Abstract
Purpose :
Posterior chronic NIU puts patients at high risk for retinal nerve damage and vision loss. Intravitreal (ITV) administration of biologic TNFα inhibitors has the potential to substantially reduce the need for corticosteroids, which are associated with serious side effects. 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 developed a single-domain anti-TNFα antibody (VHH) with motifs for in vivo stability. We used multivalent polymer (MVP) conjugation technology to covalently bind multiple copies (i.e. valency) of our VHH antibody to soluble, long-chain hyaluronic acid. We determined MVP binding affinity (Kd) using biolayer interferometry and anti-TNFα bioactivity using cell bioassays (IC50). The ITV half-life of MVPs was determined in rabbit models using radiolabeling detection. We also evaluated the efficacy of anti-TNFα MVPs in a rat model of experimental autoimmune uveitis (EAU). At 4 and 8 days after EAU induction, we delivered either 19 μg anti-TNFα MVPs or vehicle control (5 μL ITV injection) or 40 μg of triamcinolone (1 μL ITV injection). We assessed inflammation by ocular examination, multiplexed cytokine analysis of vitreous humor, and ocular histopathology.
Results :
Based on key release criteria (VHH valency, Kd, and IC50), our methods for producing anti-TNFα MVPs were highly repeatable. They were highly potent with sub-picomolar TNFα Kd and an IC50 equivalent to licensed anti-TNFα biologics. The MVP ITV half-life was 2.5–3-times longer than that of a typical IgG antibody. Ocular inflammation in rats treated with anti-TNFα MVPs was similar to those treated with triamcinolone; both treatments reduced inflammation vs vehicle controls. Finally, the anti-TNFα MVP reduced ocular inflammatory cytokine signaling to levels equivalent to triamcinolone.
Conclusions :
The MVP platform appears to be capable of increasing the potency and ITV durability of anti-TNFα biologics. 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. Our product candidate (VLTR-753) is on track to enter IND-enabling studies in 2024.
This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.