DOCSLIB.ORG

Chapter 1 of This Thesis (With Omitted Sections) Is Published As

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Chapter 1 of This Thesis (With Omitted Sections) Is Published As Thesis by Publication Development of Aggregation- Resistant Monoclonal Antibodies Through Antibody Engineering and Formulation Approaches Mouhamad Reslan This thesis is submitted in full satisfaction of the requirements for the degree of Doctor of Philosophy at the University of Sydney. School of Pharmacy Faculty of Medicine and Health 2018 i Statement of Authentication This thesis is submitted to the University of Sydney in fulfilment of the requirement for the degree of Doctor of Philosophy. The work presented in this thesis is, to the best of my knowledge and belief, original except as acknowledged in the text. I hereby declare that I have not submitted this material, either in full or in part, for a degree at this or any other institution. Signature: Date: 13th of August 2018 ii Acknowledgements I start by acknowledging the traditional owners of this land - the Gadigal people of the Eora nation - on which I have spent the last three to four years conducting research and developing new friendships. To my supervisor, Associate Professor Veysel Kayser, I thank you for your patience, support and guidance during this time. I thank you for embarking on this journey with me, while giving me the freedom to decide my own path. To my co-supervisor Associate Professor Serdar Kuyucak and the Biophysics Team, thank you for the time we worked together, the words of support as we hit roadblocks along the way, and the celebrations as we broke through and graduated. To my colleagues, Vicki, Esteban, Yusuf and the many students I met on the way, I could not have asked for a better network of friends to work alongside and to enjoy this experience with. Thank you for all the laughter and fun we had together (and all those games of ping pong!). To the amazing people I met along the way including Meryem, Zehra and David – thank you for being mentors, your time and effort has been invaluable to myself and others and has contributed significantly to the success of the work within this thesis. Thank you to everyone in the office, and the wonderful staff and academics at the School of Pharmacy, for your continued support and words of encouragement. Thank you to Sheng and Donna for your time training me and assisting with my research at MBF. Thank you to Mario, for sharing your expertise with us when we first began and supporting us throughout. Finally, thank you to my family for your constant support during the challenges and moments of joy; I can now close this chapter of my life, having gained new insights, experiences, and ideas. I look forward to writing the next chapter. iii Authorship attribution statement Chapter 1 of this thesis (with omitted sections) is published as: Elgundi, Z., Reslan, M., Cruz, E., Sifniotis, V., Kayser, V. (2017). The state-of-play and future of antibody therapeutics. Advanced Drug Delivery Reviews, 122:2-19. M. Reslan wrote several sections of the review including: parts of the section ‘Biobetters’, all ‘Physical and chemical degradation of antibodies’ including ‘Computational design tools’, made minor edits to ‘optimisation of antibody bioavailability and delivery’ and contributed to writing the abstract, introduction, and conclusion. He also critically reviewed and edited the entire manuscript to prepare it for submission. In the thesis introduction, he updated the information in each included section with current literature. Chapter 2 of this thesis is published as: Reslan, M., Demir, Y., Trout, B., Chan, H., Kayser, V. (2017). Lack of a synergistic effect of arginine-glutamic acid on the physical stability of spray-dried bovine serum albumin. Pharmaceutical Development and Technology, 22:785-791. M. Reslan co-designed the study, prepared the formulations and performed most of the formulation characterisation. He analysed most of the data and wrote the manuscript. Chapter 3 of this thesis is published as: Reslan, M., Kayser, V. (2016). The effect of deuterium oxide on the conformational stability and aggregation of bovine serum albumin. Pharmaceutical Development and Technology, 1-7. M. Reslan co-designed the study, performed all experiments and data analysis, and wrote the manuscript. Chapter 4 of this thesis is published as: Reslan, M., Kayser, V. (2018). Ionic liquids as biocompatible stabilizers of proteins. Biophysical Reviews. doi:10.1007/s12551-018-0407-6 M. Reslan performed the literature searches and co-wrote the review. iv Chapter 5 of this thesis is prepared for publication as: Reslan, M., Kayser, V. (2018). Analysis of the aggregation kinetics of Herceptin® (trastuzumab). European Journal of Pharmaceutics and Biopharmaceutics. M. Reslan co-designed the study, performed all experiments and data analysis, and wrote the manuscript. Chapter 6 of this thesis published as: Reslan, M., Vijayaraghavan R., Macfarlane D. R., Kayser, V. (2018). Choline ionic liquid enhances the stability of Herceptin® (trastuzumab). Chemical Communications, 54:10622-10625. M. Reslan co-designed the study, prepared the formulations, performed all stability characterisation experiments and data analysis, and wrote the manuscript. Chapter 7 of this thesis is published as: Elgundi, Z., Sifniotis, V., Reslan, M., Cruz, E., Kayser, V. (2017). Laboratory Scale Production and Purification of a Therapeutic Antibody. Journal of Visualized Experiments, 119: e55153. M. Reslan assisted with the writing of the manuscript. He designed and wrote all sections relating to the purification and characterisation of the antibody following