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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. -
Curriculum Vitae: Daniel J
CURRICULUM VITAE: DANIEL J. WALLACE, M.D., F.A.C.P., M.A.C.R. Up to date as of January 1, 2019 Personal: Address: 8750 Wilshire Blvd, Suite 350 Beverly Hills, CA 90211 Phone: (310) 652-0010 FAX: (310) 360-6219 E mail: [email protected] Education: University of Southern California, 2/67-6/70, BA Medicine, 1971. University of Southern California, 9/70-6/74, M.D, 1974. Postgraduate Training: 7/74-6/75 Medical Intern, Rhode Island (Brown University) Hospital, Providence, RI. 7/75-6/77 Medical Resident, Cedars-Sinai Medical Center, Los Angeles, CA. 7/77-6/79 Rheumatology Fellow, UCLA School of Medicine, Los Angeles, CA. Medical Boards and Licensure: Diplomate, National Board of Medical Examiners, 1975. Board Certified, American Board of Internal Medicine, 1978. Board Certified, Rheumatology subspecialty, 1982. California License: #G-30533. Present Appointments: Medical Director, Wallace Rheumatic Study Center Attune Health Affiliate, Beverly Hills, CA 90211 Attending Physician, Cedars-Sinai Medical Center, Los Angeles, 1979- Clinical Professor of Medicine, David Geffen School of Medicine at UCLA, 1995- Professor of Medicine, Cedars-Sinai Medical Center, 2012- Expert Reviewer, Medical Board of California, 2007- Associate Director, Rheumatology Fellowship Program, Cedars-Sinai Medical Center, 2010- Board of Governors, Cedars-Sinai Medical Center, 2016- Member, Medical Policy Committee, United Rheumatology, 2017- Honorary Appointments: Fellow, American College of Physicians (FACP) Fellow, American College of Rheumatology (FACR) -
Fontolizumab, a Humanised Anti-Interferon C Antibody
1131 INFLAMMATORY BOWEL DISEASE Gut: first published as 10.1136/gut.2005.079392 on 28 February 2006. Downloaded from Fontolizumab, a humanised anti-interferon c antibody, demonstrates safety and clinical activity in patients with moderate to severe Crohn’s disease D W Hommes, T L Mikhajlova, S Stoinov, D Sˇtimac, B Vucelic, J Lonovics, M Za´kuciova´, G D’Haens, G Van Assche, S Ba, S Lee, T Pearce ............................................................................................................................... Gut 2006;55:1131–1137. doi: 10.1136/gut.2005.079392 See end of article for Introduction: Interferon c is a potent proinflammatory cytokine implicated in the inflammation of Crohn’s authors’ affiliations ....................... disease (CD). We evaluated the safety and efficacy of fontolizumab, a humanised anti-interferon c antibody, in patients with moderate to severe CD. Correspondence to: Methods: A total of 133 patients with Crohn’s disease activity index (CDAI) scores between 250 and 450, Dr D W Hommes, Department inclusive, were randomised to receive placebo or fontolizumab 4 or 10 mg/kg. Forty two patients Gastroenterology and received one dose and 91 patients received two doses on days 0 and 28. Investigators and patients were Hepatology, Academic unaware of assignment. Study end points were safety, clinical response (decrease in CDAI of 100 points or Medical Centre, C2-111, ( Meibergdreef 9 1105 AZ, more), and remission (CDAI 150). Amsterdam, the Results: There was no statistically significant difference in the primary end point of the study (clinical Netherlands; response) between the fontolizumab and placebo groups after a single dose at day 28. However, patients d.w.hommes@ receiving two doses of fontolizumab demonstrated doubling in response rate at day 56 compared with amc.uva.nl placebo: 32% (9/28) versus 69% (22/32, p = 0.02) and 67% (21/31, p = 0.03) for the placebo, and 4 Revised version received and 10 mg/kg fontolizumab groups, respectively. -
(CHMP) Agenda for the Meeting on 22-25 February 2021 Chair: Harald Enzmann – Vice-Chair: Bruno Sepodes
