PK/PD modeling to identify optimal binding affinity of an intravitreally administered anti-IL33 antibody to maintain target engagement in vitreous and retina for the treatment of AMD

Abstract

Purpose : Blocking of IL33 binding to ST2 receptor (rST2) has been proposed as a therapeutic strategy to mitigate IL33 pathogenic activity in AMD. To test this hypothesis, intra-vitreal (ITV) administration of an anti-IL33 antibody (mAb) to neutralize IL33 in vitreous and retina was evaluated. In the ocular tissues, IL33 binds to the membrane bound form of ST2 (rST2) resulting in IL33 pro-inflammatory action. However, it also binds to the decoy soluble ST2 receptor (sST2). We use a mathematical model to determine the optimal binding affinity (K_d) required for an anti-IL33 mAb to maintain >90% levels of target neutralization in vitreous and retina.

Methods : A compartmental PK/PD model incorporating the ITV PK of the mAb as well as the binding of IL33 to both rST2 and sST2 was developed to simulate the administration of an anti-IL33 mAb and evaluate its ability to block IL33-ST2 interactions in vitreous and retina. To inform this model, K_d of IL33 to sST2 and rST2 were measured by surface plasmon resonance at 37°C. Levels of sST2 and IL33 in human vitreous were measured by an ELISA assay in post-mortem vitreous of control and AMD donors.

Results : Vitreal sST2 (concentration 20-70pM in control subjects and 10-200pM in AMD patients) was identified as a potential sink for IL-33 (IL-33 concentration in vitreous < 10pM). However, the model suggested that these concentrations result in a minimal fraction (<10%) of IL33 bound to sST2 based on the measured K_d of IL33 for sST2 (4 - 8 nM). Measured K_d of IL33 to rST2 was 62 pM. Considering typical PK properties for a mAb after ITV injection (mono-exponential decay with a vitreal volume of distribution of 4 mL and a vitreal half-life of 6 to 9 days), K_d values equal to 0.1nM to 1nM are predicted to maintain >90% target neutralization in vitreous for 9 to 13 weeks after a dose of 10 mg/eye. Assuming a retina to vitreous partition coefficient equal to 1:10, the corresponding duration of target coverage in retina is estimated to be between 4 to 9 weeks.

Conclusions : PK/PD model simulations identified optimal K_d of an anti-IL33 mAbs to be in the range of 0.1 to 1 nM to maintain greater than 90% neutralization of IL33 in vitreous and retina, if dosed at 10 mg/eye every 4 to 9 weeks. In addition, based on the model, sST2 does not appear to be a major sink for IL33 in the vitreous.

This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.