Monoclonal Antibodies are Not Always Better

For the endpoint of acute transplant rejection, SangStat's (NASDAQ: SANG) Thymoglobulin was more beneficial to kidney transplant recipients than Novartis's (NYSE: NVS) Simulect. Thymoglobulin is a polyclonal antiserum, while Simulect is a monoclonal antibody. The magnitude of benefit for high-risk kidney transplant recipients was so great that the formal study was halted early.

Polyclonal antisera are the low-tech cousin of monoclonal antibodies. Instead of an antibody of a single specificity, a polyclonal antiserum is a mixture of antibodies purified from the blood of an animal. The polyclonal serum is enriched for specific antibodies by prior immunization of the animal. In the case of Thymoglobulin, rabbits are injected with thymocytes (young T cells) to produce an antiserum that reacts to and depletes human T cells, thus inhibiting immune responses such as graft rejection.  Thymoglobulin is currently approved for the treatment of acute kidney transplant rejection, in conjunction with concomitant immunosuppression.

Simulect (basiliximab), on the other hand, is an anti-IL-2 receptor monoclonal antibody approved for the prophylaxis of acute organ rejection in patients receiving renal transplantation when used as part of a regimen containing cyclosporine and corticosteroids. Based on mediocre data presented at the December 2001 American Society of Hematology Meeting, Simulect will not quickly expand into other indications such as graft vs. host disease.

The goal of the current trial was to evaluate Thymoglobulin versus Simulect use at the same time as kidney transplant in patients at high risk of transplant rejection. Doctors have long awaited formal appraisal of the relative benefits of each of these medicines in this setting. Washington University School of Medicine investigators, led by Dr. Daniel C. Brennan, conducted a prospectively randomized, open-label, phase II comparative trial that assessed the clinical value of Thymoglobulin versus Simulect as induction therapy in high-risk kidney transplant patients who received cadaveric donations. Induction therapy is administered at the time of transplant to prevent acute organ rejection. The study showed a clear advantage for Thymoglobulin compared to Simulect.

Human clinical trial protocol halts studies early when interim data makes it clear that patients are responding significantly better to one treatment alternative. Then, study subjects receiving the other(s) are usually switched to the more beneficial therapy. In this case, an independent monitoring board halted the investigation after evaluating data from 212 of 279 current enrollees and 340 expected eventual enrollees. The acute kidney transplant rejection rate was 2.5 times lower in high-risk Thymoglobulin recipients compared to high-risk Simulect recipients. There were no statistically significant differences in terms of clinically severe adverse events.

Of the approximately 25,000 solid organ transplants in the U.S. in 2001, approximately 15,000 were kidney transplants, and about half of those were from cadaveric donors. 50%-70% of kidney transplants are considered high risk, with transplants from cadaveric donors tending to be riskier than those from live donors. 64% of the approximately 80,000 people on the U.S. transplant waiting list are awaiting kidneys.

This trial is the first significant head-to-head comparison of a polyclonal antiserum vs. a monoclonal antibody. We expect the results to create a buzz in several forums such as The International Heart and Lung Transplant meetings in April and the American Transplant Congress meetings in Washington D.C. At the Congress meeting, investigators will present the full data set in an oral presentation on April 29. Though these data are unlikely to merit label expansion, use of Thymoglobulin should increase at the proportional expense of Simulect.

In general, monoclonal antibodies have proven superior to polyclonal antisera both in terms of production and clinical utility. Polyclonal antisera are not only costly and labor intensive to produce, but they are also difficult to quality control because each immunized rabbit can produce only so much antisera and every new rabbit is different. Therapeutically, monoclonals can more precisely impact a target, often with fewer adverse effects. In this case, the lack of a precise target may have actually benefited Thymoglobulin's ability to suppress graft rejection by binding to many T cell antigens compared to the single target (IL-2 receptor) of Simulect.

BTECH NEWS
by Leon Henderson, M.D.
Bennett Weintraub, Ph.D.
Christopher Martin
www.btechnews.com
March 13, 2002

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