Cytokines And Biologic Treatment in Arthritis

Cytokines And Biologic Treatment in Arthritis
SUSIE D. AVERIA, MD, FPCP, DPRA

Objectives To define cytokines and discuss its role in the inflammatory cascade of arthritis To present cytokines and its equivalent biologic treatment in arthritis To review the use of biologicals, clinical indications and its mechanism of action available locally

CYTOKINES Hormonal messengers Biological effects in the immune system
Cell mediated immunity Allergic type responses Divided into two groups: Proinflammatory Anti-inflammatory

CYTOKINES T lymphocytes- major source
Antigen specific receptors on their cell surface Recognition of foreign pathogens Recognise normal tissue during episodes of autoimmune diseases T lymphocytes are a major source They bear antigen specific receptors on their cell surface that allow recognition of foreign pathogens. Recognise normal tissue during episodes of autoimmune diseases

CYTOKINES Two main subsets of T lymphocytes CD4 CD8
CD4 -helper T cells are subdivided into Th1-type cytokines Th2-type cytokines There are two main subsets of T lymphocytes CD4 and CD8 CD4 -helper T cells are subdivided into Th1 and Th2 - Th1-type cytokines and Th2-type cytokines

CYTOKINES Th-1 type cytokines Th-2 type cytokines
Proinflammatory responses Kill intracellular parasites Perpetuates autoimmune responses Interferon gamma In excess lead to uncontrolled tissue damage Anti-inflammatory response IL-10 Promotion of IgE and eosinophilic responses IL- 4, 5, and 13 In excess counteracts the Th1 mediated microbicidal action interleukins, cytokines that act as mediators between leukocytes.

Proinflammatory and anti-inflammatory cytokines in RA
Cytokines play a major role in the pathogenesis of RA. They can be divided into pro-inflammatory (e.g., tumor necrosis factor a (TNF-a) and interleukin-1 (IL-1)) and anti-inflammatory cytokines (including IL-10, the IL-1 receptor antagonist (IL-1ra) and the soluble receptor of TNF-a (sTNF-R). The optimal scenario would therefore seem to be that humans should produce a well balanced Th1 and Th2 response, suited to the immune challenge.

CYTOKINES One cytokine often influences the synthesis of other cytokines Produce cascades, enhance or suppress production Influence the action of other cytokines Effects can be: antagonistic additive synergistic One cytokine often influences the synthesis of other cytokines. They can produce cascades, or enhance or suppress production of other cytokines. In addition, they can often influence the action of other cytokines. The effects can be: 1) antagonistic; 2) additive; or 3) synergistic.

CYTOKINES Bind to specific receptors on target cells with high affinity Cells that respond to a cytokine: Autocrine - same cell that secreted cytokine Paracrine - a nearby cell Endocrine- a distant cell reached through the circulation Cytokines bind to specific receptors on target cells with high affinity and the cells that respond to a cytokine are either: 1) the same cell that secreted cytokine (autocrine); 2) a nearby cell (paracrine) or 3) a distant cell reached through the circulation (endocrine). Cellular responses to cytokines are generally slow (hours) because they require new mRNA and protein synthesis.

Receptors for various cytokines

CYTOKINES Cytokines are currently being used clinically as biological response modifiers for the treatment of various disorders

Pathogenesis of Rheumatoid Arthritis

Normal Synovium The synovium serves as a source of nutrients for cartilage Composed primarily of type II collagen and proteoglycans Enable low friction, high velocity movement between bones Absorbs considerable impact and stress Aggrecan is the major proteoglycan that imparts elasticity to articular cartilage Synovial cells synthesize joint lubricant such as hyaluronic acid, collagens and fibronectin Synovial Cavity 1-2.5ml of highly viscous fluid Chonsynthesize proteases and their inhibitors docytes secrete and in matrix turnover Collagen fibrils comprises 90% of the fibrillar network Provides tensile strength and provides the framework in which proteoglycan and chondrocytes are embedded These constitutes the structural framework of the synovial interstitium The synovium serves as an important source of nutrients for cartilage (since cartilage itself is avascular. ). In addition, synovial cells synthesize joint lubricants such as hyaluronic acid, as well as collagens and fibronectin that constitute the structural framework of the synovial interstitium. Articular Cartilage is composed primarily of type II collagen (cartilage specific) and proteoglycans wherein aggrecan is the major proteoglycan that imparts elasticity to articular cartilage , this is normally a very resilient tissue that absorbs considerable impact and stress. It allows low friction, high velocity movement between bones and contributes to joint stability. CLICK: Collagen fibrils impart tensile strength to articular cartilage and provide a framework in which proteoglycans and chondrocytes are embedded. Type II collagen comprises 90 percent of this fibrillar network. CLICK:Proteoglycans impart elasticity to articular cartilage. Aggrecan is the major proteoglycan imparting elasticity to articular cartilage. CLICK: Glycoproteins are secreted and synthesized by chondrocytes. These include proteases and their inhibitors that play an important role in matrix turnover. Some of these glycoproteins can retard the development of osteoclasts [99] and inhibit neovascularization. [100] Inhibitors of angiogenesis may help to maintain the avascular nature of articular cartilage and may contribute to its resistance against neoplastic infiltration. Fibronectin is important for adhesion of articular chondrocytes through cell surface integrins and may contribute also to the organization of a stable collagen network. Bone Composed primarily of type I collagen. Synovial Cavity normally has a "potential" space with 1-2ml of highly viscous (due to hyaluronic acid) fluid with few cells.

Joints are the organs most often involved in RA. In RA, the subintimal area is heavily infiltrated with inflammatory cells, including more predominantly with T than B lymphocytes, macrophages and mast cells which are localized at the sites of cartilage erosions . The synovial Cavity normally has a "potential" space with 1-2ml of highly viscous (due to hyaluronic acid) fluid with few cells. In RA, large collections of fluid ("effusions") occur with filtrates of plasma (and, therefore, exudative - i.e., high protein content). The synovial fluid is highly inflammatory with abundance of neutrophils on the synovial fluid but rarely in rheumatoid synovial tissue that is infiltrated with lymphocytes and macrophages. The intense cellular infiltrate is accompanied by new blood vessel growth (angiogenesis). The hypertrophied synovium that is a mass tissue serves as an origin of joint erosions (also called pannus). It locally invades and erodes The the synovial interface with cartilage and bones.Type B cells, which are abundant in the pannus, express large amounts of messenger RNA encoding for destructive proteins or the matrix-degrading proteolytic enzymes called matrix metalloproeinases.

Joints are the organs most often involved in RA. In RA, the subintimal area is heavily infiltrated with inflammatory cells, including more predominantly with T than B lymphocytes, macrophages and mast cells which are localized at the sites of cartilage erosions . The synovial Cavity normally has a "potential" space with 1-2ml of highly viscous (due to hyaluronic acid) fluid with few cells. In RA, large collections of fluid ("effusions") occur with filtrates of plasma (and, therefore, exudative - i.e., high protein content). The synovial fluid is highly inflammatory with abundance of neutrophils on the synovial fluid but rarely in rheumatoid synovial tissue that is infiltrated with lymphocytes and macrophages. The intense cellular infiltrate is accompanied by new blood vessel growth (angiogenesis). The hypertrophied synovium (also called pannus) invades and erodes contiguous bone and cartilage. Cartilage is composed primarily of type II collagen and proteoglycans. In RA, its integrity, resilience and water content are all impaired due to elaboration of proteolytic enzymes (collagenase, stromelysin) both by synovial lining cells and by chondrocytes themselves. Polymorphonuclear leukocytes in the synovial fluid may also contribute to this degradative process. Type B cells, which are abundant in the pannus, are thought to be the chief source of matrix-degrading proteolytic enzymes.

Cellular Components of Synovial Lesion
T cells B cells Phagocytes Neutrophils Macrophage-like cells Fibroblast-like cells These are the major cell types in the synovial joint that play a role in rheumatoid synovitis. T cells, B cells, Phagocytes , macrophage-like cells and fibroblast-like cells. T cell comprises approximately 40% of synovial tissue cells predominantly the CD4. T helper cells help B cells to divide and produce antibodies, activate phagocytes to destroy pathogens and control the level of immune response .

T-Cell Characteristics
HLA class II molecules present antigenic peptides to CD4 T cells CD4 T cells become activated Stimulates monocytes, macrophages, and synovial fibroblasts These molecules in turn produce cytokines (IL-1, IL-6, TNF α) and secrete matrix metalloproteinases Activated osteoclasts drive bone resorption T cells are present in 40% of the synovial tissue. T lymphocytes can also be distinguished by cell surface proteins or glycoproteins known as CD (clusters of differentiation) markers. The CD4 cells (helper cells) recognize antigens associated with major histocompatibility complex (MHC) class II molecules. CD4+ T cells are implicated in RA because they produce cytokines and matrix metalloproteinases and activate osteoclasts—all of which can cause damage during RA pathogenesis.

