Background/Purpose: Biologic treatment options such as TNF inhibitors have revolutionized the treatment of inflammatory diseases, such as rheumatoid arthritis (RA), psoriasis and psoriatic arthritis. However, there is still a significant unmet medical need in these diseases. In RA for example, only about half of all patients achieve an ACR50 score and many become refractory to anti-TNF treatment after a few years. Recent data suggest that full and long-lasting responses to TNF inhibitors are limited because of the activation of the pro-inflammatory T_H17/IL-17 pathway in patients. Therefore, an attractive avenue to achieve superior efficacy levels in inflammatory diseases represents dual TNF/IL-17A inhibition. In Collagen-Induced-Arthritis (CIA) animal models it was recently demonstrated that dual TNF/IL-17A inhibition resulted in significant superior activity as compared to the treatment of mice with the monospecific anti-TNF and anti-IL-17A inhibitors. We present here COVA322, a bispecific anti-TNF/IL-17A drug candidate moving towards the clinic.

Methods:  Using phage display technology we have isolated Fynomers inhibiting human IL-17A. Fynomers are small binding proteins (7 kDa) derived from the human Fyn SH3 domain which can be engineered to bind to essentially any target of interest with high affinity and specificity. After genetic fusion of the anti-IL-17A Fynomer to a commercially validated anti-TNF antibody the resulting bispecific molecule COVA322 was characterized in-depth for its biophysical and in vitro / in vivo inhibition properties.

Results: COVA322 inhibited TNF and IL-17A with picomolar inhibition potencies as shown in a variety of different cell assays. Moreover, we could show that COVA322 bound and inhibited simultaneously TNF and IL-17A, as determined by simultaneous binding studies and inhibition cell assays. Importantly, COVA322 was able to inhibit both TNF and IL-17A in an acute inflammation model in mice. In addition, the fusion of the anti-IL-17A Fynomer to the fully human anti-TNF antibody did not alter the favorable biophysical properties of the antibody: First, COVA322 could be purified with very high yields (3.5 g/l in a 10 liter fermentor) from a stable CHO cell line, using standard methods as typically applied for the purification of conventional monoclonal antibodies. Second, COVA322 was monomeric and showed no signs of aggregation even after months of storage at 4 °C in PBS as determined by size exclusion chromatography.

Conclusion: These encouraging results indicate that COVA322 has highly promising biophysical properties. Through its unique mode-of-action of inhibiting simultaneously TNF and the IL-17A/A homodimer, COVA322 has game changing potential in the treatment of inflammatory diseases.

ACR Meeting Abstracts - https://acrabstracts.org/abstract/cova322-overcoming-limitations-of-current-biologics-in-rheumatoid-arthritis-by-a-novel-bispecific-tumor-necrosis-factor-alpha-interleukin-17a-tnfil-17a-inhibitor-moving-towards-the-clinic/