CTLA-4Ig induction may reduce need for cyclophosphamide maintenance in lupus nephritis

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Rheumawire

June 3, 2004

CTLA-4Ig induction may reduce need for cyclophosphamide maintenance in

lupus nephritis

San Francisco, CA - CTLA-4Ig (Abatacept, Bristol-Myers Squibb), a

recombinant soluble fusion protein that blocks CD28-mediated T-cell

stimulation, significantly increases the ability of cyclophosphamide

(CTX) to stop lupus-related kidney damage. An initial blast of the 2

agents can almost eliminate the need for long-term, broadly

immunosuppressive CTX maintenance therapy, Dr Gaye Cunnane (University

of California, San Francisco) reports in the May 2004 issue of Arthritis

& Rheumatism [1]. The CTLA-4Ig/CTX combination is now being studied in a

clinical trial aimed at determining whether it can induce remission of

active lupus nephritis more quickly, completely, and safely than CTX

alone.

" As a single agent [in murine studies], CTLA-4Ig was generally as

effective, and in some cases more effective, than CTX in slowing

progression of renal disease. Combined therapy with these 2 agents very

effectively arrested the progression of renal damage and, in some

respects, reversed renal pathology. Induction therapy with both CTLA-4Ig

and CTX precluded the need for continuous administration of CTX, "

Cunnane writes.

Principal investigators on the planned clinical trial are Dr Betty

Diamond (Albert Einstein College of Medicine, Bronx, NY) and Dr

Wofsy (University of California, San Francisco). Other participating

investigators are Dr Anne son (Albert Einstein College of Medicine,

Bronx, NY) and Dr Daikh (University of California, San Francisco).

Daikh was also senior author on the Cunnane study.

The clinical-study protocol notes that blockade of B7-CD28 by agents

such as CTLA-4Ig diminishes autoreactivity and reduces inflammatory

infiltrates in the kidneys of lupus-prone mice. The investigators note,

" tudies of CTLA-4Ig in combination with cyclophosphamide have shown

that this treatment protocol leads to a long-term decrease in

autoantibody production extending well beyond the period of therapy and

can lead to improvement in renal function and renal histopathology in

[lupus-prone] mice. Furthermore, even when autoreactivity occurs, there

is an absence of progression of the renal disease, coincident with an

altered pattern of chemokine expression in the kidney. "

In addition to determining whether CTLA-4Ig and CTX together can induce

remission of active nephritis more effectively than CTX alone, the study

will also determine whether CTLA-4Ig alone or with CTX is better than

CTX alone at maintaining remission in lupus nephritis and whether

long-term self tolerance is induced by CTLA-4Ig, as shown by a reduction

in the incidence of lupus flares following the termination of therapy.

In the animal study, age-matched mice with active nephritis and

equivalent levels of proteinuria were randomized to treatment with

saline control, CTX, CTLA-4Ig, or combined CTX and CTLA-4Ig for 4 weeks.

Proteinuria decreased in the mice treated with CTX plus CTLA-4Ig but not

in any of the other groups.

Combined therapy also prevented active lesions from progressing to

chronic, fixed lesions and reduced renal damage more effectively than

either agent alone. The combination also reduced glomerular immune

complex deposition within the kidneys and reduced renal infiltration by

inflammatory cells. " This is the first therapy that has been shown to

achieve this important goal, and it contrasts with conventional pulse

CTX therapy, which slows but does not prevent progression of lupus

nephritis in [lupus-prone] mice, " the investigators report.

The sustained effect was particularly interesting. Four months after

completing an 8-week course of CTLA-4Ig, mice that had received only a

single injection of CTX also had significantly less proteinuria than

controls and had the same decrease in proteinuria as mice who had

received continuous CTX plus CTLA-4Ig.

Cunnane writes, " [Our data] demonstrate that the combination of CTX and

CTLA-4Ig has a profound impact on the progression of renal pathology in

lupus-prone mice, and these agents have distinct and additive effects on

the development of renal disease. Finally, our studies demonstrate that

the synergistic benefit of combined therapy may provide a means of

eliminating maintenance CTX therapy and its attendant toxicity. "

The Bristol-Myers Squibb formulation of CTLA-4Ig is currently in phase 3

clinical trials for treatment of rheumatoid arthritis.

Janis

Source

1. Cunnane G, Chan OT, Cassafer G, et al. Prevention of renal damage in

murine lupus nephritis by CTLA-4Ig and cyclophosphamide. Arthritis Rheum

2004 May; 50(5):1539-48.

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