Interaction between CD4+ T cells and antigen-presenting cells
T cells serve as crucial regulators of the immune response. The most widely accepted mechanistic hypothesis in RA is that an unknown antigen triggers a chain reaction in a genetically predisposed host. In order to induce a T-cell response, the antigen-presenting cell (APC) must interact intimately with the T lymphocyte, through the T-cell receptor on one hand and the antigenic major histocompatibility (MHC) peptide on the other. A second costimulatory mechanism is also required, in which a membrane receptor from the CD80 receptor family on the APC interacts with CD28, a transmembrane glycoprotein that is constitutively expressed on the cell surfaces of activated CD4+ T cells to deliver stimulatory signals that are independent of antigen. However, once activated, T cells express another costimulatory molecule, CD152, that is homologous to CD28. When CD152 interacts with a CD80 molecule, it induces an inhibitory signal which suppresses the production of cytokines. CD80 is also known as B7. The early progression of RA is thought to be a result of the infiltration of T cells into the synovial membrane of genetically susceptible individuals, followed by their activation by antigen, and their subsequent clonal expansion. T cells play a central role in the pathophysiology of RA. T cells with CD4 markers become activated once they are presented with antigen and that activation stimulates monocytes, macrophages, and synovial fibroblasts. These cell types then produce cytokines (IL-1, IL-6, and TNF-α) and secrete metalloproteinases. Cytokines and metalloproteinases are involved in the inflammatory response and are key molecules in RA pathogenesis. δ

Cellular Components of Synovial Lesion
B cell Express surface immunoglobulins Provide cognate help for T-cells T cells B cells B cells have a number of important roles in acquired immunity. They play a role in taking up antigens for processing and presentation and in antigen-mediated production of antibodies. B cells provide assistance to T cells and produce some of the important cytokines that support other cell types. REFER TO PICTURE: B cells carry surface immunoglobulin that acts as their antigen receptor and produce autoantibodies called rheumatoid factor. Cognate interaction between T cell and antigen-stimulated B cell : When the B cells are activated by antigen recognition, the helper T cell, which has been primed to respond to the same antigen by a professional APC, will thereby become activated. The interaction between antigen-stimulated B cells and T cells is called a cognate interaction and occurs in secondary lymphoid organs at the interface between the lymph node follicles (where B cells encounter antigen) and the T cell zones (where T cells encounter antigen). These interactions require costimulatory signals: the B cell provides costimulatory signals through CD80/CD86, which interact with CD28 on the T cell, so that the T cell becomes fully activated. It then expresses CD40L (CD154) to stimulate the B cell, which constitutively expresses CD40 (Figure 3-4). When B cells are stimulated by CD154 and by T cell cytokines (such as IL-2, IL-4, IL-5, IL-6, INF-g, and TGF-b), they become activated, and proceed to undergo clonal expansion, isotype switching (from IgM to IgG), affinity maturation, and differentiation into mature memory B cells and immunoglobulin-secreting plasma cells. Antibody-mediated immunity involves the production of antibodies in response to exposure to specific antigens. The immune system responds to invasion by a specific organism by producing clones of antibody-producing plasma cells, as well as memory cells that help produce a more robust response against the same organism in the future.

Proinflammatory Cytokines
Cell sources Functions TNFα Macrophages, lymphocytes, fibroblasts Inflammation, fever, bone and cartilage resorption IL-1α Macrophages, monocytes Targets thymocytes and neutrophils IL-1β Fibroblasts, epithelial cells Targets B and T cells and tissue cells IL-6 Macrophages, T cells, fibroblasts, some B cells Differentiation, bone resorption Cytokines provide important links between the innate and acquired immune responses. These important mediators of cell-cell communication stimulate the cells of the innate immune system and are also produced by mononuclear cells to help amplify or inhibit inflammation and acquired immune responses. The cytokines listed on this slide are implicated in autoimmune diseases; many therapeutic options for RA target the production of these cytokines. Both IL1 and TNF alpha are present in the synovial tissue and fluid. IL1 is found in 20 % of lining cells and 25% of sublining cells while TNF alpha is found in 40% and 5-10% of lining and sublining cells, respectively.

Proinflammatory and anti-inflammatory cytokines in RA
Cytokines play a major role in the pathogenesis of RA. They can be divided into pro-inflammatory (e.g., tumor necrosis factor a (TNF-a) and interleukin-1 (IL-1)) and anti-inflammatory cytokines (including IL-10, the IL-1 receptor antagonist (IL-1ra) and the soluble receptor of TNF-a (sTNF-R). TNF-a is produced by monocytes and macrophages in response to a variety of stimuli. It is found in the cartilage-pannus junction of RA patients, where it stimulates the resorption of cartilage and inhibits the synthesis of collagen and proteoglycans. TNF-a plays a central and dominant role in the inflammatory cascade. This cytokine strongly stimulates the production of IL-1. Other cytokines and chemokines such as granulocyte macrophage-colony stimulating factor (GM-CSF), IL-6, IL-8, and IL-10 are also controlled by TNF-a. (More importantly, anti-TNF-a therapies have improved the clinical outcomes in RA patients.). Apart from regulating the expression of cytokines, TNF-a exerts a wide range of other biological effects that play roles in the pathogenesis of RA. For example: It enhances the recruitment of inflammatory cells in RA synovium by upregulating adhesion molecules (E-selectin, ICAM-1, VCAM-1). It activates neutrophils and macrophages. It stimulates its own production and that of other proinflammatory mediators (IL-6, IL-1, and prostaglandins). It activates osteoclasts (by stimulating IL-1, which has a direct effect on these cells). It promotes the proliferation of fibroblasts and synoviocytes and the production of MMPs, which play a role in tissue remodelling, cartilage degradation, and bone erosion. The effects of TNF-a are mediated by binding to either of two cell surface receptors termed P55 and P75. The extracellular domains of these receptors can be shed into the circulation to form soluble receptors (sTNF-R) which can scavenge excess circulating TNF-a molecules, preventing them from interacting with their target cells. IL-1 is stimulated by TNF-a, but there is ample evidence that in RA, IL-1 is also produced independently of TNF. IL-1 exerts many deleterious effects in RA; it promotes angiogenesis, the production of adhesion molecules, TNF-a, prostaglandins, and MMPs, and stimulates osteoclast activity while inhibiting osteoblasts. All these actions lead to inflammatory cell recruitment and the degradation of cartilage and bone. Countering the effects of IL-1 is the naturally occurring anti-inflammatory cytokine IL-1ra, another member of the IL-1 family. This molecule binds to the cell surface IL-1 receptor with the same affinity as IL-1, but it does not lead to cellular activation.

IL-1b and TNF-a: Proinflammatory Cytokines in the Rheumatoid Joint
High endothelial venule B o n e O s t e o b l a s t s O s t e o c l a s t s Synovial membrane C a r t i l a g e IL-6 PGE2 IL-8 TNF-α IL-1β N e u t r o p h i l s Capsule Synovial space Interleukin-1 (IL-1) and tumour necrosis factor- (TNF-) have been identified as pivotal proinflammatory cytokines in the pathogenesis of the rheumatoid joint.1,2 In this slide, IL-1 and TNF- are shown in the joint space; however, concentrations of these cytokines are likely to be higher in the tissues.1 Increased concentrations of IL-1 and TNF- are found in the synovial fluid and tissue of patients with rheumatoid arthritis (RA). These cytokines act to stimulate the production of each other, that is, IL-1 stimulates production of TNF- and vice versa.1 Early in the RA disease process, IL-1 and TNF- act synergistically to increase production of matrix metalloproteases, such as collagenase, by chondrocytes. These enzymes degrade components of the cartilage matrix.1 IL-1 also activates osteoclasts in bone.2 IL-1 and TNF- also increase expression of adhesion molecules on the endothelium, contributing to the migration of neutrophils and lymphocytes from the circulation.1 In addition, IL-1 and TNF- stimulate synovial fibroblasts to produce additional proinflammatory mediators, such as IL-8, prostaglandin-E2, and IL-6. These mediators are responsible for the acute and chronic inflammation characteristic of RA.1 Interleukin-1 (IL-1) and tumour necrosis factor- (TNF-) have a number of overlapping proinflammatory effects.1 IL-1 and TNF- both upregulate the production of inflammatory mediators such as cyclo-oxygenase type 2, prostaglandin-E2, and nitric oxide. IL-6, a cytokine that plays a key role in activating the innate immune system, is also induced by both IL-1 and TNF-. IL-1 and TNF- also increase the expression of adhesion molecules and chemokines, which facilitate the migration of inflammatory cells into the tissues, and the production of collagenases by chondrocytes (cells responsible for cartilage remodelling).1 IL-1 and TNF- are both capable of inducing synthesis of each other.1 IL-1, but not TNF-, stimulates osteoclast activation and the production of angiogenic factors.1 TNF-, but not IL-1, appears to be an important ligand for the activation of programmed cell death.1 Destructive effects of TNF TNF triggers multiple destructive effects in RA. In part, it stimulates osteoclasts to resorb bone, ultimately resulting in bone erosions visible on x-ray.1 TNF also induces the proliferation of synoviocytes, which in turn produces inflammation due to the release of inflammatory mediators.2,3 As depicted here, inflammation not only causes pain and swelling but also has been shown to precede joint damage.2,4 Chondrocytes are a third target of TNF activation, producing collegenase that degrades cartilage and eventually causes joint space narrowing.1,5 In addition to these effects, TNF plays an early role in the inflammatory process by stimulating activation of T cells by foreign antigens.2,3 TNF also induces expression of adhesion molecules, thereby promoting the migration of macrophages and lymphocytes into the synovium.5 References: 1. Goronzy JJ, Weyand CM. Rheumatoid arthritis: epidemiology, pathology, and pathogenesis. In: Klippel JH, ed. Primer on the Rheumatic Diseases. 11th ed. Atlanta, Ga: Arthritis Foundation; 1997: Carpenter AB. Immunology and inflammation. In: Wegener ST, ed. Clinical Care in the Rheumatic Diseases. Atlanta, Ga: American College of Rheumatology; 1996: Albani S, Carson DA. Etiology and pathogenesis of rheumatoid arthritis. In: Koopman WJ, ed. Arthritis and Allied Conditions: A Textbook of Rheumatology. Vol 1. 13th ed. Baltimore, Md: Williams & Wilkins; 1997: McGonagle D, Conaghan PG, O'Connor P, et al. The relationship between synovitis and bone changes in early untreated rheumatoid arthritis: a controlled magnetic resonance imaging study. Arthritis Rheum. 1999;42: Rosenberg AE. Skeletal system and soft tissue tumors. In: Cotran RS, ed. Robbins Pathologic Basis of Disease. 5th ed. Philadelphia, Pa: W.B. Saunders Company; 1994: Effects of TNF Induces necrosis of tumor cells Recognized to mediate numerous inflammatory and immuno regulatory activities. Facilitates lymphocyte, neutrophil and monocyte accumulation at inflammatory sites Modulates growth, differentiation, and metabolism in the different cell types Induces the synthesis of several other key proinflammatory cytokines IL-1, IL-6, and granulocytes-macrophage colony-stimulating factor [GM-CAF]), chemokines (IL-8), other inflammatory mediators (prostaglandins, leukotrienes, and platelet-activating factor [PAF]) Stimulate macrophages and fibroblast: Matrix metalloproteinases (MMP) enzymes (collagenases, stromolysins) that effects damage to cartilage and bone Directly mediate pain, fever and cachexia * the pivotal role of TNF-a in mediating such diverse inflammatory activities provided the rationale for targeting this cytokine in systemic inflammatory dse. The fact that active TNF-alpha enhances IL-1 production by cells is additional evidence for its primacy in generating and sustaining rheumatoid synovitis. Primarily in the rheumatoid joint, is a target of several of the drugs we will be talking about -- in particular, the antibodies against TNF and the soluble TNF receptor, etanercept. 1. Dinarello CA. Biologic basis for interleukin-1 in disease. Blood. 1996;87: 2. Gravallese EM, Goldring SR. Cellular mechanisms and the role of cytokines in bone erosions in rheumatoid arthritis. Arthritis Rheum. 2000;43: 3. Dinarello CA, Moldawer LL. Proinflammatory and Anti-inflammatory Cytokines in Rheumatoid Arthritis. A Primer for Clinicians. 3rd ed. Thousand Oaks, Ca: Amgen Inc.; 2001. C h o n d r o c y t e s Pannus Osteoblasts Osteoclasts B o n e PGE2 = prostaglandin-E2 Dinarello C, Moldawer L. Proinflammatory and Anti-inflammatory Cytokines in Rheumatoid Arthritis: A Primer for Clinicians. 3rd ed. Thousand Oaks, Ca, USA: Amgen Inc.; 2001.

