**Author details**

Emi Hifumi<sup>1</sup> , Hiroaki Taguchi<sup>2</sup> , Ryuichi Kato<sup>3</sup> , Mitsue Arakawa<sup>4</sup> , Yoshiki Katayama<sup>5</sup> and Taizo Uda6,7\*


6 Department of Applied Chemistry, Faculty of Engineering, Oita University, Oita-shi, Oita, Japan

7 Nanotechnology Laboratory, Institute of Systems, Information Technologies and Nanotechnologies (ISIT), Fukuoka, Japan

## **References**

In the case of the AFM analysis, the #4 mutant C220A was a monomer. This is ascribed that the mica as the supporting material firmly interacts with the #4 mutant molecule. In solution, the

As stated in the abstract and introduction, the issue of structural diversity (heterogeneity) of antibodies has become a big subject along with the development of antibody drugs and catalytic antibodies. This subject has not been solved for a long period, because many difficult and complex problems were existing. For this long-period unsolved problem, copper ion showed a drastic effect and gave one of the answers for solving the structural diversity issue. Note that

In recent years, many possibilities of the development of antibody drugs and catalytic antibodies have been reported by research groups throughout the world. This article offers huge insights into the development of catalytic antibodies, maybe, as well as antibody drugs. Because the preparation can be standardized, many scientists and engineers will easily be able to produce the defined structure and the same functional antibody under any circum-

This study was supported by the Japan Science and Technology Agency (CREST/"Establishment of Innovative Manufacturing Technology Based on Nanoscience"); "Super Highway": the accelerated research to bridge university IPs and practical use; and Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan (24350085 and 16H02282). The authors thank Oxford Instruments KK (Dr. H. Sugasawa), Dr. Y. Nishikawa (High Energy Accelerator Research Organization), Dr. H. Makio (High Energy Accelerator Research

2 Faculty of Pharmaceutical Sciences, Suzuka University of Medical Science, Suzuka, Mie, Japan

, Mitsue Arakawa<sup>4</sup>

, Yoshiki Katayama<sup>5</sup>

and

Organization), and Ms. Y. Akiyoshi (Oita University) for the assistance with this study.

, Ryuichi Kato<sup>3</sup>

1 Research Promotion Institute, Oita University, Oita-shi, Oita, Japan

3 High Energy Accelerator Research Organization, Tsukuba, Japan

the antibody and/or the subunits must have a defined structure for practical use.

#4 mutant may interact with each other with a strong Van der Waals force.

**7. Perspectives and conclusions**

254 Antibody Engineering

stances and anywhere in the world.

**Acknowledgements**

**Author details**

, Hiroaki Taguchi<sup>2</sup>

\*Address all correspondence to: uda@oita-u.ac.jp

Emi Hifumi<sup>1</sup>

Taizo Uda6,7\*


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**Chapter 11**

**Provisional chapter**

**Immune-Mediated Skin Reactions Induced by**

**Recombinant Antibodies and Other TNF-Alpha** 

**Immune-Mediated Skin Reactions Induced by** 

DOI: 10.5772/intechopen.72449

Biologic agents that act by inhibiting tumour necrosis factor alpha (TNF-alpha) have become a breakthrough treatment for chronic inflammatory diseases. This highly effective treatment has surprisingly brought us new adverse effects that we had not encountered before the age of biologics. Immune-mediated reactions are a group of adverse effects with not clearly understood etiopathogenesis. It turns out that TNF-alpha inhibitors are able to disrupt the cytokine cascade in genetically predisposed individuals. Some of the theories assume a cross reaction and overproduction of interferon (INF) alpha, while others put an emphasis on dysregulation of cytokines, in particular interleukin (IL)-17. Similarly, debatable is the role of the reactions mentioned in the etiopathogenesis, the production of antibodies against biologics and the production of antinuclear antibodies. The most common immune-mediated skin reactions are psoriasis and psoriasiform reactions, lupus-like syndrome, sarcoidosis, alopecia areata, vasculitis and lichenoid reactions. Less common reactions described in our paper include pyoderma gangrenosum and morphea. Most of these reactions belong to the so-called paradoxical reactions. Paradoxical psoriasis is an adverse effect, represented by occurrence of a disease caused by the therapeutic

class of drugs normally used to cure or improve symptoms of such disease.

