Editorial
Understanding the Immunogenicity Concept
Comprender el concepto de inmunogenicidad
Lara Valor, Inmaculada de la Torre
Corresponding author
Servicio de Reumatología, Hospital General Universitario Gregorio Marañón, Madrid, Spain
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These proteins, like many other exogenous agents can induce humoral and cellular immune responses. However, in recent years we have noticed how these concepts have been interpreted haphazardly, and sometimes in the wrong way from the point of view of their clinical significance.</p><p id="par0015" class="elsevierStylePara elsevierViewall">The immune response or immunogenicity which can be triggered by a therapeutic protein has been proposed as a cause of potential clinical events, including hypersensitivity reactions, decreased effectiveness of the therapeutic molecule and induction of immune processes, including the formation of antibodies against the protein in question.<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1,2</span></a> The most dreaded immunogenicity in clinical terms occurs due to the so-called neutralizing anti-drug antibodies which, as their name implies, have the ability to bind the agent (drug) and neutralize it, preventing its biological or therapeutic function.<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">Many factors can influence the immunogenicity of therapeutic proteins, including those inherent to the patient, the disease itself or those related to the product itself. The determinants of patient-related immunogenicity that may predispose unwanted immune responses include the underlying disease, genetic factors and baseline immune status, including associated immunomodulatory therapy. Furthermore, product related factors also influence the probability of inducing an immune response; for example, the route of administration, the type of protein, aspects of the manufacturing process, impurity profile or excipients and formulation characteristics, stability, degradation products or aggregates, dosage, the dosing interval and treatment duration.<a class="elsevierStyleCrossRefs" href="#bib0020"><span class="elsevierStyleSup">4–6</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">The immune response mechanism directed against therapeutic biological molecules seems to be due to “transient” loss of immunologic tolerance, rather than the classic immune response to an exogenous protein, because when these agents are suspended, antibodies may even disappear.<a class="elsevierStyleCrossRefs" href="#bib0030"><span class="elsevierStyleSup">6,7</span></a> Some patients may develop antibodies which neutralize the biological activity of the drug, while others may develop antibodies that bind to the product, altering the pharmacokinetics or pharmacodynamics, compromising its effectiveness in both situations, but with different stages.<a class="elsevierStyleCrossRefs" href="#bib0040"><span class="elsevierStyleSup">8–13</span></a></p><p id="par0030" class="elsevierStylePara elsevierViewall">The intrinsic immunogenicity of a drug varies considerably between biological molecules. For example, interferon-γ (IFN-γ) and granulocyte colony stimulating factor may be capable of inducing an immune response that will eventually compromise their effectiveness, but appropriate techniques are yet to be developed for detecting them. In addition, molecules such as colony stimulating factor, granulocyte–macrophage, IFN-α and IFN-β appear to be inherently immunogenic.<a class="elsevierStyleCrossRefs" href="#bib0060"><span class="elsevierStyleSup">12,14–16</span></a></p><p id="par0035" class="elsevierStylePara elsevierViewall">Data on possible immune responses to therapeutic proteins must be determined and always adduced before the drugs release, but of course there are events that may occur in the post-marketing period of the drug. When undergoing application for marketing authorization, the manufacturer of a drug derived from biotechnology should include a summary of research regarding its immunogenicity.</p><p id="par0040" class="elsevierStylePara elsevierViewall">The EMEA (<span class="elsevierStyleItalic">European Medicines Agency</span>)<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a> guide recommends that the evaluation of immunogenicity be performed using validated tests for antibody determination and characterization of the immune response observed regarding safety and efficacy, establishing a correlation between the presence of antibodies and its pharmacokinetics and antibodies. Furthermore, it is recommended that the role of immunogenicity be evaluated in certain events, such as hypersensitivity, infusion reactions, autoimmunity and loss of efficacy, providing at the same time, information relevant to the adverse event. While the guide briefly describes the different methods that can be used to evaluate the immunogenicity, it does not specify any particular methodology.