Production of TNF TM-TNF TNF Activated Macrophage Activated
(transmembrane TNF) TACE (TNF alpha converting enzyme) cleaves TM-TNF from the surface TNF TNF-α is a member of a family of peptide mediators that includes lymphotoxin-alpha (LT-α), which was previously known as TNF-ß, Fas ligand (FasL), CD40 ligand (CD40L), and receptor activator of nuclear factor-kappa B (NF-kB) ligand (RANKL). TNF-α can be produced by numerous cell types: however in inflammatory conditions it is made primarily by macrophages in response to various proinflammatory stimuli. TNF is produced when TACE (TNF converting enzyme) cleaves TM-TNF (transmembrane TNF) from the surface of an activated macrophage. Human TNF-α is synthesized and expressed as a 26k-D transmembrane protein on the plasma membrane and is cleaved by a specific metalloproteinase (TNF-α converting enzyme [TACE]). Activated Macrophage Activated Macrophage

TNF Mode of Action Activated Target Mf Cell sTNFR Signal TNF
Human TNF-α is synthesized and expressed as a 26k-D transmembrane protein on the plasma membrane and is cleaved by a specific metalloproteinase (TNF-α converting enzyme [TACE]). After proteolytic cleavage, TNF-α is converted to a 17-kD soluble protein, which oligomerizes to form the active homotime. The actions of TNF-α are mediated to 2 structurally distinct cell-associated receptors: TNF-R1 (55 kD; CD120a) and TNF-RII (75 kD; CD120b). The 2 receptors differ in their binding abilities and signaling properties; these differences reflect the differences in their primary functions. Soluble forms of CD120a and CD120b bind TNF-ά with high avidity and may serve an inhibitory function. The binding of TNF-ά to its receptor can initiate several signaling pathways. Signaling cascades include activation of transcription factors (e.g. NF-kB), protein kinases (intracellular enzymes that mediate cellular responses to inflammatory stimuli, e.g. c-Jun N terminal kinase [JNK], p 33 MAP kinase), and proteases (enzymes that cleave peptide bonds, e.g. capsases).

Inhibition of Cytokines
Inflammatory cytokine Normal interaction Cytokine receptor Inflammatory signal Neutralization of cytokines Soluble receptor Monoclonal antibody No signal Activation of anti-inflammatory pathways Anti-inflammatory cytokine Suppression of inflammatory cytokines Receptor blockade Monoclonal antibody Receptor antagonist No signal Adapted with permission from Choy EH, Panayi GS. N Engl J Med. 2001;344:907–916.

What are Biologics? A class of therapeutics (either approved or in development) that are produced by means of biological processes involving recombinant DNA technology As indicated the term "biologics" can be used to refer to a wide range of biological products in medicine. However, in most cases, the term "biologics" is used more restrictively for a class of therapeutics (either approved or in development) that are produced by means of biological processes involving recombinant DNA technology.

What are Biologics? Usually one of three types:
Substances that are (nearly) identical to the body's own key signalling proteins. Eg: Erythropoetin Monoclonal antibodies Receptor constructs (fusion proteins), usually based on a naturally-occurring receptor linked to the immunoglobulin frame These medications are usually one of three types: . Substances that are (nearly) identical to the body's own key signalling proteins. Examples are the blood-production stimulating protein erythropoetin, or the growth-stimulating hormone named (simply) "growth hormone" or biosynthetic human insulin and its analogues. 2. Monoclonal antibodies. These are similar to the antibodies that the human immune system uses to fight off bacteria and viruses, but they are "custom-designed" (using hybridoma technology or other methods) and can therefore be made specifically to counteract or block any given substance in the body, or to target any specific cell type; examples of such monoclonal antibodies for use in various diseases are given in the table below. 3. Receptor constructs (fusion proteins), usually based on a naturally-occurring receptor linked to the immunoglobulin frame. In this case, the receptor provides the construct with detailed specificity, whereas the immunoglobulin-structure imparts stability and other useful features in terms of pharmacology. Some examples are listed in the table below.

Biologics in Non Rheumatologic Diseases
Cancer Psoriasis Inflammatory Bowel Diseases Inflammatory Eye Diseases Asthma

The Biologicals Inhibitors of Tumor Necrosis Factors Infliximab
Etanercept Adalimumab Interleukin-1 Receptor Antagonist and Interleukin-1 Receptor Anakinra Interleukin-6 Receptor Antagonist Tocilizumab B Cell Targeted Therapies Rituximab (Rituximab) Belimumab

Etanercept Infliximab Adalimumab
Anti-TNFα Agents Etanercept Infliximab Adalimumab

TNF Inhibition: Mechanisms of Action
Soluble TNF receptors Human TNF receptor linked to Fc portion of IgG Bind soluble and cell-bound TNF Do not fix complement or lyse immune cells (in vitro) =;here are two mechanisms of regulating TNF activity: Soluble TNF receptors to bind excess TNF TNF monoclonal antibodies to bind excess TNF Both bind soluble and cell-bound TNF. Soluble TNF receptors do not fix complement and thus don’t cause cell lysis (in vitro). TNF monoclonal antibodies can fix complement and thus can cause cell lysis (in vitro).

TNF Inhibition: Mechanisms of Action
TNF monoclonal antibodies Variable (Fab) region binds to soluble and cell-bound TNF Chimeric and human versions Can fix complement leading to cell lysis (in vitro) =;here are two mechanisms of regulating TNF activity: Soluble TNF receptors to bind excess TNF TNF monoclonal antibodies to bind excess TNF Both bind soluble and cell-bound TNF. Soluble TNF receptors do not fix complement and thus don’t cause cell lysis (in vitro). TNF monoclonal antibodies can fix complement and thus can cause cell lysis (in vitro).

Effects TNF-α Inhibitors
Down regulation of local and systemic proinflammatory cytokine production Reduction of lymphocyte migration into the joint Reduction of angiogenesis in the joints Induces necrosis of tumor cells Recognized to mediate numerous inflammatory and immuno regulatory activities. Facilitates lymphocyte, neutrophil and monocyte accumulation at inflammatory sites by upregulating endothelial expression of various adhesion molecules Modulates growth, differentiation, and metabolism in the different cell types Induces the synthesis of several other key proinflammatory cytokines (including IL-1, IL-6, and granulocytes-macrophage colony-stimulating factor [GM-CAF]), chemokines (IL-8), and other inflammatory mediators (prostaglandins, leukotrienes, and platelet-activating factor [PAF]) Stimulate macrophages and fibroblast to produce matrix metalloproteinases (MMP) enzymes (collagenases, stromolysins) that effects damage to cartilage and bone Can directly mediate pain, fever and cachexia * the pivotal role of TNF-a in mediating such diverse inflammatory activities provided the rationale for targeting this cytokine in systemic inflammatory dse.

Effects TNF-α Inhibitors
Reduction of serum levels of IL-6 and IL-1 significantly Reduction in the synthesis of MMP and production of other enzymes Dose-dependent decrease in soluble forms of intracellular adhesion molecule-1 (ICAM-1) and E-selectin Reduction of vascular endothelial growth factor (VEGF) serum levels Induces necrosis of tumor cells Recognized to mediate numerous inflammatory and immuno regulatory activities. Facilitates lymphocyte, neutrophil and monocyte accumulation at inflammatory sites by upregulating endothelial expression of various adhesion molecules Modulates growth, differentiation, and metabolism in the different cell types Induces the synthesis of several other key proinflammatory cytokines (including IL-1, IL-6, and granulocytes-macrophage colony-stimulating factor [GM-CAF]), chemokines (IL-8), and other inflammatory mediators (prostaglandins, leukotrienes, and platelet-activating factor [PAF]) Stimulate macrophages and fibroblast to produce matrix metalloproteinases (MMP) enzymes (collagenases, stromolysins) that effects damage to cartilage and bone Can directly mediate pain, fever and cachexia * the pivotal role of TNF-a in mediating such diverse inflammatory activities provided the rationale for targeting this cytokine in systemic inflammatory dse.

