**9. Acknowledgements**

This work was supported in part by the grants from the Medical University of Lodz (No 503-1093-1 and No No 503-1019-1). The authors have no conflicts of interest that are directly relevant to the content of this chapter.

#### **10. References**

268 Autoimmune Disorders – Current Concepts and Advances from Bedside to Mechanistic Insights

and inducesADCC

and apoptosis of B-cells

CD40 Human IgG1 mAb that blocks CD40/CD40L interactions

CD40 Humanized anti-CD40 IgG1 mAb, which induces ADCC

Recombinant humanized mAb binding to complement protein C5, inhibiting its enzymatic cleavage, blocking formation of the terminal complement complex

**MoAb Target Antibody characteristics** 

mentprotein C5

ADCC=antibody-dependent cellular cytotoxicity; BLyS=B-lymphocyte Stimulator;

Table 1. Monoclonal antibodies potentially useful in systemic lupus erythematosus

In recent years, clinical studies have been undertaken with selected mAbs in the treatment of SLE. The most frequently used mAb is rituximab, which is directed against CD20, a membrane protein expressed on B lymphocytes. Rituximab is effective in depleting B cells from peripheral blood, lymph nodes and bone marrow. Recent clinical studies confirm the high activity of rituximab in SLE patients, especially with lupus nephritis and neuropsychiatric involvement. Rituximab was generally well tolerated. However, occasionaly serious infections were reported. Over the last few years new generations of anti-CD20 mAbs have been developed for potential benefits over rituximab. They were engineered to have augmented antitumor activity by increasing CDC or ADCC activity and increased Fc binding affinity for the low-affinity variants of the FcγRIIIa receptor (CD16) on immune effector cells. This mAbs are are highly cytotoxic against B-cell lymphoid cells and

More recently, several newer mAbs have been developed and are being evaluated in phase I/II clinical trials. These include anti-cytokine therapies anti-CD40L mAbs, anti-CD-22 mAb, anti-BLys mAbs and anti- C5 mAbs. Belimumab is a fully human monoclonal antibody that binds to BLyS and inhibits its biological activity. Significantly positive results in both phase 3 studies have raised hopes that belimumab may be the long-awaited new effective therapy for SLE. Proinflammatory cytokines such as tumor necrosis factor (TNF) and interleukin- 6 (IL-6) play an important role in propagating the inflammatory process responsible for tissue damage. Blocking of these cytokines by mAbs can be also a successful therapy for patients with SLE. Finally, mAb eculizumab that specifically inhibits terminal complement activation has been recently developed and investigated in a phase I single dose study in SLE. These potentially useful agents should be further evaluated in well designed controlled trials.

This work was supported in part by the grants from the Medical University of Lodz (No 503-1093-1 and No No 503-1019-1). The authors have no conflicts of interest that are directly

CDC=complement-dependent cytotoxicity; mAb= monoclonal antibody;

Lucatumumab (HCD122, CHIR-

Dacetuzumab (SGN-

**8. Conclusions** 

Eculizumab Comple

SMIP=small modular immunopharmaceutical

are now being evaluated in clinical trials.

**9. Acknowledgements** 

relevant to the content of this chapter.

0.12.12)

40)


The Emerging Role of Monoclonal Antibodies in the Treatment of Systemic Lupus Erythematosus 271

Kelley, S.K.; Gelzleichter, T.; Xie, D. et al (2006). Preclinical pharmacokinetics,

King, J.K. & Hahn, B.H. (2007). Systemic lupus erythematosus: modern strategies for

Klashman, D.J.; Martin, R.A.; Martinez-Maza, O. & Stevens R.H. (1991). In vitro regulation

La Cava, A. (2010). Anticytokine therapies in systemic lupus erythematosus. *Immunotherapy,.*

