Here we report the intraocular distribution and pharmacokinetic profile of the fourth-generation compstatin analog, Cp40-KKK in cynomolgus monkeys following a single intravitreal injection. Using a sensitive surface plasmon resonance (SPR)-based competition assay and ELISA, we have quantified both the amount of inhibitor and the concentration of C3 retained in the vitreous of Cp40-KKK-injected animals. Cp40-KKK displays prolonged intraocular residence, being detected at C3-saturating levels for over 3 months after a single intravitreal injection. Moreover, we have probed the distribution of Cp40-KKK within the ocular tissue by means of immunohistochemistry and highly specific anti-Cp40-KKK antibodies. Both C3 and Cp40-KKK were detected in the retinal tissue of inhibitor-injected animals, with prominent co-localization in the choroid one-month post intravitreal injection. These results attest to the high retinal tissue penetrance and target-driven distribution of Cp40-KKK. Given its subnanomolar binding affinity and prolonged ocular residence, Cp40-KKK constitutes a promising drug candidate for ocular pathologies underpinned by deregulated C3 activation.
Authors: Hughes S, Gumas J, Lee R, Romano M, Berger N, Gautam AK, Sfyroera G, Chan AL, Gnanaguru G, Connor KM, Kim BJ, Dunaief JL, Ricklin D, Hajishengallis G, Yancopoulou D, Reis ES, Mastellos DC, Lambris JD.
Reference: Clin Immunol. 2020 Mar 27:108391. doi: 10.1016/j.clim.2020.108391. [Epub ahead of print]