Anti-CD154 antibody in lupus nephritis has considerable potential

[Guest guest]

Rheumawire

Feb 5, 2004

Bethesda, MD - An experimental approach to the treatment of lupus

nephritis, which targets the B-cell overreactivity seen in lupus with a

humanized anti-CD154 antibody (Biogen, Cambridge, MA), has shown

long-lasting and significant clinical benefit in a handful of patients

taking part in a small open-label trial carried out by the US National

Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS).

Objective measures of disease, including proteinuria and scores on a

standardized systemic lupus erythematosus disease activity index

(SLEDAI), remained significantly suppressed over a 20-month

posttreatment period.

Clinical results and details of the immunologic changes that accompanied

them (which have been previously reported on rheumawire) are outlined in

a recent issue of the Journal of Clinical Investigation [1], which

featured this research on its front cover. Although the product used in

this trial has been dropped from further development because of adverse

effects, the " substantial clinical improvements observed " suggest that

this approach offers " a therapeutic strategy of considerable potential, "

says an accompanying commentary [2].

The paper describes results obtained in 4 patients with active lupus

nephritis who received 3 or more infusions of the anti-CD154 antibody

(also known as BG9588). The trial was originally planned to involve 28

patients but was ended prematurely because of reports from other trial

centers of an increased frequency in thromboembolic events. All 4

patients showed some improvement during and after treatment, the

researchers report. Two patients, who received the largest amount of the

product, both achieved and maintained complete renal remission without

any additional clinical intervention. The other 2 patients received a

shorter course of therapy and showed a different clinical

pattern although both improved during treatment and immediately after

treatment withdrawal, they eventually exhibited disease reactivation and

required additional immunosuppressive therapy.

First author Dr Amrie Grammer (NIAMS) elaborated on the science behind

this novel therapeutic approach in a recent interview with rheumawire.

She and her colleagues at the B-cell biology unit were responsible for

the basic research described in the paper, while Dr Gabor Illei and

colleagues in the clinical unit conducted the trial. Both parts of this

translation research were coordinated by Dr Lipsky, director of

the intramural research program at NIAMS (and also editor-in-chief of

JointandBone.org).

The antibody product used in this trial targets B-cell hyperreactivity,

which is a hallmark of systemic lupus erythematosus but also

characteristic of several other autoimmune diseases. Grammer comments

that this research has implications for all autoimmune disorders that

are driven by autoantibody-producing B cells, which include myasthenia

gravis, multiple sclerosis, and Guillain-Barré syndrome.

Whereas in healthy individuals B cells are usually found in a " resting

state, " in patients with SLE and other autoimmune diseases the B cells

are activated and have escaped from normal controls, resulting in the

production of pathogenic autoantibodies (eg, the anti-double-stranded

DNA [anti-dsDNA] antibody that is associated with lupus nephritis).

The maturation of B cells into antibodies occurs in germinal centers

(GCs). These are usually found in lymphoid tissue (eg, tonsils, spleen,

and lymph nodes), although in autoimmune disorders, ectopic germinal

centers can form in other tissues, Grammer explains. For example, in a

mouse model with lupus nephritis these ectopic germinal centers have

been found in the kidney.

The process of a B cell evolving into an antibody in these germinal

centers is initiated following antigen activation by an interaction

between T cells expressing CD154 and B cells expressing CD40. This is a

fundamental first step, known as the germinal-center-founder reaction;

after this, the B cells proliferate and mature on their own, interacting

with one another (homotypic interaction).

In a healthy individual, the B-cell activity within a germinal center is

directed against foreign-body antigens, and a selection process deletes

any other antibodies that are produced. In patients with autoimmunity,

these germinal centers run out of control, and B cells develop into all

kinds of antibodies, including autoantibodies that are directed against

the patient's own tissues. Without the normal selection processes in

place, these antibodies escape and some undergo isotype switching (from

immunoglobulin-M to -G) to become even more pathogenic.

