Fragment crystallizable (Fc) region results in an increased systemic exposure with no significant difference in intra-ocular pharmacokinetics

Abstract

 

Purpose

 

The elimination pathways and pharmacokinetics (PK) of monoclonal antibodies (mAb) and antigen binding fragments following systemic administration are well characterized. Less is known about the elimination and PK of these protein drugs following intravitreal (ITV) administration. Molecules containing Fc region lead to higher systemic exposure due to recycling via the neonatal Fc receptor for IgG following ITV administration. We examined the effect of structure on the ocular and systemic PK of targeted and untargeted (directed against the gp120 glycoprotein expressed in the HIV viral envelope) sets of these protein drugs in rabbits in an effort to develop criteria for the selection of the most optimal format for the next generation of ocular therapeutics.

 

Methods

 

Protein drugs (Figure) were administered bilaterally by ITV injection (500 µg/50 µl/ eye) to male NZ rabbits. Each eye was analyzed independently. Quadruplicate blood and ocular tissues (vitreous and aqueous humor) were sampled over 28 days post-dose. Protein drug concentrations were determined by ELISA. Individual data points that appeared to have been affected by anti-therapeutic antibody (ATA) in ATA-positive animals were excluded from the analysis. Ocular and systemic PK data were analyzed using previously established compartmental PK models for protein drugs.

 

Results

 

Vitreous levels of Fab, double-Cys F(ab’)2 , single-Cys F(ab’)2, and mAb were not significantly different following ITV administration. However, serum PK profiles were significantly different between the Fab fragments and mAb. For example, the relative areas under the curve of the concentration-time profile for the anti-gp120 Fab, double-Cys F(ab')2 and single-Cys F(ab’)2 formats compared to IgG were 0.007, 0.03, and 0.008 respectively.

 

Conclusions

 

Protein drug structure did not appear to dramatically impact t_1/2 in the vitreous in rabbits. As expected the systemic exposure levels of mAb were >100-fold higher than that of Fab, which lacks Fc region. Additionally, the apparent serum t_1/2 of mAb was 3-fold longer than the Fab. Taken together, these data indicate that Fc region results in an increased systemic exposure and may also result in unwanted accumulation over long term dosing, with no obvious therapeutic benefit to treat ocular diseases.

 

 

Keywords: 688 retina • 763 vitreous