Basiliximab

Basiliximab (Simulect®) is meant for induction therapy in renal transplantation. It is a is a chimeric (human and murine) monoclonal antibody utilized in the prevention of acute organ rejection in renal transplant patients in combination with other immunosuppressant agents. In a study with renal transplant recipients, Basiliximab notably reduced acute rejection when measured against renal transplant patients who received only the standard dual-immuno therapy (cyclosporine microemulsion and corticosteroids) or triple-immunotherapy (azathioprine or mycophenolate mofetil along with dual therapy drugs). These placebo patients had graft and patient survival rates at 12 months. With the addition of the Basiliximab element of immunotherapy incidence of death, graft loss, and acute rejection was appreciably diminished at 3 years and malignancy was not increased at 5 years.

The addition of the Basiliximab to patient therapy does not harbor a higher incidence of adverse events. There is not an increase in incidence of infection (CMV infection - cytomegalovirus), malignancies, or post-transplant lymphoproliferative disorders as seen with the placebo patients.

The results in terms of efficacy for Basiliximab are on par with equine ATG and daclizumab and equal to or greater than muromonab CD3. In terms of RATG (rat antithymocyte globulin), Basiliximab was similarly effective with low risk of acute rejection transplant patients, but had less success with higher risk patients. Overall, Basiliximab elicits less adverse events in patients than in studies for both ATG or RATG recipients.

It seems that Basiliximab offers an immunotherapy option to withdraw corticosteroids from the list of immunosuppressants (using corticosteroid-free or calcineurin inhibitor-free therapy) in renal transplant patients. Another feature of this immunosuppressant agent is it did not increase the total expense of therapy in pharmaeconomic studies. Therefore, Basiliximab is a promising alternative in immunotherapy for the prophylaxis of acute renal transplant rejection due to its overall efficacy, tolerability, ease of administration, and cost effectiveness.

Basiliximab is a monoclonal antibody specific for the alpha chain of high affinity IL-2 receptor. IL-2 is a cytokine that elicits mass proliferation of lymphocytes. The IL-2 receptor (IL-2R) is the surface antigen on T lymphocytes that detects IL-2. The IL-2R comes in three forms: a low affinity, intermediate affinity, and high affinity receptor. Each level (low, intermediate, and high) refers to the receptor's ability to respond to IL-2 signals. The different levels of IL-2R expression depends on the level of T-cell activation - more activated mature T lymphocytes express the high-affinity IL-2R. There are also three subunits that combine to make up the different forms of the IL-2R: alpha, beta, and gamma. When the alpha subunit is expressed alone, it represents the low affinity IL-2R. The gamma and beta subunits in conjunction represent the intermediate version of the IL-2R. It is only when the alpha, beta, and gamma subunits are expressed concurrently that the receptor represents the high affinity version.

An antibody directed against the alpha subunit of the IL-2R, such as Basiliximab, effectively suppresses the lymphocyte's ability to proliferate in response to antigen recognition. This severely impairs the immune system's ability to respond to transplant antigens. Using concentrations greater than 0.2 µg/mL was sufficient to saturate IL-2Ra on all circulating T cells. This saturation in adult renal transplant recipients receiving 20 mg on days 0 and 4 after surgery was 36-49 days. This saturation time can be extended by the presence of the immunosuppressants azathioprine or mycophenolate mofetil. Basiliximab is minimally immunogenic, eliciting an antibody response in 4 out of 339 patients but the response is thought to mostly been a product of exposure to muromonab CD3. Because IL-2 is specific to T lymphocytes, it does not have significant effects on other cells in the body.

Anti-TAC is another drug that works by the same mechanism as Basiliximab (eg. it works by binding the alpha subunit of the IL-2R). Anti-TAC is still experimental and being studied for potential use in immunosuppressive therapy.

Anti-CD20

A treatment of Anti-CD20 Monoclonal Antibody is also being researched in the laboratory. CD20 is a marker with unknown function that is expressed on B cells. Its corresponding antibody, which is referred to as Rituximab, has shown promise in animal studies in depleting B cells from the blood and lymphatic tissues. Fittingly, Rituximab shows promise as a possible treatment for antibody-mediated acute vascular rejection, and is thus a drug that could reduce complications due to xenotransplantation. Ideally, it would be used before first antigen exposure and would effectively remove the anti-donor plasma cells of the B-cell population. Accordingly, this treatment may be an important

CP-690,550

Some of the numerous side effects plaguing individuals undergoing immunosuppressive therapy can be attributed to the fact that current drugs target enzymes found in cells throughout the body - not only immune cells. CP-690,550 is a candidate drug being researched that does not have this problem. It works by inhibiting the enzyme Jak3; this protein is only found in immune cells. Studies show that inhibiting this enzyme using CP-690,550 has the effect of suppressing the immune system, while leaving other body systems unaffected.

Studies are being conducted under a collaborative research and development agreement between Pfizer and the NIAMS Molecular Immunology and Inflammation Branch led by O'Shea and Zhou. Studies have shown that animals treated with CP-690,550 after undergoing heart transplant or kidney transplant surgery survive significantly longer than untreated animals. The treated animals also showed no signs of many common immunosuppressant side effects, such as increased cholesterol and blood pressure, or decrease in white blood cells and platelets. However, the studies did not compare transplant survival of this drug to other common drugs, such as Cyclosporine or Prednisone.

Although this drug is a promising answer to many immunosuppressant side effects, the efficacy of the drug must be determined in transplant individuals. Currently, initial animal studies are promising (including studies involving primates), and additional studies are being conducted to determine if this drug could be used successfully and safely in humans.

Antibodies targeting costimulatory proteins

Equally important as a positive identification of a foreign protein is a costimulatory signal. T and B lymphocytes require an appropriate costimulatory signal to become activated and perform effector functions. In the absence of this signal, anergy (nonresponsiveness) ensues. Costimulatory signals include the interaction between the CD28, CTLA-4, LFA-1, and CD40 Ligand on the T cell with their corresponding receptors on the APC (respectively, B7-1, B7-2, ICAM-1, and CD40). The costimulatory signal can be thought of as a final checkpoint that enables the lymphocyte to begin its destructive behavior. By blocking any of these signals through monoclonal or polyclonal antibodies, lymphocyte action will effectively be inhibited.

This has resulted in intense research involving antibodies specific for these surface proteins. Because a costimulatory signal is only needed activate immature lymphocytes, mature B and T cells needed for normal immune function (such as common diseases) are spared. Thus, only limited impairment of the immune system is experienced. Many costimulatory antibodies are currently undergoing animal trials. As a whole, they appear to be promising for clinical use.