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
|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 basophils
|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|
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 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.
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 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. However, non-neutralising antibodies may affect the pharmacokinetics of the mAbs. 8
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
- 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
- Route of administration
- Product characteristics affecting immunogenicity include: 10
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
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
- 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
- Kindt TJ, Goldsby RA, Osborne BA et al. Book - Kuby Immunology. W.H. Freeman and Company, New York, NY, USA. N/A2012;6:1-52.
- Goswami S, Wang W, Arakawa T. Developments and Challenges for mAb-Based Therapeutics. Antibodies 2013;2:452-500.
- Chan AC, Carter PJ. Therapeutic antibodies for autoimmunity and inflammation. Nature Rev Immunol, 2010;10: 301-316.
- Chames P, Regenmortel MV, Weiss E, Baty D. THEMED SECTION-VECTOR DESIGN AND DRUG DELIVERY-Therapeutic antibodies successes limitations and hopes for the future. British Journal of Pharmacology 2009; 157: 220–233.
- Foltz IN, Karow M, Wasserman SM. Evolution and Emergence of Therapeutic Monoclonal Antibodies- What Cardiologists Need to Know. Circulation 2013;127:2222-2231.
- Abonia JP, Putnam PE. Mepolizumab in eosinophilic disorders. Expert Review of Clinical Immunology 2011;7:411–417.
- Valor L, Torre ID. Understanding the Immunogenicity Concept Comprender el concepto de inmunogenicidad. Reumatol Clinic 2012;9:1-4.
- Shankar G, Arkin S, Cocea L et al. Assessment and reporting of the clinical immunogenicity of therapeutic proteins and peptides-harmonized terminology and tactical recommendations. AAPS J 2014;16(4):658-73.
- Harding FA, Stickler MM, Razo J et al. The immunogenicity of humanized and fully human antibodies: Residual immunogenicity resides in the CDR regions. MAbs 2010;2:256-265.
- Warnke C, et al.Anti-drug antibodies. Drugs Ther Studies 2012;2:e11.doi:10.4081/dts.2012.e11
- Everds NE, Tarrant JM. Unexpected Hematologic Effects of Biotherapeutics in Nonclinical Species and in Humans. Toxicologic Pathology 2013;80:280-302.
- Sampson HA, Muñoz-Furlong A, Campbell RL et al. Second symposium on the definition and management of anaphylaxis: Summary report—Second National Institute of Allergy and Infectious Disease Food Allergy and Anaphylaxis Network symposium. Journal of Allergy and Clinical Immunology 2006;117:391-397.
- Vogel WA.Infusion reactions: diagnosis, assessment, and management. Clin J Oncol Nurs 2010;14:E10-21. doi: 10.1188/10.CJON.E10-E21.
- Cheifetz A, Smedley M, Martin S et al. The Incidence and Management of Infusion Reactions to Infliximab A Large Center Experience. The American Journal of Gastroenterology 2003;98:1315-1324.
- Mepolizumab SmPC; GlaxoSmithKline 2016