Update on Therapeutic Monoclonal Antibodies

Update on Therapeutic Monoclonal Antibodies James B. Bussel, MD,a Lisa Giulino, MD,a Susan Lee, MD,c Vivek L. Patel, BS,a Christy Sandborg, MD,b and E. Richard Stiehm, MDd

onoclonal antibodies are among the most important class of drugs introduced into the therapeutic armamentarium since the introduction of antimicrobials in the 1930s. The first therapeutic monoclonal antibody, the anti T-cell monoclonal antibody OKT4, was licensed in 1986. Since then, 18 additional antibodies have been licensed in the US, with many more in the pipeline. Before 1986, many monoclonal antibodies were available for laboratory studies, notably to identify specific cells in the blood and tissues. This is best illustrated by the cluster designation (CD) system for antigens present on hematopoietic cells, now numbering over 200.

M

Discovery and Development of Monoclonal Antibodies —E. Richard Stiehm The genesis of monoclonal antibodies was the work of Georges Kohler and Cesar Milstein at Cambridge University in the 1970s. They fused a single antibody-producing cell from the spleen of an immunized mouse with a human myeloma cell to produce an immortal hybrid cell that secreted an antibody to a single antigenic epitope. The antibody-producing spleen cell provided the specificity and the myeloma cell provided the immortality. This antibody-producing hybrid cell could be perpetuated From the aDepartment of Pediatrics, Cornell University School of Medicine, New York, New York; bDepartment of Pediatrics, Stanford University School of Medicine, Stanford, California; and cDepartment of Medicine, the University of California at San Diego, San Diego, California; and dDepartment of Pediatrics, the University of California at Los Angeles, Los Angeles, California. Curr Probl Pediatr Adolesc Health Care 2007;37:118-135 1538-5442/$ - see front matter © 2007 Mosby, Inc. All rights reserved. doi:10.1016/j.cppeds.2007.02.001

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indefinitely in tissue culture. Their report in the 7 August 1975 issue of Nature (256:495-7) entitled Continuous cultures of fused cells secreting antibody of predefined specificity led to the Nobel Prize in Medicine in 1984. The first monoclonal antibodies were primarily mouse monoclonals and used to identify antigens on cells, usually by immunofluorescent techniques, particularly by automated flow cytometry. Thus they became valuable laboratory reagents and led to the many CDs for antigens on hematopoietic cells, now numbering over 250. These include the familiar CD3 (for all T cells), CD4 (helper cells and the HIV receptor), CD8 cells (cytotoxic T cells), and CD19 (for B cells). The first therapeutic monoclonal antibody was orthoclone OKT3 (muromonab), a murine monoclonal antibody directed against CD3 T-cells. It was licensed in 1986 for acute kidney graft rejection and in steroidresistant graft rejection in cardiac and liver transplant patients. Since then, 19 other therapeutic monoclonal antibodies have been licensed in the US (Table 1), and many more are in development.

Nomenclature and Structure The generic name of therapeutic monoclonal antibodies has been codified, as summarized in Table 2.1 All end in -mab or -nab. Preceding this ending is a one- or two-letter prefix that denotes the animal from which it has been produced (eg, o- for mouse as in muromonab, ufor human as in adalimumab, etc). Two types of monoclonal antibodies contain both human and murine components. Chimeric monoclonal antibodies, designated xi, contain the Fab portion of a murine immunoglobulin and the Fc portion of a human immunoglobulin, usually an IgG1 molecule (eg, rituximab). Humanized monoclonal antibodies, designated zu-, have only the antibody

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TABLE 1. U.S. licensed therapeutic monoclonal antibodies

Year licensed

Specificity (target antigen)

Generic name

Trade name

1986 1994 1997 1998 1998 1998

Anti-CD3 Anti-GPIIb/IIIa* Anti-CD20 Anti-CD25 Anti-CD25 Anti-TNF-␣

Muromomab Abciximab Rituximab Basiliximab Daclizumab Infliximab

OKT3 ReoPro* Rituxin Simulect Zenapax Remicade

1998 1998 2000 2001 2002 2003 2003 2003 2003

Anti-HER-2 Anti-RSV Anti-CD33** Anti-CD52 Anti-CD20*** Anti-CD20**** Anti-IgE Anti-CD11␣ Anti-TNF-␣

Trastuzumab Palivizumab Gemtuzumab Alemtuzumab Ibritumomab Tositumomab Omalizumab Efalizumab Adalimumab

Herceptin Synagis Myelotarg** Campath Zevalin*** Bexxar**** Xolair Raptiva Humira

2004 2004 2005 2006

Anti-VEGFR Anti-EGFR Anti-␣4 integrin Anti-VEGFR*

Bevacizumab Cetuximab Natalizumab Ranibizumab

Avastin Erbitux Tysabri Lucentis*

Principal use Immunosuppression Prevention of thrombosis Treatment of B-cell lymphoma Immunosuppression Immunosuppression Treatment of rheumatoid arthritis and inflammatory bowel disease Treatment of breast cancer Prevention of RSV infection Treatment of acute myelocytic leukemia Treatment of chronic lymphocytic leukemia Treatment of refractory B-cell lymphoma Treatment of refractory B-cell lymphoma Prevention and treatment of allergic disorders Treatment of psoriasis Treatment of rheumatoid arthritis and inflammatory bowel disease Treatment of metastatic colon cancer Treatment of metastatic colon cancer Treatment of multiple sclerosis Treatment of macular degeneration

Abbreviations: EGFR, epithelial growth factor receptor; GP, glycoprotein; HER-2, human epithelial growth factor receptor 2; RSV, respiratory syncytial virus; TNF, tumor necrosis factor; VEGFR, vascular endothelial growth factor receptor. *Fab fragment. **Conjugated with calicheamicin. ***Radiolabeled with yttrium 90. ****Radiolabeled with iodine 131.

combining site of a murine immunoglobulin (termed the complementary determinant region, CDR) and the rest of the molecule is a human IgG1 molecule. Chimeric and humanized antibodies are less antigenic and have a longer half-life than do mouse monoclonal antibodies, and thus are usually preferable. The final prefix before the latter source prefix designates the disease for which the antibody is used (eg, vir- for viral disease, lim- for immune modulation, tufor cancer, etc). Examples include palivizumab, omalizumab, transtuzumab. Sometimes the last consonant is dropped for sake of pronunciation. The beginning of the generic name is left to the manufacturer, as is, of course, the trade name.