La Cava, A. (2010). Targeting B cells with biologics in systemic lupus erythematosus. Expert Opinion *on Biological Therapy*, Vol. 10, No. 11, pp. 1555-1561, ISSN 1471-2598 Liang, B.; Gardner, D.B.; Griswold, D.E. et al. (2006). Anti-interleukin-6 monoclonal

erythematosus. *Immunology,* Vol. 119, No 3, pp. 296–305, ISSN 0022-1767 Lim, S.H.; Beers, S.A.; French R.R. et al. (2010). Anti-CD20 monoclonal antibodies:

Leandro, M.J.; Cambridge, G.; Edwards, J.C. et al. (2005). B-cell depletion in the treatment of

Leonard, J.P. & Goldenberg, D.M. (2007). Preclinical and clinical evaluation of epratuzumab

Llorente, L.; Richaud-Patin, Y.; Garcia-Padilla, C. et al. (2000). Clinical and biologic

Lu, T.Y.; Ng, K.P.; Cambridge, G. et al. (2009). A retrospective seven-year analysis of the use

Luqman, M.; Klabunde, S. Lin, K. et al (2008).The antileukemia activity of a human anti-

Merrill, J.T.; Burgos-Vargas, R., Westhovens, R. et al. (2010). The efficacy and safety of

*Blood* , Vol. 112, No 3, pp. 711-720, ISSN 0006-4971

*Rheumatology*, Vol. 44, No. 12, pp. 1542-1545, ISSN 0315-162X

*Rheum.*, Vol. 34, No. 3, pp. 276–286, ISSN 1044-2626

ISSN 1476-5381

987, ISSN 1521-6942

Vol. 2, No. 4, pp. 575-582.

ISSN 0390-6078

0950-9232

1044-2626

ISSN 1044-2626

pp. 3077-3087, ISSN 1044-2626

pharmacodynamics, and activity of a humanized anti-CD40 antibody (SGN-40) in rodents and non-human primates. *Br J Pharmacol* Vol. 148, No 8, pp. 1116-1123,

management: a moving target. *Best Pract Res Clin Rheumatol,.* Vol. 21, No. 6, pp. 971-

of B cell differentiation by interleukin-6 and soluble CD23 in systemic lupus erythematosus B cell subpopulations and antigen-induced normal B cells. *Arthritis* 

antibody inhibits autoimmune responses in a murine model of systemic lupus

historical and future perspectives. *Haematologica.,* Vol. 95*,* No 1, pp. 135*-*43,

patients with systemic lupus erythematosus: a longitudinal analysis of 24 patients.

(anti-CD22 IgG) in B-cell malignancies. *Oncogene*, Vol. 26, No. 25, pp. 3704-13, ISSN

effects of anti-interleukin-10 monoclonal antibody administration in systemic Lupus erythematosus. *Arthritis Rheum.* Vol. 43, No. 8, pp. 1790–1800, ISSN

of B cell depletion therapy in systemic lupus erythematosus at University College London Hospital: the first fifty patients. *Arthritis Rheum*, Vol. 61, No.4, pp. 482-487,

CD40 antagonist antibody, HCD122, on human chronic lymphocytic leukemia cells.

abatacept in patients with non-life-threatening manifestations of systemic lupus erythematosus: results of a twelve-month, multicenter, exploratory, phase IIb, randomized, double-blind, placebo-controlled trial. *Arthritis Rheum*. Vol.62, No.10,


Furie, R.; Stohl, W.; Ginzler, E.M.; Becker, M.; Mishra, N.; Chatham, W.W, Merrill, J.T.;

Genovese, M.C.; Kaine, J.L.; Lowenstein, M.B. et al. (2008). Ocrelizumab, a humanized anti-

Goldenberg, D.M.; Rossi, E.A., Stein, R. et al. (2009). Properties and structure-function

Grondal, G.; Gunnarsson, I.; Ronnelid, J. et al. (2000). Cytokine production, serum levels and

Hayden-Ledbetter, M.S.; Cerveny, C.G.; Espling, E. et al. (2009). CD20-directed small

