Treatment Challenges

One obvious target for any chronic autoimmune disease is to simply turn off the autoimmune response; however, little is known of what drives the chronicity of autoimmune disease. Instead, therapies tend to target points in the autoimmune/ inflammatory cascade: factors involved in lymphocyte homing to target tissues, enzymes that are critical for the penetration of blood vessels and extracellular matrix (ECM) by immune cells, cytokines that mediate pathology within the tissues, various cell types that mediate damage at the site of the disease, as well as the antigen-specific adaptive receptors of these cells - including the T cell receptor, and immunoglobulin and other toxic mediators - such as complement and nitric oxide. In each of these instances, the therapeutic target is involved in both host defense and autoimmune pathology, and so the overall risk:benefit ratio needs to be evaluated; natalizumab provides a timely example.

The dynamic character of chronic progressive autoimmune diseases presents special challenges for drug development. For instance, autoantigens can differ at various stages of a disease; this appears to be the case in MS, SLE, and

MG. Also, in the case of MS, disease most often progresses from a relapsing-remitting form to a progressive form distinguished by progressive axonal degeneration and little inflammation. Therefore, a therapy that works in one phase may be ineffectual in another; for example, most MS therapies target only relapsing forms, with little, if any, effect on progressive forms. Early intervention is always best to minimize the accumulation of cellular damage and any resulting functional deficit, as well as epitope spreading. However, early diagnosis with accurate prognostic assessment - in CIS, for example - is not always possible, and so treatments are often initiated years after the onset of the pathogenic process. The presence of both inflammatory and degenerative features presents a greater therapeutic challenge than a disease with only one of these features - another argument for early intervention when symptoms are likely to be less complex.

Molecular accessibility is an issue in the development of therapeutics. Barriers exist at the cell and tissue level. For this reason, molecular targets, particularly for biologics, are often extracellular domains of cell surface receptors or secreted molecules.

Excluding corticosteroids, the only approved therapies for the autoimmune diseases listed in Table 1 are for MS, and these are all parenteral - requiring injection or intravenous infusion - and almost all are protein based (see Table 2). Patients prefer oral therapies; in some instances, injections are not tolerated because of concomitant disease or injection site side effects, which are the focus of multiple current clinical trials. Unfortunately, protein-based therapies administered orally appear to have little or no therapeutic effect. The development of oral small-molecule agents for autoimmune disease would impact patient acceptance and adherence issues. Small-molecule agents are also favored by the fact that protein-based therapies have a much greater potential for immunogenicity (although small-molecule drugs can also elicit an autoimmune response). This potential for autoimmune response to the therapeutic itself adds a further complication to drug development, as this risk and its clinical consequences - separate from the efficacy of the therapy - need to be assessed; yet, as discussed earlier, there are no good, predictive animal models for doing so. In addition to presenting a potential clinical risk, any resulting neutralizing antibodies in humans can negatively impact efficacy. This problem of neutralization has been minimized for antibody therapeutics by the development of fully humanized monoclonals. However, it remains a concern with recombinant proteins and other antigens - for example, IFN-P therapies. On the other hand, protein-based therapies are natural body constituents, and so any toxicity from protein-based therapies is likely to be mechanism related, or a result of improper manufacturing procedures.

Blood Pressure Health

Blood Pressure Health

Your heart pumps blood throughout your body using a network of tubing called arteries and capillaries which return the blood back to your heart via your veins. Blood pressure is the force of the blood pushing against the walls of your arteries as your heart beats.Learn more...

Get My Free Ebook

Post a comment