Belatacept

Belatacept binds to CD80 and CD86 on antigen presenting cells. As a result, belatacept blocks CD28 mediated co-stimulation of T cells inhibiting their activation. Activated T cells are the predominant mediators of immunologic response to the transplanted kidney. Belatacept, a modified form of CTLA4-Ig, binds CD80 and CD86 more avidly than the parent CTLA4-Ig molecule from which it is derived. This increased avidity provides a level of immunosuppression that is necessary for preventing immune-mediated allograft failure and dysfunction.

Belatacept, a selective costimulation blocker, is a soluble fusion protein consisting of a modified extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) fused to a 14 portion (hinge-CH2-CH3 domains) of the Fc domain of a human immunoglobulin G1 antibody. Belatacept is produced by recombinant DNA technology in a mammalian cell expression system. Two amino acid substitutions (L104 to E; A29 to Y) were made in the ligand binding region of CTLA-4.

Pharmacodynamic effects

In a clinical study, approximately 90% saturation of CD86 receptors on the surface of antigenpresenting cells in the peripheral blood was observed following the initial administration of belatacept. During the first month post-transplantation, 85% saturation of CD86 was maintained. Up to month 3 post-transplantation with the recommended dosing regimen, the level of CD86 saturation was maintained at approximately 70% and at month 12, approximately 65%.

Absorption

The pharmacokinetics of belatacept in renal transplant patients and healthy subjects appeared to be comparable. The pharmacokinetics of belatacept was linear and the exposure to belatacept increased proportionally in healthy subjects after a single intravenous infusion dose of 1 to 20 mg/kg. The mean (range) pharmacokinetic parameters of belatacept after multiple intravenous infusions at doses of 5 and 10 mg/kg in renal transplant subjects were: terminal half-life, 8.2 (3.1-11.9) and 9.8 (6.1-15.1) days, respectively; systemic clearance 0.51 (0.33-0.75) and 0.49 (0.23-0.70) ml/h/kg, respectively; and distribution volume at steady state, 0.12 (0.09-0.17) and 0.11 (0.067-0.17) l/kg, respectively. At the recommended dosing regimen, serum concentration generally reached steady-state by Week 8 in the initial phase following transplantation and by Month 6 during the maintenance phase. At Month 1, 4, and 6 post-transplant, the mean (range) trough concentrations of belatacept were 22.7 (11.1-45.2), 7.6 (2.1-18.0), and 4.0 (1.5-6.6) μg/ml, respectively.

Distribution

Based on population pharmacokinetic analysis of 944 renal transplant patients up to 1 year posttransplant, the pharmacokinetics of belatacept were similar at different time periods post-transplant. The trough concentration of belatacept was consistently maintained up to 5 years post-transplant. Minimal systemic accumulation of belatacept occurred upon multiple infusions of 5 or 10 mg/kg doses in renal transplant patients every 4 weeks. The accumulation index for belatacept at steady state is 1.1.

Elimination

Population pharmacokinetic analyses in renal transplant patients revealed that there was a trend toward higher clearance of belatacept with increasing body weight. No clinically relevant effects of age, gender, race, renal function (calculated GFR), diabetes, or concomitant dialysis on clearance of belatacept was identified.

There is no data available in patients with hepatic impairment.

Belatacept has less activity in rodents than abatacept, a fusion protein that differs from belatacept by two amino acids in the CD80/86 binding domains. Because of abatacept’s similarity to belatacept in structure and mechanism of action and its higher activity in rodents, abatacept was used as a more active homolog for belatacept in rodents. Therefore, preclinical studies conducted with abatacept have been used to support the safety of belatacept in addition to the studies conducted with belatacept.

No mutagenicity or clastogenicity was observed with abatacept in a battery of in vitro studies. In a mouse carcinogenicity study, increases in the incidence of malignant lymphomas and mammary tumours (in females) occurred. The increased incidence of lymphomas and mammary tumours observed in mice treated with abatacept may have been associated with decreased control of murine leukaemia virus and mouse mammary tumour virus, respectively, in the presence of long-term immunomodulation. In a six-month and one-year toxicity study in cynomolgus monkeys with belatacept and abatacept, respectively, no significant toxicity was observed. Reversible pharmacological effects consisted of minimal decreases in serum IgG and minimal to severe lymphoid depletion of germinal centers in the spleen and/or lymph nodes. No evidence of lymphomas or preneoplastic morphologic changes was observed in either study. This was despite the presence in the abatacept study of a virus, lymphocryptovirus, known to cause these lesions in immunosuppressed monkeys within the time frame of these studies. The viral status was not determined in the belatacept study but, as this virus is prevalent in monkeys, it was likely present in these monkeys as well.

In rats, belatacept had no undesirable effects on male or female fertility. Belatacept was not teratogenic when administered to pregnant rats and rabbits at doses up to 200 mg/kg and 100 mg/kg daily, respectively, representing approximately 16 and 19 times the exposure associated with the maximum recommended human dose (MRHD) of 10 mg/kg based on AUC. Belatacept administered to female rats daily during gestation and throughout the lactation period was associated with infections in a small percentage of dams at all doses (≥ 20 mg/kg, ≥ 3 times the MRHD exposure based on AUC), and produced no adverse effects in offspring at doses up to 200 mg/kg representing 19 times the MRHD exposure based on AUC. Belatacept was shown to cross the placenta in rats and rabbits.

Abatacept administered to female rats every three days during gestation and throughout the lactation period, produced no adverse effects in offspring at doses up to 45 mg/kg, representing 3 times the exposure associated with the MRHD of 10 mg/kg based on AUC. However, at 200 mg/kg, 11 times the MRHD exposure, alterations in immune function were observed consisting of a 9-fold increase in T-cell dependent antibody response in female pups and thyroid inflammation in one female pup. It is not known whether these findings indicate a risk for development of autoimmune diseases in humans exposed in utero to abatacept or belatacept.

Studies in rats exposed to abatacept have shown immune system abnormalities including a low incidence of infections leading to death (juvenile rats) as well as inflammation of the thyroid and pancreas (both juvenile and adult rats). Studies in adult mice and monkeys have not demonstrated similar findings. It is likely that the increased susceptibility to opportunistic infections observed in juvenile rats is associated with the exposure to abatacept before development of memory responses.