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Am J Transl Res 2013;5(1):92-102
Original Article
Evaluation of a candidate anti-arthritic drug using the mouse collagen
antibody induced arthritis model and clinically relevant biomarkers
Andrew T Bender, Mark Spyvee, Takashi Satoh, Benjamin Gershman, Tyler Teceno, Laurette Burgess, Vipul
Kumar, Yin Wu, Hua Yang, Yueyun Ding, Sandeep Akare, Qian Chen
Eisai Inc. 4 Corporate Drive, Andover MA 01810, USA
Received November 16, 2012; Accepted December 25, 2012; Epub January 21, 2013; Published January 30, 2013
Abstract: The most rigorous scenario for testing a candidate rheumatoid arthritis therapeutic would be to use
clinically relevant biomarkers and readouts to monitor disease development in an animal model that has a
mechanism of disease that reflects the human condition. Treatment should begin when the full spectrum of
arthritic processes, including bone damage, is present. We have tried to take this approach to evaluate a novel
EP4 receptor antagonist (ER-886046) for its anti-arthritic potential. This work aimed not only to test a potential
drug, but to also demonstrate a strategy for performing a more clinically relevant evaluation of future candidate
arthritis treatments. A variety of biomarkers including: radiographic evaluation, clinical scoring, histology analysis,
F4/80 macrophage immunohistochemistry, luminol bioluminescent imaging and 99mTc-MDP-SPECT imaging
were evaluated as disease readouts in the mouse anti-collagen antibody induced arthritis model (CAIA). CAIA
mice were treated either prophylactically or therapeutically with ER-886046 and the compound’s efficacy was
probed using the various biomarkers and compared to the reference drugs prednisolone and celecoxib. The
various biomarkers effectively measured different aspects of arthritis pathology and consistently demonstrated
the efficacy of ER-886046. The compound was found to be effective even when dosed therapeutically after bone
damaging processes had initiated. The results presented herein demonstrate how biomarkers and a clinically
relevant experimental design can be used to evaluate a candidate therapeutic. Utilization of clinically relevant
biomarkers may provide a means for more translatable pre-clinical testing of candidate therapeutics and may
provide information on their mechanism of action. (AJTR1211006).
Keywords: Arthritis, EP4 receptor, PGE2, translational medicine, drug development, biomarkers
Address correspondence to: Dr. Qian Chen, Eisai Inc., 4 Corporate Dr., Andover, MA 01810, USA. E-mail:
Qian_Chen@eisai.com
Original Article
Evaluation of a candidate anti-arthritic drug using the mouse collagen
antibody induced arthritis model and clinically relevant biomarkers
Andrew T Bender, Mark Spyvee, Takashi Satoh, Benjamin Gershman, Tyler Teceno, Laurette Burgess, Vipul
Kumar, Yin Wu, Hua Yang, Yueyun Ding, Sandeep Akare, Qian Chen
Eisai Inc. 4 Corporate Drive, Andover MA 01810, USA
Received November 16, 2012; Accepted December 25, 2012; Epub January 21, 2013; Published January 30, 2013
Abstract: The most rigorous scenario for testing a candidate rheumatoid arthritis therapeutic would be to use
clinically relevant biomarkers and readouts to monitor disease development in an animal model that has a
mechanism of disease that reflects the human condition. Treatment should begin when the full spectrum of
arthritic processes, including bone damage, is present. We have tried to take this approach to evaluate a novel
EP4 receptor antagonist (ER-886046) for its anti-arthritic potential. This work aimed not only to test a potential
drug, but to also demonstrate a strategy for performing a more clinically relevant evaluation of future candidate
arthritis treatments. A variety of biomarkers including: radiographic evaluation, clinical scoring, histology analysis,
F4/80 macrophage immunohistochemistry, luminol bioluminescent imaging and 99mTc-MDP-SPECT imaging
were evaluated as disease readouts in the mouse anti-collagen antibody induced arthritis model (CAIA). CAIA
mice were treated either prophylactically or therapeutically with ER-886046 and the compound’s efficacy was
probed using the various biomarkers and compared to the reference drugs prednisolone and celecoxib. The
various biomarkers effectively measured different aspects of arthritis pathology and consistently demonstrated
the efficacy of ER-886046. The compound was found to be effective even when dosed therapeutically after bone
damaging processes had initiated. The results presented herein demonstrate how biomarkers and a clinically
relevant experimental design can be used to evaluate a candidate therapeutic. Utilization of clinically relevant
biomarkers may provide a means for more translatable pre-clinical testing of candidate therapeutics and may
provide information on their mechanism of action. (AJTR1211006).
Keywords: Arthritis, EP4 receptor, PGE2, translational medicine, drug development, biomarkers
Address correspondence to: Dr. Qian Chen, Eisai Inc., 4 Corporate Dr., Andover, MA 01810, USA. E-mail:
Qian_Chen@eisai.com
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