Hauptrock, B.& Hess, G. (2009). Rituximab in the treatment of non-Hodgkin's lymphoma*.* 

Hillmen, P, Young NS, Schubert J, et al. (2006). The complement inhibitor eculizumab in

Illei, G.G; Shirota, Y.; Yarboro, C.H. et al. (2010). Tocilizumab in systemic lupus

Jones, G. & Ding, C. (2010). Tocilizumab: a review of its safety and efficacy in rheumatoid

Jones, G.; Sebba, A.; Gu, J. et al. (2010). Comparison of TCZ monotherapy versus

Kalled, S.L.; Cutler, A.H.; Ferrant, J.L. (2001). Long-term anti-CD154 dosing in nephritic

Kalunian, K.C.; Davis, J.C. Jr.; Merrill, J.T. et al. (2002). IDEC-131 Lupus Study Group.

Kausar, F.; Mustafa, K.; Sweis, G. et al. (2009). Ocrelizumab: a step forward in the evolution of B-cell therapy. *Expert Opin Biol Ther,* Vol. 9, No pp. 889-895, ISSN 1471-2598

*Rheum*, Vol. 58, No 9, pp. 2652-2661, ISSN 1044-2626

*Blood*, Vol. 113, No 5, pp. 1062-1070, ISSN 0006-4971

*Biologics,* Vol. 2, No. 4, pp.619-633 , ISSN 1177-5491

Vol. 62, No. 2, pp. 542-552, ISSN 1044-2626

Vol. 10, No 1, pp. 9–22, ISSN 0961-2033

*Rheum.,* Vol. 46, No 12, pp. 3251–3258, ISSN 1044-2626

*Clin Cancer Res,* Vol. 15, No 8, pp. 2739-2746 , ISSN 1557-3265

pp. 565–570, ISSN 0392-856X

1243, ISSN 0028-4793

ISSN 1179-5441

0003-4967

6362

Weinstein, A.; McCune, W.J.; Zhong, J.; Cai, W.; Freimuth, W. (2008). Biologic activity and safety of belimumab, a neutralizing anti-B-lymphocyte stimulator (BLyS) monoclonal antibody: a phase I trial in patients with systemic lupus erythematosus. Study Group B*. Arthritis Res Ther*., Vol 110, No 5, R109, ISSN 1478-

CD20 monoclonal antibody, in the treatment of patients with rheumatoid arthritis: a phase I/II randomized, blinded, placebo-controlled, dose-ranging study. *Arthritis* 

relationships of veltuzumab (hA20), a humanized anti-CD20 monoclonal antibody.

disease activity in systemic lupus erythematosus. *Clin Exp Rheumatol,* Vol. 18, No 5,

modular immunopharmaceutical, TRU-015, depletes normal and malignant B cells.

paroxysmal nocturnal hemoglobinuria. *N Engl J Med.*, Vol. 355, No 12, pp. 1233-

erythematosus: data on safety, preliminary efficacy, and impact on circulating plasma cells from an open-label phase I dosage-escalation study. *Arthritis Rheum.*

arthritis. *Clin Med Insights Arthritis Musculoskelet Disord*., Vol. 19, No. 3, pp. 81-89,

methotrexate monotherapy in patients with moderate to severe rheumatoid arthritis: The AMBITION study. *Ann Rheum Dis.* Vol. 69, No 1, pp. 88–96, ISSN

mice is required to maintain survival and inhibit mediators of renal fibrosis. *Lupus,* 

Treatment of systemic lupus erythematosus by inhibition of T cell costimulation with anti-CD154: a randomized, double-blind, placebo-controlled trial. *Arthritis* 


The Emerging Role of Monoclonal Antibodies in the Treatment of Systemic Lupus Erythematosus 273

