Oral RA immunotherapy now in phase 2 clinical trial

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Rheumawire

Apr 1, 2004

Oral RA immunotherapy now in phase 2 clinical trial

San Diego, CA - A small, orally delivered peptide shifted T-cell

function from proinflammatory to regulatory in rheumatoid arthritis (RA)

patients and might open a new chapter in RA treatment, Dr Berent J

Prakken (University of California, San Diego [uCSD]) and colleagues

report in the March 23, 2004 issue of Proceedings of the National

Academy of Sciences [1]. The peptide, dnaJP1 or AP-001 (Androclus

Therapeutics, San Diego, CA), is now in phase 2 trials sponsored by the

US National Institute of Arthritis and Musculoskeletal and Skin Diseases

(NIAMS).

Senior author Dr Salvatore Albani (UCSD) tells rheumawire that the oral

peptide induced a shift from proinflammatory to regulatory T-cell

function and that this was due not to clonal deletion of

peptide-specific T cells but to changes in cellular immune function.

Although Albani, who founded Androclus Therapeutics, is cautious about

discussing the clinical data from the small, open-label pilot study, a

summary included in the phase 2 protocol description says that 84.6% (11

of 13) of the RA patients treated in the pilot study were responders

according to ACR20 criteria.

The pilot study enrolled 15 patients with active RA, with disease

duration of less than 5 years and in vitro responsiveness to dnaJP1,

defined by T-cell proliferation and/or production of proinflammatory

cytokines.

Patients were treated with dnaJP1 po daily at 0.25, 2.5, or 25 mg/day

for 6 months. Monthly clinical examination included joint scores for

swelling and tenderness, Rapid Assessment of Disease Activity in

Rheumatology scores, erythrocyte sedimentation rate, rheumatoid factor,

C-reactive protein, and serum chemistry.

Albani found no adverse effects associated with the peptide in this

study or subsequent patients. " I would be concerned, in theory, about

hypersensitivity, but to date, dnaJP1 has been administered to 130

patients without any attributable adverse events, " he tells rheumawire.

By the second month of treatment in the pilot study, T cells from

treated patients increased production of IL-10 and IL-4 following

exposure to dnaJP1, and there was decreased T-cell proliferation and

production of the proinflammatory cytokines IFN- and TNF-. Control

experiments with unrelated antigens showed that these changes were

antigen-specific and that the patients' other immune responses remained

intact.

Relatively little is known about T-cell responses during RA remission or

progression or in response to drug therapy. The researchers suggest that

the shared epitope contributes to the ontogeny and homeostasis of T

cells that can cross-react with peptides of microbial origin, triggering

proinflammatory responses in RA and other diseases.

This raised the possibility that changing immune responses to the shared

epitope by inducing a qualitative switch of antigen-specific T-cell

responses from a proinflammatory (TH-1) phenotype to a tolerogenic

(TH-2) phenotype might relieve some of the symptoms of RA. In the phase

1 trial, patients treated orally with dnaJP1 showed this response.

The dnaJP1 peptide was chosen as the tolerizing antigen because it is

derived from an Escherichia coli heat-shock protein that shares the RA

susceptibility sequence HLA DRB1*0401 (the " shared epitope " ) with self

HLA alleles and is a target of proinflammatory T-cell responses in

untreated RA patients.

Albani says that synthesis of the short peptide is easily scalable for

commercial production, should large-scale trials demonstrate efficacy.

The technology has been licensed from UCSD to Androclus Therapeutics.

The ongoing multicenter, randomized, double-blind trial will assign

patients to treatment with dnaJP1 25mg qd po or placebo for 6 months.

The primary end point is ACR20 response at 122, 140, and 168 days.

The trial protocol calls for 160 patients, and Albani says that 115 have

been enrolled to date. " We are actively looking for patients interested

in the trial, " Albani says. The researchers expect to report data next

year.

Janis

Source

1. Prakken BJ, Samodal R, Le TD, et al. Epitope-specific immunotherapy

induces immune deviation of proinflammatory T cells in rheumatoid

arthritis. Proc Natl Acad Sci U S A 2004 Mar 23; 101(12):4228-33.

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Mayo Clinic in Rochester

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s Hopkins Medicine

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