The anti-CD154 antibody product used in the trial blocks the first step

in the process, the interaction between the T and B cells that acts as

the germinal-center-founder reaction. " With this product, we can stop

the initiation of germinal centers and also their maintenance, so that

they lose their ability to produce plasma cells that secrete

autoantibodies, " Grammer explains.

After treatment with the Biogen product, the activated B cells seen in

the blood of SLE patients disappeared, she notes. " Not only were plasma

cells gone from the blood, they were also no longer producing

autoantibodies. " In particular, the disappearance of 1 population of B

cells, those expressing a high level of CD38, was associated with

decreases in anti-dsDNA antibody levels as well as with decreases in

proteinuria and in SLEDAI scores.

Serum levels of anti-dsDNA showed a treatment-related decrease in all 4

patients, the researchers note in the paper. The levels fell

significantly, although 6 months after treatment was withdrawn, they

rebounded back to pretreatment levels (or even slightly higher in some

cases). In addition, treatment was associated with a decrease in

circulating immunoglobulin-G-secreting cells. However, treatment had no

effect on the levels of 2 other autoantibodies anticardiolipin and

antinuclear antigen antibodies or on the total serum level of

immunoglobulin-G.

A significant decrease in proteinuria was seen in all 4 patients. Mean

proteinuria for all 4 patients pretreatment was 3.6+1.4 g per 24 hours.

After 2 months of treatment, it had fallen to 2.5+1.8 g per 24 hours,

which is 68%+35% of the pretreatment level (p<0.05). The decrease in

proteinuria remained significant at 3 and 6 months after treatment. In 3

of the 4 patients who showed a prolonged response, proteinuria was still

decreased (by 32%+31% of pretreatment levels) at 20 months after

treatment, which suggests a long-term effect of anti-CD154 treatment on

kidney function, the researchers comment.

Scores on the SLEDAI showed a decrease in disease activity, and this

favorable effect persisted after cessation of treatment, they note. In 3

patients examined at 20 months after the final treatment, the mean

SLEDAI was 2.7+2.5, compared with a mean score of 12.7+4.1 in these

patients before treatment (p<0.05).

" Although the results reported here derive from an uncontrolled

open-label study involving a small number of patients, the data suggest

a central role of CD154-CD40 interactions in SLE, since specifically

blocking this receptor-ligand pair in vivo significantly reduced serum

autoantibodies, proteinuria, and an index of disease activity, " the team

concludes.

In the accompanying commentary, Dr Garnett Kelsoe (Duke University,

Durham, NC) says: " Grammer and colleagues have taken an important step

toward defining the promise of CD154-CD40 interaction as a target of

therapy. The future is not clear the antibody used in these studies

elicited unacceptable side effects but the direction of study has been

clearly defined. "

The Biogen product used in this trial has been shelved because it was

associated with an increased frequency of thromboembolic events in other

clinical trials. The mechanism behind this side effect is not

understood, but CD154-CD40 interactions involving activated platelets

and endothelial cells in patients with underlying vascular disease may

play a significant role, the NIAMS researchers comment. They note that a

different monoclonal antibody directed against CD154 (IDEC 131) has been

tried in SLE, apparently without any thrombotic events, although the

dose used was low and it did not show any efficacy either.

Since this research was carried out, Biogen and IDEC have merged into 1

company, and there is hope that new products targeting the CD154-CD40

interaction but without the thrombotic side effect will be developed.

Zosia Chustecka

Sources

1. Grammer AC, Slota R, Fischer R, et al. Abnormal germinal center

reactions in systemic lupus erythematosus demonstrated by blockade of

CD154-CD40 interactions. J Clin Invest 2003 Nov; 112(10):1506-20.

2. Kelsoe G. Therapeutic CD154 antibody for lupus: promise for the

future? J Clin Invest 2003 Nov; 112(10):1480-2.

I'll tell you where to go!

Mayo Clinic in Rochester

http://www.mayoclinic.org/rochester

s Hopkins MedicineAnti-CD154 antibody in lupus nephritis has

" considerable potential "

http://www.hopkinsmedicine.org