Session Title: Rheumatoid Arthritis - Animal Models I
Session Type: Abstract Submissions (ACR)
Background/Purpose: Kinesins are family of motor proteins that are involved in mitosis and intracellular transport of vesicles and organelles. The mitotic kinesin, Eg5, acts during mitosis and centrosome separation. Selective inhibitors of Eg5 would be expected to be growth inhibition of inflammatory cells and synovial cells undergoing cell division. Litronesib (KF89617, LY2523355) is a newly synthesized compound at Kyowa Hakko Kirin. Litronesib is an ATP-noncompetitive, allosteric, reversible inhibitor of Eg5 that has no observed effect on microtubule formation. Litronesib has been investigated in clinical trials for the treatment of multiple cancers by Eli Lilly and Company. Remission of rheumatoid arthritis with a mitotic inhibitor taxol in patient with breast carcinoma was reported. In this study, we investigate the anti-rheumatoid activities of Litronesib on animal models of rheumatoid arthritis.
Methods: The effect of Litronesib was tested on rat adjuvant-induced arthritis (AIA) and mouse collagen-induced arthritis (CIA). KF89617 (Litronesib) or KF88373 (L-aspartate of the racemic mixture of KF89617 and its enantiomer) was synthesized in our laboratories. Mycobacterium butyricum was intradermally injected into the right hind footpad of Lewis rats (8 weeks, female), and AIA was induced. KF88373 was intravenously administered twice a week at 2 mg/kg from the day of the immunization with the adjuvant. Type 2 collagen (CII) with Freund’s complete adjuvant was intradermally injected at the base of the tail of DBA/1J mice (7 weeks, male), and CIA was induced. KF88373 at 4 mg/kg was subcutaneously administered twice a week from the day of the 2nd immunization with CII. KF89617 or KF88373 were orally administered twice a week from the day of the 2nd immunization with CII.
Results: In rat AIA, KF88373 at 2 mg/kg i.v. twice/week markedly inhibited the swelling of adjuvant-non-treated foot at 78.9% (p<0.01) on Day 21. The inhibitory activity of KF88373 was similar to that of MTX (0.1 mg/kg p.o. 5 times/week) on rat AIA. Inhibition of swelling of adjuvant-injected foot was 21.4% (p<0.05) which was less effective than that of of adjuvant-non-treated foot. Body weight loss by the induction of AIA was also improved by the treatment of KF88373 but was not by the treatment of MTX. In mouse CIA, KF88373 at 4 mg/kg s.c. twice/week markedly inhibited the arthritis score at 97.7% (p<0.001) on Day 35. Body weight loss by the induction of CIA was also improved by the treatment of KF88373. Effect of orally administered KF89617 was tested on CIA. KF89617 or KF88373 at 4 mg/kg p.o. twice/week, potently inhibited the arthritis score at 90.8% (p<0.001) or 87.1% (p<0.01) on Day 35, respectively. Intraperitoneal administration of Taxol (1 mg/kg i.p. twice/week) inhibited CIA score at 61.0% (p<0.01) which was weaker than that of KF89617. Taxol did not improve body weight loss.
Conclusion: KF89617 (Litronesib) is a newly synthesized mitotic kinesin Eg5 inihbitor. KF89617 and KF88373 markedly reduced joint inflammation on both rat AIA and mouse CIA. KF89617 and KF88373 showed pharmacological activities on various administration rute such as p.o., i.v. and s.c. The treatment of KF89617 is expected to provide a novel treatment of rheumatoid arthritis.
Kyowa Hakko Kirin,
Kyowa Hakko Kirin,
Kyowa Hakko Kirin,
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/application-of-cytostatic-agent-kinesin-eg5-inhibitor-litronesib-kf89617-on-rat-adjuvant-induced-arthritis-and-mouse-type-ii-collagen-induced-arthritis/