The role of Fc portion in the intravitreous half-life of anti-VEGF drugs

Abstract

Purpose : To identify the role of Fc portion in intraocular pharmacokinetics (PK) of protein drugs using the two identical protein drugs except the Fc portion

Methods : We generated a new VEGF-Trap without Fc portion (small VEGF-Trap, MW=100kDa) by replacing the Fc portion of conventional VEGF-Trap (MW=145kDa) with a dimerized coiled-coil domain. A total of 42 eyes of 42 rabbits were injected intravitreally with VEGF-Trap (n=21) and small VEGF-Trap (n=21). Eyes were harvested at 6 time points (1h and 1, 2, 4, 14 and 30 days after injections). The concentrations of VEGF-Trap and small VEGF-Trap in the vitreous, aqueous humor, and retina/choroid were measured by an indirect enzyme-linked immunosorbent assay, and pharmacokinetic properties of the drugs were analyzed under hypothetical compartment model system. One-compartment model was applied as the final model for the vitreous whereas two-compartment model was applied for aqueous humor and retina/choroid tissue.

Results : In all three tissues, the maximum concentrations of both small VEGF-Trap and VEGF-Trap were observed 1 hour after intravitreal injection. The estimated half-lives of small VEGF-Trap in the vitreous and retina/choroid were 1.4 and 2.3 times longer (145.02 and 102.12 hours, respectively) than those of VEGF-Trap (103.99 and 44.42 hours, respectively). The total exposure of small VEGF-Trap in the aqueous humor and retina/choroid were approximately 13.2% and 39%, respectively, of the vitreous exposure whereas VEGF-Trap concentrations were approximately 25.2% and 26.2%, indicating that small VEGF-Trap show a preference for the posterior excretion.

Conclusions : The vitreous and retina/choroid half-lives of small VEGF-Trap are significantly longer than that of VEGF-Trap in rabbit eyes despite the lower molecular weight of small VEGF-Trap. This suggests that Fc receptors in ocular tissues contribute to the elimination of anti-VEGF drugs. Truncation or mutation of Fc portion can partially prolong the residence time of VEGF-Trap and have the possibility of reducing the number of VEGF-Trap injections.

This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.

 

Protein structures of VEGF-Trap and truncated VEGF proteins. (A) Small VEGF-Trap contains a dimerized coiled coil domain instead of Fc domain of VEGF-Trap. (B) A protein 3D structure of small VEGF-Trap was predicted by I-TASSER.

 

Small VEGF-Trap concentration in the eye of rabbit. Points represent observed concentrations and lines represent estimated concentrations by models