**Keywords:** TNF-alpha inhibitors, psoriasiform reaction, paradoxical reaction,

**Recombinant Antibodies and Other TNF-Alpha**

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution,

© 2018 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

and reproduction in any medium, provided the original work is properly cited.

Immune-mediated adverse reactions are a new group of diseases developing during anti-TNFalpha treatment. Their clear etiopathogenesis is not known. Most authors assume that there

Karolína Vorčáková, Péč Juraj, Péčová Tatiana and

Karolína Vorčáková, Péč Juraj, Péčová Tatiana and

Additional information is available at the end of the chapter

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.72449

**Inhibitors**

**Inhibitors**

Martinásková Klára

**Abstract**

antibodies, Th17

**1. Introduction**

Martinásková Klára

**Provisional chapter**

### **Immune-Mediated Skin Reactions Induced by Recombinant Antibodies and Other TNF-Alpha Inhibitors Recombinant Antibodies and Other TNF-Alpha Inhibitors**

**Immune-Mediated Skin Reactions Induced by** 

DOI: 10.5772/intechopen.72449

Karolína Vorčáková, Péč Juraj, Péčová Tatiana and Martinásková Klára Martinásková Klára Additional information is available at the end of the chapter

Karolína Vorčáková, Péč Juraj, Péčová Tatiana and

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.72449

#### **Abstract**

Biologic agents that act by inhibiting tumour necrosis factor alpha (TNF-alpha) have become a breakthrough treatment for chronic inflammatory diseases. This highly effective treatment has surprisingly brought us new adverse effects that we had not encountered before the age of biologics. Immune-mediated reactions are a group of adverse effects with not clearly understood etiopathogenesis. It turns out that TNF-alpha inhibitors are able to disrupt the cytokine cascade in genetically predisposed individuals. Some of the theories assume a cross reaction and overproduction of interferon (INF) alpha, while others put an emphasis on dysregulation of cytokines, in particular interleukin (IL)-17. Similarly, debatable is the role of the reactions mentioned in the etiopathogenesis, the production of antibodies against biologics and the production of antinuclear antibodies. The most common immune-mediated skin reactions are psoriasis and psoriasiform reactions, lupus-like syndrome, sarcoidosis, alopecia areata, vasculitis and lichenoid reactions. Less common reactions described in our paper include pyoderma gangrenosum and morphea. Most of these reactions belong to the so-called paradoxical reactions. Paradoxical psoriasis is an adverse effect, represented by occurrence of a disease caused by the therapeutic class of drugs normally used to cure or improve symptoms of such disease.

**Keywords:** TNF-alpha inhibitors, psoriasiform reaction, paradoxical reaction, antibodies, Th17

### **1. Introduction**

Immune-mediated adverse reactions are a new group of diseases developing during anti-TNFalpha treatment. Their clear etiopathogenesis is not known. Most authors assume that there

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2018 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

is a link to possible significant interference of the anti-TNF-alpha therapy with the immune system, which subsequently induces the above-mentioned responses. Others associate the diseases with the production of antibodies against the biologic agents and include the symptoms among hypersensitivity reactions. However, the individual genetic predisposition, which may be essential in detecting of immune-mediated reactions, must not be overlooked. The reactions include a broad variety of diseases such as lupus-like syndrome, autoimmune arthralgia, psoriasis, sarcoidosis, dermatomyositis, hepatitis, vasculitis, neurological demyelinating diseases and the like. In this chapter, we will briefly characterise the most common skin immunemediated reactions induced by TNF-alpha inhibitors.

immune-mediated reactions. Therefore, the formation of TNF alpha-induced psoriasis is also called a paradoxical reaction. All of the mentioned TNF-alpha antagonists can induce psoriasis. Cases have been reported from all indications where anti-TNF-alpha treatment is given. According to the literature, the incidence of paradoxical psoriasis is 1.04–3.0 cases per 1000 patient-years, the percentages varying widely from 0.6 to 5.3% [8]. The incidence of the manifestation is not age and gender related; some studies also show other controversial data. Manifestation may occur in any period of time during the treatment, from weeks, months, up to the years. The average time of developing psoriasis is 10 months [9, 10]. Concomitant treatment with another immunosuppressant does not appear to prevent paradoxical psoriasis, although combined suppression is used in

