Table 3.
Current approaches for AAV delivery of antibodies.
| Disease | AAV seroype | Antibody | Animal Model | Route | AAV Dose (vector genomes; vg) |
Antibody concentration achieved |
Anti-drug antibody response |
Notes | Reference |
|---|---|---|---|---|---|---|---|---|---|
| HIV | AAV2 | B12 | Rag1 Mice | Intramuscular | 5E+10 to 5E+11 | 0.5 - 8 μg/mL | Lewis et al., 2002 | ||
| AAV1 | Immunoadhesins ( 4L6, 8S, 5L7, 3V0 | Rhesus macaques | Intramuscular | 2.00E+13 | 4L6 (100-190 μg/mL ) 5L7 (50- 175 μg/mL) |
Johnson et al., 2009 | |||
| AAV8 | B12 | NSG, B6 and Balb/C | Intramuscular | 1.00E+11 | 20-250 μg/mL | Balazs et al., 2011 | |||
| AAV8 | 3BNC117, 10-1074 | Humanized mice | 2.50E+11 | 200 μg/mL | Horwitz et al., 2013 | ||||
| AAV8 | multiple anitbodies including PG9, VRC07, 3BNC117 | NSG and BLT mice | Intramuscular | 0.05 - 390 μg/mL | Mice receiving AAV-VROC7 were completely resistant to repetitive intravaginal challenge | Balazs et al., 2014 | |||
| AAV8 | Simianized VRC07 | Rhesus macaques | Intramuscular | 30? | All animals unless Cyclosporin | First to show that immunosuppression could alleviate ADA responses | Saunders et al., 2015 | ||
| AAV1 | Immunoadhesin with rhesus IgG1 | Rhesus macaques | Intramuscular | 0.8E+13 to 2.5E+13 | 1-270 μg/mL | 9/ 12 animals | In one animal, the concetration of antibody was 270 μg/mL and the levels persisted for 2 years | Fuchs et al., 2015 | |
| AAV1 | eCD4-Ig | Rhesus macaques | Intramuscular | 2.50E+13 | 17- 77 μg/mL | Rhesus eCD4-Ig was less immunogenic than rhesus forms of bNAbs | Gardner et al., 2015 | ||
| AAV1 | 4L6, 5L7, 1NC9, 8ANC195, 3BNC117 | Rhesus macaques | Intramuscular | 1.6E+13 to 3E+13 | NA | 17/20 animals | Martinez-Navio et al., 2016 | ||
| AAV8 | anti-SIV Env mAb ITS01 and ITS06.02 | Rhesus macaques | Intramuscular | 1.00E+13 | 8-21 μg/mL | ADA in 20% animals | Welles et al., 2018 | ||
| AAV1 and AAV8 | 10E8, 3BNC117, 10-1074 | Rhesus macaques | Intramuscular | 2E+12 vg/kg | 2-200 μg/mL | Varying magnitidue of ADA present in most animals | Viremia undetectable in one monkey for over 3 years | Martinez-Navio et al., 2019 | |
| AAV1 | 3BNC117, NIH45-46, 10-1074 and PGT121 | Rhesus macaques | Intramuscular | 2E+11 to 1E+13 | 3-69 μg/mL | 12/ 12 animals | Antibodies isotyped with IgG2 were found to be less immunogenic than IgG1 isotyped antibodies | Gardner et al., 2019 | |
| AAV1 and AAV8 | 4L6 | Rhesus macaques | Intramuscular /Intravenous | 0.25E+12 vg/kg | Intramuscular : 1-7 μg/mL Intravenous : 0.3- 2.3 μg/mL AAV8 priming and AAV1 boost : 186-302 μg/mL |
ADA in 9/9 animals in intramuscular group; no ADA detected (0/3) in intravenous group | Muscle-specific or liver-specific promoters were used | Fuchs et al., 2019 | |
| AAV1 | PG9 | Human | Intramuscular | 4E+12 to 1.2E+14 | Undectectable (< 2 μg/mL) | 10/16 detectable ADA | First human clinical trial | Priddy et al., 2019 | |
