Fibronectin extra domain A as a drug delivery targeting epitope for rheumatoid arthritis

Advances in Rheumatology - 2022
Victor Sun1, Terry Melim1, Soumya Mitra1, Jon W. Erickson1, Shaughn Bryant1, Avery Farnham2, Susan V. Westmoreland1, Heather Knight1, Liang Zhang1, Wendy Ritacco1, Kristoff T. Homan3, Lorenzo Benatuil4, Annette J. Schwartz Sterman1, Andrew Goodearl1
1Drug Discovery Science and Technology, Abbvie Bioresearch Center, Worcester, USA
2Generate Biomedicines, Cambridge, USA
3Bristol Myers Squibb, Boston, USA
4Dragonfly Therapeutics Inc, Waltham, USA

Tóm tắt

Abstract Objectives To assess the ability of monoclonal antibodies (mAbs) specific for fibronectin extra-domain A (FnEDA) to target diseased tissues of mouse collagen induced arthritis (mCIA) models. To explore the parameters of the targeting exhibited by anti-FnEDA mAbs including timing and location. Methods Targeting capabilities of anti-FnEDA mAbs were demonstrated by biodistribution study where i.v. injected antibodies were detected by conjugated near-infrared (NIR) fluorophore, 125I label and immunohistochemistry (IHC) of the injected antibody. Location of FnEDA expression in both mCIA and human RA tissue were mapped by IHC. Quantification of anti-FnEDA mAbs targeted to disease tissue was measured by whole-body autoradiography (WBA). Timing of the targeting was interrogated with fluorescent and confocal microscopy using anti-FnEDA mAbs labeled with different fluorophores and injected at different times. Results Anti-FnEDA mAbs show specific targeting to diseased paws of mCIA animal. The targeting was focused on inflamed synovium which is consistent with FnEDA expression profile in both mCIA and human RA tissues. Anti-FnEDA mAbs accumulated in diseased tissue at pharmacologically relevant concentrations, the targeting was sustained for up to 14 days and FnEDA was able to support targeting of multiple doses of anti-FnEDA mAbs given 5 days apart. Conclusion FnEDA is specifically upregulated in the inflamed tissues of mCIA. Antibodies specific for FnEDA can be useful as molecular delivery vehicles for disease specific targeting of payloads to inflamed joint tissue.

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