Robak, E. & Robak, T. (2009). Monoclonal antibodies in the treatment of systemic lupus erythematosus. *Curr Drug Targets,,* Vol. 10, No 1, pp. 26–37, ISSN 1389-4501 Robak, T & Robak, E. (2011). New anti-CD20 monoclonal antibodies for the treatment of

Rubbert-Roth, A. (2010). TRU-015, a fusion protein derived from an anti-CD20 antibody, for

Ruuls, S.R.; Lammerts van Bueren J.J.; van de Winkel J.G. et al. (2008). Novel human

Schröder, J.O. & Zeuner, R.A. (2009). Biologics as treatment for systemic lupus: great efforts,

Sfikakis, P.P.; Boletis, J.N.; Lionaki, S. et al. (2005). Remission of proliferative lupus nephritis

Smith, K.G.; Jones, R.B.; Burns, S.M. & Jayne, D.R. (2006). Long-term comparison of

St Clair, E.W. (2009). Novel targeted therapies for autoimmunity. *Curr Opin Immunol.* Vol.

Terrier, B.; Amoura, Z.; Ravaud, P. et al. Club Rhumatismes et Inflammation. (2010). Safety

Tokunaga, M.; Saito, K.; Kawabata, D. et al. (2007). Efficacy of rituximab (anti-CD20) for

Toubi, E.; Kessel, A.; Rosner, I. et al. (2006). The reduction of serum B-lymphocyte activating

van Kooten, C.; Banchereau, J. (2000). CD40-CD40 ligand. *J Leukoc Biol* ,Vol. 6, pp. 2-17, ISSN

Wallace, D.J.; Stohl, W.; Furie, R.A. et al. (2009). A phase II, randomized, double-blind,

Wiglesworth, A.K.; Ennis, K.M. & Kockler, D.R. (2010). Belimumab: a BLyS-specific inhibitor

8804

123, ISSN 1355-6568

pp. 252-255, ISSN 1570-1638

No. 2, pp. 501-513, ISSN 1044-2626

21, No. 6, pp.648-657, ISSN 0952-7915

Vol. 62, No. 8, pp. 2458-66 , ISSN 1044-2626

*Rheum Dis.,* Vol. 66, No. 4, pp. 470-5, ISSN 0003- 4967

*Scand J Immunol.,* Vol. 63, No. 4, pp. 299-303, ISSN 0301-6323

ISSN 0268-2575

ISSN 1044-2626

0741-5400

1044-2626

ISSN 1060-0280

B-cell lymphoid malignancies. *BioDrugs*, 2011 Vol. 25, No. 1, pp.13-25, ISSN 1173-

the treatment of rheumatoid arthritis. *Curr Opin Mol Ther.*, Vol. 12, No. 1, pp. 115-

antibody therapeutics: the age of the Umabs. *Biotechnol J,* Vol. 3, No pp. 1157-1171,

sobering results, new challenges. *Current Drug Discovery Technologies* , Vol.6, No. 4,

following B cell depletion therapy is preceded by down-regulation of the T cell costimulatory molecule CD40 ligand: an open-label trial. *Arthritis Rheum,.* Vol. 52,

rituximab treatment for refractory systemic lupus erythematosus and vasculitis: Remission, relapse, and re-treatment. *Arthritis Rheum.,* Vol. 54, No. 9, pp. 2970-82,

and efficacy of rituximab in systemic lupus erythematosus: results from 136 patients from the French AutoImmunity and Rituximab registry. *Arthritis Rheum.,*

refractory systemic lupus erythematosus involving the central nervous system. *Ann* 

factor levels following quinacrine add-on therapy in systemic lupus erythematosus.

placebo-controlled, dose-ranging study of belimumab in patients with active systemic lupus erythematosus. *Arthritis Rheum.,* Vol. 61, No 9, pp. 1168–1178, ISSN

for systemic lupus erythematosus. *Ann Pharmacother.*, Vol. 44, No.12, pp. 1955-61,


Merrill, J.T.; Neuwelt, C.M.; Wallace, D.J. et al. (2010). Efficacy and safety of rituximab in

