (p3) the second half of the year (p18) ahead (p20) 29 July 2016 No. 3813 Scripscripintelligence.com Pharma intelligence | informa space given what’s coming.” The company has previously stressed that its leadership position in chimeric antigen receptor T-cell therapy (CAR-Ts) will get it back in the thick of it. “I believe that we have a very strong self-generated, through in-licensing and through acquisition, early-stage immuno- oncology pipeline,” he said. And, he reiterat- ed the common refrain in the industry that success in the field will be determined over the long-term through the development of combinations. In May, Novartis announced a restructur- ing to break Novartis Oncology out into a separate business unit led by its own CEO, Bruno Strigini, who will report directly to Joseph Jimenez Jimenez. Merck & Co. Inc., Bristol and Roche have already launched the first immune check- point inhibitors, the PD-1/L1 inhibitors Key- Does Novartis Need A Big Immuno- truda (pembrolizumab), Opdivo (nivolumab) and Tecentriq (atezolizumab), respectively, while many others are in mid- to late-stage Oncology Deal? Jimenez Says No clinical development by drug makers like JESSICA MERRILL [email protected] AstraZeneca and Pfizer Inc.
    [Show full text]
  • 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]
  • 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]
  • WO 2016/176089 Al 3 November 2016 (03.11.2016) P O P C T
    (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2016/176089 Al 3 November 2016 (03.11.2016) P O P C T (51) International Patent Classification: BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, A01N 43/00 (2006.01) A61K 31/33 (2006.01) DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KN, KP, KR, (21) International Application Number: KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, PCT/US2016/028383 MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, (22) International Filing Date: PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, 20 April 2016 (20.04.2016) SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (25) Filing Language: English (84) Designated States (unless otherwise indicated, for every (26) Publication Language: English kind of regional protection available): ARIPO (BW, GH, (30) Priority Data: GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, 62/154,426 29 April 2015 (29.04.2015) US TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, (71) Applicant: KARDIATONOS, INC. [US/US]; 4909 DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, Lapeer Road, Metamora, Michigan 48455 (US).
    [Show full text]
  • Lääkeaineiden Yleisnimet (INN-Nimet) 21.6.2021
    Lääkealan turvallisuus- ja kehittämiskeskus Säkerhets- och utvecklingscentret för läkemedelsområdet Finnish Medicines Agency Lääkeaineiden yleisnimet (INN-nimet) 21.6.
    [Show full text]
  • Bone-Targeted Therapies in Cancer-Induced Bone Disease
    This is a repository copy of Bone-targeted therapies in cancer-induced bone disease. White Rose Research Online URL for this paper: http://eprints.whiterose.ac.uk/152892/ Version: Accepted Version Article: Sousa, S. and Clézardin, P. (2018) Bone-targeted therapies in cancer-induced bone disease. Calcified Tissue International, 102 (2). pp. 227-250. ISSN 0171-967X https://doi.org/10.1007/s00223-017-0353-5 This is a post-peer-review, pre-copyedit version of an article published in Calcified Tissue International. The final authenticated version is available online at: http://dx.doi.org/10.1007/s00223-017-0353-5 Reuse Items deposited in White Rose Research Online are protected by copyright, with all rights reserved unless indicated otherwise. They may be downloaded and/or printed for private study, or other acts as permitted by national copyright laws. The publisher or other rights holders may allow further reproduction and re-use of the full text version. This is indicated by the licence information on the White Rose Research Online record for the item. Takedown If you consider content in White Rose Research Online to be in breach of UK law, please notify us by emailing [email protected] including the URL of the record and the reason for the withdrawal request. [email protected] https://eprints.whiterose.ac.uk/ Title: Bone targeted therapies in cancer-induced bone disease Authors: Sofia Sousa1,2 *, Philippe Clézardin1,2,3 # Affiliation/ address 1 National Institute of Health and Medical Research (INSERM), UMR 1033, Lyon 69372,
    [Show full text]
  • INN Working Document 05.179 Update 2011
    INN Working Document 05.179 Update 2011 International Nonproprietary Names (INN) for biological and biotechnological substances (a review) INN Working Document 05.179 Distr.: GENERAL ENGLISH ONLY 2011 International Nonproprietary Names (INN) for biological and biotechnological substances (a review) Programme on International Nonproprietary Names (INN) Quality Assurance and Safety: Medicines Essential Medicines and Pharmaceutical Policies (EMP) International Nonproprietary Names (INN) for biological and biotechnological substances (a review) © World Health Organization 2011 All rights reserved. Publications of the World Health Organization are available on the WHO web site (www.who.int) or can be purchased from WHO Press, World Health Organization, 20 Avenue Appia, 1211 Geneva 27, Switzerland (tel.: +41 22 791 3264; fax: +41 22 791 4857; email: [email protected]). Requests for permission to reproduce or translate WHO publications – whether for sale or for noncommercial distribution – should be addressed to WHO Press through the WHO web site (http://www.who.int/about/licensing/copyright_form/en/index.html). The designations employed and the presentation of the material in this publication do not imply the expression of any opinion whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted lines on maps represent approximate border lines for which there may not yet be full agreement. The mention of specific companies or of certain manufacturers’ products does not imply that they are endorsed or recommended by the World Health Organization in preference to others of a similar nature that are not mentioned.