</p><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">How Are the Therapeutic Antiprotein Antibodies Developed (Commonly Known as Anti-Drug Antibodies)?</span><p id="par0045" class="elsevierStylePara elsevierViewall">An antibody is a particular type of protein produced by an immune system cell, the B lymphocyte. Each antibody molecule has two interconnected different amino acids polymers, one of these known as the heavy chain and the other as the light chain. An antibody has two heavy chains and two light chains, each heavy chain is about 450 amino acids long and each light chain has 250 amino acids.<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">18</span></a></p><p id="par0050" class="elsevierStylePara elsevierViewall">Each B cell produces, when faced with certain stimuli (antigens, in this case immunogenic therapeutic proteins), antibodies that differ from those of antibodies produced by other B cells. The difference is subtle, but critical in recognizing and fixing antigen. The antibody site (paratope) that binds to the epitope of the antigen that triggered its formation is very specific. The paratope “recognizes” a particular molecular shape and if the shapes are not complementary, then it does not bind to the molecule. Thus, the antibody, although formed under the stimulus of a particular antigen, neutralizing or not is not effective against this antigen it has induced.<a class="elsevierStyleCrossRefs" href="#bib0090"><span class="elsevierStyleSup">18,19</span></a></p><p id="par0055" class="elsevierStylePara elsevierViewall">The antibodies produced by B lymphocytes, specifically by plasma cells, which are more differentiated forms of this cell line are found in the peripheral blood and in the lymph. The antibodies generated in response to a foreign substance with which we have somehow come into contact, such as a bacteria, viruses (after vaccination or infection) or therapeutic proteins, may be found anywhere on the body. In addition, when these circulating antibodies come in contact with the antigen against which they were generated, they bind to it. This union will have several possible outcomes-inactivatation of the “antigen”, so it can be more easily destroyed by macrophages (cells that engulf the antigen coated with antibody molecules) or covering of the binding sites of the “antigen” to the target cell and preventing its entrance. If contact was reestablished with the antigen, the immune response would lead to an improvement in producing more specific antibodies, without hardly perceiving it. This phenomenon, known as immunological memory, which in some cases is beneficial to the body, may be responsible for the failure of different protein-based therapies which are very useful under certain conditions.<a class="elsevierStyleCrossRefs" href="#bib0090"><span class="elsevierStyleSup">18–20</span></a></p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Have We Reached the Point of Being Able to Unify Criteria for the Detection of Neutralizing Anti-Drug Antibodies?</span><p id="par0060" class="elsevierStylePara elsevierViewall">The standardization of routine laboratory procedures to detect neutralizing anti-drug antibodies, remains a huge challenge. Controversy due to the variability of the results obtained in different populations in studies carried out so far does not allow us to unify criteria and establish objective parameters to determine the presence of anti-drug antibodies used for the treatment of various diseases. Furthermore, the presence of anti-drug antibodies is not always a risk factor for the patient in terms of side effects, or something that predicts primary or secondary efficacy loss.</p><p id="par0065" class="elsevierStylePara elsevierViewall">In connection with the standardization of the techniques for the detection of antibodies, we have a clear example in the field of rheumatology. Throughout the nineties there was discussion on the procedures used for the detection of antibodies to cyclic citrullinated-peptide in view of the high variability of the results obtained and published.<a class="elsevierStyleCrossRefs" href="#bib0105"><span class="elsevierStyleSup">21–24</span></a> But today no one doubts the positivity or negativity of the result of anti-CCP reported by a routine laboratory in diagnosing and treating a patient with rheumatoid arthritis, as it has been shown, through standardization, high specificity and sensitivity, not only a highly predictive, intra- and interassay reproducibility, but also intra- and interlaboratory agreement, making the test cost effective and providing a key tool for the diagnosis, prognosis and treatment implementation of early onset RA.