22 February 2021 EMA/CHMP/107904/2021 Human Medicines Division Committee for medicinal products for human use (CHMP) Agenda for the meeting on 22-25 February 2021 Chair: Harald Enzmann – Vice-Chair: Bruno Sepodes 22 February 2021, 09:00 – 19:30, room 1C 23 February 2021, 08:30 – 19:30, room 1C 24 February 2021, 08:30 – 19:30, room 1C 25 February 2021, 08:30 – 19:30, room 1C Disclaimers Some of the information contained in this agenda is considered commercially confidential or sensitive and therefore not disclosed. With regard to intended therapeutic indications or procedure scopes listed against products, it must be noted that these may not reflect the full wording proposed by applicants and may also vary during the course of the review. Additional details on some of these procedures will be published in the CHMP meeting highlights once the procedures are finalised and start of referrals will also be available. Of note, this agenda is a working document primarily designed for CHMP members and the work the Committee undertakes. Note on access to documents Some documents mentioned in the agenda cannot be released at present following a request for access to documents within the framework of Regulation (EC) No 1049/2001 as they are subject to on- going procedures for which a final decision has not yet been adopted. They will become public when adopted or considered public according to the principles stated in the Agency policy on access to documents (EMA/127362/2006). Official address Domenico Scarlattilaan 6 ● 1083 HS Amsterdam ● The Netherlands Address for visits and deliveries Refer to www.ema.europa.eu/how-to-find-us Send us a question Go to www.ema.europa.eu/contact Telephone +31 (0)88 781 6000 An agency of the European Union © European Medicines Agency, 2021. -
New Biological Therapies: Introduction to the Basis of the Risk of Infection
New biological therapies: introduction to the basis of the risk of infection Mario FERNÁNDEZ RUIZ, MD, PhD Unit of Infectious Diseases Hospital Universitario “12 de Octubre”, Madrid ESCMIDInstituto de Investigación eLibraryHospital “12 de Octubre” (i+12) © by author Transparency Declaration Over the last 24 months I have received honoraria for talks on behalf of • Astellas Pharma • Gillead Sciences • Roche • Sanofi • Qiagen Infections and biologicals: a real concern? (two-hour symposium): New biological therapies: introduction to the ESCMIDbasis of the risk of infection eLibrary © by author Paul Ehrlich (1854-1915) • “side-chain” theory (1897) • receptor-ligand concept (1900) • “magic bullet” theory • foundation for specific chemotherapy (1906) • Nobel Prize in Physiology and Medicine (1908) (together with Metchnikoff) Infections and biologicals: a real concern? (two-hour symposium): New biological therapies: introduction to the ESCMIDbasis of the risk of infection eLibrary © by author 1981: B-1 antibody (tositumomab) anti-CD20 monoclonal antibody 1997: FDA approval of rituximab for the treatment of relapsed or refractory CD20-positive NHL 2001: FDA approval of imatinib for the treatment of chronic myelogenous leukemia Infections and biologicals: a real concern? (two-hour symposium): New biological therapies: introduction to the ESCMIDbasis of the risk of infection eLibrary © by author Functional classification of targeted (biological) agents • Agents targeting soluble immune effector molecules • Agents targeting cell surface receptors -
Study Protocol