| AAV8 | VRC07 | Human | Intramuscular | 5E+10 to 2.5E+12 vg/kg | <1 - 3.3 μg/mL | 3/8 detected ADA (2/8 lost transgene) | Clinical trial ongoing | Casazza et al., 2022 | |
| AAV8 | VRC07 containing Fc region of different human IgG subclass | huPBMC and BLT mice | Intramuscluar | <1 - 70 μg/mL | VRC07-IgG2 exhibited redued protection in vivo relative to other IgG subclasses. | Brady et al., 2022 | |||
| Cancer | AAV1 | anti-EGFR antibody 14E1 | A431 xenograft tumor model | Intramuscular | 1E+11 to 5E+11 | over 1000 μg/mL | Ho et al., 2009 | ||
| Malaria | AAV8 | 2A10, 2C11 | C57BL/6(6NCr) | Intramuscular | 1.00E+11 | 50-1000 μg/mL | Deal et al., 2014 | ||
| C. difficile | AAV6.2FF | actoxumab, bezlotoxumab | Mice and Syrian Hamsters | Intramuscualar | Mice : 1E+11 Hamsters : 1E+12 |
90-195 μg/mL | Guilleman et al., 2021 | ||
| Parkinson's Disease | AAV8 | anti-Synuclein (NAC32) | Rats (DAT-Cre) | Intracerebral | 2E+12 vg per injection site | Chen et al., 2021 | |||
| Ebola | AAV6.2FF | 2G4, 5D2 (murine IgG2a ebola virus mAbs) EBOV mAb 100, 114, FVM04, ADI-15876, CA45 (as human IgG1) |
Mice (BALB/c) | Intramuscular | 8E+9 to 4E+11 | Dose dependent (<1 to 900 μg/mL) | Sustained expression in mice for more than 400 days. Minimum serum antibody level of 2 μg/mL was found to be protective. | Leishout et al., 2022 | |
| AAV9 | 2G4, 4G7, c13C6 | Mice | Intramusclar/ Intranasal | 1.00E+11 | 9 μg/mL in serum; 3 μg/mL in BALF | Humanization of mouse antibodies improved expression profile | Limberis et al., 2016 | ||
| AAV9 | c2G4, c4G7, c13C6 | Mice | Intramuscular/ Intravenous/ Intranasal | 2.7E+10 to 3E+11 | Intramuscular : <1 - 26 μg/mL Intravenous : 5.3 - 33 μg/mL Intranasal : not detected |
Robert et al., 2018 | |||
| Herpes simplex virus (HSV) | AAV8 | CH42, CH43, E317 (HSV mAbs targeting gD) | Mice (C57BL/6) | Intramuscular | 1.00E+11 | Passive transfer of HSV-specific mAbs delivered via AAV from dams to their offspring | Backes et al., 2022 | ||
| Respiratory syncytial virus (RSV) | AAV6.2FF | Palivizumab, hRSV90 | Mice | Intramuscular / Intranasal | Mice : 1E+11 | 174 - 397 μg/mL ( on day 70) | Antibody detected in the serum and at various mucosal surfaces. Maternal passive transfer of antibodies observed. | Rghei et al., 2022 | |
| Keratitis ichthyosis deafness | AAV8 | abEC1.1 | Cx26G45E mouse | Intravenous | 1.25E+12 | 50 μg/mL | Peres et al., 2023 | ||
| SARS-CoV-2 | AAV8 and AAV9 | NC0321 | hACE2-expressing mice | Intramuscular/Intranasal | 1.00E+11 | AAV8 given IM : 3.9 μg/mL in serum; 18 μg/mL in BALF AAV9 given IN : 0.9 μg/mL ; 65 μg/mL in BALF |
Du et al., 2022 | ||
| Influenza | AAV8 | F10, CR6261 | Mice (BALB/c and NSG) | Intramuscular | 1.00E+11 | F10 :100-200 μg/mL CR6261 : 0.1-100 μg/mL |
Balazs et al., 2013 | ||
| AAV9 | FI6 | Mice | Intranasal | 1.00E+11 | Adam et al., 2014 | ||||
| AAV9 | MD3606 | Mice | Intranasal | 4E+7 to 5E+9 | Laursen et al., 2018 | ||||
| AAV8 | R1a-B6 | Mice | Intramuscular | 1.00E+11 | 0.5 - 1100 μg/mL | Del Rosario et al., 2020 |