</p><p id="par0070" class="elsevierStylePara elsevierViewall">In this sense, a prerequisite for immunogenicity studies is associated with the detection and characterization of antibodies using methods that are both reliable and, above all, reproducible.<a class="elsevierStyleCrossRefs" href="#bib0125"><span class="elsevierStyleSup">25,26</span></a> Thorpe and Wadhwa<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a> have reviewed several techniques currently available to determine the presence of antibodies generated against therapeutic proteins in biological fluids; for example, immunoassays (Enzyme-Linked Immuno-Sorbent Assay, ELISA), radioimmunoprecipitation (RIA), useful as screening procedures, “surface plasmon resonance”, expensive, automated procedures that demonstrate antibody–antigen interactions in real time and, above all, bioassays, which are essential to determine whether or not antibodies are neutralizing.<a class="elsevierStyleCrossRefs" href="#bib0065"><span class="elsevierStyleSup">13,25,27</span></a> Each of these methods has advantages and disadvantages, and it is noteworthy that neither alone is sufficient to define the characteristics of the antibodies that are produced against a biological molecule. Applying a strategy involving the use of various methods is necessary for a thorough understanding of the amount and the type of antibodies generated against a therapeutic product.</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Current Controversy Regarding Anti-Drug Antibodies</span><p id="par0075" class="elsevierStylePara elsevierViewall">In a review published in 2008, Purcell and Lockey<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">28</span></a> describe the term immunogenicity applied to numerous therapeutic agents, including coagulation factors, growth factors, hormones, enzymes, cytokines, monoclonal antibodies including recombinant insulin, an identical human insulin which is less immunogenicity, logically, than porcine or bovine derived insulin.<a class="elsevierStyleCrossRefs" href="#bib0145"><span class="elsevierStyleSup">29–31</span></a> We have not achieved, however and despite numerous studies, the identification of the clinical significance of antibodies to recombinant insulin.<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">32</span></a></p><p id="par0080" class="elsevierStylePara elsevierViewall">Many factors may contribute to the alteration in the structure of the protein to elicit an immune response including antibody formation, glycosylation, pollutants; changes in temperature and the storage media may also have a decisive role.<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3,33,34</span></a> Such is the case of a formulation of IFN-α, which is determined to be abnormally oxidized at room temperature, changing the tertiary structure of the protein leading to an immune response with antibody production. Later, a change in storage and formulation resulted in a reduction of the formation of substantial anti-drug antibodies.<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a></p><p id="par0085" class="elsevierStylePara elsevierViewall">The clinical consequences of anti-drug antibody formation are extremely variable; while some have no clinically relevant effect (recombinant insulin antibodies), others have side effects ranging from loss of efficiency to effects that may even endanger the life of the patient, as is the case of pure red cell aplasia induced by recombinant erythropoietin, an effect produced by an IgE-independent anaphylaxis.<a class="elsevierStyleCrossRefs" href="#bib0170"><span class="elsevierStyleSup">34,35</span></a></p><p id="par0090" class="elsevierStylePara elsevierViewall">Also noteworthy are the recombinant factor <span class="elsevierStyleSmallCaps">VIII</span> and factor <span class="elsevierStyleSmallCaps">IX</span> which were developed in the late eighties for the treatment of patients with hemophilia A and B, respectively. Although the use of these therapeutic agents was successful in the treatment of these diseases, the formation of neutralizing antibodies was a significant problem directly related to the severity of the disease. The incidence of antibody formation to recombinant factor <span class="elsevierStyleSmallCaps">VIII</span> was 15%–35% in mild-moderate forms of hemophilia A, and in severe cases, where <span class="elsevierStyleSmallCaps">FVIII</span> produced naturally was practically absent (<5%), antibody formation was 52%.