Fragmented and Conjugated Monoclonal Antibodies Two of the licensed monoclonal antibodies are Fab fragments of the whole molecule. Fragmented molecules retain their antibody activity but their survival and therapeutic duration is markedly shortened. These include abciximab (ReoPro) directed against platelet glycoprotein IIb/IIIa for prevention of thrombosis, and ranibizumab (Lucentis) directed against vascular en-

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dothelial growth factor receptor (VEGFR) for intravitreous injection into the eye for macular degeneration. It is derived from bevacizumab (Avastin) used for treatment of metastatic cancers. Three of the licensed monoclonal antibodies are combined with other molecules to increase their therapeutic effectiveness. Two of these are anti-CD20 (B-cell) antibodies similar to rituximab that are radiotagged and used for rituximab-refractory B-cell lymphomas. Ibritumomab (Zevulin) is conjugated with yttrium 90 and tositumomab (Bexxar) is conjugated with iodine 131. Thus these monoclonal antibodies deliver radiation only to cells carrying the CD20 antigen. A third tagged antibody is gemtuzumab-ozogamicin (Mylotarg) used in the treatment of relapsed acute myelocytic leukemia. It is conjugated with the potent antitumor antibiotic calichheamicin to increase the concentration of the drug on myeloid cells expressing CD33.

Summary and Overview Therapeutic monoclonal antibodies developed to date are licensed for graft rejection, cancer, auto-

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TABLE 2. USAD* monoclonal antibody nomenclature

The following guidelines have been developed for monoclonal antibodies: The suffix –mab is used for monoclonal antibodies and fragments

Excellent summaries are available that discuss the technology, the monoclonal antibodies in the pipeline, and the future of the field.1-4

The following letters were approved as product source identifiers: u ⫽ human e ⫽ hamster o ⫽ mouse i ⫽ primate a ⫽ rat xi ⫽ chimeric zu ⫽ humanized These identifiers precede the –mab suffix stem, eg: -umab (human) -omab (mouse)

-ximab (chimeric) -zumab (humanized)

The general disease state subclass is incorporated into the name by use of a code syllable preceding the above. These include the following: Disease or target class: Viral Bacterial Immune Infections Lesions Cardiovascular Tumors Colon Melanoma Mammary Testis Ovary Prostate Miscellaneous

-vir-bac-lim-les-circ-col-mel-mar-got-gov-pr(o)-tum-

*United States Adopted Name.

immunity (eg, rheumatoid arthritis, inflammatory bowel disease, immune cytopenias), thrombosis, infectious disease, multiple sclerosis, asthma, and macular degeneration. Like many new drugs, monoclonal antibodies are sometimes used for disorders other than the one(s) for which they are licensed. This next two sections focus on the anti-TNF monoclonal antibodies (and the related fusion protein etanercept) and the anti-CD20 (B-cell) monoclonal antibody rituximab since these are widely used in pediatric practice for several disorders. We did not include palivizumab (Synagis) for prevention of respiratory synctial virus infection in infants, another widely used pediatric monoclonal antibody, since it has a single well-defined indication, the dose schedule is established, and it is used without major controversy. The final section focuses on the adverse effects of monoclonal antibodies including the near fatalities that occurred during testing of an experimental monoclonal antibody to CD52 in the UK last year.

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Anti-TNF-␣ and Other Cytokine Inhibitors in Rheumatic and Related Diseases —Christy Sandborg The advent of the biologic era is revolutionizing the outcome of inflammatory arthritis and other autoimmune diseases in adults and children. Inhibitors of pro-inflammatory cytokines and cell-surface receptors have become important therapies in pediatric rheumatic diseases, particularly juvenile idiopathic arthritis (JIA). Retrospective studies of outcome of JIA over the 1970s-1990s supported the statement that JIA was the most common cause of acquired disability in childhood.5-7 Most children with the subtypes of JIA associated with polyarticular joint involvement had active disease two-thirds of the time, and less than 50% ever achieved remission. The probability of arthroplasty ranged from 13 to 57% after 15 years of disease. These discouraging outcomes prompted pediatric rheumatologists to use aggressive therapy earlier in the course of disease. Improved outcomes with the most commonly used disease-modifying antirheumatic drug, methotrexate, occurred for 50 to 60% of children. Since 1999, however, the anticytokine therapies have been effective for the large majority of children, even those not responsive to methotrexate.7 Anecdotally, pediatric rheumatologists observed that, before this time, they spent their summers rehabilitating multiple adolescents following arthroplasty. Now, arthroplasty is uncommon, and we can confidently say that the outcome looks very good for children with JIA. A handful of cytokines were described in the 1960s and 1970s and, by 1980, several were recognized and studied with the idea that these entities might become important therapeutic tools8 (Table 3). Interferons, lymphocyte-activating factor (interleukin (IL-2), and the endogenous pyrogens (IL-1 and tumor necrosis factor (TNF-␣)) were among the first described. Now there are estimated to be several hundred cytokines with more than 50 currently well characterized and being actively used or considered as therapy. Early on it was recognized

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TABLE 3. Major pro-inflammatory cytokines and activities