PROTOCOL SYNOPSIS A Multicentre, Randomised, Double-blind, Placebo-controlled, Phase 3 Study Evaluating the Efficacy and Safety of Two Doses of Anifrolumab in Adult Subjects with Active Systemic Lupus Erythematosus International Coordinating Investigator Study site(s) and number of subjects planned Approximately 450 subjects are planned at approximately 173 sites. Study period Phase of development Estimated date of first subject enrolled Q2 2015 3 Estimated date of last subject completed Q2 2018 Study design This is a Phase 3, multicentre, multinational, randomised, double-blind, placebo-controlled study to evaluate the efficacy and safety of an intravenous treatment regimen of anifrolumab (150 mg or 300 mg) versus placebo in subjects with moderately to severely active, autoantibody-positive systemic lupus erythematosus (SLE) while receiving standard of care (SOC) treatment. The study will be performed in adult subjects aged 18 to 70 years of age. Approximately 450 subjects receiving SOC treatment will be randomised in a 1:2:2 ratio to receive a fixed intravenous dose of 150 mg anifrolumab, 300 mg anifrolumab, or placebo every 4 weeks (Q4W) for a total of 13 doses (Week 0 to Week 48), with the primary endpoint evaluated at the Week 52 visit. Investigational product will be administered as an intravenous (IV) infusion via an infusion pump over a minimum of 30 minutes, Q4W. Subjects must be taking either 1 or any combination of the following: oral corticosteroids (OCS), antimalarial, and/or immunosuppressants. Randomisation will be stratified using the following factors: SLE Disease Activity Index 2000 (SLEDAI-2K) score at screening (<10 points versus ≥10 points); Week 0 (Day 1) OCS dose 2(125) Revised Clinical Study Protocol Drug Substance Anifrolumab (MEDI-546) Study Code D3461C00005 Edition Number 5 Date 18 May 2016 (<10 mg/day versus ≥10 mg/day prednisone or equivalent); and results of a type 1 interferon (IFN) test (high versus low). -
Final Scope PDF 184 KB
Appendix B NATIONAL INSTITUTE FOR HEALTH AND CARE EXCELLENCE Health Technology Appraisal Anifrolumab for treating active autoantibody-positive systemic lupus erythematosus Final scope Remit/appraisal objective To appraise the clinical and cost effectiveness of anifrolumab within its marketing authorisation for treating active autoantibody-positive systemic lupus erythematosus. Background Systemic lupus erythematosus (SLE) is a chronic autoimmune condition that causes inflammation in the body's tissues. The manifestations of SLE vary greatly between people and can affect the whole body including the skin, joints, internal organs and serous membranes. SLE can result in chronic debilitating ill health. The cause of SLE is unknown though a combination of genetic, environmental and hormonal factors is thought to play a role in disease development and progression. SLE can lead to mucocutaneous disease, arthritis, kidney failure, heart and lung inflammation, central nervous abnormalities and blood disorders. Over 90% of people with SLE develop problems with their joints and muscles such as arthralgia (joint pain) and myalgia (muscle pain). Up to 40% develop renal disease, which significantly contributes to morbidity and mortality.1 Disease activity varies over time and, at the onset, symptoms are very general and may include unexplained fever, extreme fatigue, muscle and joint pain and skin rash. Active SLE involves frequent flares and more severe symptoms compared with disease that is inactive or under control (in remission). Persistent disease activity and side effects from cumulative doses of corticosteroids contribute significantly to the accrual of irreversible long-term organ damage. It is estimated that in 2019 there were around 60,000 people with SLE in England and Wales and around 3,000 people are being diagnosed with SLE each year.2,3 The prevalence of SLE is significantly related to ethnicity, and is highest among people of African-Caribbean family background. -
Collaborations on Imaging – the Medimmune’S Innovative Way
