Table 2.
Summary of the main characteristics of treatments tested in the 31 original articles analyzed in this work.
| Treatment | |||||||
|---|---|---|---|---|---|---|---|
| Target | Antibody | Model | Stage | Delivery, frequency and duration | Observed outcomes | Observed limitations | References |
| mSOD1 | mAb: C4F6 | SOD1G93A mice | Pre-symp. (85 days) | Continuous ICV infusion for 28 days | Delayed body weight loss and motor impairments, increased survival | Urushitani et al., 2007 | |
| mMAb: D3H5, A5C3 | SOD1G93A mice (females) | Pre-symp. (65 days) and symp. (95 days) | Continuous ICV infusion for 42 days | D3H5 reduced levels of mSOD1, delayed symptom onset and prolonged lifespan | A5C3 failed to confer protection | Gros-Louis et al., 2010 | |
| Fab fragment: D3H5 | Fab fragment extended lifespan | ||||||
| HuMAb: HuMAb120c, HuMAb37L-63 | SOD1G93A mice (males) | Pre-symp. (65 days) | Continuous IT infusion for 50 days | Increased survival | No evaluation of MN loss, muscle strength, neuroinflammation or SOD1 aggregates | Broering et al., 2013 | |
| IP injections: 3 daily doses at the beginning then once every 7 days | |||||||
| mMAb: DSE2-3H1 | HEK293FT cells | Ab added in cells medium prior to patient tissues homogenates | Reduced aggregated SOD1 propagation | No studies in vivo | Pokrishevsky et al., 2017 | ||
| hMAb: chα-mSOD1 | SOD1G93A and SOD1G37R mice | Pre-symp. (60 days) | Continuous ICV infusions | Delayed onset, extended survival, reduced SOD1 pathology and MN degeneration, decreased neuroinflammation | Maier et al., 2018 | ||
| Weekly IP injections. | |||||||
| scFv: derived from D3H5 | SOD1G93A mice | Pre-symp. (45 days) | Continuous production after one IT injection of AAV | Delayed disease onset and extension of life span in correlation with scFv titers in the spinal cord. Reduced neuronal stress signals, levels of mSOD1, gliosis and MN loss | Patel et al., 2014 | ||
| SOD1 | mMAb: α-SOD1 a143-153, α-SOD1 a65-72 | SOD1G85R mice | Symp. (78 days) | IT inoculation of seed pre-incubation with the antibody | α-SOD1143-153 attenuated transmission of pathogenic aggregation and prolonged the survival | Poor access to intracellular aggregation and insufficient antibody titer in the CNS | Lehmann et al., 2020 |
| IT inoculation of seed and weekly IP injections till end-stage of the disease | α-SOD1 a65-72 showed adverse effects and increased seed-induced disease | ||||||
| scFv: B1, B12 | NSC-34 cells | Transfection of heavy and light chain | Decreased SOD1 aggregation, improved cell survival | Ghadge et al., 2013 | |||
| scFv: B1, B12 | SOD1G93A mice | Neonatal and early-symp. (120 days) | IV infusion of AAV | Decreased MN loss, neuroinflammation and SOD1 burden and aggregation. Increased survival | No significant difference in disease onset | Ghadge et al., 2019 | |
| B12 was toxic for neonatal mice | |||||||
| scFv: W20 | SOD1G93A mice | Pre-symp. | IN daily administration for 3 weeks | Reduced SOD1 aggregates and total SOD1 levels. Improved motor functions. Reduced weight loss, gliosis and neuroinflammation. Delayed symptoms onset | Dong et al., 2018 | ||
| TDP-43 | mMAb: E6 | TDP-43A315T mice | 9 months old | IT injections twice a week, for 5 weeks | Decreased TDP-43 mislocalization and reduction of nuclear p65 in MN | Induced a general microglial activation in lumbar spinal cord | Pozzi et al., 2020 |
| N2A and BV2 cells | In the cell medium | Reduced cytoplasmic TDP-43 by TRIM-21/proteasome pathway | |||||
| scFv: 3B12A | HEK293A cells | Transfection in cells | In cells: Increase cell viability and enhanced TDP-43 aggregate clearance via proteasome | Tamaki et al., 2018 | |||
