Towards Biosimilar Monoclonal Antibodies Pros And Cons
Towards biosimilar monoclonalantibodiesPros and consEMEA Workshopon Biosimilar Monoclonal AntibodiesChristian K Schneider, MDBMWP ChairmanEuropean Medicines Agency (EMEA), UKPaul-Ehrlich-Institut, Germany
Can more complex biologicals bebiosimilars?In principle, the concept of “similar biological medicinalproducts” applies to any biological medicine.Guideline CPMP/BWP/437/04www.lucky-lions.comHow much do we need to know?Idea: C. NickHow much „similarity“ do we need?Christian K Schneider2
Why „biosimilar“ (and not „biogeneric“)?Aspirin180 DaltonsInsulin5 700 DaltonsMAb150 000 DaltonsChristian K SchneiderSource: Cecil Nick, Parexel3
Why „biosimilar“ (and not „biogeneric“)?“The process is the product. “- Fluctuations in the manufacturing process(e.g., pH, temperature, culture media):Batch inconsistency(glycosylation spectra, aggregates)- Changes in the manufacturing process(e.g., expression system):New product? „One process – one product“ paradigmBiotechnological medicinal products are „individuals“Biotechnological medicinal products are more than the drug substanceSmall changes can have high impactChristian K Schneider4
Terminology that mattersCave terminology!Pieter Bruegel der Ältere (1525/1530(1525/1530-1569)The Tower of Babel, 1563» Biosimilar mAb– Similarity of active substance– Aim is to establish similarity to licensed product– Same indications (but not necessarily all)» 2nd generation mAb– Different active substance(Humira is not a biosimilar to Remicade !)– Stand-alone development, might however be comparative– Can be different indications– (would these be the „follow-on“ biologicals?)Christian K Schneider5
Monoclonal antibodies – a success storyReichert J et al: Monoclonal antibody successes in the clinic. Nature Biotechnol.23(9): 1073 (2005)Christian K Schneider6
Evolution of monoclonal antibodiesEvolution of monoclonal antibodies („-mab“):Murine mAbChimaeric mAbHumanized mAbFully Human Arcitumomab(CEA-Scan )(1996)Infliximab(Remicade )(1999)Trastuzumab(Herceptin )(2000)Adalimumab(Humira )(2003) murine humanNew constructs- bispecific antibodies- diabodies- single chain fragments- engineered Fc mAbs- conjugated mAbs- .ImmunogenicityChristian K Schneider7
We have experience!Christian K SchneiderReichert J et al: Monoclonal antibody successes in the clinic. Nature Biotechnol.23(9): 1073 (2005)8
Non-clinical testing: A question ofrelevanceCentral aspect: biotechnological products arespecies-specific.A relevant species is one in which the test material ispharmacologically active due to the expression of thereceptor or an epitope (in the case of monoclonalantibodies)*.*NfG on preclinical safety evaluation of biotechnology derived pharmaceuticals(CPMP/ICH/302/95; ICH S6)Relevant species for licensed mAbs describedChristian K Schneider9
Potency assays are availableProductSpecificityPotency liferation bioassay(inhibition of rhVEGF-inducedproliferation of Human UmbilicalVein Endotheliae CellsHUVEC).Assay chosen as drugsubstance release testbased on its sensitivity(ability to detect significantchanges in the activity),robustness, precision(RSD 10%) and accuracy(98-102%)(relative number of viable cells,quantified by ion of binding ofradiolabelled IL-2 to IL-2receptor expressed on Tlymphocytes (and thus inhibitionof lymphocyte proliferation)Synagis(Palivizumab)Anti-RSVIn vitro: RSVMicroneutralisation Assay, RSVFusion Inhibition Assay,BIAcore AnalysisIn vivo potency: Reduction ofRSV titre in the lungs of infectedcotton ratsTysabri(Natalizumab)Anti-α4-integrinIn vitro assay: Ability to bindα4-integrins and block itsinteraction with its co-receptor.Xolair(Omalizumab)Anti-IgEInhibition of binding: Ability ofomalizumab to inhibit binding ofIgE to its receptorChristian K SchneiderComparison of differentpredecessor products withpalivizumab duringdevelopmentShown to correlate to theinhibition of release ar/eparintro.htm10
Current methodology: IncreasingsensitivityOOOOPhysicochemical characterisation, e.g.» Capillary electrophoresis with laser-induced fluorescencedetection (CE-LIF)» Mass spectrometry techniques (e.g., MALDI-TOF)» Nuclear magnetic resonanceAntigen-antibody interaction, e.g.» Surface plasmon resonanceSecondary structure detection, e.g.» Circular dichroism in near- and far-UV spectraCombination of methodologies, e.g.» liquid chromatography combined with mass spectrometry(e.g. Beck, A. et al, J Chromatogr B Analyt Technol Biomed Life Sci. 819(2): 203-218 (2005))Christian K Schneider11
Licensed mAbs: Efficacy and safetyOFor example: Remicade (Infliximab)(anti-TNFα)OLicensed indications:»»»»»»»Rheumatoid arthritisAdult Crohn‘s diseasePaediatric Crohn‘s diseaseUlcerative colitisAnkylosing spondylitisPsoriatic arthritisPsoriasisChristian K s/EPAR/remicade/remicade.htm12