Cytokine

Activities

IL-1␣, -␤ TNF-␣ IL-6 IL-12 IL-8 IFN-␥ IFN-␣ IFN-␤

Immune stimulation Constitutional symptoms Adhesion molecule induction Activation of cytokine networks Induction of NO synthesis and oxygen metabolites Increases oxygen metabolites Induction of proteolytic enzymes Metalloproteinase induction Cartilage damage Fibroblast proliferation

that there was a duality in types of cytokines, with some being more pro-inflammatory and others antiinflammatory; indeed, some cytokines may be stimulatory for some of their activities and inhibitory for others. Anti-inflammatory cytokines, such as IL-4, IL-10, transforming growth factor-␤, IL-1 receptor antagonist (IL-1RA), and soluble receptors such as soluble TNF-␣ receptor, can counteract many of these activities through decreasing production or interfering with activity of pro-inflammatory cytokines. The earliest interest in TNF-␣ and IL-1 as therapeutic agents was based on the observation that these cytokines were markedly elevated in Gramnegative septic shock and inhibition by monoclonal antibody to TNF-␣ markedly improved outcomes in animal models of sepsis.9 Unfortunately, this effect was found only if the antibodies were administered 1 hour before the infection. Molecular manipulation of a murine monoclonal antibody to TNF-␣ to decrease its immunogenicity resulted in a chimeric murine-human TNF-␣ antibody, which was tested in human sepsis and, although not effective, was shown to be safe. Interestingly, evaluation of the role of inflammatory and inhibitory cytokines in fatal meningococcal disease revealed that individuals with genetic polymorphisms leading to decreased TNF-␣ production and increased IL-10 production had family members more likely to die from meningococcal disease.10 Thus, pro-inflammatory cytokines mediate many of the adverse effects of overwhelming sepsis, but may also enhance survival in major bacterial infection. Pro-inflammatory cytokines are increased in a variety of autoimmune diseases including rheumatoid arthritis, multiple sclerosis, Crohn’s disease, and JIA.11,12 Conversely, anti-inflammatory cytokines are decreased13-15 leading to an imbalance

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FIG 1. Balance between pro- and anti-inflammatory cytokines in autoimmunity. These key pro-inflammatory cytokines have been recognized to be increased in autoimmunity. (Color version of figure is available online.)

between pro- and anti-inflammatory cytokines as shown in Figure 1. The concept that increasing antiinflammatory cytokines or inhibiting pro-inflammatory cytokines would be effective in inflammatory autoimmune diseases is based on these observations. JIA is a family of inflammatory arthritides in children, with very different cytokine profiles as well as clinical manifestations. Murray and coworkers13 showed that the anti-inflammatory cytokine IL-4 appeared to be elevated in synovial fluid from the mildest form of JIA, oligoarticular with limited joint involvement. In contrast, IL-1, TNF-␣, and especially IL-6, were found to be elevated in blood and synovial fluid from children with systemic JIA.13,16,17 De Benedetti and coworkers18,19 describe a correlation between high IL-6 levels and growth failure in IL-6 transgenic mice and children with systemic JIA, and an anecdotal report of improved growth in children with systemic JIA treated with the IL-6 blocking therapy, tocilizumab.

Tumor Necrosis Factor-␣ Inhibitors Three TNF-␣ inhibitors are currently available: etanercept, infliximab, and adalimumab. Etanercept, a fusion protein of the soluble TNF-␣ receptor and the Fc portion of IgG, was the first TNF-␣ inhibitor approved for use in RA in 1998. The landmark trial that led to its approval was based on a novel trial design suited for use in pediatric populations with small sample sizes. The randomized withdrawal trial design begins with an open-label portion, followed by blinded randomization of responders to continue on active drug or placebo. The primary endpoint is time to flare. Using this study design,

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Lovell and coworkers20 studied 69 children with polyarticular JIA who had failed therapy with lowdose methotrexate, previously the most effective therapy for severe juvenile arthritis. Using an improvement of 30% overall in key clinical laboratory factors, the response rate in the open-label portion was 74%. The randomized phase showed a statistically significant difference in median time to flare where patients on placebo had a median time to flare of 28 days compared with greater than 116 days in patients receiving etanercept (P ⬍ 0.001). Infliximab, the human-murine chimeric antiTNF-␣ monoclonal antibody originally used in sepsis trials, was approved for use in RA in 1999, and a trial was completed in juvenile arthritis in 200521; however, the study did not reach high enough significance to allow FDA approval for JIA. The trial itself does demonstrate a clear trend toward effectiveness. In addition, the trial illustrates some of the challenges facing studies in children. Many new therapies are required to be tested in children with certain disease criteria based on the Pediatric Rule (Pediatric Research Equity Act of 2003). This law permits dosing to be based on safety and efficacy trials in adults. In the JIA infliximab trial, the primary dose based on adult studies gave lower serum levels in children compared with adults possibly based on differing pharmacokinetics in children.21 It is possible that, if pharmacokinetic studies had been done before final trial design, dosing would have been different and the trial would have been successful. The most recently developed TNF-␣ inhibitor, adalimumab, is a fully human anti-TNF-␣ monoclonal antibody. Recently approved for use in RA, the pediatric trial has just finished and has shown a statistically significant decrease in the flare rate with adalimumab using a randomized withdrawal study design.22 FDA approval is pending. The TNF-␣ inhibitors have made a dramatic improvement in the outcomes in RA, polyarticular JIA, psoriatic arthritis, and ankylosing spondylitis. They are also effective in Crohn’s disease and psoriasis and are being tested in uveitis and other autoimmune diseases. Interestingly, although pro-inflammatory cytokines appear to contribute to the pathogenesis of multiple sclerosis, clinical trials showed that patients’ outcomes were worse with TNF-␣ inhibitors.23,24

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IL-1 and IL-6 Inhibitors Anakinra is currently the only IL-1 inhibitor approved by the FDA. Anakinra is identical to the naturally occurring IL-1 receptor antagonist (IL1RA), which blocks IL-1 activity by competing for receptor binding. Although never compared in a trial, the general impression suggests that anakinra is not as effective in RA or polyarticular JIA as the TNF-␣ inhibitors. One contributing factor is that a huge excess of IL-1RA is required to block IL-1, requiring high doses and frequent dosing of anakinra to achieve IL-1 inhibition. However, IL-1 inhibition has been shown to be more effective than TNF-␣ inhibition in certain arthritis animal models25 and certain types of inflammatory arthritis. Strong anecdotal evidence suggests that anakinra is very effective in the systemic form of JIA,26,27 and the TNF-␣ inhibitors are less effective.28 More powerful IL-1 inhibitors are currently being developed and evaluated in trials. The IL-1 Trap is a fusion protein consisting of the extracellular domains of the two human receptor components required for IL-1 signaling, IL-1 Type I receptor, and the IL-1 receptor accessory protein, connected by the Fc portion of human IgG1.29 This molecule is currently in Phase II trails in systemic JIA. A chimeric monoclonal antibody to the IL-6 receptor, tocilizumab, has been shown to be effective in Phase III studies in adult RA and has been evaluated in open-label trials in systemic JIA. The open-label trials in systemic JIA show marked improvement in disease activity,30 and Phase III trials are being planned.

