Half-life of therapeutic molecules in the vitreous depends on molecular weight, vitreous network mesh size and eye size

Abstract

 

Purpose

 

A long ocular half-life contributes to long effect duration and is critical for biotherapeutics to avoid frequent intravitreal injections. For the development of novel biotherapeutics it is therefore important to understand the process of ocular disposition, the factors dominating half-life and how animal data translates to human.

 

Methods

 

A biophysical model was used to investigate diffusion-driven distribution and clearance of molecules in the eye. The model was calibrated with fluorophotometry data obtained for tagged Fab fragment injected in rabbit eyes and validated against published rabbit and human data which included small molecules, scFv, Fab fragments, Fc fusion proteins and antibodies covering a molecular weight (MW) range of 100 to 150’000 Da.

 

Results

 

The model predicted well the dependency on MW supporting that diffusion is a key process of clearance (Figure 1 A). The main factors contributing towards a longer half-life were a higher MW, a smaller mesh size of the vitreous network and a larger eye. These results also suggested that differences in eye size (Figure 1 B) and in vitreous mesh size are among main factors in translating half-life data from animal to human.

 

Conclusions

 

A biophysical model provides a basis for mechanistic interpretation of ocular PK data in animals and can be used to predict the ocular half-life in human and guide optimal design and selection of long acting molecules.

 

 

Figure 1: (A) Vitreal half-life as a function of MW: literature data vs. model prediction in the rabbit eye. (B) Comparison of the data and the model predictions for biotherapeutics injected in rabbit and human eyes. Solid lines denote model predictions assuming the average vitreous network mesh size equal to 100 nm. Shaded area in panel A covers a range of mesh sizes from 30 nm (upper boundary) to infinity (lower boundary, diffusion in water).

 

Keywords: 412 age-related macular degeneration • 763 vitreous • 473 computational modeling