Table 1.
Passive immunization studies in Parkinsonian animal models.
| Target (αsyn) | Antibody/Clone | Binding Site (aa) | Ab Origin Immunization Method | Injection Frequency Duration Amount |
Animal Model | αsyn Pathological Effects | Neuronal Effects | Other Non-Neuronal Effects | Behavioral Effects | Ref. |
|---|---|---|---|---|---|---|---|---|---|---|
| C-term. | 9E4 (IgG1) | C-term. 118–126 | human Full-length (FL) αsyn (h-αsyn) | i.p., weekly 6 m 10 mg/kg b.w. |
PD/DLB: PDGFb αsyn mice (line D) | ↓ FL αsyn in neocortex neuropils; ↓ Reduced CC-αsyn in neocortex (intraneuronal and neuropil), Hippocampus (intraneuronal/neuropil); ↓ Reduced insoluble-FL-αsyn oligo.; ↓ soluble-CC-αsyn mono./oligo.; ↓ insoluble-CC-αsyn mono./oligo. |
↑ synaptic densities; ↑ Pre-synaptic terminals; ↑ PSD95; ↑ Synapsin. |
↓ Astrogliosis in PFC. | ↑ Rotarod time; ↓ Path in Morris water maze. |
[106] |
| C-term. | Ab274 (IgG2a) | C-term. 120–140 | h-αsyn | i.p., weekly 4 wks 1 mg/mL hippocampal injection |
PD: PDGFb αsyn mice (line M) | ↓ αsyn (70–80% in cortex and hippocampus; ↓ αsyn (30–35% in striatum); ↓ αsyn in brain homogenates; ↓ αsyn in neurons and glial cells (total) (neocortex, Hippocampus, Striatum); ↑ Cathepsin-D and αsyn coloc.; ↑ αsyn clearance by microglia. |
↓ NeuN cell loss; ↓ NeuN cell loss (hipp); ↑ increased synaptophysin (Hippocampus). |
↓ TNF-a and IL-6; ↑ Iba-1 in hippocampus; ↓ Astrogliosis. |
↓ latency to turn (Pole test); ↓ Total activity in open field. |
[107] |
| NAC to C-term. | 1H7 (IgG1) | 91–99 (NAC to C-terminal) | FL h-αsyn | i.p., weekly 6 m 10 mg/kg b.w. |
PD: Thy1 αsyn (line 61) mice | ↓ αsyn and αsyn aggre. (temporal and striatal neuropil) ↓ axonal αsyn (striatum) |
↓ TH loss in striatum; ↑ synapto-physin + MAP2 (neocortex and striatum) |
↓ Astrogliosis ↓ Microgliosis |
↓ Memory and learning deficits; ↓ error on transversal beam) |
[18] |
| 5C1 (IgG1) (9E4 analog) | C-term. 118–126 | GCC-VDPDNEAYE peptide | ↓ αsyn and αsyn aggr. (temporal and striatal neuropil) ↓ axonal as αsyn yn (striatum) |
↓ TH loss in striatum; ↑ synaptophysin + MAP2 (neocortex and striatum |
↓ Astrogliosis ↓ Microgliosis |
↓ Memory and learning deficits; |
||||
| 5D12 (IgG1) (9E4 analog) | C-term. 118–126 | VDPDNEAYE-GCC peptide | ↓ αsyn (neocortex) | - | - | - | ||||
| 9E4 | C-term. 118–126 | FL h-αsyn | ↓ αsyn and αsyn aggre. (temporal and striatal neuropil) ↓ axonal αsyn (striatum) |
↓ TH loss in striatum; ↑ synaptophysin + MAP2 (neocortex and striatum |
↓ Astrogliosis ↓ Microgliosis |
↓ Memory and learning deficits; ↓ error on transversal beam) |
||||
| N/C-term. | Syn303 | N-term. 1–5 | human phos./nitr. αsyn | i.p., weekly 180 days 30 mg/kg b. w. |
