Anti-TNFα conjugates for treatment of posterior chronic non-infectious uveitis

Abstract

Purpose : Chronic non-infectious uveitis (NIU) can result in nerve damage and vision loss. Most patients are treated using corticosteroids, which can lead to serious side effects. Intravitreal (ITV) administration of biologic TNFα inhibitors can substantially reduce the need for steroids. However, these products were not designed or validated for ITV use, and off-label ITV treatment with existing TNFα inhibitors is not recommended. Valitor is developing an anti-TNFα biologic specifically designed for ITV administration with a projected treatment frequency of only 2-3 times per year as a steroid-sparing treatment for chronic NIU.

Methods : We synthesized multivalent protein (MVP) conjugates comprising multiple copies (i.e. valency) of anti-TNFα antibodies bound to soluble hyaluronic acid biopolymers. We determined MVP binding affinity to TNFα using biolayer interferometry and cell bioassays. We assessed the ITV half-life of MVPs by delivering 50 μL of fluorescently-tagged MVP to rabbit eyes and measuring the amount of drug remaining in the eye after over time. We also evaluated the efficacy of anti-TNFα MVPs in a rat model of experimental autoimmune uveitis (EAU). Ocular inflammation was induced in rats by injecting 50 μg of interphotoreceptor retinoid-binding protein in 200 μL of complete Freund’s adjuvant. At early stages of disease onset (6 and 8 days after induction), we delivered either 12.6 μg anti-TNFαMVPs, 40 μg of dexamethasone (dex), or vehicle control via 5 μL ITV injection. We assessed inflammation by ocular examination and ocular tissue histopathology.

Results : Based on binding affinity measurements, we found that MVP potency increased directly with valency, and at high valency, the potency of MVPs were substantially (~100X) greater than the unconjugated protein controls. The ITV half-life of the MVPs was also to 6-8 times longer than unconjugated therapeutics. EAU inflammation in rats treated with anti-TNFα MVPs was similar to those treated with dex, and both treatments reduced inflammation compared to the vehicle control.

Conclusions : The MVP platform appears capable of increasing the potency and ITV durability of anti-TNFα inhibitors. By generating a sustained anti-inflammatory response with minimal systemic exposure, we expect our anti-TNFα MVP conjugates will enable a better overall safety profile compared other current treatment strategies for chronic NIU.

This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.