Background/Purpose: Rheumatoid arthritis (RA) is an inflammatory joint disease of autoimmune etiology.  If insufficiently treated, RA leads to joint damage and irreversible disability.  Although there is no cure, remission is possible with biological and synthetic disease-modifying antirheumatic drugs (DMARDs).  Steroid treatment is highly efficacious in many autoimmune diseases, but significant side effects prevent their chronic use.  With current treatment options many patients still do not achieve remission, thus prompting the need for improved therapeutics.  An antibody drug conjugate (ADC) has been developed that combines TNF inhibition via the antibody with selective delivery of glucocorticoid into inflammatory cells, allowing disease inhibition while preventing the steroid side effects.  In this study we evaluated longitudinal in vivo treatment effects of this anti-TNF-steroid ADC in the rat collagen-induced arthritis (CIA) model by multimodal translational imaging.

Methods: Inflammatory arthritis was induced in female Lewis rats by immunization with bovine type II collagen in incomplete Freund’s adjuvant (IFA) on days 0 and 6.  Rats were treated starting at peak inflammation on day 17 with either 10 mg/kg anti-TNF-steroid ADC, ip, qw; 10 mg/kg unconjugated anti-TNF mAb, ip, qw; or 3 mg/kg of the steroid payload po, qd; for three weeks.  Paw swelling was assessed by measuring hindlimb volumes with a plethysmometer.  Longitudinal in vivo magnetic resonance (MR) and X-ray micro-computed tomography (µCT) imaging of the hindlimb were used to monitor pathological changes in soft tissues and in bones, respectively, from day 0 before treatment to day 42.  Rats were sacrificed on day 42 for histopathological assessment of hindlimb pathology including pannus and bone remodeling.  In addition, ex vivo µCT was performed on hindlimb samples collected at the study endpoint (day 42).

Results: T2-weighted (T2W) images revealed that treatment with anti-TNF-steroid ADC for one week reduced joint tissue edema, while anti-TNF mAb elicited only a modest reduction.  To further explore these changes in T2W contrast, we employed a histogram-based approach to divide the tibia-talus-tarsal hindlimb region into two compartments based on the T2W images.  Anti-TNF-steroid ADC displayed superior treatment effects in both compartments as compared to anti-TNF mAb.  Treatment effects in preserving bone integrity were evaluated by quantifying bone density, roughness, volume, and surface area with µCT.  Three weeks of treatment with anti-TNF-steroid ADC significantly protected bone from damage indicated by an increased high-density bone volume and reduced surface area and roughness relative to the control.  Both in vivo MRI and µCT and ex vivo µCT metrics corresponded well with histologic evaluation at the study endpoint (day 42). 

Conclusion: These results demonstrate improved treatment efficacy of the anti-TNF-steroid ADC showing both resolution of inflammation as well as preservation of bone integrity when compared to anti-TNF mAb treatment alone. The quantitative imaging metrics were sensitive to treatment effects and may serve as biomarkers in a clinical trial.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/translational-imaging-of-treatment-effects-for-a-novel-anti-tnf-steroid-antibody-drug-conjugate-in-a-rat-model-of-rheumatoid-arthritis/