From Pages to Practice
On a recent season of the fictional television series House of Cards, the President of the United States needs an organ transplant. His chief of staff tampers with the waitlist and moves the President to the top of the list, saving him at the cost of another man’s life.
This sort of scenario plays to what most people understand implicitly to be true: When it comes to organ transplants, the demand is high for a limited supply. In kidney transplants, the supply-demand mismatch continues to grow; today, over 100,000 patients are on the deceased donor waitlist. But availability is just the surface of the problem. Nearly one third of patients on the waitlist carry antibodies against HLA or other antigens, due to pregnancy, blood transfusions, or other prior exposures. Therefore, their immune systems are likely to attack and reject any transplanted organ. Therapies to reduce this antibody count, or “desensitize” patients, have helped to mitigate the problem, but often incompletely remove donor-specific antibodies and can result in rebound antibody production. Such treatments are also expensive and can be cumbersome.
A new strategy proposes desensitization by degrading immunoglobulin G (IgG) with the use of an enzyme produced by bacteria. The IgG degrading enzyme of Streptococcus pyogenes (IdeS) is a recombinant cysteine protease— produced in Escherichiacoli — that cleaves IgG into fragments with strict specificity. This action diminishes the immune response by affecting both antibody-dependent cytotoxicity and complement-mediated injury. (In vitro, the enzyme has also been shown to cleave B-cell receptors from circulating B-cells, but the clinical significance of this additional capacity has yet to be determined.)
In two open-label, single-arm phase I/II studies published this week in NEJM, Jordan et al. assessed the safety and efficacy of IdeS as a desensitization therapy in 25 patients on kidney transplant waitlists (14 in the U.S. and 11 in Sweden). All patients were highly sensitized (median calculated panel reactive antibody, 95%) and had been offered positive deceased donor crossmatches that were turned down because of donor-specific antibodies.
The patients were scheduled for kidney transplantation and, when an organ was available, received IdeS intravenously 4 to 6 hours before the transplant procedure. Post-transplant, patients were maintained on standard immunosuppression with tacrolimus, mycophenolate mofetil, glucocorticoids, and prophylactic antibiotics. The U.S. patients also received intravenous immunoglobulin (IVIg) 1 to 2 weeks after transplant, and rituximab if they had not received it pre-transplant. Crossmatch and donor-specific antibody tests were assessed periodically, starting at 6 and 24 hours after infusion of IdeS, then at 1 week and 1, 2, 3 and 6 months. Patients also underwent renal biopsy at 6 months.
A total of 24 of the 25 kidney transplants were successful. All patients displayed near or complete reduction in HLA antibodies and donor-specific antibodies at 6 and 24 hours. In the Swedish study group, antibody levels remained undetectable until 1 to 2 weeks post-transplant, when a rebound was observed. In the U.S. group, significantly fewer patients experienced rebound, likely reflecting the use of IVIg and rituximab. Ten patients (3 in the Swedish group and 7 in the U.S. group) developed antibody-mediated rejection 2 weeks to 5 months after transplantation that resolved after treatment. Patients in both groups had low levels of inflammation on the protocol biopsy at 6 months, and both groups showed good renal function.
The one allograft loss in the study was thought to be due to hyperacute rejection immediately after revascularization. The patient was later found to have non-HLA antibodies that could not be cleaved by IdeS
Although infection was an anticipated concern, no significant infectious complications were observed in the U.S. cohort. One Swedish patient experienced prolonged parvovirus B19 viremia and persistent myalgias. No patient developed positivity for cytomegalovirus, Epstein–Barr virus, polyoma BK, or JC viremia. Of 37 serious adverse events in 15 patients, 5 events were thought to be possibly attributable to IdeS. No deaths were reported.
Given the study’s small sample size and lack of long-term follow-up to date, these results should be interpreted with cautious optimism and considered an invitation for investigation on a larger scale. In an accompanying editorial, NEJM Deputy Editor Dr. Julie Ingelfinger notes, “Although…patients with high anti-HLA antibody titers are unlikely to receive kidneys without desensitization, a comparison group of candidates who are treated by other means of desensitization would be of interest. Without doubt, future randomized, controlled trials that compare IdeS with other means of decreasing the levels of preformed antibodies and that follow the recipients long term will be important.”