Newer Biologics for Rheumatic Diseases Biologic therapies targeting cellular receptors have been found to be effective in autoimmune diseases. The B-cell depleting monoclonal antibody against CD20, rituximab, has been used in B-cell neoplasms for years and has recently been evaluated in autoimmune diseases. It was effective in a randomized clinical trial in RA and anecdotal reports in systemic lupus erythematosus (SLE).31,32 Rituximab and other anti B-cell therapies, such as antiBlyS antibodies, are currently in trials in SLE and inflammatory myositis. Another potential value in the treatment of autoimmune diseases is costimulatory blockade. Two agents have been developed and studied in SLE and

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inflammatory arthritis. The first one developed was anti-CD40 ligand (CD40L) monoclonal antibody, which was shown to be very effective in animal models of lupus. However, the human trials were discontinued because of an apparent increase in thromboses. The second agent, CTLA4Ig, is based on the endogenous inhibitor, CTLA4, of the B7 (CD80) and CD28 costimulatory signal. A Phase III trial has shown this agent to be effective in RA,33 and a Phase III study in polyarticular JIA is undergoing final data analysis. This agent is currently being studied in SLE as well and may hold promise as the first “tolerizing” therapy in autoimmune disease.

Pharmacoeconomics of Cytokine Inhibitors The high cost of cytokine inhibitors for diseases such as RA (⬃$12,000/y) has raised the question of whether these therapies are really cost-effective enough to justify widespread use. Complex pharmacoeconomic studies have looked at quality-oflife-year analysis for adults with RA and demonstrated overall a positive benefit in terms of preserved productivity and decreased medical complications and surgeries. The anecdotal experience of many adult and pediatric rheumatologists suggests that these new therapies can transform many patients who would have developed mild to moderate disability to individuals with essentially normal function.

Summary The current goal for treating JIA is not just disease control but remission, largely achievable with new biologics. Matching the right biologic therapy for certain diseases or patients is the next step in the therapies of autoimmune disease.

Rituximab: Vitamin R for Children with Autoimmune Disease —James B. Bussel, Lisa Giulino, Vivek L. Patel Rituximab (Rituxin) is a chimeric mouse– human monoclonal IgG1 antibody directed at CD20, an antigen expressed on pre-B- and B-cells (but not pro-B-cells or most plasma cells).34 Although first approved in 1997 for the treatment of B-cell nonHodgkin’s lymphoma (NHL), its efficacy and rela-

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tive lack of toxicity has led to its use in a number of B-cell-mediated autoimmune diseases. Rituximab causes rapid depletion of circulating CD20⫹ B-cells through a variety of mechanisms, including antibody-mediated FcR-dependent clearance, antibody-dependent cellular cytotoxicity (ADCC), complement-mediated lysis, apoptosis, and inhibition of cell growth.35-38 The depletion is sufficiently rapid that circulating B-cells often disappear by the end of the first infusion.39 In contrast, the fate of bone marrow and especially nodal B-cells following rituximab is uncertain. Despite substantial B-cell depletion, which typically persists for 6 months before returning to baseline at 12 months,40 an increased risk of infection has not been demonstrated. This is likely due to a combination of the relatively long half-life of IgG and the continued presence of plasma cells in the peripheral circulation and possibly B-cells in lymph nodes.34 The use of rituximab has been reported in a number of pediatric autoimmune diseases including autoimmune hemolytic anemia,41-43 immune thrombocytopenic purpura (ITP),44-46 as well as diverse multisystem autoimmune disease such as systemic lupus erythematosus.47 Approximately 700,000 patients have been treated worldwide, of whom ⬎98% are adults with NHL.48 Virtually all diseases in adults and children have been treated with 375 mg/m2 per dose for four doses administered weekly for 4 weeks.49 There has been limited exploration of other doses except in chronic lymphocytic leukemia in adults in which doses up to 2250 mg/m2 have been used49 and in rheumatoid arthritis in children and adults in which single doses of 600 mg/m2 have been combined with cyclophosphamide.

Rituximab in Immune Thrombocytopenic Purpura Many but not all studies of the use of rituximab in children have involved ITP.50-53 ITP is mediated by antiplatelet antibodies,52 which bind to circulating platelets and result in their accelerated destruction. In addition, these antibodies may inhibit platelet production via their effects on megakaryocytes. In view of these pronounced antibody-mediated effects and the ease of measurement of the platelet count, ITP is considered the prototypic humoral autoimmune disease and thus a natural target for exploration of the efficacy of rituximab.

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TABLE 4. Results of the use of rituximab in immune thrombocytopenic purpura

Authors and year Saleh et al, 2000 Stasi et al, 2001 Giagounidis et al, 2002 Zaja et al, 2002 Zaja et al, 2003 Narang et al, 2003 Cooper et al, 2004 Braendstrup et al, 2005 Narat et al, 2005 Wang et al, 2005 Penalver et al, 2006 Bennett et al, 2006 Total

Ref. 57 71 54 58 79 55 39 53 89 46 56 44

No of patients 13 25 12 13 15 6 57 35 6 24 89 36 331

Response to treatment no. (%) Complete (>150 k/␮l)

Partial (50-150 k/␮l)

None (<50 k/␮l)

Total responses

2 (15) 5 (20) 5 (42) 6 (46) 6 (40) 3 (50) 18 (32) 6 (17) 4 (67) 15 (63) 41 (46) Not declared 111/(295) (37.6)