Etanercept (Enbrel) Soluble portion of the
Human p75 chain TNFareceptor (binds extracellular TNF) Fragment crystallizable (Fc) portion of Human IgG1 (prolongs its circulating half-life) This cartoon is a schematic representation of recombinant human TNF receptor (p75) Fc fusion protein (TNFR:Fc). It consists of two molecules of the extracellular domain of p75 TNFR linked to the Fc region of human IgG1. Because of its bivalent nature, TNFR:Fc is an effective competitive inhibitor of TNF binding to cell surface receptors. Fusion protein of soluble portion of the human TNF p75 chain of the receptor and the fragment crystallizable (Fc) portion of human immunoglobulin G1 (IgG1). The receptor portion binds extracellular TNF-a, effectively neutralizing it and the Fc moiety prolongs its circulating half-life. Approved in 1998 The first biologic response modifier drug for treatment of rheumatoid arthritis Administered via subcutatneous injection 25mg twice weekly/ 50mg once a week July 15, 1997 Slide No. 13

Etanercept Mode of Action
sTNFR:Fc Activated M Target Target M f f Cell Cell TNFR TNFR Signal Signal sTNFR TNF Etanercept is formed by the linkage of 2 p75 TNF-R extracellular domains to the fragment crystallizable (Fc) portion of the human IgG. The resultant molecule is a dimeric, soluble TNF-R that binds both TNF-α and LT-α with high affinity and specificity. The TNF-R domains in etanercept binds to 2 of the receptor binding sites on the TNF to interact with the cell-bound TNF-R a prerequisite for signal transduction. The dimeric structure of etanercept results in a high binding ability for the TNF and thereby inhibits TNF-α induced proinflammatory activity. TNF sTNFR:Fc

Etanercept INDICATIONS: Rheumatoid Arthritis (RA)
Juvenile Idiopathic Arthritis (JIA) Psoriatic Arthritis (PsA) Ankylosing Spondylitis (AS) Plaque Psoriasis FDA APPROVED INDICATIONS: Rheumatoid Arthritis (RA) – To reduce signs and symptoms, induce major clinical response, inhibit the progression of structural damage, and improve physical function in patients with moderately to severely active RA. Etanercept can be initiated in combination with methotrexate (MTX) or used alone.  Juvenile Idiopathic Arthritis (JIA) – To reduce signs and symptoms of moderately to severely active polyarticular-course JRA in patients ages 2 and older.  Psoriatic Arthritis – To reduce signs and symptoms, inhibit the progression of structural damage of active arthritis, and improve physical function in patients with Psoriatic Arthritis. Etanercept can be used in combination with methotrexate in patients who do not respond adequately to MTX alone.  Ankylosing Spondylitis – To reduce signs and symptoms in patients with active Ankylosing Spondylitis.  Plaque Psoriasis – Treatment of adult patients (18 years or older) with chronic moderate to severe Plaque Psoriasis who are candidates for systemic therapy or phototherapy. ENBREL® Package Insert

Characteristics Etanercept1 Structure Human fusion protein receptor
Administration 25 mg SC biweekly JIA 0.4 mg/kg SC biweekly Half-life 3 to 4.8 days Fixes complement (in vitro) No Lyses TNF-expressing cells (in vitro) Antibodies < 5% (non-neutralizing) Etanercept: SQ, mean peak duration of approximately 50 hrs after single dose of 25mg; Ig structures affords a half life days. Self administered subQ injection twice weekly. Recent study the efficacy of 50mg SQ weekly is comparable Infliximab: ENBREL® Package Insert

Most common side effects
Etanercept Most common side effects Injection site reactions (redness, rash, swelling, itching, or bruising) 37 % Sinus infection 35% Headache 17% Runny nose 12% In these studies, the side effects occurring in a group of people taking the drug were documented and compared to the side effects that occurred in a similar group of people not taking the medicine. As a result, it is possible to see what side effects occur, how often they appear, and how they compare to the group not taking the medicine. Based on these studies, the most common side effects of Enbrel include: * Injection site reactions (redness, rash, swelling, itching, or bruising) -- in up to 37 percent of people * Infections such as the common cold or a sinus infection -- up to 35 percent * Headaches -- up to 17 percent * Irritated or runny nose -- up to 12 percent * Dizziness -- up to 7 percent * Sore throat -- up to 7 percent * Cough -- up to 6 percent * General weakness -- up to 5 percent * Abdominal pain (stomach pain) -- up to 5 percent * Breathing problems -- up to 5 percent * Heartburn -- up to 4 percent * Vomiting -- up to 3 percent * Mouth ulcers (canker sores) -- up to 2 percent. The following heart or blood vessel problems were reported in less than 1.5 percent of people taking Enbrel: * Congestive heart failure * Heart attack * High blood pressure (hypertension) * Low blood pressure (hypotension) * Blood clot deep in a leg vein (known medically as deep vein thrombosis or DVT). ENBREL® Package Insert

Infliximab Adalimumab Mouse Human IgG1 Human IgG1 Ximab- chimeric
Umab- human monoclonal antibody

Infliximab/Adalimumab Mode of Action
Activated M f Target Cell Signal TNF TNFR Infliximab neutralizes the biologic activity of TNF-α by binding with high affinity to the soluble and transmembrane forms of TNF-a, and it inhibits binding of TNF-a with the receptors. Adalimumab neutralizes the biologic activity of TNF-a by binding with high affinity to the soluble and transmembrane forms of TNF-a and inhibiting the TNF-a receptors.

Characteristics Infliximab1 Adalimumab2 Structure
Chimeric MAb (mouse/human) Human MAb Administration 3 –10 mg/kg Q 4-8 weeks intravenous 40 mg q 1 to 2 wks; MTX not allowed when given 1/wk Half-life 8 to 9.5 days 10-14 days Fixes complement (in vitro) Yes Yes2 Lyses TNF-expressing cells (in vitro) Antibodies 13% (HACA) 1-12% antibodies; 5% neutralizing Etanercept: SQ, mean peak duration of approximately 50 hrs after single dose of 25mg; Ig structures affords a half life days. Self administered subQ injection twice weekly. Recent study the efficacy of 50mg SQ weekly is comparable Infliximab: Remicade ® Package Insert 2. HumiraTM Package Insert

Infliximab/Adalimumab*
INDICATIONS: Rheumatoid Arthritis (RA) * Juvenile Idiopathic Arthritis (JIA)* Psoriatic Arthritis (PsA)* Ankylosing Spondylitis (AS)* Plaque Psoriasis* Crohn’s Disease* Ulcerative Colitis Infliximab is used to help reduce the symptoms associated with inflammatory conditions that affect the joints, skin, or digestive system. Conditions that it is used to treat include rheumatoid arthritis, Crohn's disease, ankylosing spondylitis, and plaque psoriasis. The medication comes in the form of an injection that is administered through an intravenous line at your healthcare provider's office. Potential side effects of Remicade include headaches, anemia, and coughing

Dosages Remicade ® Package Insert 2. HumiraTM Package Insert
Infliximab1 Adalimumab2 Rheumatoid Arthritis 5mg/kg 0,2,6, then Q 8 weeks IV (may increase to 10mg) 40 mg q 1 to 2 wks; MTX not allowed when given 1/wk Ankylosing Spondylitis 5 mg/kg 0,2,6 then Q 6 weeks Psoriatic Arthritis 0,2,6, then Q 8 weeks Plaque Psoriasis 80 mg then 40mg Q 2 wks starting the week after the 1st dose Crohn’s Disease May increase to 10mg) 160 mg for the first dose (taken as four separate injections over one or two days), 80 mg two weeks later, then 40 mg Q other wk. Ulerative Colitis JIA 33 to 66 pounds- 20 mg Q other wk. 66 pounds or heavier-40 mg Q other wk. Etanercept: SQ, mean peak duration of approximately 50 hrs after single dose of 25mg; Ig structures affords a half life days. Self administered subQ injection twice weekly. Recent study the efficacy of 50mg SQ weekly is comparable Infliximab: Remicade ® Package Insert 2. HumiraTM Package Insert

Drug Interactions Abatacept Anakinra Azathioprine Etanercept
"Live" vaccinations Mercaptopurine Tocilizumab * Abatacept (Orencia®) * Anakinra (Kineret®) * Azathioprine (Azasan®, Imuran®) * Etanercept (Enbrel®) * "Live" vaccinations, including: Chickenpox vaccine (varicella vaccine); FluMist® (the nasal vaccine for influenza; the injected vaccine is not live); MMR vaccine (measles, mumps, rubella vaccine); Polio vaccine; Rotavirus vaccine; Smallpox vaccine; Yellow fever vaccine; BCG vaccine (used in some countries for tuberculosis) * Mercaptopurine (Purinethol®) * Tocilizumab (Actemra®). Interactions With Remicade Explained The following sections explain in detail the potentially negative interactions that can occur when Remicade is combined with any of the drugs listed above. Abatacept Taking Remicade with abatacept can increase your risk of infection. In general, these two medications should not be taken together. Anakinra Taking Remicade with anakinra can increase your risk of infection. In general, these two medications should not be taken together. Azathioprine There have been reports of a very aggressive and fatal form of cancer known as hepatosplenic T-cell lymphoma in people who took Remicade with azathioprine, especially in young males being treated for Crohn's disease or ulcerative colitis. Etanercept Combining Remicade with etanercept can increase your risk of infection. In general, these two medications should not be taken together.

Toxicity: in Clinical Trials
Etanercept Infliximab Injection site reaction in 35% Rate of infections < MTX Serious infections Malignancy as per normal Haematological sfx < MTX No SLE/demyelination No neutralising antibodies Anaphylaxis/infusion reaction Rate of infections ~MTX Serious infections Malignancy as per normal Haematological sfx ~MTX No SLE/demyelination Autoantibodies Infection in study: has more propensity to the URTI

Toxicity: Real Life Infliximab Etanercept Rate of infections > MTX
Injection site reaction in 35% Rate of infections > MTX Conventional bacterial, TB No dose adjustment Malignancy? Haematological sx ~ MTX No neutralising antibodies Anaphylaxis/infusion reaction Rate of infections > MTX Frequency of TB etc Dose adjustment Malignancy? Haematological sx ~MTX Autoantibodies; lupus-like syndrome

Absolute Contraindications
ONGOING INFECTIONS: pneumonia, cellulitis, sepsis, skin ulceration, UTI and abscess TUBERCULOSIS (screen patients with PPD and CXR)

Philippine Guidelines on the Screening for TB prior to the use of Biologic Agents
Recommendations 1. Patients for biologic therapy should be screened for latent and active TB prior to initiating tx 2. . All patients who are candidates for biologic agents should be screened by tuberculin skin test TB, a chest radiograph for active TB 3. . Household and close contacts of candidate patients should be screened for active TB 4. All household and close contacts of candidate patients should be screened for active TB using CXR 5. Treat latent and active TB according to local guidelines 6. Delay tx with biologic agents in patients with latent and active TB 7. Administer TB prophylaxis to the patient for biologic therapy exposed to household contacts with active TB JJ Lichauco, S. Tanke Torres, S. Navarra, L. Dans Philippine guidelines on the screening for TB prior to the use of biologic agents APLAR J of Rheumatol 2006; 9:

Full diagnostic work up?
EVALUATE PATIENT History and PE EVALUATE CONTACTS Hx and PE CXR (PA/APL view) CXR (PA/APL view) Perform TST Currently active TB? <8mm >8mm NO YES Interpret according to risk of latent TB infection and/or state of immunosuppression 1. Multidrug TB tx 2. Provide TB prophylaxis to candidate patient for biologic tx Active TB ? Full diagnostic work up? Philippine guidelines on the screening for TB prior to the use of biologic agents NEGATIVE POSITIVE NO YES Proceed with anti TNF tx but with awareness of: 1. non-specific TB manifestations 2. Extrapulmonary TB 1. Tx latent TB infection 2. Delay TNF blockade 1. Multidrug TB tx 2. Postpone anti-TNF tx until TB therapy is completed

Safety Issues with Biologic
Serious infections Opportunistic infection Malignancies Demyelination Congestive heart failure Autoantibodies and lupus-like syndrome Administration reactions Long-Term Safety of Biologic Therapies Rheumatologists are concerned relative to the long-term safety of biologic agents and our new aggressive therapy. I have tried to gather some postmarketing surveillance, as well as data from clinical trials, available on these agents. As we look at therapies and we look at safety issues with biologic therapies, I think we've learned very clearly that the sources of the safety data that we're looking at are very important in trying to identify how those issues may affect our patients and the patients that we're treating with these drugs. Clearly, the cleanest safety evidence that we get comes from the placebo-controlled trials, where you have a population of patients who are receiving the drugs and a comparable population of patients who are being treated with placebo so that you have a good comparison. If there are adverse events, you presume to know that they are coming from the drug in question and not a random event. On the other hand, the placebo-controlled trials that we have are relatively short in duration and they include a relatively small number of patients so they don't give us information on more rare safety events, which, frankly, are the events that are probably of more concern with these drugs, particularly infections, which don't come up every day. That's where the postmarketing data have become very useful. What we're learning from registries, such as the registries that Dr. Van Vollenhoven has in Sweden, the ones in the US -- the Corona registry, for instance -- these long-term follow-ups will give us information on safety issues over time. In a registry, we're able to actually look at patients on drug and a comparable group of patients who aren't receiving that drug. Though they're not randomized and it's not quite as clean as a placebo-controlled trial, at least you have a comparison group. The other source of safety data that we use for signals are the postmarketing reporting systems of the FDA, for example, in which adverse events are reported to the FDA. The problem there is that there's no sense of comparison. We get a signal of events, but we may not know what the true denominator is; we may not know how many patients were actually treated with the drug and what the real risk of that event is, so we don't have a good comparison tool. In the end, we get our early signals from the placebo-controlled trials. We get some signals from the postmarketing reporting system or anecdotal case reports. But we're going to get our best sources of safety data, which we've learned very clearly, from ongoing registries. What we found is that we have pretty good data now on the TNF antagonists. We have limited data on the newer agents because there just isn't that much postmarketing experience; so we're working off clinical trial data that's just a relatively limited dataset. When we look at the data that we have out there, when we look at the types of safety issues that we're concerned about, it's interesting that it's largely the same issues we worried about from day one when these studies were published with the original placebo-controlled trials. Frankly, even before the studies came out, these were the sorts of things we knew we were likely to be worried about. Infections -- both bacterial infections and opportunistic and atypical infections with the TNF antagonists -- have been and continue to be a concern. I think that as more of the registry data come in, it's clear that it's perhaps not as much of a concern as we originally worried, though it's real. We're learning from some of these data, and some of these registries, ways in which we can modify some of these events. Screening for tuberculosis, for instance, has made a tremendous impact in reducing the risk for TB when being treated with these drugs. The other concern that we had from day one was malignancies. Very early on, there was a potential signal of an increase in lymphoma with TNF antagonists. In some of the early postmarketing reports, we saw increase in the risk for lymphoma. In the clinical trials, we actually saw more lymphomas than we thought we would see in a background population. The problem is, maybe we weren't comparing those to the right population. Now, as we've looked at registries, interestingly, I think the concern for that risk has dropped over time. Most of the registries show that if there is indeed a risk for lymphoma, it's probably very small and not a tremendously high increased risk over the background risks that already come from the rheumatoid arthritis itself. Other malignancies, by and large, have not turned up (both in trials and in the registries) to be of any tremendous concern with these agents, with the one probable exception of skin cancers; not melanomas, but skin cancers, which are obviously a risk. We've learned more from both the studies and the registries about the risk for demyelinating disease and congestive heart failure. Again, early concerns probably suggest that these are issues, but not as large issues as we might have worried that they would have been up front. Other issues, like autoimmune reactions, autoantibody reactions, and infusion reactions, are real, but probably smaller issues with these agents. In sum, I think from the safety data that we have, we've learned signals from the clinical trials -- some of the same signals coming up in early postmarketing reports, but ongoing registries which have informed us about those signals and the real risk in clinical practice, which probably turns out to be lower than we might have worried about up front, although still real.

Other Considerations Monitoring during Anti-TNF- α Therapy
CBC Sign of demyelinating disease and malignancy Pregnancy and breast feeding Not recommended during pregnancy Relative rates of live births, miscarriages, and therapeutic termination were relatively comparable to healthy women Not also use in nursing mothers Anti-TNF- α therapy for other diseases Assessed its used in JIA, psoriasis, PsA, ankylosing spondylitis and Wegener’s Granulomatosis Open-labeled study: use in Bechet’s Syndrome, Still’s dse, uveitis, Scleroderma, Sjogren’s syndrome, sarcoidosis,pyoderma granulomatosum, and polymyositis or dermatomyositis Monitoring: required because of rare occurrences of myelosuppression and concern about the risk of infections…

Interleukin-1 Receptor Antagonist
Anakinra

Interleukin 1 Members of the super family include IL-1α, IL-1ß, and the IL-1 receptor antagonist (IL-1Ra). IL-1α and IL-1ß are synthesized as leader peptides. The molecular weight of each precursor is 31 kDa. Specific cellular proteases process IL-1α and IL-1ß to their 17 kDa mature forms. IL-1 produced by rheumatoid synovium and other tissues, predominantly by macrophages.

Targets interleukin-1 (IL-1) Another type of immune factor MOA:
IL-1Ra (Anakinra) Approved in 2002 Targets interleukin-1 (IL-1) Another type of immune factor MOA: blocks the activity of IL-1 by competitively inhibiting IL-1 binding to the IL-1RI receptor Anakira (IL-1ra) is a recombinant nonglycosylated homologue of IL-1Ra that differs from the native human IL-1Ra by the addition of a single methionine residue at its amino terminus. Levels of the naturally occurring IL-1Ra, which are elevated in the synovium and synovial fluid from RA patients, appear to be insufficient with the excess amount of locally produced IL-1. Kineret® (anakinra) is a recombinant, nonglycosylated form of the human interleukin-1 receptor antagonist (IL-1Ra). Kineret® (anakinra) differs from native human IL-1Ra in that it has the addition of a single methionine residue at its amino terminus. Kineret® (anakinra) consists of 153 amino acids and has a molecular weight of 17.3 kilodaltons. It is produced by recombinant DNA technology using an E colibacterial expression system.

Interleukin-1Ra (Anakinra)
IL-1Ra is the endogenous receptor antagonist inhibiting IL-1-mediated effects. IL-1Ra competitively inhibits the binding of IL-1 to the IL-1 receptor. IL-1Ra is the most important physiological regulator of synovial IL-1 activity. RA patients show an imbalance between IL-1 and IL-1Ra levels. In RA, IL-1 levels can not be sufficiently countered by endogenous IL-1Ra10,11 The active ingredient of Kineret® (anakinra) is the first recombinant form of the naturally occurring human IL-1Ra.

Anakinra Human recombinant anti-IL-1 receptor antagonist
Daily 100mg subcutaneous injection ACR 20 response rates were only 38% Modest reductions in radiographic progression of joint disease Clinical benefits of anakinra are less than those of the TNF blockers Limited to selective patients with refractory disease Anakinra is a human recombinant anti-IL-1 receptor antagonist approved for the treatment of RA, administered as daily 100mg subcutaneous injection and has been shown to improve the signs and symptoms of RA. However, in a randomized, controlled trial the ACR 20 response rates were only 38%. Modest reductions in radiographic progression of joint disease were also compared to controls. Overall, the clinical benefits of anakinra are less than those of the TNF blockers. For this reason the use of anakinra in RA has been limited to selective patients with refractory disease

We have the tumor necrosis factor (TNF) antagonist, the soluble receptor, etanercept, the monoclonal antibody infliximab, and, as of yesterday, approved by the Food and Drug Administration (FDA), the interleukin-1 receptor antagonist (IL-1ra) anakinra as available anti-cytokine biologic agents. These biologic agents are somewhat different. Their half-lives 7 to 8 hours with anakinra. Anakinra is a Type 1 IL receptor target. The construct is human in the case of etanercept and anakinra. Human and part mouse construct in the case of infliximab. Does not fix complement .Does this determine any problems with safety? We don't know, but there is some thought about that. Anakinra is a daily subcutaneous injection.

Interleukin-6 Receptor Antagonist
Tocilizumab

IL-6 Elevated IL-6 plays a central role in RA: Produced by a range of cells (macrophages, fibroblasts, T cells and B cells Induction of auto-antibodies Induction of acute-phase proteins; Activation of osteoclast Suppression of T-regulatory cells thereby activating T cell Maturation of megakaryocytes leads to thrombocytosis Expression induced by a variety of inflammatory factors, including TNF-alpha, IIL-1B and IL-175

IL-6 Receptor Antagonist (Tocilizumab)
Humanised anti-IL-6 receptor antibody Indication: Moderate to severe active rheumatoid arthritis who have had an inadequate response to one or more TNF antagonist therapies. ACTEMRA (tocilizumab) is a recombinant humanized anti-human interleukin 6 (IL-6) receptor monoclonal antibody of the immunoglobulin IgG1κ (gamma 1, kappa) subclass with a typical H2L2 polypeptide structure. Each light chain and heavy chain consists of 214 and 448 amino acids, respectively. The four polypeptide chains are linked intra- and inter-molecularly by disulfide bonds. ACTEMRA (tocilizumab injection) has a molecular weight of approximately 148 kDa.

IL-6 Receptor Antagonist
IL-6 has a pivotal role in cell signalling and is associated with diverse physiological effects that contribute to the system-wide pathogenesis of RA . ACTEMRA/RoACTEMRA binds both soluble and membrane-bound IL-6 receptors (sIL-6R and mIL-6R) which inhibits IL=6 binding to its receptor blocking IL-6 signalling and gene activation ( thereby preventing the signalling associated with IL-6 binding to its receptor.)