Immune-Mediated Skin Reactions Induced by Recombinant Antibodies and Other TNF-Alpha…

http://dx.doi.org/10.5772/intechopen.72449

261

The clinical manifestation of paradoxical psoriasis may be variable in nature. Paradoxical psoriasis includes not only newly developed psoriasis but also a radical worsening of already existing psoriasis. The disease is most commonly manifested in the area of palms and soles in the form of palmoplantar pustulosis, which is reported in 56% of cases, other most common forms include chronic plaque psoriasis in 50% of the patients and guttate manifestations, which affect 12% of the patients. Patients may also suffer from multiple forms of disease simultaneously (15%) [11]. Other manifestations include scalp or nail involvement. There are also cases of alopecia areata and paradoxical psoriasis. Some authors assume that monoclonal antibodies are associated with development of de novo-induced psoriasis, while the etaner-

The exact etiopathogenesis of paradoxical psoriasis is not clear, and there are several opinions and theories. The first of them states that the manifestations are a hypersensitive reaction to a drug, not a newly developed classical disease. There are papers that due to the increased production of antibodies against biologics describe manifestations of induced generalised pustulosis that could fit into the spectrum of hypersensitivity reactions. Other papers disprove this theory on the basis of skin biopsy of the patients with TNF-alpha-induced psoriasis. The incidence of palmoplantar pustulous psoriasis in the common psoriatic population is significantly lower, representing 1.7% compared to 46.2% in patients with paradoxical reaction. This

The most widespread theory links the relationship between TNF-alpha and type 1 interferon alpha. TNF-alpha inhibits the maturation of plasma dendritic cells that produce IFN-alpha.

**Figure 1.** Patient with severe palmoplantar pustular psoriasis induced after 4 weeks of using adalimumab, this severe

cept fusion protein causes a worsening of pre-existing psoriasis [12] (**Figure 1**).

fact supports the theory that it should not be a new classical form of psoriasis [13].

the treatment of immune-mediated reactions.

reaction lead to discontinuation of adalimumab.

TNF is produced as a transmembrane protein (tmTNF), which is later cleaved by an enzyme metalloproteinase to its soluble form, sTNF [1]. Both TNFR1 and TNFR2 receptors signal through pathways that are proinflammatory and anti-apoptotic. Moreover, TNFR1 can signal directly through death domain caspase-dependent pathways that lead to apoptosis [2]. TNFR1 plays a role in response to bacterial infection [3] and TNFR2 may downregulate inflammatory signals driven by TNF [4].

Currently, five complete recombinant antibodies—infliximab, etanercept, adalimumab, golimumab and certolizumab pegol—are available TNF-α inhibitors. They are biotechnologically produced and administered as systemic drugs modifying the biological response and signalisation on the molecular level. The structural differences are key to different risk for adverse effects such as granulomatous infections, with TNF antibodies associated with higher risk compared to soluble receptor, possibly due to binding to tmTNF receptor on the activated cells [5].

Infliximab is a recombinant chimeric monoclonal antibody containing human IgG1 Fc and variable murine regions, which forms complexes with both sTNF and tmTNF. It induces the lysis of macrophages and monocytes by cytotoxicity dependent on complement and antibodies [6]. The intravenous administration is applied by a weight-dependent dose. Drugmediated apoptosis and monocytopenia are linked to infliximab as well as its ability to bind more avidly to different forms of TNF-α [7]. Adalimumab is a humanised monoclonal antibody containing human IgG1 Fc and human variable regions that bind sTNF as well as tmTNF. The other available humanised monoclonal antibody, cetrolizumab pegol is a pegylated monoclonal Fab fragment with polyethylene glycol binding to soluble and membrane-bound TNF-α, inhibiting the proinflammatory actions of this cytokine. Unlike other TNF inhibitors, owing to its lack of the Fc component, it is incapable of fixing complement or binding to Fc receptors. Golimumab is a human anti-TNF monoclonal antibody containing the IgG1 constant region.

The other group of TNF inhibitors consists solely of etanercept, which is soluble TNF receptor containing the human IgG1 Fc portion fused to the extracellular portion of human TNFRp75. It creates less stable complexes with tmTNF and firmly binds to trimeric forms of soluble TNF.
