Immunomodulating Agents - Drug Design and Discovery

Biomedical Engineering Reference

In-Depth Information

self-antigens to form immune complexes that deposit in the tissues and instigate an inl ammatory

process. Rituximab has shown very promising clinical results in the treatment of SLE. Antibodies

against other surface antigens are being pursued for B cell depletion therapy; these include CD19,

CD22, CD32, CD38, and CD138.

22.5.5 T ARGETING T C ELLS

Agents that can interfere with T cell functions open up an important new avenue to the treatment of

various autoimmune diseases as well as transplantation. There are several mechanisms that can be

exploited: depletion of the T cells, interfering with TCR-mediated signaling and targeting costimu-

latory signaling to induce anergy (immune unresponsiveness), and i nally targeting several cytok-

ines indirectly modulates the T cell function (see Section 22.5.3). Below are examples of mAbs

developed for depletion of T cells as well as mAbs interfering with the TCR described.

Anti-CD3 (Muromomab-CD3) is the i rst type of murine mAb directed against the epsilon chain

of the CD3 molecule (an integral part of the TCR complex). It thereby inactivates T-cell function

blocking both naive T cells and CTLs. This results in rapid depletion of T cells from circulation

and cytokine release. This antibody is used to treat acute graft rejection in transplantation. Several

severe adverse effects as a result of Muromonab-CD3 are thought to be a product of the cytokine

release (also known as cytokine storm). Humanized versions of this antibody are being pursued that

are also engineered in the Fc part of the molecule to be nondepleting and to decrease the cytokine

storm. The antibodies are believed to induce tolerance by up regulation of regulatory T cells. These

antibodies are being investigated in clinical trials for treatment of Type I diabetes and other autoim-

mune and inl ammatory diseases such as RA, psoriasis, and inl ammatory bowel disease.

Alemtuzumab (Campath ® ) is a humanized anti-CD52 mAb that has emerged as an effective

lymphocyte-depleting agent for organ transplantation, RA, MS, and vasculitis. Most of the depleted

T cells return to near normal in 3 months after dosing. There is a risk that anti-CD52 treatment elic-

its autoimmune diseases; this is believed to be due to depletion of the regulatory T cells.

Abatacept (Orencia ® ) is a fusion protein of CTLA-4 (a surface protein of CTLs) and the Fc frag-

ment of the human immunoglobulin IgG. It acts at the level of the T-lymphocytes where it blocks

activation by interference with the path of costimulation between the APC and the T-lymphocyte.

Abatacept thus modulates the activity of the B cells, DCs, macrophages, and other cells implicated

in the inl ammatory cascade and it is currently being developed for treatment of RA.

22.6 PROSPECTS OF IMMUNE MODULATING AGENTS

The immune system is highly complex and new immunological mechanisms and how they relate to

human disease is still being identii ed. In this chapter, focus has been on the more established thera-

peutic approaches, general immune suppression that is still the i rst line treatment in autoimmune

disease, depleting antibodies against cell surface ligands, the messenger proteins of the immune

system—the cytokines and i nally the targeting of the T cells. There are several other molecular

avenues that can be explored, the i rst inhibitory antibody to the complement system has just reached

the market; some are in clinical development including inhibitory antibodies to the innate immune

system and blocking of the Th17 pathway. We expect to see many more immunological pathways to

be explored over the years to come as we learn more about this highly fascinating biological system

with plenty of therapeutic opportunities.