Tocilizumab Given IV Monotherapy or concomitantly with mtx or other DMARDs Recommended dose: Starting dose: 4mg/kg followed by an increase to 8mg/kg once every 4 weeks as a 60-minute single intravenous drip infusion Given IVACTEMRA (tocilizumab injection) may be used as monotherapy or concomitantly with methotrexate or other DMARDs. The recommended dose of ACTEMRA (tocilizumab injection) for adult patients given once every 4 weeks as a 60-minute single intravenous drip infusion is: Recommended Adult Dosage Every 4 Weeks Patients who have had an inadequate response to one or more TNF antagonists When used in combination with DMARDs or as monotherapy the recommended starting dose is 4 mg/kg followed by an increase to 8 mg/kg based on clinical respons

Frequently reported AE’s
URTI Headache Nasopharyngitis RA worsening ALT increase

Adverse events Infusions generally well tolerated
Low incidence of adverse GI events (1 peridiverticular abscess, 1 gastroenteritis) Transient ALT elevation- no evidence of clinical hepatitis or hepatic failure Lipid levels initially increased and subsequently stabilized at the upper level of normal-no relevant change in atherogenic risk index Slight increase in infections (including serious infections) over placebo- no occurrence of TB Adverse events: consistent with those seen in previous studies

B Cell Targeted Therapies
Rituximab Belimumab

B cells Produce antibodies against target antigens
Present antigen to T lymphocytes Produce cytokines that support mononuclear cells Regulate and organize inflammatory response Direct infiltration of end organs (kidneys and joints) Ref: B cells in autoimmunity ; J of Exp Medicine

(D20 is a pan B cell surface glycoprotein
(D20 is a pan B cell surface glycoprotein .Initiation and differentiation of B cells.First expressed in early pre B cell stage remains until differentiation into plasma cell. Plasma cells do not express CD 20). CD20 is expressed in almost all the B cells with 2 major exceptions; the very early stage, or the pro-B cells, and the plasma cells. All the other B-cell compartments are targeted if you apply anti-CD20 antibody. Since CD20 is not expressed on other cells in the body, it is a very unique therapy that does not target other cells.

Rituximab Anti-CD20 Chimeric murine/human monoclonal antibody
Indication: Moderately- to severely- active rheumatoid arthritis who have had an inadequate response to one or more TNF antagonist therapies In combination with methotrexate Novel genetically engineered anti-CD20 therapeutic monoclonal antibody that selectively targets CD20+ B cells. Variable light and heavy chain regions from murine model. It was originally developed as therapy for B cell malignancies and selectively depletes B cells. Observation was made by Protheroe and colleagues in They treated a patient with RA, who had developed a B-cell non-Hodgkin's lymphoma, with an anti-CD20 antibody and observed a remission of the inflammatory arthropathy. Subsequently, the clinical development of anti-CD20 was initiated. This also was confirmed by Stewart and colleagues in another study. The patients with RA, and especially the patients with high disease activity, have a higher risk of developing B-cell non-Hodgkin's lymphoma. This, once again, indicates that the B cell plays a very important role, at least in patients with very severe disease activity. Predominantly by antibody dependent and complement dependent cell lysis No action on lymphoid stem cells and plasma cells Long serum half-life

It is a very effective depleter of peripheral B cells
It is a very effective depleter of peripheral B cells. It is believed to do this by 3 different mechanisms, but the predominant mechanism is felt to be antibody-dependent, cellular-mediated cytotoxicity (ADCC). It is shown here in this cartoon with the anti-CD20 antibody (in green) attaching to CD20 and the Fc portion of the molecule attaching to the Fc-gamma receptor, leading to ADCC. Complement-dependent cytotoxicity also is believed to play a role, as is apoptosis. What do B cells do? The "raison d'etre" for B cells is that they recognize antigen and make antibodies to it. They do have other activities. They have a costimulatory function -- they secrete cytokines -- and the ultimate result of all that is infections, serious infections. Any time we do a poster, we are going to ask, what is the infection rate? What is the serious infection rate? Just as we do for any therapy, we are going to do that for B-cell directed therapies -- maybe with an eye toward those types of infections that we would think might be expected, based on inhibiting the humoral immune response, and we will come back to that in a second. It is a surrogate marker. What about vaccine responses? It is always important to us; it is important to our patients. It is a good thing; it is a tangible thing that we can do for our patients, so we like to do it. It is important to know what that is going to do. Agent-related types of considerations in adverse events will be different -- different from agent to agent, different from construct to construct, even for those who have, perhaps, the same proximate target. So, those may relate to the agent itself, in the ways that it is administered. We have a fair amount of data with rituximab; as you will see, there are the most data with that, certainly far more than with any other B-cell directed therapy. We will use that as our paradigm and consider where other therapies differ from this in the future. With regard to infusion reactions, a lot of us have heard this or learned this, if we have had the experience or the ability to use this in our practices. Most infusion reactions are seen on the first infusion; they tend to be less over time. With subsequent courses, reactions can be mild to severe. One of the things that we will cover is that infusion reactions tend to be a little bit more severe in the patients with the cancers, such as non-Hodgkin's lymphoma, than they seem to be in our patients with rheumatic disease. There is less frequency and less severity, which is certainly a good thing. Immunogenicity is too hard to speak about from a safety standpoint, because we just do not know much. We do have information on the prevalence of human antichimeric antibodies (HACAs), which is about 1% in non-Hodgkin's lymphoma studies. Remember, in those studies, patients also are getting pretty serious concomitant immunosuppressive medication. The prevalence of HACAs varies in rheumatoid arthritis studies from about 4% to 12%, but we still do not know all the implications. What is the clinical relevance of these antibodies to the treating agent, from a safety standpoint? We are watching that and we want to know, but right now we just do not know. Figure 2: Mechanism of action of abatacept and rituximab APC=antigen presenting cell; MHC=major histocompatibility complex; TCR=T-cell receptor; ADCC=antibody-dependent cell-mediated cytotoxicity; NK=natural killer. Abatacept is a soluble, fully-human fusion protein, consisting of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen-4, linked to the modified Fc (hinge, CH2 and CH3 domains) portion of human immunoglobulin GI (IgG1). Abatacept modulates the full activation of T cells, an event that occurs early in the immune cascade, which, if unopposed, may lead to the progressive inflammatory and destructive changes characteristic of RA (30). T cells require an antigen-specific and a co-stimulatory signal (of which there are several) in order to become fully activated (30,31,32,33). The engagement of CD80/CD86 on antigen presenting cells (APCs) with CD28 on T cells is the best characterized of the co-stimulatory pathways (30,34,35). By competitively binding to CD80/CD86 on APCs, abatacept prevents their interaction with CD28 on T cells (34) (Figure 2), inhibiting the full activation of T cells, and thereby suppressing multiple downstream events in the immunopathology of RA. These include a dampening of B-cell activation and its consequent auto-antibody formation and B-cell cytokine release, as well as the inhibition of macrophage activation, thereby preventing the production of TNF-α, IL-6 and other pro-inflammatory mediators

It is a very effective depleter of peripheral B cells
It is a very effective depleter of peripheral B cells. It is believed to do this by 3 different mechanisms, but the predominant mechanism is felt to be antibody-dependent, cellular-mediated cytotoxicity (ADCC). It is shown here in this cartoon with the anti-CD20 antibody (in green) attaching to CD20 and the Fc portion of the molecule attaching to the Fc-gamma receptor, leading to ADCC. Complement-dependent cytotoxicity also is believed to play a role, as is apoptosis. What do B cells do? The "raison d'etre" for B cells is that they recognize antigen and make antibodies to it. They do have other activities. They have a costimulatory function -- they secrete cytokines -- and the ultimate result of all that is infections, serious infections. Any time we do a poster, we are going to ask, what is the infection rate? What is the serious infection rate? Just as we do for any therapy, we are going to do that for B-cell directed therapies -- maybe with an eye toward those types of infections that we would think might be expected, based on inhibiting the humoral immune response, and we will come back to that in a second. It is a surrogate marker. What about vaccine responses? It is always important to us; it is important to our patients. It is a good thing; it is a tangible thing that we can do for our patients, so we like to do it. It is important to know what that is going to do. Agent-related types of considerations in adverse events will be different -- different from agent to agent, different from construct to construct, even for those who have, perhaps, the same proximate target. So, those may relate to the agent itself, in the ways that it is administered. We have a fair amount of data with rituximab; as you will see, there are the most data with that, certainly far more than with any other B-cell directed therapy. We will use that as our paradigm and consider where other therapies differ from this in the future. With regard to infusion reactions, a lot of us have heard this or learned this, if we have had the experience or the ability to use this in our practices. Most infusion reactions are seen on the first infusion; they tend to be less over time. With subsequent courses, reactions can be mild to severe. One of the things that we will cover is that infusion reactions tend to be a little bit more severe in the patients with the cancers, such as non-Hodgkin's lymphoma, than they seem to be in our patients with rheumatic disease. There is less frequency and less severity, which is certainly a good thing. Immunogenicity is too hard to speak about from a safety standpoint, because we just do not know much. We do have information on the prevalence of human antichimeric antibodies (HACAs), which is about 1% in non-Hodgkin's lymphoma studies. Remember, in those studies, patients also are getting pretty serious concomitant immunosuppressive medication. The prevalence of HACAs varies in rheumatoid arthritis studies from about 4% to 12%, but we still do not know all the implications. What is the clinical relevance of these antibodies to the treating agent, from a safety standpoint? We are watching that and we want to know, but right now we just do not know.