Molloy, E.S.& Calabrese, LH. (2008). Progressive multifocal leukoencephalopathy: a national

Navarra, S.V.; Guzmán, R.M.; Gallacher, A.E. et al. BLISS-52 Study Group. (2011). Efficacy

Ng, K.P.; Cambridge, G., Leandro, M.J. et al. (2007). B cell depletion therapy in systemic

Østergaard, M.; Baslund, B.; Rigby, W. et al. (2010). Ofatumumab, a human anti-CD20

Parker, C.J.; Kar, S. & Kirkpatrick, P. (2007). Eculizumab. *Nat. Rev. Drug Discov*. Vol. 6, No 7,

Pepper, R.; Griffith, M.; Kirwan, C. et al. (2009). Rituximab is an effective treatment for lupus

Ravirajan, C.T.; Wang, Y.; Matis, L.A. et al. (2004) Effect of neutralizing antibodies to IL-10

Robak, T. (2004). Monoclonal antibodies in the treatment of autoimmune cytopenias. *Eur J f* 

Robak, E.; Kulczycka, L.; Sysa-Jedrzejowska, A. et al. (2007). Circulating proangiogenic

erythematosus. *Eur Cytokine Netw.,* Vol. 18, No. 4, pp. 181-7, ISSN 1148-5493 Robak, T. (2008). Ofatumumab, a human monoclonal antibody for lymphoid malignancies

Robak, T. (2009). GA-101, a third-generation, humanized and glyco-engineered anti-CD20

Robak, T.; Robak, P. & Smolewski P. (2009). TRU-016, a humanized anti-CD37 IgG fusion

trial. *Arthritis Rheum.*, Vol. 62, No. 1, pp. 222-233, ISSN 1044-2626

*Clin Oncol.* Vol. 27, No. 20, pp. 3346-3353, ISSN 0732-183X

*Dis,.* Vol. 66, No. 9, pp. 1259-62, ISSN 0003-4967

Vol. 62, No. 8, pp. 2227-2238, ISSN 1044-2626

Vol. 24, No. 12, pp. 3717-3723, ISSN 0931-0509

*Haematol.,* Vol. 72, No. 2, pp.79-88, ISSN 0902-4441

Vol. 10, No. 6, pp. 588-596, ISSN 1472-4472

Vol. 10, No pp. 1383-1390, ISSN 1472-4472

*Rheumatology.* Vol. 43, No 4, pp. 442–447. , ISSN 0315-162X

pp. 515–625, ISSN 1474-1776

1355-6568

731, ISSN 0140-6736

diseases. *Arthritis Rheum.*, Vol. 60, No. 12, pp. 3761-5, ISSN 1044-2626 Morschhauser, F.; Leonard, J.P.; Fayad, L. et al. (2009). Humanized anti-CD20 antibody,

moderately-to-severely active systemic lupus erythematosus: the randomized, double-blind, phase II/III systemic lupus erythematosus evaluation of rituximab

estimate of frequency in systemic lupus erythematosus and other rheumatic

veltuzumab, in refractory/recurrent non-Hodgkin's lymphoma: phase I/II results. *J* 

and safety of belimumab in patients with active systemic lupus erythematosus: a randomised, placebo-controlled, phase 3 trial. *Lancet.*, Vol. 377, No. 9767, pp. 721-

lupus erythematosus: long-term follow-up and predictors of response. *Ann Rheum* 

monoclonal antibody, for treatment of rheumatoid arthritis with an inadequate response to one or more disease-modifying antirheumatic drugs: results of a randomized, double-blind, placebo-controlled, phase I/II study. *Arthritis Rheum.*,

nephritis and allows a reduction in maintenance steroids. *Nephrol Dial Transplant.*,

and C5 on the renal damage caused by a pathogenic human anti-ds DNA antibody.

