APC0576: a novel small molecule, immunosuppressive agent effective in primate models.
BACKGROUND
APC0576, 5-(((S)-2,2-dimethylcyclopropanecarbonyl)amino)-2-(4-(((S)-2,2-dimethylcyclopropanecarbonyl)amino)phenoxy)pyridine is a novel synthetic compound with an inhibitory activity on NF-kappaB-dependent gene activation and chemokine synthesis in human endothelial cells. This article describes the effect of APC0576 on T-cell-dependent immune functions in vitro and in vivo in primate models, because NF-kappaB is known to be one of the potent mediators in T-cell activation.


METHODS
The effects of APC0576 on interleukin-2 production and proliferative responses in human peripheral blood mononuclear cells were studied under various stimuli with in vitro culture assay. Next, female rhesus monkeys were immunized with tetanus toxoid (TTx), and APC0576 was orally administered for 4 weeks. Serum-specific antibody for TTx was monitored weekly using an enzyme-linked immunosorbent assay, and delayed-type hypersensitivity reaction was examined after 4 weeks of APC0576 treatment. To evaluate the immunosuppressive activity, APC0576 was orally administered for 32 days to rhesus monkeys that received transplants of allogeneic kidney.


RESULTS
APC0576 effectively suppressed interleukin-2 production and proliferation in activated human peripheral blood mononuclear cells. Both delayed-type hypersensitivity reaction and specific antibody formation evoked by TTx was significantly and dose-dependently attenuated by 4 weeks treatment of APC0576 without any serious toxicologic signs. Allogeneic kidneys grafted in rhesus monkeys were not rejected and fully functioned during the 32 days of APC0576 treatment, although they were rapidly rejected after the withdrawal of the drug.


CONCLUSIONS
A novel, orally available immunosuppressive agent, APC0576, effectively inhibited T-cell-based immune responses both in vitro and in vivo. APC0576 may have potential for a therapeutic agent in clinical organ transplantation and various cytokine-mediated diseases.
Yuzawa
Kenji
K
Department of Surgery, Institute of Clinical Medicine, University of Tsukuba, Tsukuba City, Ibaraki, Japan. kyuzawa@md.tsukuba.ac.jp
Konishi
Atsushi
A
Takehana
Kenji
K
Iino
Yukio
Y
Ohnuki
Akiko
A
Kobayashi
Tsuyoshi
T
Fukao
Katashi
K
Ohkohchi
Nobuhiro
N
D000818:Animals; D003521:Cyclopropanes / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D006968:Hypersensitivity, Delayed / Q000517:prevention & control; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007376:Interleukin-2 / Q000096:biosynthesis; D016030:Kidney Transplantation; D008213:Lymphocyte Activation / Q000187:drug effects; D008253:Macaca mulatta; D023421:Models, Animal; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D011725:Pyridines / Q000494:pharmacology*
C457774:5-((2,2-dimethylcyclopropanecarbonyl)amino)-2-(4-((2,2-dimethylcyclopropanecarbonyl)amino)phenoxy)pyridine; D003521:Cyclopropanes; D007166:Immunosuppressive Agents; D007376:Interleukin-2; D016328:NF-kappa B; D011725:Pyridines