    [Show full text]
  • Stembook 2018.Pdf
    The use of stems in the selection of International Nonproprietary Names (INN) for pharmaceutical substances FORMER DOCUMENT NUMBER: WHO/PHARM S/NOM 15 WHO/EMP/RHT/TSN/2018.1 © World Health Organization 2018 Some rights reserved. This work is available under the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 IGO licence (CC BY-NC-SA 3.0 IGO; https://creativecommons.org/licenses/by-nc-sa/3.0/igo). Under the terms of this licence, you may copy, redistribute and adapt the work for non-commercial purposes, provided the work is appropriately cited, as indicated below. In any use of this work, there should be no suggestion that WHO endorses any specific organization, products or services. The use of the WHO logo is not permitted. If you adapt the work, then you must license your work under the same or equivalent Creative Commons licence. If you create a translation of this work, you should add the following disclaimer along with the suggested citation: “This translation was not created by the World Health Organization (WHO). WHO is not responsible for the content or accuracy of this translation. The original English edition shall be the binding and authentic edition”. Any mediation relating to disputes arising under the licence shall be conducted in accordance with the mediation rules of the World Intellectual Property Organization. Suggested citation. The use of stems in the selection of International Nonproprietary Names (INN) for pharmaceutical substances. Geneva: World Health Organization; 2018 (WHO/EMP/RHT/TSN/2018.1). Licence: CC BY-NC-SA 3.0 IGO. Cataloguing-in-Publication (CIP) data.
    [Show full text]
  • NETTER, Jr., Robert, C. Et Al.; Dann, Dorf- (21) International Application
    ll ( (51) International Patent Classification: (74) Agent: NETTER, Jr., Robert, C. et al.; Dann, Dorf- C07K 16/28 (2006.01) man, Herrell and Skillman, 1601 Market Street, Suite 2400, Philadelphia, PA 19103-2307 (US). (21) International Application Number: PCT/US2020/030354 (81) Designated States (unless otherwise indicated, for every kind of national protection av ailable) . AE, AG, AL, AM, (22) International Filing Date: AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, 29 April 2020 (29.04.2020) CA, CH, CL, CN, CO, CR, CU, CZ, DE, DJ, DK, DM, DO, (25) Filing Language: English DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IR, IS, JO, JP, KE, KG, KH, KN, KP, (26) Publication Language: English KR, KW, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, (30) Priority Data: MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, 62/840,465 30 April 2019 (30.04.2019) US OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, SD, SE, SG, SK, SL, ST, SV, SY, TH, TJ, TM, TN, TR, (71) Applicants: INSTITUTE FOR CANCER RESEARCH TT, TZ, UA, UG, US, UZ, VC, VN, WS, ZA, ZM, ZW. D/B/A THE RESEARCH INSTITUTE OF FOX CHASE CANCER CENTER [US/US]; 333 Cottman Av¬ (84) Designated States (unless otherwise indicated, for every enue, Philadelphia, PA 191 11-2497 (US). UNIVERSTIY kind of regional protection available) . ARIPO (BW, GH, OF KANSAS [US/US]; 245 Strong Hall, 1450 Jayhawk GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, TZ, Boulevard, Lawrence, KS 66045 (US).
    [Show full text]
  • IUPAC Glossary of Terms Used in Immunotoxicology (IUPAC Recommendations 2012)*
    Pure Appl. Chem., Vol. 84, No. 5, pp. 1113–1295, 2012. http://dx.doi.org/10.1351/PAC-REC-11-06-03 © 2012 IUPAC, Publication date (Web): 16 February 2012 IUPAC glossary of terms used in immunotoxicology (IUPAC Recommendations 2012)* Douglas M. Templeton1,‡, Michael Schwenk2, Reinhild Klein3, and John H. Duffus4 1Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada; 2In den Kreuzäckern 16, Tübingen, Germany; 3Immunopathological Laboratory, Department of Internal Medicine II, Otfried-Müller-Strasse, Tübingen, Germany; 4The Edinburgh Centre for Toxicology, Edinburgh, Scotland, UK Abstract: The primary objective of this “Glossary of Terms Used in Immunotoxicology” is to give clear definitions for those who contribute to studies relevant to immunotoxicology but are not themselves immunologists. This applies especially to chemists who need to under- stand the literature of immunology without recourse to a multiplicity of other glossaries or dictionaries. The glossary includes terms related to basic and clinical immunology insofar as they are necessary for a self-contained document, and particularly terms related to diagnos- ing, measuring, and understanding effects of substances on the immune system. The glossary consists of about 1200 terms as primary alphabetical entries, and Annexes of common abbre- viations, examples of chemicals with known effects on the immune system, autoantibodies in autoimmune disease, and therapeutic agents used in autoimmune disease and cancer. The authors hope that among the groups who will find this glossary helpful, in addition to chemists, are toxicologists, pharmacologists, medical practitioners, risk assessors, and regu- latory authorities. In particular, it should facilitate the worldwide use of chemistry in relation to occupational and environmental risk assessment.
    [Show full text]
  • WO 2017/095848 Al 8 June 2017 (08.06.2017) W P O P C T
    (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2017/095848 Al 8 June 2017 (08.06.2017) W P O P C T (51) International Patent Classification: DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, A61K 47/42 (2017.01) A61K 39/395 (2006.01) HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KN, KP, KR, A61K 39/00 (2006.01) A61K 47/00 (2006.01) KW, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, (21) International Application Number: OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, PCT/US20 16/064080 SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, (22) International Filing Date: TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, 30 November 2016 (30.1 1.2016) zw. (25) Filing Language: English (84) Designated States (unless otherwise indicated, for every kind of regional protection available): ARIPO (BW, GH, (26) Publication Language: English GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, (30) Priority Data: TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, 62/260,677 30 November 2015 (30. 11.2015) US TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, (71) Applicant: MEDIMMUNE, LLC [US/US]; One Medim- LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, mune Way, Gaithersburg, MD 20878 (US).
    [Show full text]