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About biologics

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Antibodies

Antibodies are immunoglobulins that specifically interact with antigens. They elicit responses from immune cells that neutralise or eliminate the antigen.1

All antibodies share a common structure of two identical light chains and two identical heavy chains, bound by disulphide bonds.1There are five classes of antibodies in humans, each of which has a unique function or purpose as summarised in the table.1

Features of the five antibody classes

  IgG IgM IgA IgD IgE
Structure Monomer Pentamer Dimer Monomer
Monomer
Antibody in plasma (%) 75–85 5–10 10–15 0.001 0.2
Presence in sites other than blood, connective tissue and lymphoid organs Foetal circulation in pregnant women Surface of B cells (as a monomer) Secretions, e.g. saliva, tears, milk Surface of B cells Surface of mast cells and b111sophils
Known functions Activates phagocytosis, neutralises antigens First antibody produced in initial immune response; activates complement Protects mucosae Antigen receptor triggering initial B cell activation
Destroys parasitic worms and participates in allergic response

Ig, immunoglobulin.
Adapted from Kindt, et al. 2008.1

IgG molecules can be engineered into therapeutic antibodies.2Three elements of the molecule may be engineered to alter antibody function.3

  • Chimeric antibodies

    Chimeric antibodies are 70% human and possess a fully human Fc region. Their creation involves fusion of human constant domains with murine variable regions that are responsible for antigen binding.4

    Chimeric antibodies are considerably less immunogenic than early therapeutic antibodies, which were fully murine in construction. Having a fully human Fc region also lets the antibody interact with human effector cells and the complement cascade.4

How therapeutic antibodies work

Therapeutic antibodies can have various MoAs. The simplest of these is an antibody binding to its antigen, which interferes with the antigen’s activity and interaction with its normal receptor. This is known as ligand blockade. 3-4

Alternatively, the antibody can target a cell surface receptor rather than the ligand that binds to it. This is known as receptor blockade. 3-4

Ligand and receptor blockade with a therapeutic antibody

Ligand and receptor blockade with a therapeutic antigen.

Ligand blockade occurs when a therapeutic antibody binds to and inhibits the activity of a soluble antigen. Receptor blockade occurs when a therapeutic antibody binds to and inhibits the activity of a cell-surface receptor.

Adapted from Chan and Carter 20103and Chames et al. 2009.4

Theoretically, antibodies that target cell surface receptors rather than soluble ligands have greater potential for inducing an immunogenic response. Antibody-bound receptor internalisation can result in processing and presentation of MHC Class II molecules to initiate a CD4+ T cell-dependent humoral response.3

Considerations for therapeutic antibody prescription

  • Anti-drug antibodies

    Therapeutic proteins, including targeted mAbs, have the potential to trigger an immune response in the patient. 6-7 Such reactions involve the production of anti-drug antibodies. 8

    Anti-drug antibodies are caused either by antibodies generated in response to mAb, or pre-existing antibodies that are reactive against the mAb. Anti-drug antibodies can be neutralising or non-neutralising and have the potential to affect the safety and long-term efficacy of a mAb: 8

    • Neutralising anti-drug antibodies might bind to the active site of the mAb. This inhibits the mAb’s biologic activity, thereby affecting its potency 8

    Non-neutralising antibodies might bind to sites other than the active site. In this case, the mAb’s biologic activity is not hindered so its potency would not be directly affected. 8

  • Immunogenicity

    Immunogenic responses to therapeutic mAbs can affect both safety and pharmacokinetic properties, potentially impacting the efficacy and utility of the drug. 7-8 9 However, there is no clear understanding of the clinical consequences of neutralising antibodies to date.

    The factors that influence immunogenicity are varied and may be inherent to the patient, the product or the disease.

    • Product characteristics affecting immunogenicity include: 10 
      • Formulation 
      • Protein aggregation 
      • Protein modification, e.g. glycosylation status (glycosylated mAbs are less immunogenic); variations in protein sequence 
      • Administration frequency (higher frequency is associated with an increased risk of anti-drug antibodies
    • Patient-specific factors include: 10 
      • Concurrent illness and medications 
      • Genetic background 
      • Disease state 
    • Treatment-related factors include: 10 
      • Frequency 
      • Dose 
      • Route of administration
  • Hypersensitivity reactions

    Hypersensitivity reactions typically occur after one or more doses. Most, but not all, hypersensitivity reactions occur after multiple doses and are due to cross-reacting or drug-specific IgG or IgE antibody production. 11Clinical signs of hypersensitivity may occur during or immediately after dosing or within a few days of dosing. 11

  • Anaphylaxis with biologics

    Anaphylaxis is a serious allergic reaction that is rapid in onset and may cause death. 12 Anaphylaxis can occur in response to the formation of anti-drug antibodies. 8The Sampson criteria are used to accurately identify anaphylactic reactions. 12

  • Infusion reactions with biologics

    Infusion reactions can also be a consequence of anti-drug antibodies. 8They can be either allergic reactions to foreign proteins (and thus classed as Type I hypersensitivity reactions) or non-IgE mediated (i.e. anaphylactoid) reactions. 13