Collaborations on Imaging – The Medimmune’s Innovative Way Jerry Wu, PhD, Medimmune Developments in Healthcare Imaging – Connecting with Industry 18th October 2017 Contents 1 A brief overview of Medimmune 2 Scientific collaborations 3 Scientific Interest Group for Imaging 2 A brief overview of Medimmune Global Biologics Research and Development Arm of ~2,200 Employees in the US and UK Robust pipeline of 120+ Biologics in Research & Development with 40+ projects in Clinical Stage Development California Gaithersburg Cambridge 3 Medimmune – Biologics arm of AstraZeneca Late-stage Discovery and Early Development Development Innovative Medicines and Early Development Unit (Small Molecules) Global Internal and Collaboration and Medicines external combinations Development Market opportunities MedImmune (Biologics) 4 Current therapeutic areas Respiratory, Inflammation and Cardiovascular and Infectious Disease Oncology Autoimmunity Metabolic Disease Neuroscience Main Therapeutic Areas Opportunity-driven Protein Biologics Small Molecules Immuno-therapies Devices Engineering 5 RESPIRATORY, INFLAMMATION AND AUTOIMMUNITY ONCOLOGY (RIA) Medimmune R&D pipeline INFECTIOUS DISEASE (ID), NEUROSIENCE AND CARDIOVASCULAR AND METABOLIC DISEASE (CVMD) GASTROINTESINAL DISEASE PHASE 1 PHASE 2 PHASE 2 PIVOTAL/PHASE 3 Durvalumab + MEDI-573 Durvalumab MEDI-565 MEDI0562 MEDI4276 Durvalumab MEDI0680 Metastatic ≥2nd Line Advanced Solid Tumors Solid Tumors Solid Tumors Stage III NSCLC Solid Tumors Breast Cancer Bladder Cancer Durvalumab/AZD5069/ Durvalmab + MEDI0680 -
New Treatments for Systemic Lupus Erythematosus on the Horizon: Targeting Plasmacytoid Dendritic Cells to Inhibit Cytokine Production Laura M
C al & ellu ic la n r li Im C m Journal of Clinical & Cellular f u o Davison and Jorgensen et al., J Clin Cell Immunol n l o a l n o 2017, 8:6 r g u y o J Immunology DOI: 10.4172/2155-9899.1000534 ISSN: 2155-9899 Commentary Open Access New Treatments for Systemic Lupus Erythematosus on the Horizon: Targeting Plasmacytoid Dendritic Cells to Inhibit Cytokine Production Laura M. Davison and Trine N. Jorgensen* Department of Immunology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio, USA *Corresponding author: Dr. Trine N. Jorgensen, Department of Immunology, NE40, Lerner Research Institute, Cleveland Clinic Foundation, Ohio, USA, Phone: +1 216-444-7454; Fax: +1 216-444-9329; E-mail: [email protected] Received date: December 4, 2017; Accepted date: December 13, 2017; Published date: December 20, 2017 Copyright: © 2017 Davison LM, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Abstract Patients with systemic lupus erythematosus (SLE) often have elevated levels of type I interferon (IFN, particularly IFNα), a cytokine that can drive many of the symptoms associated with this autoimmune disorder. Additionally, the presence of autoantibody-secreting plasma cells contributes to the systemic inflammation observed in SLE and IFNα supports the survival of these cells. Current therapies for SLE are limited to broad immunosuppression or B cell- targeting antibody-mediated depletion strategies, which do not eliminate autoantibody-secreting plasma cells. -
Tanibirumab (CUI C3490677) Add to Cart
5/17/2018 NCI Metathesaurus Contains Exact Match Begins With Name Code Property Relationship Source ALL Advanced Search NCIm Version: 201706 Version 2.8 (using LexEVS 6.5) Home | NCIt Hierarchy | Sources | Help Suggest changes to this concept Tanibirumab (CUI C3490677) Add to Cart Table of Contents Terms & Properties Synonym Details Relationships By Source Terms & Properties Concept Unique Identifier (CUI): C3490677 NCI Thesaurus Code: C102877 (see NCI Thesaurus info) Semantic Type: Immunologic Factor Semantic Type: Amino Acid, Peptide, or Protein Semantic Type: Pharmacologic Substance NCIt Definition: A fully human monoclonal antibody targeting the vascular endothelial growth factor receptor 2 (VEGFR2), with potential antiangiogenic activity. Upon administration, tanibirumab specifically binds to VEGFR2, thereby preventing the binding of its ligand VEGF. This may result in the inhibition of tumor angiogenesis and a decrease in tumor nutrient supply. VEGFR2 is a pro-angiogenic growth factor receptor tyrosine kinase expressed by endothelial cells, while VEGF is overexpressed in many tumors and is correlated to tumor progression. PDQ Definition: A fully human monoclonal antibody targeting the vascular endothelial growth factor receptor 2 (VEGFR2), with potential antiangiogenic activity. Upon administration, tanibirumab specifically binds to VEGFR2, thereby preventing the binding of its ligand VEGF. This may result in the inhibition of tumor angiogenesis and a decrease in tumor nutrient supply. VEGFR2 is a pro-angiogenic growth factor receptor -