<a class="elsevierStyleCrossRefs" href="#bib0180"><span class="elsevierStyleSup">36,37</span></a></p><p id="par0095" class="elsevierStylePara elsevierViewall">In rheumatology specifically, the lack of response, loss of efficacy or reactions to treatment in connection with the use of monoclonal antibodies against TNF-α or its soluble receptor have been directly related to the development of anti-drug antibodies (anti-human chimeric antibody, HACA) and low or undetectable plasma levels of the same.<a class="elsevierStyleCrossRefs" href="#bib0190"><span class="elsevierStyleSup">38,39</span></a> While the concept of anti-drug neutralizing antibody is not demonstrated <span class="elsevierStyleItalic">in vivo</span> for these therapies the reality is that a percentage of patients develop these antibodies in association to the loss of response or infusion reactions.</p><p id="par0100" class="elsevierStylePara elsevierViewall">Some studies report a prevalence of HACA by ELISA in rheumatoid arthritis patients ranging from 17.45% to 44% for anti-TNF-α and in a range of 15% to 30% in patients with ankylosing spondylitis,<a class="elsevierStyleCrossRefs" href="#bib0200"><span class="elsevierStyleSup">40–43</span></a>. Different statistics are seen when using a different technique of ELISA detection.<a class="elsevierStyleCrossRefs" href="#bib0220"><span class="elsevierStyleSup">44,45</span></a> It has been speculated that the presence of HACA may explain cases of treatment failure, but not all nonresponders have HACA, suggesting that other factors may be involved in treatment failure.</p><p id="par0105" class="elsevierStylePara elsevierViewall">The immunogenicity of anti-TNF is dependent on its structure, being higher when using those of murine origin compared to the humanized or those modified by genetic recombination.<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">46</span></a> In the latter, it would be virtually impossible to detect the paratope binding the antigen epitope and, therefore, difficult to develop ELISA to quantify it. Heterogeneity in the techniques for detection (ELISA, RIA) and nonstandard procedures make it impossible to know the real meaning of the presence of these antibodies. Discrepancies between the presence of anti-drug antibodies and low drug levels and side effects point increasingly to the levels of drug than to the development of antibody itself, as the main cause of loss of effectiveness.<a class="elsevierStyleCrossRefs" href="#bib0235"><span class="elsevierStyleSup">47,48</span></a> Furthermore, inconsistent results regarding different anti-TNF in various diseases do not explain the variations between the presence of anti-drug antibodies and the loss of response associated with each disease and every therapy.<a class="elsevierStyleCrossRefs" href="#bib0200"><span class="elsevierStyleSup">40,41,48–50</span></a></p><p id="par0110" class="elsevierStylePara elsevierViewall">While there appears to be a statistically significant association between the presence of anti-drug antibody-levels and drug levels and efficacy loss-infusional reaction according to data from different research groups using different techniques, we do not know in detail the clinical application (positive predictive value, negative predictive value, odds ratio or relative risk), nor the intra-interassay reproducibility according to the procedures followed, and intra-interlaboratory variations according to the techniques used that these findings may offer for a variety of diseases, for different patients and with different therapeutic strategies.</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Conclusions</span><p id="par0115" class="elsevierStylePara elsevierViewall">A lot of factors may be responsible for variations in the profile of immunogenicity of different biological products, which makes for cautious interpretation of this data. The results could be truly comparative if the molecules were evaluated under the same conditions, using the same clinical and laboratory protocols, and determining the anti-drug antibodies using standardized procedures in all laboratories.</p><p id="par0120" class="elsevierStylePara elsevierViewall">No doubt immunogenicity plays an important role in the therapeutic effect of a drug, but previous examples, such as insulin or recombinant erythropoietin, make us cautious in interpreting the results for those drugs commonly used in our specialty. Other factors to consider, such as the route of administration or drug conservation, the clinical profile of the patient and the type of illness or changes in the detection methods need to be weighed and analyzed before the clinical relevance of this phenomenon is determined.