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Biological drugs targeting the immune response in the therapy of psoriasis.

Pastore S, Gubinelli E, Leoni L, Raskovic D, Korkina L - Biologics (2008)

Bottom Line: A new generation of biological drugs, targeting molecules and cells involved into perturbed pro-inflammatory immune response in the psoriatic skin and joints, has been recently designed and applied clinically.The growing body of clinical data on the efficacy and safety of antipsoriasis biological drugs is reviewed as well.Particular focus is given to long-term safety concerns and feasibility of combined therapeutic protocols to ameliorate clinical results.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Tissue Engineering and Cutaneous Physiopathology;

ABSTRACT
Chronic plaque psoriasis affects more than 2% of world population, has a chronic recurrent behavior, gives a heavy burden to the patients' quality of life, and hence remains a huge medical and social problem. The clinical results of conventional therapies of psoriasis are not satisfactory. According to the current knowledge of the molecular and cellular basis of psoriasis, it is defined as an immune-mediated chronic inflammatory and hyperproliferative skin disease. A new generation of biological drugs, targeting molecules and cells involved into perturbed pro-inflammatory immune response in the psoriatic skin and joints, has been recently designed and applied clinically. These biological agents are bioengineered proteins such as chimeric and humanized antibodies and fusion proteins. In particular, they comprise the antitumor necrosis factor-alpha agents etanercept, infliximab, and adalimumab, with clinical efficacy in both moderate-severe psoriasis and psoriatic arthritis, and the anti-CD11a efalizumab with selective therapeutic action exclusively in the skin. Here, we overview recent findings on the molecular pathways relevant to the inflammatory response in psoriasis and present our clinical experience with the drugs currently employed in the dermatologic manifestations, namely etanercept, infliximab, and efalizumab. The growing body of clinical data on the efficacy and safety of antipsoriasis biological drugs is reviewed as well. Particular focus is given to long-term safety concerns and feasibility of combined therapeutic protocols to ameliorate clinical results.

No MeSH data available.


Related in: MedlinePlus

Strategies for targeted biological therapy of psoriasis. These include existing and potential biological drugs for the therapy of psoriasis, such as anti-TNF-α (A) or anti-LFA-1 (B) antibodies, inhibitors of CD2 expression on the surface of activated pathogenic T cells (C), or cytokines to balance the Th1-skewed immune response (D), these last presently under investigation.Abbreviations: APC, antigen-presenting cell; LFA-1, lymphocyte function-associated antigen-1; TNF-α, tumor necrosis factor-α.
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f2-btt-2-687: Strategies for targeted biological therapy of psoriasis. These include existing and potential biological drugs for the therapy of psoriasis, such as anti-TNF-α (A) or anti-LFA-1 (B) antibodies, inhibitors of CD2 expression on the surface of activated pathogenic T cells (C), or cytokines to balance the Th1-skewed immune response (D), these last presently under investigation.Abbreviations: APC, antigen-presenting cell; LFA-1, lymphocyte function-associated antigen-1; TNF-α, tumor necrosis factor-α.

Mentions: Bioactive TNF-α can be found in two forms, a membrane-bound form and a proteolytically solubilized form. Its biological effects are mediated by two cell surface receptors, respectively. One is the ubiquitously expressed TNF-R1 (synonyms, p55 and CD120a) and the other one is TNF-R2 known also as p75 or CD120b. The role of TNF-R1 in skin inflammation has been confirmed experimentally (Pasparakis et al 2002). TNF-R2 is predominantly found on hematopoietic and endothelial cells and crucially implicated in the TNF-α-driven cell apoptosis (Locksley et al 2001). Both soluble and membrane-bound forms of TNF-α are the molecular targets for biological therapy of psoriasis. In particular, the anti-TNF-α drugs used for the therapy of psoriasis are based either on anti-TNF-α monoclonal antibodies such as infliximab or on TNF-R-based reagents such as etanercept (Gisondi et al 2004) (Figure 2A). They were first used for the treatment of patients with moderate-to-severe rheumatoid arthritis who failed to respond to conventional therapies. Infliximab is a chimeric anti-TNF-α monoclonal immunoglobulin G1a (IgG1a) antibody, with a human constant region and a murine variable portion. Infliximab binds and neutralizes the soluble form of TNF-α with extremely high affinity. It also binds the membrane-bound form, with lower affinity though. Thus, by binding to TNF-α, infliximab triggers the elimination of TNF-α-producing cells by both complement-mediated and antibody-dependent, cytotoxic mechanisms. Infliximab is also currently approved by the United States Food and Drug Administration (US FDA) to be used in combination with methotrexate for the treatment of active rheumatoid arthritis and Crohn’s disease. Etanercept is a genetically engineered fusion protein consisting of an homodimer of the extracellular portion of TNF-R p75 subunit fused with the constant region of human IgG1. The complexes of TNF-α with etanercept are quite unstable. Nonetheless, they diminish or even prevent the biological actions of the soluble forms of TNF-α. Etanercept is the US FDA-approved drug for the treatment of psoriatic arthritis, rheumatoid arthritis, and polyarticular-course juvenile rheumatoid arthritis. Finally, the genetically engineered recombinant human IgG1 monoclonal antibody adalimumab, which binds both soluble and membrane-bound TNF-α with high affinity, is presently limited to the therapy of active, progressive psoriatic arthritis that failed to respond to one or more antirheumatic drugs.


