RESEARCH - New approach to RA: 4-1BB-mediated immunotherapy

[Guest guest]

New approach to RA: 4-1BB-mediated immunotherapy

Rheumawire

Sep 29, 2004

Zosia Chustecka

New Orleans, LA - A new approach to the treatment of rheumatoid

arthritis (RA) is suggested by the results of animal experiments with a

monoclonal antibody (MAb) that acts as an agonist at the T-cell

costimulatory receptor 4-1BB (CD137) [1]. As a therapeutic approach,

this triggering of 4-1BB " holds much promise, " as the process leads to

an antigen-specific immunosuppression with no deleterious effects on

global immune responses, the researchers comment in their study in

Nature Medicine, published online September 26, 2004.

The work was carried out in mice with collagen-induced arthritis, the

most commonly used animal model of rheumatoid arthritis. The agonist MAb

strongly suppressed disease activity and demonstrated a " robust

therapeutic effect, " the researchers report.

The agonistic anti-human 4-1BB monoclonal antibody (known as IRC75) was

developed by the researchers themselves. " This is a therapeutic MAb, but

the name is not known publicly, " lead researcher Dr Byoung Kwon

(Louisiana State University, New Orleans), tells rheumawire.

" Bristol-Myers Squibb once had an interest in developing the reagents,

but I do not know whether they are still working on it, " he added.

The new approach homes in on T cells found in the inflammatory lesions

of rheumatoid arthritis. The 4-1BB receptor is expressed on T cells only

after they have engaged with antigens, so therefore 4-1BB activities are

basically antigen specific, Kwon comments. His team found that

triggering 4-!BB with the agonistic MAb induced CD8 T cells into a new

phenotype of CD11cCD8 T cells and " expanded the population massively. "

This new T-cell population produced interferon-gamma, and this in turn

eventually led to a deletion of the arthritis-causing autoreactive CD4 T

cells. It is this last step that results in the therapeutic effect.

The final effector mechanism of this approach is similar to that of the

costimulation blocker abatacept (CTLA4-Ig), which has been shown to be

clinically useful in rheumatoid arthritis. (Abatacept is currently

completing phase 3 clinical trials and so could be available by 2006.)

However, the effect of this new agonist Mab on the production of T cells

" is so profound that this method is far superior to injecting

gamma-interferon or CTLA4-Ig effects in terms of directing dendritic

cells to delete CD4+T cells, " says Kwon.

I'll tell you where to go!

Mayo Clinic in Rochester

http://www.mayoclinic.org/rochester

s Hopkins Medicine

http://www.hopkinsmedicine.org