1 (8) 5 (20) 4 (33) 1 (8) 2 (13) 2 (33) 13 (23) 6 (17) 1 (17) 2 (8) 8 (9) Not declared 45/(295) (15.3)

10 (77) 15 (60) 3 (25) 6 (46) 7 (47) 1 (17) 25 (44) 23 (66) 1 (17) 7 (29) 40 (45) Not declared 138/(295) (46.8)

3 (23) 10 (40) 9 (75) 7 (53) 8 (53) 5 (83) 31 (54) 12 (34) 5 (83) 17 (71) 49 (55.1) 11 (31) 167/(331) (50.4)

Rituximab has marked efficacy in both children and adults with chronic refractory ITP. There are at least nine rituximab trials in ITP with a minimum of five patients each, totaling 331 patients.39,44,46,52-58 (Table 4). The response rate, complete and partial, to initial treatment with rituximab (375 mg/m2) in these patients was approximately 50%. The complete response rate was about 35%, and the partial response rate was about 15%. A better initial response, ie, a complete response (CR: platelet count ⬎150 ⫻ 109/L), as compared with a less complete initial response, ie, a partial response (PR: platelet count 50-150 ⫻ 109/L), was significantly more likely to lead to a sustained response.39,44,52-58 Among these 331 patients, there are two principal studies of the use of rituximab in children (60 patients).44,46 The response rate in these two studies, 47%, is comparable to the overall response rate cited above. One of these studies included more refractory patients but did not distinguish complete and partial responses.44 The other report had a 63% CR rate but a higher, early relapse rate such that the lasting complete response rates were similar to that of adults.46 A recent ITP study in adults and children assessed the very long-term (⬎1 year) efficacy of rituximab in approximately one-third of treated patients whose response to initial treatment, whether a PR or CR, lasted at least for 1 year.59 In 47 patients with chronic ITP whose response had lasted at least 1 year, durable responses to rituximab were seen in 62%. We therefore estimate that long-term responses occur in approximately 20% of the starting group of rituximab-treated chronic ITP patients.59

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There were only eight pediatric patients with responses ⬎1 year and 63% had sustained responses at a median follow up of 2 years.59-61

Rituximab in Systemic Lupus Erythematosus SLE is a multisystem autoimmune disease characterized by the presence of pathogenic antibodies to a variety of human antigens. Although the clinical manifestations of SLE are similar in children and adults, children tend to have more severe disease with higher rates of hematologic and renal involvement, necessitating aggressive treatment.67 While the outcome for children with SLE has improved dramatically with the use of steroids, cyclophosphamide, and other immunosuppressive agents, the long-term side effects of these medications are significant and include growth failure, infertility, and the risk of malignancy. Additionally, some children do not respond to any of these treatments.68 Although the exact etiology of SLE remains a mystery, there is growing evidence for a role of B lymphocytes. The formation of autoantibodies leads to immune complex deposition and complement activation with tissue damage.69 B lymphocytes produce autoantibodies to a number of cell-surface antigens that result in glomerulonephropathy, hemolytic anemia, and thrombocytopenia.67,70-85 Other B-cell abnormalities may also contribute to the pathogenesis of SLE. SLE-prone mIgM transgenic MRLlpr/lpr mice, known to have incompetent B-cells incapable of immunoglobulin formation, have been found to develop interstitial nephritis and vasculitis, whereas the innately B-cell-deficient MRLlpr/lpr mice did not.86-88 This animal model

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implies a role of B cells in the pathogenesis of SLE other than autoantibody production. Abnormalities in activation, signaling, and migration of B-cells in patients with SLE have been identified.86 Some of these abnormalities may be explained by finding that T cells in patients with SLE overproduce a number of cytokines, which further stimulate B cell function, including IL-6 and IL-10.86 In addition to making autoantibodies, B cells can also act as highly efficient antigen-presenting cells and provide costimulatory, antiapoptotic signals to autoreactive CD4⫹ T cells.88 Thus the multifactorial role of B lymphocytes in promulgation of immune dysregulation makes them a desirable therapeutic target in many forms of autoimmunity. Rituximab has been reported to be safe and efficacious in a number of studies of adults with SLE.84,90-92 Two cohort studies and two case reports have described the use of rituximab in children with SLE. An open label trial of 7 children with active SLE followed for a median of 1 year and were found to have significant decreases in the British Isles Lupus Assessment Group global scores. A trend toward an increase in total complement levels and reduction in anti-dsDNA titers was also noted. No severe adverse events were reported. In a second report, 11 females with SLE were treated with 2-12 infusion of ritusimab dosed between 350-450 mg/m2 with maintenance infusions in 2 patients.85 All had severe disease which persisted despite standard immunosuppressive agents. Patients were followed for a mean of 13.8 months. Of the 8 children with renal disease, 2 achieved a complete response and 4 achieved a partial response. Anti ds-DNA titers decreased in 5 patients (4 of whom achieved remission) and complement levels normalized in three patients. Preliminary studies have combined rituximab 600 mg/m2 and cyclophosphamide 1000 mg/m2 as paired infusions given 2 weeks apart every 6 months with good success. In this setting, it is difficult to distinguish the effect of the rituximab from that of the cyclophosphamide but the combination appears substantially more effective than cyclophosphamide alone.

Rituximab in Autoimmune Hemolytic Anemia The efficacy of rituximab in children with autoimmune hemolytic anemia, at a standard dose using two to six infusions, appear to be even better than

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those in ITP, although the data are more limited.41 In two studies with 18 children (median age, 2 years), almost all patients were able to discontinue treatment (ie, steroids) altogether following rituximab.42,43 Because of their young age, they also received monthly IVIG 400 mg/kg as prophylaxis against infection. Despite the apparent efficacy of rituximab, spontaneous improvement cannot be excluded in a small percentage of these cases. Retreatment with rituximab is feasible if there has been a response and then a relapse but not if there was not a response to initial treatment. In the limited data available, the response the second time is very similar to that following the first course of infusions.93 However, approximately 20% of initially responding patients did not respond to retreatment and virtually no patient had a better response to the second course of treatment.93 In an attempt to improve the efficacy of retreatment, augmented rituximab was used in two separate pilot studies. The augmentation consisted of either the addition of intensive chemotherapy or else the doubling of the dose of rituximab. Preliminary results suggest that neither augmentation strategy seemed to result in better responses than the initial course of rituximab. In summary, rituximab provides a novel approach to treatment of ITP with its long-term effects.

