Effects of the Novel PKCθ Selective Inhibitor AS2521780 on Acute Rejection in Rats and Monkeys
Molecular Medicine Research Labs, Astellas Pharma Inc., Tsukuba, Ibaraki, Japan
Pharmacological Research Labs, Astellas Pharma Inc., Tsukuba, Ibaraki, Japan
Chemical Research Labs, Astellas Pharma Inc., Tsukuba, Ibaraki, Japan
Meeting: 2013 American Transplant Congress
Abstract number: D1505
Background
Inhibition of T-cell activation is the most effective to prevent acute cellular rejection. Protein kinase C (PKC) theta is a crucial signaling enzyme in the activation of T lymphocytes. The research for the PKC theta inhibitor led to the development of AS2521780. We investigated the PKC isozyme selectivity of AS2521780 and the effects of this compound on acute rejection both in a rat cardiac transplant model and a non-human primate (NHP) renal transplant model.
Methods
PKC isozyme selectivity of AS2521780 was examined using human PKC isozymes (Α, Β, Γ, Δ, Ε, Ζ, ð, and Θ). Heterotopic cardiac transplantation from ACI to Lewis rats were performed and cardiac allograft survival was evaluated by daily monitoring palpation. Life-supporting renal transplantations were performed between ABO-compatible, MLR-mismatched NHPs and renal allograft survival was evaluated by the determination of the level of plasma creatinine and the general symptoms of recipients.
Results
AS2521780 inhibited PKC theta more potently than other PKC isozymes. AS2521780 prolonged cardiac allograft survival in rats dose dependently both by monotherapy and combination therapy with FK506 or MMF. AS2521780 also prolonged renal allograft survival in NHPs by combination therapy with FK506. AS2521780 was well tolerated in both rats and NHPs transplant recipients.
| Α | Β | Γ | Δ | Ε | Θ | ð | Ζ |
| 160 | > 840 | > 1000 | 160 | 18 | 0.48 | > 1000 | > 1000 |
| AS2521780 (mg/kg, b.i.d.) | FK506 (mg/kg, u.i.d.) | number of animals | survival days | median survival days |
| 0 | 0 | 4 | 5, 6, 6, 7 | 6 |
| 0 | 1 | 7 | 8, 18, 19, 21, 21, 22, 39 | 21 |
| 3 | 1 | 6 | 9, 25, 35, 77, >90, >90 | 56 |
Conclusions
These studies are the first to demonstrate that AS2521780, a PKC theta selective inhibitor, could prolong allograft survival not only in rats but also in NHPs. Thus, AS2521780 may have the potential to offer an alternative to the therapies in the transplantation fields.
To cite this abstract in AMA style:
Chida N, Kawashima T, Tasaki M, Matsuoka H, Maeda M, Tanaka A, Higashi Y. Effects of the Novel PKCθ Selective Inhibitor AS2521780 on Acute Rejection in Rats and Monkeys [abstract]. Am J Transplant. 2013; 13 (suppl 5). https://atcmeetingabstracts.com/abstract/effects-of-the-novel-pkc-selective-inhibitor-as2521780-on-acute-rejection-in-rats-and-monkeys/. Accessed May 15, 2025.« Back to 2013 American Transplant Congress