    Patients experiencing infusion reactions might have the following symptoms: 8

    • Headache
    • Nausea
    • Fever
    • Chills
    • Dizziness
    • Flush
    • Pruritus
    • Chest or back pain

    The incidence of infusion reactions in response to mAbs varies. However, most reactions occur during the first infusion. Furthermore, most infusion reactions related to mAbs are mild (Grade 1 or 2) and the incidence of severe (Grade 3 or 4) reactions is low. 14-15 As biologic therapy for severe asthma is administered in a clinical setting, patients should be observed for an appropriate period of time after administration and the clinician should be prepared to manage anaphylaxis. 15

References:

  1. Kindt TJ, et al. Kuby Immunology. 6th ed. W.H. Freeman and Company, New York, NY, USA: 2008.
  2. Goswami S, et al. Antibodies 2013;2:452–500.
  3. Chan AC, Carter PJ. Nat Rev Immunol 2010;10:301–16.
  4. Chames P, et al. Br J Pharmacol 2009;157:220–33.
  5. Foltz IN, et al. Circulation 2013;127:2222–30.
  6. Abonia JP, Putnam PE. Expert Rev Clin Immunol 2011;7:411–7.
  7. Valor L, de la Torre I. Reum Clinica 2013;9:1–4.
  8. Shankar, G. et al. AAPS J 2014;16:658–73.
  9. Harding FA, et al. mAbs 2010;2:256–65.
  10. Warnke C, et al. Drugs Ther Studies 2012;2:e11.
  11. Everds NE, Tarrant JM. Toxicol Pathol 2013;41:280–302.
  12. Sampson HA, et al. JACI 2006;11:391–7.
  13. Vogel WA. Clin J Oncol Nurs 2010;14:e10.
  14. Cheifetz A, et al. Am J Gastroenterol 2003;98:1315–24.
  15. Mepolizumab SmPC; GlaxoSmithKline 2016

NUCALA (mepolizumab), 100 mg pulver till injektionsvätska, lösning, 100 mg injektionsvätska, lösning i förfylld spruta, 100 mg injektionsvätska, lösning i förfylld penna. Medel vid obstruktiva luftvägssjukdomar, övriga systemiska medel för obstruktiva lungsjukdomar
Rx (F), ATC kod: R03DX09.
Terapeutiska indikationer: Nucala är indicerat som tilläggsbehandling vid svår refraktär eosinofil astma hos vuxna patienter, ungdomar och barn från 6 års ålder. (För barn 6 till 11 år är endast Nucala 100 mg pulver till injektionsvätska godkänd). Dosering: Rekommenderad dos för mepolizumab hos vuxna och ungdomar från 12 års ålder är 100 mg administrerat subkutant en gång var fjärde vecka. Rekommenderad dos för mepolizumab hos barn från 6 till 11 år är 40 mg administrerat subkutant en gång var fjärde vecka. Nucala är avsett för långtidsbehandling. Behovet av fortsatt behandling ska omprövas minst en gång om året baserat på läkarens bedömning av sjukdomens svårighetsgrad och patientens kontroll över exacerbationer. Ytterligare information: I kliniska studier visades effekt hos följande subpopulation: aktuell standardbehandling som minst inkluderade högdosbehandling med inhalerade kortikosteroider (ICS) plus ytterligare en underhållsbehandling, två eller fler exacerbationer under de senaste 12 månaderna eller beroende av systemiska kortikosteroider samt blodeosinofilvärde minst 150 celler/μl vid behandlingsstart eller minst 300 celler/μl under de senaste 12 månaderna. Kontraindikationer: Överkänslighet mot den aktiva substansen eller mot något hjälpämne. Varningar och försiktighet: För att underlätta spårbarheten av biologiska läkemedel ska den administrerade produktens namn och batchnummer tydligt anges i patientjournalen. Mepolizumab ska inte användas för att behandla akuta astmaexacerbationer. Astmarelaterade biverkningar eller exacerbationer kan förekomma under behandling. Abrupt utsättning av kortikosteroider efter behandlingsstart med mepolizumab rekommenderas ej. Akuta och fördröjda systemiska reaktioner, inklusive överkänslighetsreaktioner (t.ex. anafylaxi, urtikaria, angioödem, hudutslag, bronkospasm, hypotoni), har förekommit efter administrering av mepolizumab. Patienter med befintliga maskinfektioner ska behandlas innan behandling med mepolizumab påbörjas. Om patienten blir infekterad under behandling med Nucala och inte svarar på maskmedel ska temporär utsättning av Nucala övervägas. 
Subventionsbegränsning: Subventioneras endast för patienter med svår eosinofil astma som är otillräckligt kontrollerade trots standardbehandling och antingen behandling med perorala kortikosteroider (OCS) i doser som ger ökad risk för biverkningar eller när OCS är kontraindicerat.

För fullständig förskrivningsinformation och pris, se www.fass.se. Datum för översyn av produktresumén: 2021-06-15. 
GlaxoSmithKline AB, Box 516, 169 29 Solna. Tel 08-638 93 00, www.se.gsk.com.