Background/Purpose: TNF-inhibitors are a well established therapy for autoimmune diseases including rheumatoid arthritis, Crohn’s disease, psoriasis and ankylosing spondylitis but they have limited efficacy in some patients.  Corticosteroid treatment is highly effective in autoimmunity but prolonged use at efficacious doses is contraindicated by significant side effects.  We have developed a plasma stable antibody drug conjugate (ADC) that has steroid molecules linked to an anti-TNF a mAb.  This ADC is targeted to TNF-a expressing inflammatory cells and internalized to cellular lysosomes.  Once in the lysosome the ADC is digested and delivers steroid molecules into the cell.  This significantly reduces the efficacious steroid dose to below levels that induce undesired side effects.  In an acute in vivo model, contact hypersensitivity in C57BL/6 mice, we have shown that an anti-TNF-steroid ADC can significantly inhibit the inflammatory response with a minimal effect on the steroid biomarkers, corticosterone and P1NP.  Additionally, in a mouse model of rheumatoid arthritis, collagen induced arthritis (mCIA), we have demonstrated that a single therapeutic treatment with an anti-TNF-steroid ADC is able to completely inhibit disease for a greater than 30 days, while anti-TNF mAb only partially inhibits disease.

Methods: To evaluate whether the anti-TNF-ADC can reverse joint damage in mCIA we modified the mCIA model so that treatment was initiated 7 days after disease onset.

Results: To evaluate whether the anti-TNF-ADC can reverse joint damage in mCIA we modified the model so that treatment was initiated 7 days after disease onset.  At this time there is significant pannus invasion as well as bone and cartilage destruction in the tarsal region of the ankle joint in these mice.  We demonstrate that anti-TNF-steroid ADC treatment, after established disease, appears to heal the joints of previously arthritic mice when compared to a group of satellite animals sacrificed 7 days after disease onset.  The tarsal joints from these mice were evaluated using micro computed tomography and by histologic evaluation.  Restoration of normal joint architecture was seen in at least 40% of mice with TNF-steroid ADC treatment that was not seen with either an isotype control ADC or with the anti-TNF mAb alone.

Conclusion: These promising results suggest that a steroid targeted to cells involved in joint destruction via TNF binding has the potential to achieve not only lasting remission but also repair of the arthritic joints in RA patients, while sparing patients from steroid induced side effects.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/development-of-a-novel-anti-tnf-steroid-antibody-drug-conjugate-that-shows-promising-efficacy-at-doses-that-avoid-steroid-side-effects-in-a-mouse-model-of-rheumatoid-arthritis/