NEW TREATMENTS FOR SYSTEMIC 

LUPUS ERYTHEMATOSUS

By targeting specific immunologic responses, administration of these biologic agents may

avoid nonspecific immunosuppression. More aggressive treatments under investigation
include gene therapy and stem cell transplantation.

Pharmaceutic treatments used for many years include hydroxycholoroquine and

corticosteroids, including methylprednisolone, cyclophosphamide, and azathioprine, all of
which have been demonstrated to be effective in one or more controlled trials. Weekly
methotrexate and cyclosporine therapy has offered benefit in SLE; controlled trials to
demonstrate their efficacy are currently underway. Promising pharmaceutic treatments
include several immunomodulators and agents.

BIOLOGIC AGENTS

T-Cell Activation and T-cell-B-Cell Collaboration

Several agents currently under investigation have been designed to inhibit the coactivation
steps necessary for T-cell interaction and 

o Anti-CD40 ligand (CD40L) monoclonal antibodies (mAbs)

o CTLA-4Ig

o Anti-B7-1 and B7-1 mAbs

o Anti-CD40L mAbs

CTLA-4Ig

Another coactivation step that regulates T-cell-B-cell interactions includes CTLA-4/B7.

Although low in number, CTLA-4 is expressed on the surface of T-cells after activation and
has a high affinity for the B7 antigen present on B cells and antigen-presenting cells. A
soluble receptor, CTLA-4Ig is a fusion protein derived from the extracellular domain of CTLA-
4 and the Fc portion of IgG1, which serves as a soluble receptor, thereby preventing CTLA-
4/B7 interactions.

Anti-B7 Monoclonal Antibodies

Apparently, inhibition of both B7-1 and B7-2 antigens simultaneously is required to

downmodulate T-cell-B-cell collaboration. When NZB/W mice are treated with mAbs to both
B7-1 and B7-2, anti-DNA antibody production is decreased.

Inhibition of Production of Anti-dsDNA Antibodies

Murine models of SLE have shown that development of glomerulonephritis is the result of
an underlying process of deposition of cationic DNA-anti-DNA immune complexes in the
negatively charged glomerular basement membrane. Complement activation and neutrophil
chemotaxis follow immune complex deposition. It seems that the anti-DNA antibodies cross-
react.

A therapy used for many years in the treatment of SLE, intravenous immunoglobulin (IVIg),
may partially reverse severe organ system manifestations by decreasing anti-DNA Ab levels. 
It is useful in treating thrombocytopenia associated with SLE and during pregnancy in the
presence of antiphospholipid antibodies, although controlled clinical trials are lacking.  Its
use remains controversial, however, in the treatment of SLE nephritis. A recent study in
patients with SLE class III or IV glomerulonephritis.

3E10: Murine Monoclonal Antibody Idiotypic Vaccine

One therapy currently in development, referred to as 3E10, is a murine IgG2a mAb prepared
using isolated anti-dsDNA antibodies from MRL/lpr mice. When 3E10 mAb was used to
immunize MRL/1 mice.

The 3E10 therapy has been tested in a phase 1-2 placebo-controlled study. Twelve patients
with stable SLE and a previous history of nephritis were enrolled, and all had been taking
less than 20 mg of prednisone daily without immunosuppressive agents for at least 3
months. The 12 patients were evenly assigned to one of four groups: 50, 100, or 200
mug/mL of 3E10 or placebo.
LJP 394: B-Cell Toleragen

LJP 394 is a B-cell toleragen and consists of a trietheleneglycol backbone with four attached
oligonucleotides. Its administration cross-links anti-dsDNA on the B-cell surface, resulting in
downregulation of anti-dsDNA Ab production.

Inhibition of Anti-dsDNA Antibody Deposition

Recombinant Human DNAase

Daily treatment with 5 mg of recombinant murine DNAse for 3 weeks reduced the number
of splenic B cells secreting anti-DNA Abs and the amount of IgG anti-DNA Abs in experiments
with NZB/W mice with active nephritis.

Inhibition of Complement Activation and Deposition

Active SLE is associated with complement activation with decreased levels of C3, C4, and
CH50. Complement activation can be predictive of long-term outcome and serves as a
measure to assess treatment efficacy in some patients.

Anti-Complement 5 Monoclonal Antibody

In NZB/W mice that developed dsDNA Abs at approximately 4 months, treatment with a
mAb to murine C5 delayed proteinuria, improved renal histology, and prolonged survival
when these mice were compared with control animals. Proteinuria was also significantly
reduced in SCID mice implanted with PBMCs from patients with SLE producing anti-dsDNA
mAbs.

Cytokine Activation and Modulation

Another characteristic of active SLE disease includes increases in serum IL-10 levels and
spontaneous and stimulated PBMC production of IL-10. Increased levels of IL-10 are evident
in first-degree relatives and spouses in multicase SLE families.

Anti-Interleukin-10 Monoclonal Antibody

Research in preautoimmune NZB/W mice has demonstrated that although continuous
administration of IL-10 accelerated disease onset, treatment with anti-IL-10 mAbs retarded
the onset of disease. Similarly, anti-dsDNA antibody production in SCID mice.

Gene Therapy

Currently, clinical trials are being conducted in RA patients undergoing metacarpal joint
replacements using ex vivo gene transfer with a retroviral vector to encode human IL-1
receptor antagonist production.

Stem Cell Transplantation

Following a precedent set from the treatment of a variety of autoimmune diseases in which
bone marrow aplasia or malignant lymphoproliferative disorders have been induced by drug
therapies, bone marrow transplantation.

PHARMACEUTIC INTERVENTIONS

Promising pharmaceutic interventions for the treatment of SLE include a variety of

immunomodulators and therapies designed to alter sex hormone levels or function.

Immunomodulators

Thalidomide

Despite its controversial history, thalidomide has recently been approved in the United
States for the treatment of erythema nodosum leprosum. Other indications under study
include graft versus host disease. The most common adverse event associated with
thalidomide is peripheral neuropathy, which occurs in 20% to 50% of patients treated.

AS101
Primarily studied as a cancer therapy, AS101 has been shown to decrease the spontaneous
production of IL-10 when added to peripheral blood adherent cell cultures from patients
with SLE. This response was confirmed in SCID mice.

2-Cholordeoxyadenosine (Cladaribine)

By depleting resting and proliferating T and B lymphocytes while sparing neutrophils,

monocytes, red blood cells, and platelets, 2-cholordeoxyadenosine (2CdA) has proved to be
effective in the treatment of hairy cell leukemia.

Mycophenolate Mofetil

Approved for treatment of renal allograft rejection, mycophenolate mofetil has been used in
patients with SLE following renal transplantation. Its immunomodulatory properties may be
directly applied to the treatment of SLE.

Bindarit

In models of acute and chronic inflammation, including murine nephritis, bindarit appears to
regulate cytokine and chemokine production and thus inhibits the acute phase response.
This agent has increased the length of survival in NZB/W mice.

Methimazole

Methimazole has been shown to be effective in the treatment of Grave's disease, in which it
has been demonstrated to inhibit class I major histocompatibility complex expression in
thymocytes. A slow-release formulation of methimazole was given to BALB/c mice
immunized with the 16/6 idiotype mAb, resulting in significant reductions in dsDNA and
other autoantibodies.

Sex Hormones
Based on the observation that female NZB/W mice develop nephritis earlier and with more
severity than male mice, researchers have suggested that treatment with male hormones or
estrogen antagonists may delay the onset of disease or reduce its severity. An early attempt
used 19-nortestosterone, a synthetic androgen.