Rituximab Safety These short- and long-term studies of rituximab in children and adults have revealed little toxicity.39,44,56,52-58 There have been continued concerns about long-term consequences of B-cell depletion but nothing specific has become apparent as of the current time. Commonly reported toxicity primarily in adults has included first infusion reactions and also more prolonged and severe neutropenia following chemotherapy if simultaneous rituximab is used.61 As many as 5 to 10% of children with ITP treated with rituximab have developed serum sickness necessitating its discontinuation after one to three infusions.44,46 Less common toxicities coincident with diffuse lymphoid malignancies (ie, lymphoma) and solid tumors include arthritis, kidney disease, hepatitis, heart disease (myocardial infarction or cardiomyopathy), and stroke. In SLE specifically, long-term use of rituximab has been linked to respiratory problems and hypogammaglobulinemia.49 Given the lack of such consequences in patients with ITP, these complications may be due

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TABLE 5. Safety issues with TNF inhibitors

Target related Definite Probable

Possible

Agent related Injection site reactions, infusion reactions, immunogenicity (eg, serum sickness, anaphylaxis)

Infections, serious infections opportunistic infections (eg, coccidioidomycosis), TB autoantibodies, lupus-like syndromes, hepatotoxicity Malignancies (lymphoma), demyelinating disorders (MS), hematologic abnormalities, CHF

CHF, congestive heart failure; MS, multiple sclerosis; TB, tuberculosis.

to the greater degree of systemic illness in nonHodgkin’s lymphoma and SLE.94 The area of initially greatest concern is an increased incidence of infection. Initial studies indicated that, despite the absence of B-cells, there is to no fall in levels of IgG, IgM, and IgA.41 Serious infections have been identified in two settings. Some patients who are carriers of hepatitis B (ie, HBsAg positive) may develop active hepatitis B.62,63 A very small number of patients receiving rituximab as part of myeloblative treatment for bone marrow transplantation have developed progressive multifocal leukoencephalopathy.64-66

Summary Rituximab is an important treatment option for refractory autoimmune disease in children. In addition to the studies described above in ITP, autoimmune hemolytic anemia, and SLE, smaller series have suggested potential efficacy in thrombotic thrombocytopenic purpura and hemophiliacs with inhibitors of factor VIII.95,96 Furthermore it is the treatment of choice for posttransplant lymphoproliferative disorder. Studies to clarify the role of autoreactive T-cells, their interactions with B-cells, and how rituximab alters these interactions are anticipated.

Downside and Future of Monoclonal Antibody Therapy —Susan Lee Since biologic therapeutic agents target specific components of the immune response, they have the potential to optimize outcomes and minimize potential adverse events (AEs) related to broader methods of immunosuppression. However, because these biological agents also serve key functions in normal

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immunosurveillance, they have the potential of certain AEs. This section will review important AEs of several monoclonal antibodies currently available or under investigation for the treatment of common autoimmune conditions.

Tumor Necrosis Factor-␣ Inhibitors Adverse Reactions In general, the three approved TNF-␣ inhibitors (infliximab, etanercept, and adalimumab) have been well tolerated in clinical trials. In vitro evidence has suggested that TNF-␣ inhibitors selectively decrease pro-inflammatory cytokines. However, longer term follow-up and pharmacovigilance have highlighted several safety issues regarding their use. AEs associated with TNF-␣ inhibitors may be broadly classified as target/class related or agent related (Table 5). Target-related AEs include those potentially attributable to the immunosuppression inherent in blocking a key cytokine such as an increased susceptibility to infections and malignancies. In addition, specific inhibition of TNF-␣ may predispose patients to increased susceptibility to tuberculosis (TB), autoantibody production, hepatotoxicity, possibly the development of demyelinating disease, and clinical worsening of congestive heart failure (CHF). Allergic reactions and antigenicity are idiosyncratic reactions that relate to the particular agent used. These are summarized in Table 6.

Target-Related Reactions: Consequences of Generalized Immunosuppression Safety data from clinical trials have shown a small but consistent increase in infections among treated patients. The most common infections were upper respiratory infections, pneumonias, urinary tract infections, and postoperative infections.97-100 However, the excess risk attributable to treatment is hard

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TABLE 6. Adverse effects of therapeutic monoclonal antibodies*

Drugs

Description

Associated adverse effects

Abciximab Adalimumab Alemtuzumab Basiliximab Bevacizumab Cetuximab Daclizumab Efalizumab Ibritumomab Infliximab Natalizumab Omalizumab Palivizumab Rituximab Tositumomab Trastuzumab

Chimeric monoclonal Fab fragment to platelet IIb/IIIa Humanized mAb to TNF-␣ Humanized mAb to CD52 Chimeric mAb to IL-2R Humanized mAb to VEGF Chimeric mAb to EGFR Humanized mAb to IL-2R Humanized mAb to LFA-1 (CD11a) Murine mAb to CD20 Chimeric mAb to TNF-␣ Humanized IgG4 mAb to ␣4 subunit of ␣4␤1 Humanized mAb to IgE Humanized mAb to RSV Chimeric mAb to CD20 Murine mAb to CD20 Humanized mAb to HER-2

Thrombocytopenia, bleeding, hypersensitivity reactions (see text) Infusion reaction, fever, infection Infections, fever, electrolyte changes, hypertension Hypertension, proteinuria, deep venous thrombosis Fever, rash, edema, anemia, luekopenia Edema, polyuria, tachycardia (see text) Infection, lymphopenia (see text) (see text) Injection site reaction, infection Fever, anemia, liver test abnormalities (see text) Anaphylaxis, neutropenia, thrombocytopenias Fever, rash, infection, edema

