Synergistic Reversal of Arthritis By Synoviocyte-Targeted Therapy and TNF Immunomodulation

Christian Secchi^1,2,3, Karen M. Doody², Mattias N. D. Svensson^2,4, Frances Humby⁵, Rebecca Hands⁵, Eugenio Santelli^1,2, Cristiano Sacchetti^2,6, Kuninobu Wakabayashi⁷, Dennis J. Wu⁸, Ardita Aliko⁹, Piotr Mydel^9,10, Tsuyoshi Kasama⁷, David L. Boyle¹¹, Francesco Galimi¹², Michel L. Tremblay¹³, Gary S. Firestein⁶, Costantino Pitzalis⁵, Stephanie Standford^8,14 and Nunzio Bottini^2,4, ¹Medicine, University of California San Diego, San Diego, CA, ²Cellular Biology, La Jolla Institute for Allergy and Immunology, La Jolla, CA, ³Medicine, National Institute of Biostructures and Biosystems, University of Sassari Medical School, Sassari, Italy, ⁴Department of Medicine, University of California San Diego, La Jolla, CA, ⁵Centre for Experimental Medicine and Rheumatology, William Harvey Research Institute, Barts and The London, School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom, ⁶Medicine, University of California San Diego, La Jolla, CA, ⁷Div of Rheumatology, Showa University School of Med, Shinagawa-ku Tokyo, Japan, ⁸University of California San Diego, San Diego, CA, ⁹University of Bergen, Bergen, Norway, ¹⁰Clinical Science, Broegelmann Research Laboratory, Bergen, Norway, ¹¹University of California San Diego, La Jolla, CA, ¹²National Institute of Biostructures and Biosystems, University of Sassari Medical School, Sassari, Italy, ¹³Goodman Cancer Centre, McGill University, Montréal, QC, Canada, ¹⁴La Jolla Institute for Allergy and Immunology, La Jolla, CA

Meeting: 2017 ACR/ARHP Annual Meeting

Date of first publication: September 18, 2017

Keywords: anti-TNF therapy, Biologic agents, Rheumatoid arthritis (RA), synovial cells, synovial fluid and therapeutic targeting

Session Information

Date: Monday, November 6, 2017

Title: Rheumatoid Arthritis – Small Molecules, Biologics and Gene Therapy Poster II: Prognostic Factors, Imaging and Miscellaneous Reports

Session Type: ACR Poster Session B

Session Time: 9:00AM-11:00AM

Background/Purpose:

Despite the availability of immunosuppressive disease-modifying anti-rheumatic agents (DMARDs), many rheumatoid arthritis (RA) patients still fail to achieve remission. Fibroblast-like synoviocytes (FLS) are non-immunological joint-lining cells that become invasive during RA. Non-immunosuppressive agents targeting FLS in combination with DMARDs have the potential to improve control of RA without enhancing the risk of infections. We recently reported that disrupting the interaction between the receptor protein tyrosine phosphatase sigma (RPTPσ) and the proteoglycan syndecan-4 using an RPTPσ decoy biologic (RPTPσ-Ig1&2) reduces FLS cartilage invasion. Here we examined the therapeutic potential of RPTPσ-Ig1&2 in combination with tumor necrosis factor-a (TNF) inhibition.

Methods:

The relationship between RPTPσ and TNF was evaluated in RA FLS, murine FLS and collagen-induced arthritis (CIA) mice by qPCR. The anti-rheumatic effect of RPTPσ-Ig1&2 was assessed in spontaneous KBxN (sKBxN) and collagen antibody induced arthritis (CAIA). Also, RPTPσ-Ig1&2 was administered to CIA mice either alone or in combination with a mouse anti-TNF receptor agent.

Results:

TNF was found to negatively regulate the expression of RPTPσ in RA FLS (P<0.0001). Anti-TNF treatment of CIA mice increased the joint expression of RPTPσ (P=0.031). RPTPσ-Ig1&2 administration attenuated arthritis in multiple mouse models (sKBxN P<0.001; CAIA P<0.001, CIA P=0.0079). Combining RPTPσ-Ig1&2 with anti-TNF receptor treatment enhanced the reversal of CIA (P<0.0001).

Conclusion:

Our study provides the first evidence that an FLS-targeting therapy is efficacious in multiple mouse models of RA and enhances TNF blockade in experimental arthritis.

Disclosure: C. Secchi, None; K. M. Doody, None; M. N. D. Svensson, None; F. Humby, None; R. Hands, None; E. Santelli, None; C. Sacchetti, None; K. Wakabayashi, None; D. J. Wu, None; A. Aliko, None; P. Mydel, None; T. Kasama, None; D. L. Boyle, None; F. Galimi, None; M. L. Tremblay, None; G. S. Firestein, None; C. Pitzalis, None; S. Standford, None; N. Bottini, None.

To cite this abstract in AMA style:

Secchi C, Doody KM, Svensson MND, Humby F, Hands R, Santelli E, Sacchetti C, Wakabayashi K, Wu DJ, Aliko A, Mydel P, Kasama T, Boyle DL, Galimi F, Tremblay ML, Firestein GS, Pitzalis C, Standford S, Bottini N. Synergistic Reversal of Arthritis By Synoviocyte-Targeted Therapy and TNF Immunomodulation [abstract]. Arthritis Rheumatol. 2017; 69 (suppl 10). https://acrabstracts.org/abstract/synergistic-reversal-of-arthritis-by-synoviocyte-targeted-therapy-and-tnf-immunomodulation/. Accessed .

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