Biological drugs targeting the immune response in the therapy of psoriasis.

Pastore S, Gubinelli E, Leoni L, Raskovic D, Korkina L - Biologics (2008)

Strategies for targeted biological therapy of psoriasis. These include existing and potential biological drugs for the therapy of psoriasis, such as anti-TNF-α (A) or anti-LFA-1 (B) antibodies, inhibitors of CD2 expression on the surface of activated pathogenic T cells (C), or cytokines to balance the Th1-skewed immune response (D), these last presently under investigation.Abbreviations: APC, antigen-presenting cell; LFA-1, lymphocyte function-associated antigen-1; TNF-α, tumor necrosis factor-α.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2727880&req=5

f2-btt-2-687: Strategies for targeted biological therapy of psoriasis. These include existing and potential biological drugs for the therapy of psoriasis, such as anti-TNF-α (A) or anti-LFA-1 (B) antibodies, inhibitors of CD2 expression on the surface of activated pathogenic T cells (C), or cytokines to balance the Th1-skewed immune response (D), these last presently under investigation.Abbreviations: APC, antigen-presenting cell; LFA-1, lymphocyte function-associated antigen-1; TNF-α, tumor necrosis factor-α.
Mentions: Bioactive TNF-α can be found in two forms, a membrane-bound form and a proteolytically solubilized form. Its biological effects are mediated by two cell surface receptors, respectively. One is the ubiquitously expressed TNF-R1 (synonyms, p55 and CD120a) and the other one is TNF-R2 known also as p75 or CD120b. The role of TNF-R1 in skin inflammation has been confirmed experimentally (Pasparakis et al 2002). TNF-R2 is predominantly found on hematopoietic and endothelial cells and crucially implicated in the TNF-α-driven cell apoptosis (Locksley et al 2001). Both soluble and membrane-bound forms of TNF-α are the molecular targets for biological therapy of psoriasis. In particular, the anti-TNF-α drugs used for the therapy of psoriasis are based either on anti-TNF-α monoclonal antibodies such as infliximab or on TNF-R-based reagents such as etanercept (Gisondi et al 2004) (Figure 2A). They were first used for the treatment of patients with moderate-to-severe rheumatoid arthritis who failed to respond to conventional therapies. Infliximab is a chimeric anti-TNF-α monoclonal immunoglobulin G1a (IgG1a) antibody, with a human constant region and a murine variable portion. Infliximab binds and neutralizes the soluble form of TNF-α with extremely high affinity. It also binds the membrane-bound form, with lower affinity though. Thus, by binding to TNF-α, infliximab triggers the elimination of TNF-α-producing cells by both complement-mediated and antibody-dependent, cytotoxic mechanisms. Infliximab is also currently approved by the United States Food and Drug Administration (US FDA) to be used in combination with methotrexate for the treatment of active rheumatoid arthritis and Crohn’s disease. Etanercept is a genetically engineered fusion protein consisting of an homodimer of the extracellular portion of TNF-R p75 subunit fused with the constant region of human IgG1. The complexes of TNF-α with etanercept are quite unstable. Nonetheless, they diminish or even prevent the biological actions of the soluble forms of TNF-α. Etanercept is the US FDA-approved drug for the treatment of psoriatic arthritis, rheumatoid arthritis, and polyarticular-course juvenile rheumatoid arthritis. Finally, the genetically engineered recombinant human IgG1 monoclonal antibody adalimumab, which binds both soluble and membrane-bound TNF-α with high affinity, is presently limited to the therapy of active, progressive psoriatic arthritis that failed to respond to one or more antirheumatic drugs.

Bottom Line: A new generation of biological drugs, targeting molecules and cells involved into perturbed pro-inflammatory immune response in the psoriatic skin and joints, has been recently designed and applied clinically.The growing body of clinical data on the efficacy and safety of antipsoriasis biological drugs is reviewed as well.Particular focus is given to long-term safety concerns and feasibility of combined therapeutic protocols to ameliorate clinical results.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Tissue Engineering and Cutaneous Physiopathology;

ABSTRACT
Chronic plaque psoriasis affects more than 2% of world population, has a chronic recurrent behavior, gives a heavy burden to the patients' quality of life, and hence remains a huge medical and social problem. The clinical results of conventional therapies of psoriasis are not satisfactory. According to the current knowledge of the molecular and cellular basis of psoriasis, it is defined as an immune-mediated chronic inflammatory and hyperproliferative skin disease. A new generation of biological drugs, targeting molecules and cells involved into perturbed pro-inflammatory immune response in the psoriatic skin and joints, has been recently designed and applied clinically. These biological agents are bioengineered proteins such as chimeric and humanized antibodies and fusion proteins. In particular, they comprise the antitumor necrosis factor-alpha agents etanercept, infliximab, and adalimumab, with clinical efficacy in both moderate-severe psoriasis and psoriatic arthritis, and the anti-CD11a efalizumab with selective therapeutic action exclusively in the skin. Here, we overview recent findings on the molecular pathways relevant to the inflammatory response in psoriasis and present our clinical experience with the drugs currently employed in the dermatologic manifestations, namely etanercept, infliximab, and efalizumab. The growing body of clinical data on the efficacy and safety of antipsoriasis biological drugs is reviewed as well. Particular focus is given to long-term safety concerns and feasibility of combined therapeutic protocols to ameliorate clinical results.

No MeSH data available.


Related in: MedlinePlus