EGFR, epidermal growth factor receptor; HER-2, human epidermal growth factor receptor 2; LFA, leukocyte function antigen; mAb, monoclonal antibody; PDGF, platelet derived growth factor; RSV, respiratory syncytial virus; TNF, tumor necrosis factor; VEGF, vascular endothelia growth factor. *Accessed 7/1/06: www.fda.gov/cder/biologics/biologics_table.htm.

to define and is confounded by the higher baseline prevalence of infection in RA patients, particularly those with most active and severe disease. Of note, such patients have been the ones for whom TNF-␣ inhibitors have been most widely utilized to date. The relative impact of dose and duration of TNF-␣ inhibitor therapy, and host factors such as comorbidities (eg, diabetes, chronic obstructive pulmonary disease), genetic polymorphism, and concomitant medications on the rate of infection remain incompletely defined. The risk of infection appears to increase significantly when biologic agents are combined. For example, the combination therapy with etanercept and the interleukin-1 receptor antagonist (anakinra) has been associated with a higher rate of serious infections than with either agent alone despite the failure of the combination therapy to achieve any additive clinical benefit.101 Similarly, when TNF-␣ inhibitors were combined with an inhibitor of T-cell costimulation (abatacept), a higher incidence of infections was noted.102 Until further longer term data are available, combination therapy with biologic agents should be discouraged. In addition to common infections, pharmacovigilance data have shown a number of opportunistic infections with fungal and intracellular pathogens such as Pneumocystis carinii, Listeria, Legionella, atypical Mycobacteria, Coccidioides, Histoplasma, and Aspergilla in patients treated with TNF-␣ inhibitors.103-106 Despite this increased risk of opportunistic infections, studies have failed to demon-

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strate any specific testable defects in humoral immunity (B-cell numbers, immunoglobulin levels, immunoglobulin responses to vaccination), cellmediated immunity (T-cell numbers and function, delayed-type hypersensitivity), or in other components of host defense (neutrophil numbers and function, NK-cell numbers, macrophage numbers and function) in patients treated with TNF-␣ inhibitors.107 Another potential sequelae of immunosuppression is an increased risk of malignancy. With a few notable exceptions, the bulk of the data does not support an increased risk of solid tumors with TNF-␣ inhibitors. However, greater numbers of hematological malignancies, particularly NHL, have been observed with a standardized incidence ratio (SIR) ranging from 2.3 to 6.4.108-114 Of note, a recent black box warning has been added for infliximab based on six reports of rare but fatal hepatosplenic T-cell lymphoma.115 Complicating the assessment of the risk attributable to therapy is the increased baseline risk of lymphoma among RA patients. However, RA patients, especially those with more severe disease, appear to have a higher risk for developing lymphoma compared with the general population.

Target-Related Reactions: Specific Consequences of TNF-␣ Inhibition Data from numerous animal studies have shown that TNF-␣ plays a critical role in defense against 127

mycobacterial infection.116,117 A number of TB cases have been noted in postmarketing surveillance among patients treated with TNF-␣ inhibitors.99,118-120 In contrast to typical presentation of TB where 80% or more present with pneumonia, these patients presented with either extrapulmonary or disseminated diseases in about half the cases.118,119 Many of these TB cases appear to be reactivation of latent TB, with infection occurring within the first few months of therapy. The incidence of cases may be greater with the monoclonal antibody TNF-␣ inhibitors than with the fusion protein inhibitor. Fortunately, screening for latent TB before initiating TNF-␣ inhibitor therapy has been an effective strategy with a reduction in incidence of new TB cases by approximately 85%.121,122 Several cases of multiple sclerosis (MS) and other demyelinating conditions have been identified among patients on TNF-␣ inhibitors.123-125 However, the unknown prevalence of MS among RA patients makes it difficult to assess the true impact of TNF-␣ inhibitors on the development of MS. Treatment with TNF-␣ inhibitors has also been associated with development of autoantibodies. These include antinuclear antibody (ANA; which develops in about half of RA patients treated with TNF-␣ inhibitors), anti-double-stranded DNA antibody (anti-dsDNA; which develops in approximately 10-15% of patients treated with TNF-␣ inhibitors), and anticardiolipin antibodies.126,127 The clinical implications of these autoantibodies remain to be defined, as progression to a lupus-like illness appears to be uncommon. Interestingly, in an open-label study of six active lupus patients treated with infliximab, their disease activity actually improved despite an increased level of dsDNA antibodies in four patients.128 Among many factors, levels of TNF-␣ have correlated with disease activity in patients with cardiovascular disease and CHF. However, multiple clinical trials assessing the efficacy of TNF-␣ inhibitors on CHF have failed to show any benefit and, in some, have resulted in increased morbidity and mortality.129,130 In contrast, RA patients treated with TNF-␣ inhibitors had a lower prevalence and incidence of CHF and cardiovascular disease than their age- and sex-matched RA counterparts. In RA, disease severity and disability appeared to correlate more with the risk of CV events.131,132 TNF-␣ inhibitors may exert a protective effect by decreasing the overall

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disease activity and inflammation. Although their use in patients with moderate/severe CHF is strongly discouraged, recent studies seem to indicate their safety when used for the treatment of RA.

