Abstract
Purpose :
Intraocular inflammation in the form of a foreign body reaction (FBR) is a common adverse finding in preclinical toxicology studies of long-acting delivery (LAD) modalities. We hypothesized that FBR following intravitreal (IVT) injection of antibody fragment (Fab)-hydrogel microsphere conjugates was mediated by an immunogenicity response that may have limited relevance to the clinic.
Methods :
Unconjugated hydrogel microspheres were well tolerated following IVT injection in rabbits (n=3, single dose). The toxicity of humanized Fab-hydrogel microspheres and unconjugated microspheres were assessed in cynomolgus monkeys following IVT injection (n=6/ group, single dose). A subsequent investigative study in rabbits compared the toxicity of IVT injections of humanized and species matched Fab-hydrogel microspheres, and with co-administration of unconjugated microspheres and Fabs (n=3/ group, single dose). Assessment of toxicity included clinical signs, ocular exams, intraocular pressure measurements, anti-drug-antibody (ADA) measurements, and histopathology of the globe.
Results :
The monkey study was terminated due to severe ocular inflammation beginning day 29 in eyes that received the humanized Fab-hydrogel microspheres. There were high systemic ADA titers and histopathology confirmed intraocular FBR. In the rabbit study, similarly high ADA titers and ocular FBRs were observed in animals administered the humanized Fab-hydrogel microspheres, and separate injections of unconjugated humanized Fab and placebo hydrogel microspheres. In contrast, ocular FBR was not present in animals that received species-matched Fab-hydrogel microspheres except in a single animal that developed ADA despite the species matched Fab.
Conclusions :
IVT injection of LAD modalities that carry humanized Fabs may result in adverse, immunogenicity-mediated ocular FBR in nonclinical studies. A species-matched surrogate Fab may minimize the likelihood of this occurrence, but does not de-risk the potential of immunogenicity of the candidate molecule in the clinic. While systemic ADA can be monitored in clinical trials, the prolonged intraocular residence time of LAD modalities following a single IVT injection makes safe withdrawal of drug in a patient with emergent ADA challenging. Novel clinical trial designs would be necessary to progress molecules with FBR liabilities into the clinic.
This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.