Humoral Immune Response After Intravitreal But Not After Subretinal AAV8 in Primates and Patients

Reichel, Felix F.; Peters, Tobias; Wilhelm, Barbara; Biel, Martin; Ueffing, Marius; Wissinger, Bernd; Bartz-Schmidt, Karl U.; Klein, Reinhild; Michalakis, Stylianos und Fischer, M. Dominik (2018): Humoral Immune Response After Intravitreal But Not After Subretinal AAV8 in Primates and Patients. In: Investigative Ophthalmology & Visual Science, Bd. 59, Nr. 5: S. 1910-1915

Abstract

PURPOSE. To study longitudinal changes of anti-drug antibody (ADA) titers to recombinant adeno-associated virus serotype 8 (rAAV8) capsid epitopes in nonhuman primates (NHP) and patients. METHODS. Three groups of six NHP each received subretinal injections (high dose: 1 x 10(12) vector genomes [vg], low dose: 1 x 10(11) vg, or vehicle only). Four additional animals received intravitreal injections of the high dose (1 x 10(12) vg). Three patients received 1 x 10(10) vg as subretinal injections. ELISA quantified ADA levels at baseline and 1, 2, 3, 7, 28, and 90 days after surgery in NHP and at baseline and 1, 3, and 6 months after surgery in patients. RESULTS. Two out of 22 animals lacked ADA titers at baseline and developed low ADA titers toward the end of the study. Titers in the low-dose group stayed constant, while two of six animals from the high-dose group developed titers that rose beyond the range of the assay. All animals from the intravitreal control group showed a rise in ADA titer by day 7 that peaked at day 28. Preliminary data from the clinical trial (NCT02610582) show no humoral immune response in patients following subretinal delivery of 1 x 10(10) vg. Conclusion: S. No significant induction of ADA occurred in NHP when mimicking the clinical scenario of subretinal delivery with a clinical-grade rAAV8 and concomitant immunosuppression. Likewise, clinical data showed no humoral immune response in patients. In contrast, intravitreal delivery was associated with a substantial humoral immune response. Subretinal delivery might be superior to an intravitreal application regarding immunologic aspects.

• Dokumententyp: Zeitschriftenartikel
• Fakultätsübergreifende Einrichtungen: Center for Integrated Protein Science Munich (CIPSM)
• Themengebiete: 500 Naturwissenschaften und Mathematik > 540 Chemie
• ISSN: 0146-0404
• Sprache: Englisch