New approach to psoriatic arthritis: modified anti-CD3 Mab

[Guest guest]

Sep 25, 2002

New approach to psoriatic arthritis: modified anti-CD3 Mab

Chicago A modified anti-human CD3 monoclonal antibody has potential as a

new treatment of psoriatic arthritis (PsA), according to a phase 1/2

clinical trial described in the September issue of the Journal of

Rheumatology [1]. Researchers tested huOKT31 (ala-ala) in 7 patients with

PsA and found that 8 to 10 days of treatment (after escalating the dose

gradually) led to improvements in the number of tender and swollen joints

and in a pain scale score for up to 90 days after treatment.

According to Dr Tammy O Utset (University of Chicago, IL) and colleagues,

" [These] results suggest that huOKT31 (ala-ala) may offer a viable approach

to the treatment of chronic type 1 T lymphocyte mediated autoimmune diseases

such as PsA. "

Unlike the monoclonal antibody rituximab, which acts by depleting B cells

and has shown promise in treating rheumatoid arthritis (RA), the non-Fc

receptor binding huOKT31 (ala-ala) is thought to deliver a partial signal to

the T-cell receptor instead of activating T cells. It has been shown to have

lower toxicity than the conventional murine OKT3 (which is marketed for

acute graft rejection), and the results from this small trial lead Utset and

colleagues to describe it as a " promising agent. "

Eight patients were initially enrolled in the study and assigned to 1 of 4

dose protocols, escalating to a maximum dose of 4.0 mg/day over 1 to 6 days.

The 7 patients who completed the study all received this dose for 8 to 10

days. The 1 patient who received the maximum dose with no dose escalation

experienced significant toxicity and was discontinued from the trial.

Of the 7 patients who completed the trial, 6 showed >75% improvement in the

number of tender and swollen joints and an average improvement of 63% on the

patient pain scale at 30 days. The researchers describe the response as

" dramatic " and note that 5 patients had no swollen joints at 30 days. Only 2

of these patients showed continued improvement at 90 days. They also note

that the remaining 4 of the 6 responding patients had a recurrence of

disease activity but were still improved compared with disease activity at

entry. One patient was excluded from the analysis " because it became

apparent thatŠ (she) was aberrant in both her disease and her response, " the

authors comment. Of the 8 patients, 7 had active cutaneous psoriasis; 3

patients showed improvement, but this was not statistically significant.

" Some patients in this small trial had clinical benefit that extended

significantly longer that the period of active treatment, " the researchers

note. They suggest that " the failure of the majority of patients to gain a

complete, persistent response may reflect heterogeneity of the T-cell

effector populations involved in autoimmune responses " and is unlikely to be

due to inadequate dosing. Repeated exposure to huOKT31 (ala-ala) would more

effectively modulate asynchronous populations of T lymphocytes and may

prevent recurrence of synovitis, they add.

Safety profile good with dose escalation

Only the patient who received an initial maximum dose of 4.0 mg of huOKT31

(ala-ala) with no escalation developed symptoms suggestive of mild cytokine

release syndrome compared with the severe symptoms of cytokine release

syndrome seen in treatment with conventional murine OKT3. The patient whose

dose was escalated to the maximum dose over 2 days showed " mild symptoms " on

the first day but quickly recovered and completed the study without further

complication. The researchers conclude that side effects " may be mitigated

or avoided by using a dose escalation over at least 2 days prior to

administration of full-dose huOKT31 (ala-ala). "

Two patients in the 4-day escalation protocol developed anti-huOKT31

(ala-ala) antibodies; however, this was not associated with a poor clinical

response. According to study investigator Dr Marcus R (University of

Chicago, Chicago, IL), further studies will be done looking at concurrent

treatment with methotrexate, which has been shown to minimize anti-idiotypic

responses to infliximab in the treatment of RA.

told rheumawire that a phase 2 study of approximately 120 patients at

multiple institutions funded by the Immune Tolerance Study has been approved

by the FDA, and it is hoped to be started by the beginning of 2003. He added

that huOKT31 (ala-ala) is being pursued by individual investigators (with 1

study in diabetes published earlier this year in the New England Journal of

Medicine [2]). However, he added that it " was unclear how it would come to

market. "