Advances in Interferon-Alpha Targeting-Approaches for Systemic Lupus Erythematosus Treatment
Full title: Advances in Interferon-alpha targeting-approaches for Systemic Lupus Erythematosus treatment Running title: Interferon-alpha targeting in SLE Authors: Filipa Farinha - Rheumatology Department, Centro Hospitalar do Baixo Vouga E.P.E. – Aveiro, Portugal David A Isenberg - Centre for Rheumatology, Division of Medicine, University College London – London, UK Correspondence to: Professor David Isenberg The Rayne Building Room 424, 4th Floor 5 University Street London WC1E 6JF E-mail: [email protected] Tel: 0044 203 108 2148 Fax: 0044 203 108 2152 1 Contents Summary 1. Introduction 1.1. IFN alpha 1.2. IFN alpha and SLE 2. IFN alpha targeting approaches 2.1. Anti-IFN alpha antibodies 2.2. Anti-IFN alpha receptor antibodies 2.3. IFN alpha Kinoid 3. Discussion 4. Conclusion Acknowledgements References 2 Summary Conventional therapies seem to have reached the limit of their ability to treat patients with Systemic Lupus Erythematosus (SLE). To improve the outcome for these patients, new drugs are needed. Several attempts have been made to introduce targeted therapies for this complex disease. One of these targets is Interferon (IFN) alpha, whose production is increased in SLE, contributing to its pathogenesis. In this review we consider some recent advances in IFN alpha targeting-approaches. Three monoclonal antibodies (mAbs) against several IFN alpha subtypes have been tested in phase I and II trials, showing an acceptable safety profile and promising results in terms of reducing the IFN signature and disease activity. A mAb specific for the IFN alpha receptor and active immunization against IFN alpha are also being tested. Further trials will be essential to ascertain the safety and efficacy of all these approaches. -
110 Identification and Treatment of Rheumatologic Diseases
4/2/2021 Describe common rheumatologic diseases Identification • Kristine M. Lohr, MD, MS and Treatment • Professor of Medicine and Chief of Determine routine diagnostic of Rheumatology Division Objectives evaluations for rheumatologic • University of Kentucky College of Medicine diseases prior to referral Rheumatologic • April 20, 2021 Diseases Describe new treatment modalities and alternative therapies for rheumatologic diseases 1 2 Prevalence Rates of Common Rheumatic Diseases • Osteoarthritis • Rheumatoid arthritis Most common • Gout rheumatologic • Lupus diseases • Fibromyalgia • Psoriatic arthritis • Ankylosing spondylitis Centers for Disease Control and Prevention March 2017 Vital Signs https://nccd.cdc.gov/cdi/rdPage.aspx?rdReport=DPH_CDI.ExploreByTopic&islTopic=ART&islYear=9999&go=GO 3 4 Arthritis among Adults Aged >18 yr. in Kentucky Age-adjusted Prevalence (%) Rheumatic Joint Disorders: History Male Female Survey Year Inflammatory Non-inflammatory (Mechanical) All adults aged > 18 yr. 27.8 33.3 2018 Joint pain In the AM, at rest, & with use With use, improved with rest With obesity 32.9 40.0 2018 Stiffness Prolonged morning (>1 hr.) Short-lived after inactivity With diabetes 64.7 40.6 2018 Fatigue Significant Minimal With heart disease 47.2 53.9 2018 Activity May improve stiffness May worsen symptoms Activity limitation due to doctor-diagnosed arthritis 49.5 64.0 2015 Rest May cause gelling May improve symptoms Severe joint pain due to doctor-diagnosed arthritis 35.3 38.3 2017 Instability Buckling, give-way Work limitation