Recommended Dose for Rheumatoid Arthritis (RA)
Administer as two-1000 mg intravenous infusions separated by 2 weeks. Glucocorticoids administered as methylprednisolone 100 mg intravenous or its equivalent 30 minutes prior to each infusion are recommended to reduce the incidence and severity of infusion reactions. Subsequent courses should be administered every 24 weeks or based on clinical evaluation, but not sooner than every 16 weeks. Given in combination with methotrexate. Premedicate before each infusion with acetaminophen and an antihistamine

There is another mechanism that I want to draw your attention to; these are T-cell independent B-cell-activation processes. Our immunologic textbooks tell us that most of the B-cell activation is derived by T-cell dependency; in the last few years, we have made some progress. One of the important issues here is that, by using a certain molecule path -- or B-cell activating factor (BAFF)/B lymphocyte stimulator protein (BLyS) -- by using 3 different receptors on the surface of expressed B cells, this can lead to the activation of B cells, further contributing to a continuous autoimmune antibody-mediated inflammation in the affected tissues. The third mechanism for how B cells can get activated in the absence of T cells, is using the Toll-like receptors (TLRs), very primitive receptors (also called pathogen-associated molecular pattern receptors, or pattern recognition receptors). These receptors are expressed on almost all of our body's cells in different settings. For the B cells, the most important ones are TLR7 and TLR8, as well as TLR9, as you can see here. The natural ligand leading to the activation of the cells is bacterial DNA, leading to an NF-kappa-B-dependent activation of these cells, and to the release of proinflammatory cytokines and chemokines of these cells.

Belimumab (Benlysta) Human monoclonal antibody that recognizes and inhibits the biological activity of B-lymphocyte stimulator (Blys) FDA approved the use in March 9, 2011 First drug approved for the treatment of lupus in 56 years . Belimumab is a monoclonal antibody directed against BLyS, a B-cell survival factor. The neutralization of BLyS results in increased programmed cell death (apoptosis) of B cells and decreased B-cell survival. As a result, B-cell production of autoantibodies is reduced and thereby autoantibody deposition and immune complex deposition in organs are also reduced, leading to reduced disease activity.

Belimumab (Benlysta) Indication:
Active, antibody-positive SLE who are receiving other treatments for SLE Recommended dose: 10 mg/kg at two-week intervals for the first three doses and at four-week intervals thereafter, administered intravenously over a one-hour period.

Other Biologics: No Human Trial
Adhesion Molecule Chemokines IL-8; ENA-78; CTAP-III; MCP-1 Inflammatory cells B cells T cells Fibroblast – like synoviocytes Trimolecular complex of T cell Receptor-Antigen-MHC Costimulatory Molecules Chemokines: IL-8 interleukin-8…. ENA-78 epithelial neutrophil activating protein-78…. CTAP-III Connective Tissue Activating Protein-III…. MCP-1 monocyte chemoattractant protein-1

Quote of the Day "Continuous attention span, or the amount of time a human can focus on an object without any lapse at all, is very brief and may be as short as 8 seconds. “ “After this amount of time, it is likely that an individual's eyes will shift focus, or that a stray thought will briefly enter consciousness."

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Other Biologics Abatacept (Orencia)
Tocilizumab (Actemra) AMG-714 HuMax-CD20 Belimumab (Lymphostat-B) Golimumab (CNTO 148) > T-cell co-stimulator modulator > IL-6 receptor > IL-15 receptor > regulates CD20 B cell activity > B cell depletion > tumor necrosis factor alpha Abatacept (Orencia) Approved in 2005 for adults with moderate-to-severe RA who have not responded to DMARD or anti-TNF drugs and known as a T cell co-stimulation modulator and blocks T cell activation Used alone or in combination with other DMARDs aside from anti-TNF drugs Belimumab (Lymphostat-B) also focuses on B cell depletion. The drug is in Phase II trials and is also being investigated for treatment of lupus. Golimumab (CNTO 148) targets tumor necrosis factor alpha. It is currently in Phase III trials. In a Phase II trial, 62% of patients treated with golimumab and methotrexate experienced at least 20% improvement in RA symptoms, and 27% achieved remission Tocilizumab (Actemra) targets the IL-6 receptor. In Phase III trials, the drug worked better than DMARDs in slowing joint destruction. It has also shown promise in Phase III trials for systemic juvenile arthritis. AMG-714 is a monoclonal antibody that targets the IL-15 receptor. In a Phase II/III trial of patients who had not responded to DMARD treatment, AMG-714 reduced disease symptoms. HuMax-CD20, like rituximab, regulates CD20 B cell activity. It is currently in Phase II trials.

No. of Studies Selecteda
Active Biologic Therapy by Drug Class FDA Approval Date2 No. of Studies Selecteda B-cell depletor Rituximab November 26, 1997 1 IL-1 receptor antagonist Anakinra November 14, 2001 3 Costimulatory blocker Abatacept December 23, 2005 Tumor necrosis factor-α antagonist Infliximab August 24, 1998 4 Etanercept November 2, 1998 5 Adalimumab December 31, 2002 6 Certolizumab April 22, 2008 Golimumab April 24, 2009 IL-6 receptor antagonist Tocilizumab January 8, 2010

We have the tumor necrosis factor (TNF) antagonist, the soluble receptor, etanercept, the monoclonal antibody infliximab, and, as of yesterday, approved by the Food and Drug Administration (FDA), the interleukin-1 receptor antagonist (IL-1ra) anakinra as available anti-cytokine biologic agents. These biologic agents are somewhat different. Their half-lives 7 to 8 hours with anakinra. Anakinra is a Type 1 IL receptor target. The construct is human in the case of etanercept and anakinra. Human and part mouse construct in the case of infliximab. Does not fix complement .Does this determine any problems with safety? We don't know, but there is some thought about that. Anakinra is a daily subcutaneous injection.

Clinical Study P: treatment of active RA (24wks)
I: 30mg, 75mg, 150mg, and placebo : extension of 55weeks (placebo grp) O: ACR 20 Radiographic changes: decrease in the rate of progressive joint damage M: 24 week placebo control study P: RA patients I: Anakinra + MTX vs (0; 0.04; 0.1; 1.0; 2.0 mg/kg) MTX alone O: ACR 20 response 24wks - 42% (optimum dose MTX) - 23% (placebo + MTX) P: 24 wk randomized, double-blind placebo controlled study

Rituximab (Mabthera) Approved in 2006
Targets CD20-positive B cells and blocks their activation Used in combination with methotrexate for patients with moderate-to-severe RA who have not responded to anti-TNF therapies.

Toxicity and Monitoring
Signs & symptoms of infection Neutrophils counts at baseline and monthly for 3mos and every 4 mos up to 1 yr Pregnancy & breastfeeding: Used only if it is clearly needed and discontinued in nursing mothers Injection site reaction (ISR): mild and transient Infections: cellulitis; pneumonia and bone & joint infection Headache Nausea; Diarrhea; abdominal pain Sinusitis; Influenza like syndrome Malignancy

If you go then into the pathogenic roles of B cells in RA -- and more or less we can generalize this to other autoimmune diseases -- we can identify or differentiate at least 4 different processes or specific roles for how the B cells are involved in the immunopathogenesis. On the one hand, B cells also are producers of proinflammatory cytokines, like tumor necrosis factor (TNF)-alpha, interleukin (IL)-6. Producing TNF-alpha, via the B cells, can activate macrophages and then amplify the proinflammatory signal, resulting in enhanced production of IL-1, IL-6 and additional TNF-alpha, contributing to the inflammatory damage. The other very important cytokine produced by B cells is IL-10. It is still under investigation, but we know that this IL-10 is able to activate dendritic cells thereby enhancing the antigen presentation and, with the help of T cells, further allowing the differentiation of B cells into the plasma cells. The B cell also is a very important antigen-presenting cell, as I mentioned earlier. These plasma cells then, differentiating in the synovial membrane, are producing rheumatoid factor and CCP antibodies. We know, in particular, that rheumatoid factor is a very highly complement-activating antibody, contributing also to the inflammatory damage leading to cartilage loss and this synovitis.

There are several potential targets on B cells. Dr
There are several potential targets on B cells. Dr. Dörner mentioned the cluster of differentiation (CD) 20 molecule and the anti-CD20 monoclonal antibody, rituximab. As you know, rituximab has been available for 7 years, for the treatment of non-Hodgkin's lymphoma; over 700,000 patients have received this treatment, and it is undergoing intensive investigation presently. We will go through the clinical trial data that have been presented in the public domain to date. Belimumab is a fully human monoclonal antibody to the B-lymphocyte stimulator (BLyS) protein. The first study presented in a peer-reviewed setting was recently reported, and I will present some of that information. The anti-CD22 monoclonal antibody, epratuzumab, has been looked at, and is still being looked at, in systemic lupus erythematosis (SLE) and Sjögren's syndrome; we do not really have data in the public domain for rheumatoid arthritis (RA). There are studies ongoing with the BLyS-receptor fusion proteins. Dr. Dörner mentioned the receptors for BLyS (TACI-Ig, Br3); they are fusion proteins that have been developed and are undergoing preclinical investigation. A poster was presented recently looking at animal data with TACI-Ig, and there is some Phase I work ongoing with the Br3 fusion protein. CD20 is not expressed on stem cells, early pre-B cells, dendritic cells, or plasma cells. It is a B cell-lineage antigen, and it does not rapidly modulate upon binding anti-CD20 antibodies

Rilonacept-IL-1 Trap, is a dimeric fusion protein consisting of the extracellular domain of human interleukin (IL)-1 receptor and the FC domain of human immunoglobulin G-1 (IgG1) that binds and neutralizes IL-1. Rilonacept is currently approved for use in cryopyrin-associated periodic syndromes Cryopyrin-Associated Periodic Syndromes, or CAPS, are a group of rare inherited auto-inflammatory conditions. Signs and symptoms include recurrent rash, fever/chills, joint pain, fatigue, and eye pain/redness. In more severe forms, additional symptoms occur, such as deafness, systemic amyloidosis (protein accumulation in tissues and organs, such as the kidneys), significant central nervous system disabilities, including mental retardation and vision loss, and substantial joint and bone deformities. Three syndromes comprise CAPS: Familial Cold Auto-inflammatory Syndrome (FCAS), (previously termed Familial Cold Urticaria), Muckle-Wells Syndrome (MWS) and Neonatal-Onset Multisystem Inflammatory Disease (NOMID), which also is referred to as Chronic Infantile Neurologic Cutaneous Articular Syndrome (CINCA).

Recombinant DNA biologics
As indicated the term "biologics" can be used to refer to a wide range of biological products in medicine. However, in most cases, the term "biologics" is used more restrictively for a class of medications (either approved or in development) that are produced by means of biological processes involving recombinant DNA technology. These medications are usually one of three types: Substances that are (nearly) identical to the body's own key signalling proteins. Examples are the blood-production stimulating protein erythropoetin, or the growth-stimulating hormone named (simply) "growth hormone" or biosynthetic human insulin and its analogues. Monoclonal antibodies. These are similar to the antibodies that the human immune system uses to fight off bacteria and viruses, but they are "custom-designed" (using hybridoma technology or other methods) and can therefore be made specifically to counteract or block any given substance in the body, or to target any specific cell type; examples of such monoclonal antibodies for use in various diseases are given in the table below. Receptor constructs (fusion proteins), usually based on a naturally-occurring receptor linked to the immunoglobulin frame. In this case, the receptor provides the construct with detailed specificity, whereas the immunoglobulin-structure imparts stability and other useful features in terms of pharmacology. Some examples are listed in the table below.