molecules PIGF, SDF-1 and sVCAM-1 in patients with systemic lupus

and autoimmune disorders. *Curr Opin Mol Ther.,* Vol. 10, No. 3, pp. 294-309, ISSN

mAb for the treatment of B-cell lymphoid malignancies. *Curr Opin Investig Drugs.*,

protein for the potential treatment of B-cell malignancies. *Curr Opin Investig Drugs*,


Willems, M.; Haddad, E.; Niaudet, P.; Koné-Paut, I. et al. French Pediatric-Onset SLE Study Group. (2006). Rituximab therapy for childhood-onset systemic lupus erythematosus. *J Pediatr.*, Vol. 148, No. 5, pp. 623-627, ISSN 0271-6798

**14** 

*Japan* 

**Treatment of Pediatric-Onset Lupus** 

**Cytotoxic Immunosuppressive Therapy** 

*1Department of School Health Science, Faculty of Education Hirosaki University,* 

*3Department of Vascular Biology, Hirosaki University Graduate School of Medicine* 

Optimal treatment for lupus nephritis in adolescents is still a great challenge. Systemic lupus erythematosus (SLE) is a chronic disease characterized by frequent disease flares for which effective and safe maintenance therapy is required (Chan et al., 2005; Lai et al., 2005). Since diffuse proliferative lupus nephritis (DPLN) is a major concern regarding treatment of young patients with SLE, the optimal immunosuppressive therapy for controlling the activity of DPLN in this population remains controversial (Niaudet, 2000; Tanaka et al., 2004, 2009). Intermittent monthly pulses of intravenous cyclophosphamide (CPA) have been reported to be effective even for patients with pediatric-onset SLE (Lehman & Onel, 2000); however, CPA is a potent immunosuppressive agent associated with myelotoxicity, gonadal toxicity, and an increased risk of secondary malignancy (Chan et al., 2000; Lai et al., 2005). Since therapy related-adverse events are a major therapeutic risk of the immunosuppressive treatment in patients with SLE, selecting a safe and effective treatment protocol poses a big dilemma for physicians treating young patients. Thus, optimal maintenance treatment for controlling the clinical activity of SLE, particularly in young patients with pediatric-onset

SLE, remains to be established (Yang et al., 1994; Niaudet, 2000; Tanaka et al., 2001).

Mycofenolate mofetil (MMF) has recently been reported to be as effective as and less toxic than oral CPA or monthly intermittent pulse therapy with intravenous CPA (iv-CPA) for SLE patients (Chan et al., 2000; Lai et al., 2005; Sinclair et al., 2007). However, clinical use of MMF, in patients other than those undergoing solid organ transplantation, has not been approved by the Japanese Ministry of Health and Welfare yet. On the other hand, mizoribine (MZR), a selective inhibitor of inosine monophosphate dehydrogenase in the *de novo* pathway of purine nucleotides, which acts very similar to MMF (Burkhardt & Kalden, 1997; Yokota, 2002), has been successfully used without any serious adverse effects for the long-term treatment of young patients with lupus nephritis (Tanaka et al., 2004; Yumura et al., 2005). We hypothesized that calcineurin inhibitors, other than MZR, might be a feasible alternative treatment for patients with pediatric-onset lupus nephritis (Tanaka et al., 2007a, 2009). Tacrolimus (Tac) is a T-cell-specific calcineurin inhibitor that prevents the activation of helper T cells, thereby inhibiting the transcription of the early activation genes of interleukin (IL)-2

**1. Introduction** 

 **Nephritis: A New Option of Less** 

*2Department of Pediatrics, Hirosaki University Hospital and* 

Hiroshi Tanaka1,2 and Tadaatsu Imaizumi3

Yap, DY.; Lai, KN. (2010). Cytokines and their roles in the pathogenesis of systemic lupus erythematosus: from basics to recent advances. *J Biomed Biotechnol,* 2010:365083. Epub 2010 May 6. ISSN 1110-7243.
