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Many chronic inflammatory diseases such as rheumatoid arthritis, multiple sclerosis, psoriasis, and Crohn’s disease to name just a few are caused by an overreactive immune system. Carrier substances that falsely inform the body about an ongoing infection are produced in large quantities. The immune system answers by starting a strong immune response. The body’s own tissues are attacked and continuously destroyed. Specific models of reaction have to be understood to find a possible key to altering this perpetual process of destruction. On the other hand, the immune system may overlook the destructive process of cancer by neglecting its surveillance task, by allowing itself to be fooled by the tumor cell’s deceiving tactics. Here specific biologic reagents are needed to jump-start the immune reaction or simply for highly specific targeting of drugs to kill specifically the tumor. The development of biologics has both of these aims in mind.

Infliximab is a monoclonal antibody that neutralizes the cytokine tumor necrosis factor (TNF)-α by binding selectively and with high affinity to soluble and membrane- bound TNF-α . Infliximab does not bind to TNF-β (lymphotoxin α ), a related cytokine that utilizes the same receptors as TNF-α. Thus infliximab was developed as a therapeutic agent for various inflammatory chronic diseases that are believed to be driven by the pro-inflammatory cytokine TNF-α.

Adalimumab (Humira, Abbott Laboratories, Abbott Park, IL, USA) is the first fully human recombinant IgG1 monoclonal antibody that acts by inhibiting tumor necrosis factor-alpha (TNF-α or TNF) (Fig. 3.1) ( Abbott Laboratories 2006 ). In contrast to infliximab, a chimeric antibody comprising both mouse and human domains that may elicit immune responses that potentially limit its long-term use in patients with chronic conditions such as rheumatoid arthritis, adalimumab is fully human, lowering the potential for immunogenicity ( van de Putte et al. 2003 ).

Etanercept is a tumor necrosis factor-α (TNF-α) antagonist used in the treatment of adult and juvenile rheumatoid arthritis, psoriasis, psoriatic arthritis, and ankylosing spondylitis. It is a recombinant, fully human, soluble, dimeric fusion protein that consists of two copies of the extracellular ligand-binding domain of the human 75-kDa TNF-α receptor linked to the Fc portion of human immunoglobulin (Ig) G1 (European Medicines Agency 2005). It is produced by recombinant DNA technology in a Chinese hamster ovary mammalian cell expression system (European Medicines Agency 2005; Enbrel: US Full Prescribing Information 2006). A simplified structure of etanercept is provided in Fig. 4.1. The CH2 and CH3 domains and the hinge region of the Fc portion of IgG1 are included but not the CH1 domain. It consists of 934 amino acids (fully human amino acid sequences) with an apparent molecular weight of 150 kDa (European Medicines Agency 2005; Enbrel: US Full Prescribing Information 2006).

Efalizumab is a humanized monoclonal antibody binding to the lymphocyte function-associated antigen (LFA-1). LFA-1 belongs to the family of β_2 integrins and is expressed on the surface of T cells (CD4^+ cells, Thelper cells; CD8^+ cells, cytotoxic T cells). LFA-1 is essential for every step in the process of immune surveillance and mounting an immune response ( Dustin et al. 2004 ): (1) firm adherence to the wall of blood vessels under blood flow, (2) scanning by T cells of other cells within tissues, and (3) formation of the immunological synapse between T cells and antigen-presenting cells (APCs).

Rituximab (Rituxan), a monoclonal antibody (mAb) against CD-20, and trastuzumab (Herceptin), a mAb against HER2, have shown efficacy in clinical trials and have gained approval for therapeutic use from the Food and Drug Administration (FDA). Mylotarg, an anti-CD33 mAb conjugated with the exceedingly cytotoxic antibiotic calicheamicin, has also proven effective for treating patients with acute myeloid leukemia (AML) and it has also received FDA approval. A major area of development in mAb therapeutics involves the use of radionuclides to augment the inherent mAb activity and to exploit specific targeting properties. Zevalin, an anti-CD20 mAb armed with ^90Y, and Bexxar, an anti-CD20 mAb armed with ^131I, are two radionuclide-bearing mAbs that have recently been approved by the FDA. This chapter presents the background and strategies pertaining to radiolabeled monoclonal antibody therapy.

The term biologics refers to a broad class of medicinal products that share a number of common features. Unlike traditional medicines that are made by chemical synthesis, biologics are made by biosynthesis in living cells. Biologics are generally much larger than traditional synthetic medicinal products and range from highly complex inactivated vaccines and plasma-derived factors to highly purified, well characterised recombinant therapeutic proteins. As new biological therapies come to market, the term biologics may encompass a diverse portfolio and include therapeutic options such as gene and cellular therapies, therapeutic vaccines, and nucleic acid preparations. The scope of this chapter focuses primarily on therapeutic proteins produced in mammalian cell culture processes.

Autoimmune bullous skin disorders represent a group of severe, chronic skin diseases which are characterized by the presence of autoantibodies targeting distinct adhesionmolecules of the epidermis and dermoepidermal basement membrane zone leading to a loss of adhesive function of the target antigen(s) (Fig. 8.1). The appearance of blisters and erosions of the skin and/or mucous membranes is the leading clinical sign of autoimmune bullous skin disorders (Fig. 8.2). While histopathology reveals the location of the blister formation, the detection of tissue bound autoantibodies by immunofluorescent staining of uninvolved perilesional skin biopsies is mandatory for diagnosing autoimmune bullous skin disorders. Circulating autoantibodies can be visualized by indirect immunofluorescence using tissue substrates such as monkey esophagus and sodium chloride-split human skin. Based on the specificity of the targeted antigens, several clinically and immune serologically distinct bullous disorders have been defined (Fig. 8.2).

As a better understanding of cutaneous diseases has been gained, more specific, targeted therapies have emerged. More recently, many of the T-cell immune mediated inflammatory changes seen in psoriasis have been elucidated, leading to the development of biologics that specifically act on immunological mechanisms, which are thought to be pathogenic in psoriatic lesions. By acting on specific immunological actions in the large cascade that results in psoriasis, many of the systemic toxicities that accompanied older treatments such as methotrexate and cyclosporinemay be avoided. Currently, there are three biologics approved in the United States for the treatment of psoriasis including alefacept, efalizumab, and etanercept, with several others currently under clinical investigation. A summary of the biologics currently used for the treatment of psoriasis can be found in Table 9.1.

Psoriatic arthritis (PsA) is a chronic, progressive form of inflammatory arthritis that occurs in individuals with psoriasis. It affects at least 0.3%of the population, although estimates of its prevalence vary widely, and is generally considered an autoimmune disease with unknown antigenic determinants. There currently is no predictive marker indicating which psoriasis patients will develop arthritis (Mease 2004). PsA often is classified as a subtype of spondyloarthropathy, due to shared HLA associations among those with spinal involvement, and characteristic inflammatory clinical and immunopathologic features ( Kruithof et al. 2005 ). Although it is heterogeneous in presentation, this disease often results in significant functional impairment and reduced quality of life ( Husted et al. 2001 ).