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:5 [ 0 => array:2 [ "identificador" => "sec0005" "titulo" => "How Are the Therapeutic Antiprotein Antibodies Developed (Commonly Known as Anti-Drug Antibodies)?" ] 1 => array:2 [ "identificador" => "sec0010" "titulo" => "Have We Reached the Point of Being Able to Unify Criteria for the Detection of Neutralizing Anti-Drug Antibodies?" ] 2 => array:2 [ "identificador" => "sec0015" "titulo" => "Current Controversy Regarding Anti-Drug Antibodies" ] 3 => array:2 [ "identificador" => "sec0020" "titulo" => "Conclusions" ] 4 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara">Please cite this article as: Valor L, de la Torre I. 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| Year/Month | Html | Total | |
|---|---|---|---|
| 2024 November | 50 | 12 | 62 |
| 2024 October | 408 | 78 | 486 |
| 2024 September | 424 | 64 | 488 |
| 2024 August | 459 | 87 | 546 |
| 2024 July | 457 | 56 | 513 |
| 2024 June | 461 | 65 | 526 |
| 2024 May | 573 | 108 | 681 |
| 2024 April | 347 | 53 | 400 |
| 2024 March | 500 | 72 | 572 |
| 2024 February | 418 | 53 | 471 |
| 2024 January | 1278 | 49 | 1327 |
| 2023 December | 631 | 56 | 687 |
| 2023 November | 465 | 68 | 533 |
| 2023 October | 577 | 54 | 631 |
| 2023 September | 354 | 58 | 412 |
| 2023 August | 239 | 23 | 262 |
| 2023 July | 147 | 30 | 177 |
| 2023 June | 162 | 42 | 204 |
| 2023 May | 168 | 20 | 188 |
| 2023 April | 225 | 24 | 249 |
| 2023 March | 311 | 41 | 352 |
| 2023 February | 217 | 38 | 255 |
| 2023 January | 221 | 31 | 252 |
| 2022 December | 224 | 49 | 273 |
| 2022 November | 253 | 43 | 296 |
| 2022 October | 262 | 58 | 320 |
| 2022 September | 203 | 44 | 247 |
| 2022 August | 201 | 61 | 262 |
| 2022 July | 195 | 42 | 237 |
| 2022 June | 198 | 50 | 248 |
| 2022 May | 253 | 56 | 309 |
| 2022 April | 204 | 64 | 268 |
| 2022 March | 200 | 63 | 263 |
| 2022 February | 209 | 45 | 254 |
| 2022 January | 250 | 60 | 310 |
| 2021 December | 162 | 45 | 207 |
| 2021 November | 189 | 55 | 244 |
| 2021 October | 214 | 62 | 276 |
| 2021 September | 247 | 50 | 297 |
| 2021 August | 390 | 47 | 437 |
| 2021 July | 497 | 50 | 547 |
| 2021 June | 411 | 63 | 474 |
| 2021 May | 309 | 57 | 366 |
| 2021 April | 644 | 146 | 790 |
| 2021 March | 387 | 42 | 429 |
| 2021 February | 159 | 29 | 188 |
| 2021 January | 136 | 21 | 157 |
| 2020 December | 124 | 21 | 145 |
| 2020 November | 82 | 21 | 103 |
| 2020 October | 36 | 16 | 52 |
| 2020 September | 40 | 19 | 59 |
| 2020 August | 27 | 23 | 50 |
| 2020 July | 23 | 23 | 46 |
| 2020 June | 34 | 25 | 59 |
| 2020 May | 32 | 25 | 57 |
| 2020 April | 27 | 20 | 47 |
| 2020 March | 27 | 10 | 37 |
| 2020 February | 2 | 0 | 2 |
| 2020 January | 4 | 0 | 4 |
| 2019 September | 4 | 0 | 4 |
| 2019 June | 1 | 0 | 1 |
| 2019 May | 0 | 1 | 1 |
| 2019 March | 1 | 0 | 1 |
| 2019 January | 1 | 0 | 1 |
| 2018 May | 6 | 0 | 6 |
| 2018 April | 46 | 10 | 56 |
| 2018 March | 60 | 6 | 66 |
| 2018 February | 36 | 2 | 38 |
| 2018 January | 41 | 4 | 45 |
| 2017 December | 52 | 6 | 58 |
| 2017 November | 59 | 8 | 67 |
| 2017 October | 35 | 10 | 45 |
| 2017 September | 44 | 8 | 52 |
| 2017 August | 41 | 23 | 64 |
| 2017 July | 44 | 28 | 72 |
| 2017 June | 50 | 42 | 92 |
| 2017 May | 84 | 26 | 110 |
| 2017 April | 47 | 28 | 75 |
| 2017 March | 58 | 45 | 103 |
| 2017 February | 88 | 23 | 111 |
| 2017 January | 44 | 20 | 64 |
| 2016 December | 106 | 21 | 127 |
| 2016 November | 92 | 15 | 107 |
| 2016 October | 106 | 20 | 126 |
| 2016 September | 130 | 10 | 140 |
| 2016 August | 122 | 11 | 133 |
| 2016 July | 72 | 19 | 91 |
| 2016 June | 2 | 19 | 21 |
| 2016 May | 0 | 18 | 18 |
| 2016 April | 1 | 25 | 26 |
| 2016 February | 0 | 29 | 29 |
| 2016 January | 1 | 0 | 1 |
| 2015 December | 2 | 28 | 30 |
| 2015 October | 0 | 15 | 15 |
| 2015 September | 0 | 14 | 14 |
| 2015 August | 2 | 12 | 14 |
| 2015 July | 31 | 5 | 36 |
| 2015 June | 43 | 13 | 56 |
| 2015 May | 85 | 20 | 105 |
| 2015 April | 74 | 17 | 91 |
| 2015 March | 49 | 15 | 64 |
| 2015 February | 57 | 19 | 76 |
| 2015 January | 55 | 11 | 66 |
| 2014 December | 60 | 24 | 84 |
| 2014 November | 52 | 10 | 62 |
| 2014 October | 52 | 15 | 67 |
| 2014 September | 52 | 14 | 66 |
| 2014 August | 57 | 18 | 75 |
| 2014 July | 62 | 17 | 79 |
| 2014 June | 77 | 15 | 92 |
| 2014 May | 77 | 19 | 96 |
| 2014 April | 69 | 15 | 84 |
| 2014 March | 77 | 20 | 97 |
| 2014 February | 61 | 10 | 71 |
| 2014 January | 67 | 19 | 86 |
| 2013 December | 60 | 5 | 65 |
| 2013 November | 37 | 11 | 48 |
| 2013 October | 57 | 8 | 65 |
| 2013 September | 61 | 11 | 72 |
| 2013 August | 60 | 16 | 76 |
| 2013 July | 53 | 17 | 70 |
| 2013 June | 46 | 12 | 58 |
| 2013 May | 51 | 11 | 62 |
| 2013 April | 52 | 22 | 74 |
| 2013 March | 63 | 33 | 96 |
| 2013 February | 30 | 14 | 44 |
Show all