PD: Intra-striatal injection of PFF in wt mice |
↓ insoluble αsyn aggre. and pS129-αsyn; ↓ Reduced αsyn spread in SNc (30%) and contra- and ipsilateral amygdala (40%). | ↓ neuron loss; ↓ PFF neuron entry and PFF transmission; ↓ TH cell loss. | - | ↑ latency to hang (Wirehang time) | [108] |
| Syn211 | C-term. 121–125 (mono./oligo./Fibrils) | h-αsyn positive for DNEAY-peptide | ↓ insoluble αsyn aggre. and pS129-αsyn | ↓ neuron loss; ↓ PFF neuron entry and PFF transmission. |
- | - | ||||
| Proto-fibril | mAB47 (IgG1) | Conformational | h-αsyn oligomers (hybridoma) | i.p., weekly 14 wks 10 mg/kg b.w. |
PD: Thy-1 H[A30P] mice |
↓ αsyn protofibrils in spinal cord |
- | - | - | [109] |
| N/C-term. | AB1 | N-term. 16–35 | αsyn peptide (16–35aa) | i.p., 14 days 3 m, 1 mg/rat (2x first), then 0.5 mg/mL |
PD: Nigral AVV-CBA-αsyn in wt rats | ↓ αsyn in SN | ↓ DA and NeuN cell loss. |
↓ Microgliosis | - | [110] |
| AB2 | C-term. 93–115 | αsyn peptide (93–115aa) | ↓ αsyn brain homogenate | - | ↓ Microgliosis | - | ||||
| Oligo and late aggre. | Syn-01 | Conformational (Oligo./aggre.) | αsyn -> hybridomas | i.p., weekly 3 m 30 mg/kg b.w. |
PD/DLB: mThy1 αsyn (Line 61) Mice |
↓ αsyn (neocortex, hippocampus, striatum, SN); ↓ PK-resistant αsyn (neocortex, hippocampus, striatum); ↓ oligomeric αsyn; ↓ 5G4 aggregated αsyn |
↓ NeuN hippocampal loss (CA3); ↑ Synapsin I/Synaptophysin ratio;↓ αsyn/synaptophysin ratio | ↓ Astrogliosis; ↓ Microgliosis |
↓ beam breaks (total activity) | [111] |
| Syn-02 | ↓ αsyn (striatum);↓ PK-resistant αsyn (hippocampus, striatum); ↓ total αsyn; ↓ oligo. αsyn;↓ 5G4 aggregated αsyn. | - | - | - | ||||||
| Syn-04 | ↓ αsyn (neocortex, hippocampus, Striatum, SN);↓ PK-resistant αsyn (neocortex, hippocampus, striatum); ↓ total αsyn; ↓ oligomeric αsyn; ↓ 5G4 aggregated αsyn |
↓ NeuN hippocampal loss (CA3); ↑ Synapsin I/Synaptophysin ratio;↓ αsyn/synaptophysin ratio | ↓ Astrogliosis; ↓ Microgliosis |
↓ beam breaks (total activity) | ||||||
| Syn-F1 | Conformational (late aggre.) | ↓ αsyn (neocortex, hippocampus, striatum, SN); ↓ PK-resistant αsyn (hippocampus); ↓ oligomeric αsyn. |
↓ NeuN hippocampal loss (CA3); ↑ Synapsin I/Synaptophysin ratio;↓ αsyn/synaptophysin ratio | - | ↓ beam breaks (total activity) | |||||
| Syn-F2 | ↓ αsyn (neocortex, striatum, SN); ↓ PK-resistant αsyn (hippocampus); ↓ oligomeric αsyn. |
↓ αsyn/synaptophysin ratio | - | - | ||||||
| Aggre. | 1H7 | C-term. 91–99 | FL h-αsyn | i.p., weekly 3 m 30 mg/kg b.w. |
PD: mThy1 αsyn (61) mice, intra-hippocampal inj. of LV-αsyn | ↓ axonal αsyn ↑ coloc. of αsyn and microglia |
↑ axonal integrity | - | ↓ water maze time to localization | [112] |
