Felix F Reichel1,2, Tobias Peters3, Barbara Wilhelm3, Martin Biel4, Marius Ueffing2, Bernd Wissinger2, Karl U Bartz-Schmidt1, Reinhild Klein5, Stylianos Michalakis4, M Dominik Fischer1,2,3,6. 1. University Eye Hospital, University of Tübingen, Tübingen, Germany. 2. Institute for Ophthalmic Research, Centre for Ophthalmology, University of Tübingen, Tübingen, Germany. 3. STZ Eyetrial at the Center for Ophthalmology, University of Tübingen, Tübingen, Germany. 4. Center for Integrated Protein Science Munich (CIPSM) at the Department of Pharmacy, Center for Drug Research, Ludwig-Maximilians-Universität München, Munich, Germany. 5. Department of Internal Medicine II, University Hospital Tuebingen, Germany. 6. Nuffield Laboratory of Ophthalmology, Nuffield Department of Clinical Neurosciences, University of Oxford, United Kingdom.
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 × 1012 vector genomes [vg], low dose: 1 × 1011 vg, or vehicle only). Four additional animals received intravitreal injections of the high dose (1 × 1012 vg). Three patients received 1 × 1010 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 × 1010 vg. Conclusions: 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.
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 × 1012 vector genomes [vg], low dose: 1 × 1011 vg, or vehicle only). Four additional animals received intravitreal injections of the high dose (1 × 1012 vg). Three patients received 1 × 1010 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 × 1010 vg. Conclusions: 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.
Authors: Peter M Quinn; Thilo M Buck; Aat A Mulder; Charlotte Ohonin; C Henrique Alves; Rogier M Vos; Monika Bialecka; Tessa van Herwaarden; Elon H C van Dijk; Mays Talib; Christian Freund; Harald M M Mikkers; Rob C Hoeben; Marie-José Goumans; Camiel J F Boon; Abraham J Koster; Susana M Chuva de Sousa Lopes; Carolina R Jost; Jan Wijnholds Journal: Stem Cell Reports Date: 2019-04-04 Impact factor: 7.765