expression, performed those experiments and prepared the figures. Chapter 8 of this thesis is prepared for publication as: Reslan, M., Sifniotis, V., Cruz, E., Sumer-Bayraktar, Z., Kayser, V. (2018). Enhancing the stability of adalimumab by engineering additional glycosylation motifs. European Journal of Pharmaceutics and Biopharmaceutics. M. Reslan co-designed the experiments and conducted most of the experimental work including mutagenesis, sequencing analysis, expression of the antibody variants, purification and characterisation. He also wrote most sections of the manuscript and compiled it together for publication. In addition to the statements above, in cases where I am not the corresponding author of a published item, permission to include the published material has been granted by the corresponding author. v Mouhamad Reslan, Signature: 13th of August 2018 As supervisor for the candidature upon which this thesis is based, and corresponding author for the publications, I can confirm that the authorship attribution statements above are correct. Veysel Kayser, Signature: 13th of August 2018 vi Table of Contents Statement of authentication .................................................................................... ii Acknowledgements ................................................................................................. iii Authorship attribution statement ........................................................................... iv Thesis abstract ........................................................................................................ xi Thesis introduction ................................................................................................ xii Conferences and publications .............................................................................. xv Chapter 1: The state-of-play and future of antibody therapeutics ...................... 1 Graphical abstract ................................................................................................... 1 Abstract ................................................................................................................... 2 1. Introduction ........................................................................................................ 2 2. Antibody discovery strategies ............................................................................ 2 3. Manufacture of antibodies ................................................................................. 4 4. Biobetter antibodies ........................................................................................... 6 4.1. Fc engineered antibodies with enhanced effector function ......................... 12 5. Physical and chemical degradation of antibodies ............................................ 13 5.1. Aggregation ................................................................................................ 14 5.2. Denaturation ............................................................................................... 14 5.3. Fragmentation ............................................................................................ 15 5.4. Deamidation ............................................................................................... 15 5.5. Oxidation .................................................................................................... 16 6. Computational design tools ............................................................................. 17 7. Optimisation of antibody bioavailability and delivery ........................................ 19 8. Conclusion ....................................................................................................... 21 Acknowledgements ............................................................................................... 22 Disclosures ........................................................................................................... 22 References ...........................................................................................................
Load more

Recommended publications
  • Fig. L COMPOSITIONS and METHODS to INHIBIT STEM CELL and PROGENITOR CELL BINDING to LYMPHOID TISSUE and for REGENERATING GERMINAL CENTERS in LYMPHATIC TISSUES
    (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 Χ 23 February 2012 (23.02.2012) WO 2U12/U24519ft ft A2 (51) International Patent Classification: AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, A61K 31/00 (2006.01) CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, (21) International Application Number: HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, PCT/US201 1/048297 KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, (22) International Filing Date: ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, 18 August 201 1 (18.08.201 1) NO, NZ, OM, PE, PG, PH, PL, PT, QA, RO, RS, RU, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, (25) Filing Language: English TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, (26) Publication Language: English ZW. (30) Priority Data: (84) Designated States (unless otherwise indicated, for every 61/374,943 18 August 2010 (18.08.2010) US kind of regional protection available): ARIPO (BW, GH, 61/441,485 10 February 201 1 (10.02.201 1) US GM, KE, LR, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, 61/449,372 4 March 201 1 (04.03.201 1) US ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, (72) Inventor; and EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, ΓΓ, LT, LU, (71) Applicant : DEISHER, Theresa [US/US]; 1420 Fifth LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, Avenue, Seattle, WA 98101 (US).