Tumor necrosis factor-α (TNF-α) is a cytokine central to many aspects of the inflammatory response. Macrophages, mast cells, and activated TH cells (especially TH1 cells) secrete TNF-α. TNF-α stimulates macrophages to produce cytotoxic metabolites, thereby increasing phagocytic killing activity. TNF-α has been implicated in numerous autoimmune diseases. Rheumatoid arthritis, psoriasis, and Crohn’s disease are three disorders in which inhibition of TNF-α has demonstrated therapeutic efficacy. Rheumatoid arthritis illustrates the central role of TNF-α in the pathophysiology of autoimmune diseases. Although the initial stimulus for joint inflammation is still debated, it is thought that macrophages in a diseased joint secrete TNF-α, which activates endothelial cells, other monocytes, and synovial fibroblasts. Activated endothelial cells up-regulate adhesion molecule expression, resulting in recruitment of inflammatory cells to the joint. Monocyte activation has a positive feedback effect on T-cell and synovial fibroblast activation. Activated synovial fibroblasts secrete interleukins, which recruit additional inflammatory cells. With time, the synovium hypertrophies and forms a pannus that leads to destruction of bone and cartilage in the joint, causing the characteristic deformity and pain of rheumatoid arthritis.

Key Actions Attributed to TNF
(VEGF)

Anti TNF agents molecular characteristics
Etanercept (Enbrel): Soluble TNF receptor fusion protein. As you can see in the image, etanercept molecule consists of 2 extracellular domains of human soluble TNF receptor p75 that binds to TNF and a Fc fragment of human IgG that serves as a stabilizer.

Infliximab (Remicade): chimeric human-mouse anti-TNF alpha
Infliximab (Remicade): chimeric human-mouse anti-TNF alpha . This drug is 25% murinal (mouse) derived and 75% human. The binding epitope for TNF is of murine origin while the IgG fragment is of human origin. Adalimumab (HUMIRA- Human Monoclonal Antibody in Rheumatoid Arthritis-): fully human anti-tumor necrosis factor alpha monoclonal antibody produced by phage-display technology.

Newer TNF alpha blockers
Certolizumab pegol (Cimzia): pegylated humanized Fab’ fragment that binds tumor necrosis factor alpha. FDA approved it in April 2008 for the treatment of Crohn’s disease. Golimumab (Simponi). Approved in April 2009 for: moderate-to-severe rheumatoid arthritis, active psoriatic arthritis, and active ankylosing spondylitis.

TNF blockers adverse effects: risks of tuberculosis reactivation and invasive fungal infections
TNF inhibitors have a number of known side effects, mainly related to their immunosuppressant activity. Since TNF is a important cytokine when fighting against tuberculosis, these drugs can reactivate a latent tuberculosis infection. The official FDA presentation below discusses adverse effects associated with TNF blockers: infections (tuberculosis, histoplasmosis and other invasive fungal infections) , congestive heart failure, neurologic events, malignancies and autoimmunity.

Certolizumab- called polyethylene glycol (PEG) is added to the Fab', enabling dosing only once every 4 weeks table dosing Stable serum levels were achieved with no dose escalation in clinical trials2,6* Q4-week subcutaneous dosing2*

A molecule

Schematic of TNF inhibitors and their mode of action. Receptor (i. e
Schematic of TNF inhibitors and their mode of action. Receptor (i.e. etanercept, lenercept) and antibody based (i.e. infliximab, adalimumab, golimumab) anti-TNF biologics inhibit both solTNF and tmTNF. TNF variants (DN-TNFs) exchange with native solTNF monomers to form heterotrimers with drastically reduced abilities to bind TNF receptors, making them selective for solTNF signaling inhibition. Small molecule inhibitors of TNF signaling include minocycline which decreases TNF synthesis, thalidomide which enhances degradation of TNF mRNA, and TACE inhibitors which prevent TACE induced release of solTNF.

ive non-overlapping mechanisms of action are depicted
ive non-overlapping mechanisms of action are depicted. Examples of therapeutic antibodies are listed for each mechanism of action depicted. Ligand blockade with full length IgG therapeutic antibodies (for example, infliximab, adalimumab or golimumab), antibody fragments (for example, certolizumab pegol) or receptor immunoadhesins (for example, etanercept and those indicated with ‡) can prevent ligands from activating their cognate receptors. Binding of ligands (for example, interleukin-6 (IL-6)) to receptors (for example, IL-6R) can also be blocked by antibodies directed to their cognate receptors and inhibit receptor activation or function. Binding of cell surface receptors by antibodies can also result in their internalization and downregulation to limit cell surface receptors that can be activated by the ligand. Note that binding of cell surface receptors by antibodies (for example, αL integrin by efalizumab) or binding of a ligand (for example, free serum IgE by omalizumab) can indirectly also result in downregulation of cell surface receptors available for cellular activation. Binding of cell surface receptors can result in depletion of antigen-bearing cells through complement-mediated lysis and opsonization, as well as Fc receptor for IgG (FcγR)-mediated clearance. Therapeutic antibodies can also induce active signals that alter cellular fates. Binding of the T cell receptor (TCR)–CD3 complex by teplizumab can induce TCR-mediated signals and alter T cell functions and differentiation. MAC, membrane attack complex; TNF, tumour necrosis factor; TNFRI; TNF receptor I. *Antibodies with several mechanisms of action.

TGN1412 (also known as CD28-SuperMAB) is the working name of an immunomodulatory drug which was withdrawn from development after inducing severe inflammatory reactions in the first human subjects to receive the drug. Originally intended for the treatment of B cell chronic lymphocytic leukemia (B-CLL) and rheumatoid arthritis,[1] it is a humanised monoclonal antibody that not only binds to, but is a strong agonist for, the CD28 receptor of the immune system's T cells.[2] CD28 is the co-receptor for the T cell receptor; It binds to receptors on the interacting partner in the reaction through one of its ligands (B7 family).

abatacept

Figure 1. Mechanism of action of biologic therapies in reducing airway inflammation. At bottom of figure: Pathways of cytokine/IgE-induced airway inflammation in asthma. Agents currently in use or in development are illustrated. Red octagon indicates inhibition as mechanism of action. IFN-γ = interferon-gamma; IgE, immunoglobulin E; TGF-β = transforming growth factor-β; TH0 = TH0 cell; TH1 = TH1 cell; TH2 = TH2 cell. Anti-Immunoglobulin E IgE contributes to the pathophysiology of allergic asthma. Omalizumab is a recombinant humanized monoclonal immunoglobulin G1 antibody (Ab) and binds to the Fc portion of free IgE to prevent its attachment to the Fcε receptor of mast cells, basophils, and dendritic cells (Fig 1). This action also decreases circulating IgE, which in turn leads to a downregulation of IgE receptor expression. Approved in 2003, omalizumab was the first biologic agent used in the treatment of asthma.4

Anakinra for RA Orencia® (abatacept) works by reducing the activation of T-cells, which reduces the activation of other cells in the RA inflammatory process. Humera®(adalimumab), Enbrel®( etanercept) and Remicade® (infliximab) block the action of TNF-alpha, an inflammatory cytokine that leads to tissue damage. Mabthera® (rituximab) targets B cells, one of the key players in the pathogenesis of RA. Kineret® (anakinra) blocks the actions of the cytokine, IL-1.

Figure 2: Mechanism of action of abatacept and rituximab
APC=antigen presenting cell; MHC=major histocompatibility complex; TCR=T-cell receptor; ADCC=antibody-dependent cell-mediated cytotoxicity; NK=natural killer. Abatacept is a soluble, fully-human fusion protein, consisting of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen-4, linked to the modified Fc (hinge, CH2 and CH3 domains) portion of human immunoglobulin GI (IgG1). Abatacept modulates the full activation of T cells, an event that occurs early in the immune cascade, which, if unopposed, may lead to the progressive inflammatory and destructive changes characteristic of RA (30). T cells require an antigen-specific and a co-stimulatory signal (of which there are several) in order to become fully activated (30,31,32,33). The engagement of CD80/CD86 on antigen presenting cells (APCs) with CD28 on T cells is the best characterized of the co-stimulatory pathways (30,34,35). By competitively binding to CD80/CD86 on APCs, abatacept prevents their interaction with CD28 on T cells (34) (Figure 2), inhibiting the full activation of T cells, and thereby suppressing multiple downstream events in the immunopathology of RA. These include a dampening of B-cell activation and its consequent auto-antibody formation and B-cell cytokine release, as well as the inhibition of macrophage activation, thereby preventing the production of TNF-α, IL-6 and other pro-inflammatory mediators

Figure 1: Immunopathogenesis of rheumatoid arthritis, depicting the targets of biologic therapies
IL=interleukin; TNF=tumor necrosis factor; RF=rheumatoid factor; IL-6R=interleukin 6 receptor; MMP=matrix metalloprotease. Until recently, available biologic therapies directly targeted pro-inflammatory cytokines generated downstream in the immunopathogenesis of RA. A more comprehensive understanding of the cellular elements involved in RA immunopathology has led to the development and approval of two medications with alternate mechanisms of action – abatacept (ORENCIA®, Bristol-Myers Squibb, Princeton, NJ) (28) and rituximab (RITUXAN®, Genentech Incorporated, San Francisco, CA) (29). Unlike the TNF-α antagonists, abatacept and rituximab target earlier, initiating events in the immune cascade that, ultimately, result in the downregulation of pro-inflammatory cytokines (28,29) (Figure 1). These newer agents act via the depletion of B cells (rituximab) and by the modulation of a necessary second co-stimulatory signal required for full T-cell activation (abatacept). Both agents have demonstrated effective and sustained reductions in rheumatoid disease activity and provide new treatment options for those patients experiencing an inadequate response to TNF-α inhibition.

Cytokines And Biologic Treatment in Arthritis

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