Abstract
Purpose :
Geographic atrophy (GA) leads progressive and irreversible vision loss, which affects about 1.93 million patients in China and about 1.6 million patients in US. Only 2 complement inhibitors, Syfovre (APL-2) and izervay (avacincaptad pegol), were approved by FDA in 2023. While both of these complement inhibitors slow the GA growth, additive effects should be considered by next-generation treatment strategy.
IAR045-001 is consisted of biparatopic anti-C5 VHHs and anti-HTRA1 VHH, which blocks both complement cascade and HTRA1 enzyme activity.
This abstract reports for the first time preliminary IAR045-001 data in GA preclinical study.
Methods :
The biofunction of complement cascade and HTRA1 activity were evaluated by hemolysis and enzymatic assay respectively.
Anti-C5 VHHs are screened from immune library. Anti-HTRA1 VHH is screened from synthetic library. IAR045-001 is constructed by linking these VHHs after protein engineering.
The pharmacokinetics of IAR045-001 was validated in rabbit. Vitreous, aqueous, retina and choroid samples were collected and measured for IAR045-001 concentration by self-developed ELISA.
The rescue efficacy was validated in NaIO3-induced GA mouse model. H&E staining were conducted after section to calculate the thickness of ONL and POS layer and the integrity of RPE.
Results :
IAR045-001 showed better inhibition potency in both classical and alternative complement pathway than ARC1905 (completely in AP).
IAR045-001 showed better or comparable HTRA1 enzyme inhibition than galegenimab.
IAR045-001 showed well PK data in rabbit intravitreal study.
IAR045-001 showed better rescue efficacy in NaIO3-induced GA model than ARC1905 and galegenimab.
Conclusions :
IAR045-001 shows complement cascade and HTRA1 dual blockade activity with superior potency in vitro.
IAR045-001 also shows better in vivo efficacy than ARC1905 and galegenimab in a NaIO3-induced GA mouse model.
IAR045-001 retains well PK data in rabbit intravitreal study with molecule mass of about 40kD.
IAR045-001 are potential to provide better therapeutic efficacy in GA patients.
This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.