    [Show full text]
  • Of Anti-CD3 Action? This Information Is Current As of September 26, 2021
    Differential Response of Regulatory and Conventional CD4 + Lymphocytes to CD3 Engagement: Clues to a Possible Mechanism of Anti-CD3 Action? This information is current as of September 26, 2021. Li Li, Junko Nishio, André van Maurik, Diane Mathis and Christophe Benoist J Immunol published online 28 August 2013 http://www.jimmunol.org/content/early/2013/08/27/jimmun ol.1300408 Downloaded from Supplementary http://www.jimmunol.org/content/suppl/2013/08/28/jimmunol.130040 Material 8.DC1 http://www.jimmunol.org/ Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication by guest on September 26, 2021 *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2013 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Published August 28, 2013, doi:10.4049/jimmunol.1300408 The Journal of Immunology Differential Response of Regulatory and Conventional CD4+ Lymphocytes to CD3 Engagement: Clues to a Possible Mechanism of Anti-CD3 Action? Li Li,* Junko Nishio,* Andre´ van Maurik,† Diane Mathis,* and Christophe Benoist* Several clinical trials have shown anti-CD3 treatment to be a promising therapy for autoimmune diabetes, but its mechanism of action remains unclear.
    [Show full text]
  • Promising Therapeutic Targets for Treatment of Rheumatoid Arthritis
    REVIEW published: 09 July 2021 doi: 10.3389/fimmu.2021.686155 Promising Therapeutic Targets for Treatment of Rheumatoid Arthritis † † Jie Huang 1 , Xuekun Fu 1 , Xinxin Chen 1, Zheng Li 1, Yuhong Huang 1 and Chao Liang 1,2* 1 Department of Biology, Southern University of Science and Technology, Shenzhen, China, 2 Institute of Integrated Bioinfomedicine and Translational Science (IBTS), School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China Rheumatoid arthritis (RA) is a systemic poly-articular chronic autoimmune joint disease that mainly damages the hands and feet, which affects 0.5% to 1.0% of the population worldwide. With the sustained development of disease-modifying antirheumatic drugs (DMARDs), significant success has been achieved for preventing and relieving disease activity in RA patients. Unfortunately, some patients still show limited response to DMARDs, which puts forward new requirements for special targets and novel therapies. Understanding the pathogenetic roles of the various molecules in RA could facilitate discovery of potential therapeutic targets and approaches. In this review, both Edited by: existing and emerging targets, including the proteins, small molecular metabolites, and Trine N. Jorgensen, epigenetic regulators related to RA, are discussed, with a focus on the mechanisms that Case Western Reserve University, result in inflammation and the development of new drugs for blocking the various United States modulators in RA. Reviewed by: Åsa Andersson, Keywords: rheumatoid arthritis, targets, proteins, small molecular metabolites, epigenetic regulators Halmstad University, Sweden Abdurrahman Tufan, Gazi University, Turkey *Correspondence: INTRODUCTION Chao Liang [email protected] Rheumatoid arthritis (RA) is classified as a systemic poly-articular chronic autoimmune joint † disease that primarily affects hands and feet.
    [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]
  • Antigen-Targeted Monoclonal Antibody Otelixizumab and C
    Supplemental material to this article can be found at: http://jpet.aspetjournals.org/content/suppl/2018/10/17/jpet.115.224899.DC1 1521-0103/355/2/199–205$25.00 http://dx.doi.org/10.1124/jpet.115.224899 THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS J Pharmacol Exp Ther 355:199–205, November 2015 Copyright ª 2015 by The American Society for Pharmacology and Experimental Therapeutics Temporal Pharmacokinetic/Pharmacodynamic Interaction between Human CD3« Antigen–Targeted Monoclonal Antibody Otelixizumab and CD3« Binding and Expression in Human Peripheral Blood Mononuclear Cell Static Culture s Kevin R. Page, Enrica Mezzalana, Alexander J. MacDonald, Stefano Zamuner, Giuseppe De Nicolao, and Andre van Maurik GlaxoSmithKline, Stevenage, United Kingdom (K.R.P., A.J.M., S.Z., A.vM.); University of Pavia, Pavia PV, Italy (E.M., G.D.N.) Received April 22, 2015; accepted August 17, 2015 Downloaded from ABSTRACT Otelixizumab is a monoclonal antibody (mAb) directed to human a shorter apparent half-life at low concentration. Correspondingly, CD3«, a protein forming part of the CD3/T-cell receptor (TCR) a rapid, otelixizumab concentration–, and time-dependent re- complex on T lymphocytes. This study investigated the temporal duction in CD3/TCR expression was observed. These combined interaction between varying concentrations of otelixizumab, bind- observations were consistent with the phenomenon known as jpet.aspetjournals.org ing to human CD3 antigen, and expression of CD3/TCR complexes target-mediated drug disposition (TMDD). A mechanistic, mathe- on lymphocytes in vitro, free from the confounding influence of matical pharmacokinetic/pharmacodynamic (PK/PD) model was changing lymphocyte frequencies observed in vivo.