| Oligo | Rec47 (mAB47 as in [109]) | Conformational, Binding to C-terminal 121–127 | h-αsyn oligomers (hybridoma) | i.p., bi-weekly 3 m 20 mg/kg b.w. |
MSA: PLP αsyn transgenic mice | ↓ soluble and insoluble αsyn (hippocampus) ↓ GCI’s in spinal cord; ↑ pS129 αsyn (SNpc, pontine nuclei and inferior olives) ↑ Co-localization of LCS (autophagy) and p-S129 αsyn. |
↓ Microgliosis; ↓ activated MG; ↑ Iba-1 and olig-αsyn co-localization |
- | [113] | |
| Aggre. | MEDI1341 (IgG1) | C-term. | Human phage library cloned into IgG1 | i.p., weekly 13 wks 20 mg/kg b.w. |
PD: mThy1 αsyn (Line 61) mice – intra-hippocampal injection of LV-αsyn |
↓ contralateral and ipsilateral αsyn (hippocampus); ↓ contralateral axonal αsyn ↓ αsyn (neocortex) ↓ interstitial fluid αsyn levels ↓ CSF fluid αsyn levels ↓ αsyn positive neurons (neocortex and hippocampus) |
- | - | - | [114] |
| Mono. and Oligo. | nAb isolated from IViG | nAbs isolated from IViG using αsyn column chromatography | s.c., weekly 4 wks Low dosage: 0.8 mg/kg b.w. |
PD: A53T tg mice | ↓ pS129-αsyn (brainstem) ↓ soluble αsyn (brainstem) |
↓ Astrogliosis(Striatum);↑ Microglia and αsyn coloc. | ↓ Pole test (time to descend/time to turn). | [115] | ||
| s.c., weekly 4 wks High dosage: 2.4 mg/kg b.w. |
↓ pS129-αsyn (brainstem and neocortex) ↓ soluble αsyn (brainstem) ↓ Reduced total soluble and insoluble h-αsyn (brainstem); ↓ fibrillary-oligo. αsyn; ↓ pS129-αsyn/NfL ratio. ↑ Microglia and αsyn co-localization. |
↑ PSD95 (brainstem), ↑ synaptophysin (brainstem); ↓ TH cell loss (striatum, brainstem) |
↓ astrogliosis(striatum) ↓ microgliosis(striatum); ↓ MCP-1(brainstem). | ↓ Pole test (time to descend/time to turn); ↑ Body suspension test (hanging); ↑ Y maze (duration in new arm/new entries). |
||||||
| Aggre. | Syn9048 (IgG1) | C-term. | hybridoma | i.p., weekly 6 m 30 mg/kg |
PD: wt + αsyn PFF (5µg) unilateral inj. in dorsal striatum | ↓ αsyn ipsilateral SN; ↓ Contralateral amygdala. |
↓ DA cell loss; ↑ DOPAC | - | - | [116] |
| N-term. | Syn303 ([108]) | N-term. 1–5 | phos./nitr. h- αsyn | - | ↓ TH cell loss (ipsilateral) | - | - | |||
| Aggre. | BIIB054/cinpanemab | N-term: 1–10 (800-fold greater affinity to aggregated αsyn) | Healthy human memory B cells -> clones | i.p., weekly 60, 90 or 100 days 30 mg/kg b.w. |
PD: wt C57BL/6JRccHsd mice + αsyn PFF intrastrial inj. |
↓ truncated αsyn 6kd (100d) | - | - | ↑ Hangwire (latency to fall, 60d) | [117] |
| PD: Tg αsyn A53T (M83) + αsyn PFF inoc. | - | - | - | ↓ paralysis (7 d) ↓ severe paralysis (5 d); ↓ weight loss (9 d). |
||||||
| PD: BAC αsyn A53T + αsyn PFF intrastrial inj. | - | ↑ contralateral DAT levels (striatum, 90d) | - | - | ||||||
