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In a prospective randomized trial, BT563, a murine IgG, anti-interleukin-2 receptor antibody, was compared with OKT3 for use as an early rejection prophylaxis after heart transplantation. Patients received either BT563 (n=31) or OKT3 (n=29) during the first 7 days after transplantation; cyclosporine was started on day 3. Median follow-up was 34 months. A cytokine release syndrome occurred in the majority of patients of the OKT3-treated group but in none of the BT563 recipients. The mean duration of electrical stimulation of the heart in the BT563 group was longer than in the OKT3 group (5.1 vs. 2.1 days). In both groups, one patient required insertion of a permanent pacemaker. Freedom from acute rejection at 3 months was not significantly different between the two groups (BT563: 5/29, 17%; OKT3: 6/29, 21%). In the BT563 group, however, rejection tended to occur earlier after transplantation. There was no difference in the overall incidence of rejection. The incidence of infectious complications was evenly distributed in both groups. Malignancies occurred in two patients, both in the OKT3 group. In conclusion, the use of this anti-interleukin-2 receptor monoclonal antibody in heart transplant recipients is safe and devoid of the side effects that accompany the use of OKT3. OKT3 and BT563 result in a similar freedom from rejection at 3 and 12 months after heart transplantation.

A mouse monoclonal antibody (BT563) directed to the alpha-chain of the IL-2 receptor was administrated immediately after transplantation in a dose of 10 mg/day prophylactically to 30 heart transplant recipients (HTx) and 40 renal transplant recipients (RTx) to induce immunosuppression. Plasma levels increased to a plateau level of 5300 ng/ml in HTx and 5900 ng/ml in RTx. BT563 plasma disappearance curves gives a mean T1/2 of respectively 39 h (range 14-112 h) and 42 h (range 8-122 h) for HTx and RTx respectively. The CD25 marker (IL-2R) on the peripheral blood lymphocytes disappeared within hours after the first gift and returned to normal within 0-20 days after the last gift. In HTx more often CD25+ cells were found in the presence of BT563 and more rejections occurred shortly after discontinuation of BT563 compared to the RTx group. Rejectors and non-rejectors within the HTX group did not differ with respect to the period of depletion of CD25 positive cells in the peripheral blood. In 56% of the patients a substantial IgM antibody response was detected. This response was similar for HTx and RTx and not related to rejection. The frequency of IgG responses was low in both HTx (13%) and RTx (21%) patients and the IgG response was not related with graft rejection or with antirejection treatment. Peripheral monitoring showed that mAb plasma levels, antimurine antibody responses and number of CD25 positive cells were not related with the clinical results. The mAb BT563 proved to be safe with respect to the generation of antimurine antibodies and, when given in combination with CsA, is a therapy with a potential for high efficacy.

In a double-blind, randomized, placebo-controlled trial, BT563, a murine IgG1 anti-IL-2R antibody, was given as a rejection prophylaxis after kidney transplantation. Drug-related side effects were not observed. During the 10-day course of BT563, no rejections (0/27) were found, whereas a rejection episode occurred in 7 patients (7/29) (P = 0.01) during placebo treatment. Within the first 4 postoperative weeks, freedom from rejection in the BT563 group and in the placebo group was 96% vs. 76% (P = 0.05). Due to rejection in the placebo group, 2 grafts were lost. At 3 months, an overall rejection incidence in the BT563 and placebo group was found of 3/27 (11%) vs. 8/29 (28%) patients (P = 0.18). Infectious complications were distributed equally between the 2 groups. CMV disease, found in 3 placebo-treated patients, occurred after rejection treatment (2/3). Within the BT563 group, 1 patient lost his graft due to renal artery thrombosis, 2 grafts were lost as a result of technical failure, and 2 patients had a squamous cell carcinoma that could be treated curatively. We conclude that the use of the anti-IL-2R mAb BT563 effectively prevents rejection after kidney transplantation without increasing infectious complications.

Background: Anti-interleukin-2 receptor monoclonal antibodies have been used successfully in the prevention of rejection in cardiac allografts in several animal models., Methods: In an open randomized study murine monoclonal CD3 antibody and BT563, a murine anti-interleukin-2 receptor monoclonal antibody, were given as rejection prophylaxis during the first week after heart transplantation. Cyclosporine therapy was initiated at the third postoperative day., Results: In half the BT563-treated patients an early rejection was histologically shown at week 1, whereas heart transplant recipients treated with murine monoclonal CD3 antibody had a rejection incidence at week 1 of only 9%. During BT563 treatment CD25-positive cells (i.e., cells bearing the interleukin-2 receptor) were not detectable in peripheral blood. However, immunohistologic studies of endomyocardial biopsy specimens taken 1 week after transplantation showed the presence of CD25-positive cells within these specimens in 8 of 10 (80%) of patients with rejection. In patients without rejection CD25-positive cells were present in the biopsy specimens of only two of nine patients (22%). Reverse-transcriptase polymerase chain reaction studies on biopsy material showed the presence of messenger RNA for the interleukin-2 receptor in all and for interleukin-2 in three of five (60%) of biopsy specimens of rejecting grafts., Conclusions: Although CD25-positive cells were not detectable in peripheral blood during BT563 treatment, these cells were at the same time found to be present within 80% of the endomyocardial biopsy specimens from the rejecting grafts. By initiating cyclosporine treatment at day 0, the synergistic effect of combining cyclosporine and anti-interleukin-2 receptor monoclonal antibodies may result in a lower rejection incidence.

BT 563, a murine anti-IL-2R MoAb, was found to be more potent than anti-Tac in inhibiting proliferation in the mixed lymphocyte reaction. Results obtained with 33B3.1 in these experiments were similar to those with BT 563. The anti-IL-2R MoAb 2A3 was shown to be a suitable agent for monitoring the effect of BT 563 on peripheral blood. IL-2R-positive cells were not detected in peripheral blood samples from 1 h after the first dose until 8 days after the last dose. Plasma trough levels were measured in patients receiving 5 or 10 mg daily. The administration of BT 563 to allograft recipients did not lead to clinically significant side effects.

Sixteen kidney transplant recipients received the IgG2a anti-CD3 monoclonal antibody OKT3 and azathioprine as rejection prophylaxis during the first two postoperative weeks. Concomitant immunosuppression consisted of low dose steroids while cyclosporine A therapy was instituted on day 12. Side effects included fever, bronchospasm, hypotension and diarrhoea. OKT3 caused T cell modulation resulting in CD3 dim+, CD4+ or CD8+, CD5+, WT31- and 11F2- cells. Anti-OKT3 antibodies were found in approximately 50% of the patients. The protocol induced a 100% patient and graft survival and a 81% actuarial freedom of rejection at 18 months. It prevented CsA associated nephrotoxicity in the direct postoperative phase. These beneficial effects outweighed the side effects of OKT3.