    [Show full text]
  • TNF-A Antibody Therapy in Combination with the T-Cell–Specific Antibody Anti-TCR Reverses the Diabetic Metabolic State in the LEW.1AR1-Iddm Rat
    2880 Diabetes Volume 64, August 2015 Anne Jörns,1,2 Ümüs Gül Ertekin,1 Tanja Arndt,1 Taivankhuu Terbish,1 Dirk Wedekind,3 and Sigurd Lenzen1 TNF-a Antibody Therapy in Combination With the T-Cell–Specific Antibody Anti-TCR Reverses the Diabetic Metabolic State in the LEW.1AR1-iddm Rat Diabetes 2015;64:2880–2891 | DOI: 10.2337/db14-1866 Anti–tumor necrosis factor-a (TNF-a) therapy (5 mg/kg b-cell death (1–3). The infiltrate in the pancreatic islets is body weight), alone or combined with the T-cell–specific composed of different immune cell types, especially macro- antibody anti–T-cell receptor (TCR) (0.5 mg/kg body phages and T cells (2–4). Upon activation, the immune cells weight), was performed over 5 days immediately after release proinflammatory cytokines and other cytotoxic disease manifestation to reverse the diabetic metabolic mediators, causing b-cell apoptosis (3,5). state in the LEW.1AR1-iddm rat, an animal model of hu- Effective prevention strategies require a combination man type 1 diabetes. Only combination therapy starting therapy (6–8) to target the proinflammatory cytokines pro- at blood glucose concentrations below 15 mmol/L re- duced in the different immune cell types. Of crucial impor- stored normoglycemia and normalized C-peptide. In- tance is in this context the proinflammatory cytokine tumor b creased -cell proliferation and reduced apoptosis led necrosis factor-a (TNF-a). It is expressed in all immune cell to a restoration of b-cell mass along with an immune types infiltrating the pancreatic islets in patients with T1D ISLET STUDIES cell infiltration–free pancreas 60 days after the end as well as in the spontaneous mouse (NOD mouse) and rat of therapy.
    [Show full text]
  • Antibody Engineering to Develop New Antirheumatic Therapies John D Isaacs
    Available online http://arthritis-research.com/content/11/3/225 Review Antibody engineering to develop new antirheumatic therapies John D Isaacs Wilson Horne Immunotherapy Centre and Musculoskeletal Research Group, Institute of Cellular Medicine, Newcastle University, Framlington Place, Newcastle-Upon-Tyne, NE2 4HH, UK Corresponding author: John D Isaacs, [email protected] Published: 19 May 2009 Arthritis Research & Therapy 2009, 11:225 (doi:10.1186/ar2594) This article is online at http://arthritis-research.com/content/11/3/225 © 2009 BioMed Central Ltd Abstract the light chain two distinct domains, where a domain is a There has been a therapeutic revolution in rheumatology over the discrete, folded, functional unit (Figure 2a). The first domain past 15 years, characterised by a move away from oral immuno- in each chain is the V domain, VH and VL on the heavy and suppressive drugs toward parenteral targeted biological therapies. light chains, respectively. The rest of the heavy chain The potency and relative safety of the newer agents has facilitated comprises three (four for IgE) constant domains (CH1 to a more aggressive approach to treatment, with many more patients CH3), whilst the light chains have one constant domain (CL). achieving disease remission. There is even a prevailing sense that There is a flexible peptide segment (the hinge) between the disease ‘cure’ may be a realistic goal in the future. These develop- ments were underpinned by an earlier revolution in molecular CH1 and CH2 domains. biology and protein engineering as well as key advances in our understanding of rheumatoid arthritis pathogenesis. This review will The antibody V region is composed of the VH and VL focus on antibody engineering as the key driver behind our current domains.