Licensed mAbs: Efficacy and safetyOFor example: Moderate to severe psoriasisBefore treatmentChristian K SchneiderAfter s/EPAR/remicade/remicade.htm13
Licensed mAbs: Efficacy and safetyOSafety data in 2005:– TREAT-Registry (only patients with Crohn‘s disease)(Crohn’s Therapy Resource Evaluation and Assessment Toolregistry)O 6290 patients, 3235 of them treated with RemicadeO Ca. 25.000 Infusions– Cumulative safety data (August 1998 – August 2004):O 1.350.000 Patient yearsO 576.000 PatientsChristian K EPAR/Remicade/EMEA-H-240-II-69-AR.pdf14
Toward biosimilar mAbs andCon‘sChristian K Schneider15
Complexity of monoclonal antibodiesChristian K SchneiderCarter PJ: Potent antibody therapeutics by design, Nature Rev Immunol 6, 343 (2006)16
Glycosylation of mAbsChristian K Schneider17
GlycosylationChristian K Schneider18
Complexity of monoclonal antibodiesTypical antibody manufacturing processeh“TChristian K Schneiderssecorpiseht.tcudopr“Carson KL. Flexibility – The guiding principle for antibody manufacturing.Nature Biotechnol 23(9): 1054 (2005)19
Current methodology: IncreasingsensitivityOOOO?hPhysicochemical characterisation, e.g.gu» Capillary electrophoresis with laser-inducedfluorescenceodetection (CE-LIF)ne» Mass spectrometry techniques(e.g., MALDI-TOF)e» Nuclear magnetic resonanceti ivsAntigen-antibody interaction,e.g.ne» Surface plasmon resonancesSecondary structuredetection, e.g.es in near- and far-UV spectra» Circular dichroismethof methodologies, e.g.Combinationer» liquid chromatography combined with mass spectrometryA(e.g. Beck, A. et al, J Chromatogr B Analyt Technol Biomed Life Sci. 819(2): 203-218 (2005))Christian K Schneider20
Biosimilar mAbs:Signs or fiction?Are obviously approaching?!Christian K Schneider21
EMEA WorkshopOOOOOOPhilosophy: Open discussion on pros andcons of biosimilar mAbsPossibility and feasibilityNo conclusion (yet) but scientific evolutionQuestions as a starting pointFocussed presentations, not meant to beexhaustive, but to initiate discussions.If issues come up that are important, but donot fit to the topic of session: Move to end ofworkshop (where there should be time)Christian K Schneider22
The floor is yours!Christian K Schneider23
*NfG on preclinical safety evaluation of biotechnology derived pharmaceuticals (CPMP/ICH/302/95; ICH S6) Relevant species for licensed mAbs described. Christian K Schneider 10 Potency assays are available . OPhilosophy: Open discussion on pros and cons of biosimilar mAbs
MRC reagents catalogue for monoclonal antibodies Category Reference Number . J.Exp.Med. 162:117 86100903 Monoclonal Antibody A857/0065 anti-CD25 (IL-2R alpha) monoclonal antibody OX39 CD25 cell surface
The promise, for many years, of useful diagnostic and therapeutic monoclonal antibodies has begun to be realized. The applications for use of antibodies, their derivatives and fragments continues to hold . There are two major methods of classifying human immune system components. One method is based on the characteristic of adaptability .
Providers who are educated on biosimilar safety and efficacy become comfortable prescribing biosimilars Biosimilar competition thrives in markets where government policies set fair and even playing fields Payor rules need to support strong and early market formation, and recogn
Introduction and Report Overview Foreword: A Word From Our VP of US Value and Access 4 About Amgen 5 2021 Biosimilar Trends Report Key Takeaways 6 . The cumulative reduction in drug spend for classes with biosimilar competition is estimated to have been 9.8 billion over the past 5 years. 3
RESEARCH ARTICLE Open Access Long-term efficacy, safety, and immunogenicity of the adalimumab biosimilar, PF-06410293, in patients with rheumatoid arthritis after switching from reference adalimumab (Humira ) or continuing biosimilar therapy: week 52-92 data from a randomized, double-blind, phase 3 trial
Achieving Robust cIEF Analysis of Monoclonal Antibodies While Increasing Capillary Run-Life and Maintaining High Resolution and Reproducibility Subject: An analytical cIEF method designed to extend capillary run-life and maximize pI resolution and experimental repeatability and reproducibility for the analysis of mAbs. Created Date: 20180314213503Z
GCSE Biology Only . Students should be able to describe how monoclonal antibodies are produced. Students should be able to describe some of the ways in which monoclonal antibodies can be used. Some examples include: for diagnosis such as in pregnancy tests in laboratories
Introduction to Groups, Rings and Fields HT and TT 2011 H. A. Priestley 0. Familiar algebraic systems: review and a look ahead. GRF is an ALGEBRA course, and specifically a course about algebraic structures. This introduc-tory section revisits ideas met in the early part of Analysis I and in Linear Algebra I, to set the scene and provide motivation. 0.1 Familiar number systems Consider the .