| NAC-region | NAC32 | 53–87 | Yeast surface display library of an entire naïve repertoire of human scFV antibodies | Stereotaxis (AAV-NAC32) post 12 wks after αsyn inj. Beh. 4,8 and 12 wks after NAC32 inj. |
PD: DAT-Cre rats + AAV-DIO- αsyn in SNpc. | ↓ αsyn (25%) (SNpc dorsal). | ↓ TH cell loss (SNpc dorsal) | - | ↓ Horizontal activity; ↓ Total distance travelled; ↓ Movement number; ↓ Movement time; ↑ Rest time; ↓ Vertical activity | [118] |
| Aggre. (Oligo/Proto-fibrils) | ABBV-0805/mAB47 for murine experiments | Humanized mAB47, binding to C-term. 121–127 | h-αsyn oligo. ->hybridoma, same as prior | i.v., bolus, starting at 2 m old, sampled multiple times. 0.1, 1, 10 mg/kg |
wt C57BL/6 mice (pharmacokinetics) | - | 0.3% in the brain dose-dependent plasma content |
- | - | [119] |
| i.p., weekly starting at age 12 m, 10mg/kg |
PD: Thy-1-h[A30P] αsyn tg mice | - | - | - | ↑ Mean survival from 84 days to 160 days | |||||
| i.p., weekly starting at age 12 m, 20 mg/kg |
PD: Thy-1-h[A30P] αsyn tg + 10 µg gastrocnemius i.m PFF inj., after mab treatment |
- | - | - | ↑ Mean survival from 84 days to 95 days | |||||
| Starting 4 wks prior to PFF inj.; weekly mab inj. Prophylactic: 2–4 m, until severe motor deficits, 20 mg/kg |
PD: Thy-1-h[A30P] αsyn tg + gastrocnemius PFF inj. 1 µg i.m. |
↓ soluble and insoluble αsyn (brain); ↓ insoluble pS129-αsyn; ↓ CSF pS129-αsyn; ↓ LB-509 αsyn inclusions (reticular nucleus); ↓ pS129-αsyn inclusion (midbrain). |
- | - | - | |||||
| Post 2 wks after PFF inj.; weekly mab inj. Therapeutic: 2–4 m. until severe motor deficits, 20 mg/kg |
PD: Thy-1-h[A30P] αsyn tg + gastrocnemius PFF inj. 1 µg i.m. |
↓ soluble and insoluble αsyn (brain); ↓ insoluble pS129-αsyn ↓ CSF pS129-αsyn; ↓ Dose-dependent soluble and insoluble αsyn (brain); ↓ soluble αsyn at low mab administration (0.25 mg/kg); ↓ insoluble αsyn (5 mg/kg); ↓ LB-509 αsyn inclusions in (reticular nucleus); ↓ pS129-αsyn inclusion (midbrain). |
- | - | - | |||||
| weekly 16 wks 20 mg/kg |
PD: A53T+/− mice (83) + i.c. (anterior olfactory nucleus) PFF inj. | ↓ pS129- αsyn pathology spreading to the contralateral hippocampus (CA1) (58%). | - | - | - |
Abbreviations: PFF: preformed fibrils, αsyn: alpha-synuclein, FL: full-length, h-αsyn: human αsyn, CC: Calpain cleaved, pS129-ayn: phosphorylated αsyn, phos.: phosphorylated, nitr.: nitrated, mab: monoclonal antibodies, mono.: monomeric, oligo.:oligomers/oligomeric, aggre: aggregates/aggregated, m: months, wks: weeks, inj.: injection, i.p.: intraperitoneal, i.m.: intramuscular, i.c.: intracerebral, inoc.: inoculation, b.w.: bodyweight, SNpc: substantia nigra pars compacta, tg: transgenic, wt: wild-type, LV: lentivirus.