    [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]
  • (INN) for Biological and Biotechnological Substances
    WHO/EMP/RHT/TSN/2019.1 International Nonproprietary Names (INN) for biological and biotechnological substances (a review) 2019 WHO/EMP/RHT/TSN/2019.1 International Nonproprietary Names (INN) for biological and biotechnological substances (a review) 2019 International Nonproprietary Names (INN) Programme Technologies Standards and Norms (TSN) Regulation of Medicines and other Health Technologies (RHT) Essential Medicines and Health Products (EMP) International Nonproprietary Names (INN) for biological and biotechnological substances (a review) FORMER DOCUMENT NUMBER: INN Working Document 05.179 © World Health Organization 2019 All rights reserved. Publications of the World Health Organization are available on the WHO website (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; e-mail: [email protected]). Requests for permission to reproduce or translate WHO publications –whether for sale or for non-commercial distribution– should be addressed to WHO Press through the WHO website (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 and dashed 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]
  • Therapeutic Monoclonal Antibodies: Past, Present, and Future
    &PART I ANTIBODY BASICS COPYRIGHTED MATERIAL &CHAPTER 1 Therapeutic Monoclonal Antibodies: Past, Present, and Future WILLIAM R. STROHL 1.1 Introduction 4 1.2 Historical Aspects 19 1.2.1 Historical Aspects: Origins of Serum Therapy, Forerunner to the Monoclonal Antibody Business 20 1.2.2 IVIG Therapeutics and Prophylactics 21 1.3 Technologies Leading to the Current Monoclonal Antibody Engineering 23 1.3.1 Fundamental Breakthroughs Allowing for Recombinant Monoclonal Antibodies 23 1.3.2 Hybridoma Technology 23 1.3.3 Transfectomas and Chimeric Antibodies 24 1.3.4 Humanization Technology 24 1.3.5 Humanized Mice 25 1.3.6 Phage Display Technology 26 1.3.7 Human Antibody Libraries 27 1.3.8 Summary of Core Therapeutic Mab Technologies Leading to Therapeutics 28 1.4 From Biotechnology to BioPharma 28 1.4.1 From OKT3 to Remicade: Early Successes and Disappointments 28 1.4.2 Examples of Other Early Mabs 29 1.4.3 Evolution of the Biotechnology Industry to the New BioPharma Industry 31 1.5 Challenges and Opportunities for Monoclonal Antibodies 32 1.5.1 SWOT Analysis 32 1.5.2 Competition on “Hot” Targets 32 1.5.3 Targets 33 1.5.4 Differentiation and Fit-for-Purpose Biologics 35 1.6 Summary, and “Where Do We Go From Here” 42 References 43 ABSTRACT In this chapter, an overview of the therapeutic antibody industry today, including the many commercial antibodies and Fc fusions and the rich clinical pipeline, is presented and analyzed. The long history of antibodies is given to bring context to the therapeutic antibody industry.
    [Show full text]
  • Zacks Small-Cap Research April 12, 2021
    Zacks Small-Cap Research April 12, 2021 Sponsored – Impartial – Comprehensive John D. Vandermosten, CFA 312-265-9588 / [email protected] scr.zacks.com 10 S. Riverside Plaza, Suite 1600, Chicago, IL 60606 Tiziana Life Sciences PLC (TLSA - NASDAQ) INITIATION In A Tizzy about Tiziana Tiziana is a research and development company developing three main candidates for a variety of indications in autoimmune disease, cancer and COVID. The lead candidate, foralumab, is a fully human anti-CD3 Based on our DCF model and a 15% discount rate, Tiziana is antibody, being investigated in multiple sclerosis (MS), Crohn’s disease valued at approximately $7.50 per ADR share. Our model ap- (CD) and COVID, administered intranasally and orally via enteric coated capsules. milciclib is the second candidate and is being investigated as a plies a 15% probability of ultimate approval and commercializa- tion for the portfolio of assets including foralumab and milciclib. combination product in multiple oncology indications. The third candi- The model includes contributions from the United States and date, TZLS-501, is an anti-IL-6R receptor antibody expected to be the subject of an IND submitted in 2021. TZLS-501 is being investigated as a global developed markets. treatment for COVID and other pulmonary diseases such as ARDS. Ph2 foralumab clinical trials for MS and CD are targeted for 2021 & Ph2 combination trials for milciclib in coming quarters. Tiziana differentiates Current Price (4/9/2021) $2.67 itself in the use of intranasal, oral and inhaled formulations of mAbs that are able to avoid shortcomings of infused & subcutaneous administra- Valuation $7.50 tion.
    [Show full text]