Agent-Related Reactions Agent-related adverse effects such as allergic reactions and antigenicity are idiosyncratic reactions that relate to the particular TNF-␣ inhibitor used. Intermittent use and use without concomitant immunosuppressants have been associated with a greater propensity for the development of antibodies to TNF-␣ inhibitor, especially with chimeric antibody.133-137 The extent to which these antibodies influence response rates or the duration of response to treatment remains to be fully defined. In addition, etanercept and adalimumab have been associated with injection site reactions.138,139 Mild to moderate liver function test elevation (generally ⬍3 times the upper limit of normal) has been observed with TNF-␣ inhibitors.99 In rare instances, TNF-␣ inhibitors have been associated with the development of pancytopenia and aplastic anemia.107 However, many of these cases were confounded by concomitant use of potentially hepatotoxic and bone marrow suppressive drugs. Last, the effect of TNF-␣ inhibitors on pregnancy outcome remains unknown but, in clinical trials where patients unintentionally became pregnant, the rate of birth complications did not seem to differ from that of the general population.140,141

Rituximab Adverse Reactions B-cell activity may contribute significantly to the initiation and perpetuation of the immune response in various autoimmune diseases. Rituximab is a chimeric monoclonal IgG1 antibody directed against B-lymphocyte surface antigen, CD20. CD20 is restricted to the surface of pre-B and activated mature B cells. Rituximab was approved in 1997 for the treatment of CD20-positive B cell NHL and more recently for refractory RA. Within 24 to 48 hours of infusion, rituximab markedly depletes peripheral B cells, with effects lasting up to 9 months after a single course of therapy. Despite the potential for immunodeficiency related to depletion of mature B cells, no significant changes in the overall levels of serum immunoglobulin and the prevalence of infections have been noted.142,143 This could be related to preserved

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function of plasma cells, which lack CD20 and are, therefore, not depleted by rituximab. However, if rituximab is used as a recurrent or maintenance therapy for autoimmune conditions, this may become more of a safety concern as plasma cells are not replenished by memory B cells. While treatment has been well tolerated, rituximab infusions have been associated with hypersensitivity reactions, Stevens–Johnson syndrome, and type III serum sickness-like illness.144-147 In lymphoma patients, rituximab infusions have been associated with a severe, potentially life-threatening infusion reaction referred to as cytokine release syndrome where patients present with fever, rash, multiple laboratory abnormalities (eg, elevated liver function tests, uric acid, lactate dehydrogenase, thrombocytopenia, prolonged coagulation time), and high cytokine levels (eg, TNF-␣, IL-6). Seventy percent of cases occur during the first infusion and more frequently in those with higher baseline lymphocyte counts (⬎50 ⫻ 106/L).148 The infusion reactions are more common during the first infusion. Other rare AEs include neutropenia and fatal reactivation of hepatitis B.143,149

Natalizumab Adverse Reactions Natalizumab, approved in 2004 for the treatment of multiple sclerosis (MS), is a recombinant humanized IgG4 monoclonal antibody directed against the ␣4 subunit of ␣4␤1, an adhesion molecule.150 In two large clinical trials, natalizumab, either alone or in combination with interferon-␤-1a, was associated with significantly lower relapse rates, disability, and fewer new MS lesions on MRI. However, only months after FDA approval, natalizumab was withdrawn from the market after three cases of progressive multifocal leukoencephalopathy (PML) were reported.150,151 PML is caused by the human polyomavirus JC virus and natalizumab is thought to cause PML through reactivation of this virus. The exact mechanism by which natalizumab reactivates JC virus remains unknown but is hypothesized to be related to the mobilization of JC virus from bone marrow stores.152,153 These unexpected cases further highlight the importance of pharmacovigilance and potential unforeseen long-term adverse effects related to biological agents.

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Efalizumab Adverse Reactions Efalizumab, approved in 2003 for the treatment of psoriasis, is a humanized IgG1 mAb directed against the cell adhesion molecule CD11a. CD11a is the ␣-subunit of the LFA-1 molecule on T-cells that bind to ICAM-1 on endothelial and antigen-presenting cells. In addition to inhibiting activation of T-cells, efalizumab also blocks trafficking of lymphocytes into skin by blocking LFA-1/ICAM-1 interaction.154 Overall, efalizumab has been well tolerated without an increased risk of infections and malignancy. Although a few cases of hemolytic anemia and thrombocytopenia have been noted, most AEs were mild with flu-like illness, rash, injection site reactions, and arthritis.155

Tocilizumab (Anti-IL-6 Receptor Antibody) Adverse Reactions Tocilizumab is a humanized monoclonal antibody to the IL-6 receptor that inhibits the binding of IL-6 to IL-6 receptor. The results of early studies of tocilizumab in JIA have been promising without an increased incidence of serious AEs and infections. No significant increases in ANA or anti-dsDNA antibodies were observed. Liver function abnormalities and neutropenia were noted but both were mild and transient. Interestingly, dose-dependent increases in total cholesterol, HDL, and triglycerides were also observed but the clinical implications of this are not known.156-159

Anti-CD28 Monoclonal Antibody TGN1412 Adverse Reactions TGN1412 is a humanized superagonistic antiCD28 monoclonal antibody that stimulates T-cells independent of the T-cell receptor molecule activation. CD28 is present on T-cells and serves as a potent stimulator of T-cells on its ligation with CD80/CD86 on antigen-presenting cells. Early animal studies have shown that superagonistic antiCD28 antibody led to the preferential differentiation of regulatory T-cells that downregulate autoreactive T-cells that may have escaped negative selection.160 Despite its promising results in animal autoimmune disease models, TGN1412 resulted in a near fatal cytokine storm syndrome in a Phase 1 trial involving six healthy volunteers. All these patients developed multiorgan failure and disseminated intravascular coagulation secondary to rapid and sud-

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den release of pro-inflammatory cytokines.161,162 Unlike in the animal studies, superagonistic antiCD28 resulted in activation of pathogenic effect or T-cells in humans, resulting in a cytokine storm syndrome. This Phase 1 study of TGN1412 further highlights the limitations of preclinical studies and potential dangers of immunomodulating therapy.

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Summary The introduction of biologic agents has dramatically improved the clinical status of many patients with various autoimmune diseases. The balance between achieving higher levels of efficacy needs to be balanced against safety considerations. As many of the targets of biological therapeutics are also important in normal host immunosurveillance, there is some concern that immunosuppression and its consequences may be observed with the use of these agents. Also, reactions to the treating agents may cause various allergic and other hypersensitivity reactions. Although clinical trials provide crucial information on drugs efficacy, they are an incomplete source of safety information, particularly for long-term safety data and data on larger numbers of more heterogeneous patients. Whether the development of these AEs relates more to the underlying disease itself or to treatment requires further study and follow-up. In the meantime, clinicians must be aware of these potential complications of therapies with biologic agents.

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