| in utero electroporation of mutant TDP-43 | Embryo stage | Constant production from embryonic stage after scFv plasmid in utero | In mice: reduced TDP-43 aggregates in embryonic mouse brain, induced HSP70 transcription and enhanced TDP-43 clearance by promoting protein refolding | ||||
| scFv: VH7Vk9 derived from E652 | TDP-43G348C mice and TDP-43A315T mice | Symp. (8 months) | IC or IT single AAV injection | Reduced cognitive and motor deficits in mice | Pozzi et al., 2019 | ||
| Reduced TDP-43 proteinopathy and neuroinflammatory | |||||||
| HEK293 cells | Transfection | Decreased of total cellular levels of TDP-43 promoting its degradation via proteasomal and autophagic pathways | |||||
| C9ORF72 repeats expansion | mMAb: 5F2 | HEK293 cells, Primary neurons | In the cell medium | Reduced poly-GA levels, inhibited intracellular poly-GA aggregation and blocked the seeding activity of C9orf72 brain extracts | Zhou et al., 2017 | ||
| mMAb: 5F2 | Primary neurons | In the cell medium | Reduced poly-GA aggregation and transmission, and reduced cytoplasmic levels of TDP-43 | Khosravi et al., 2020 | |||
| hAb: α-GA1, α-GP1, α-GA2 | Female C9-BAC mice | 6 weeks of age | Single IP injection | Reduced GA aggregates, improved behavioral deficits, decreased neuroinflammation and neurodegeneration, and increased survival | Anti-GA antibodies more efficient than anti-GP | Nguyen et al., 2020 | |
| HEK293T cells | In the cell medium | ||||||
| Nogo-A | HuMAb: Ozanezumab | sALS human patients | 18–80 years old | IV injections, single dose or two repeated doses, four weeks apart (various dosage). | Treatment was well tolerated. | Did not show changes in functional endpoints. Inclusion criteria and small sample size might have caused bias. | Meininger et al., 2014 |
| HuMAb: Ozanezumab | sALS human patients | 18–80 years old | IV injection every two weeks, for 46 weeks | Treatment was well tolerated. | Did not show changes in functional endpoints nor survival. | Meininger et al., 2017 | |
| mMAb: GSK577548 | SOD1G93A mice | Pre-symp. (70 days) | IP weekly injections, until symp. stage (90 days) or end stage (120 days) | Improved muscle innervation, increased muscle strength and motor unit survival, increased MN survival. | Effect was limited to early stages of the disease. | Bros-Facer et al., 2014 | |
| MuSK | hMAb: #13, #21, #22 | SOD1G93A mice | Symp. (90 days) | Single IP injection, or repeated every 24 days. | Slowed muscle denervation, promoted neuron survival, improved motor system output and extended lifespan. | Cantor et al., 2018 | |
| Chimeric Ab: #13 | SOD1G93A mice | Pre-symp. (6 weeks) | IP injections every two weeks for 12 or 16 weeks. | Preserved innervation of the NMJ. | Did not preserve diaphragm function, MN, nor increased survival. | Sengupta-Ghosh et al., 2019 | |
| IL-6R | HuAb: Tocilizumab | sALS human patients | Mean age: 55 years old | IV injections every 4 weeks for 4 to 8 months. | Inhibited IL6 signaling and downregulated inflammation. | Fiala et al., 2013 | |
| HuAb: Tocilizumab | Rat cortical neurons exposed to ALS-PBMC supernatant | PBMC supernatant and antibody added to medium. | Inhibited ALS-PBMC supernatant toxicity. | Lam et al., 2016 | |||
| NRP-1 | HuMAb: α-NRP1A | SOD1G93A mice | Pre-symp. (40 days) or advanced stage (90 days) | IP injections twice a week, until end-stage | Temporarily reversed motor functional decline and prolonged the life span, reduced NMJ denervation and attenuated pathologic alterations in ventral roots | No significant efficacy when applied at a late disease stage | Venkova et al., 2014 |
| NSC-34 cells | In cell medium. | Prevented Sema3A-induced growth cone collapse | |||||
| Myostatin | Mab: RK35 | SOD1G93A mice and rats | Pre-symp. (28 days) | IP injections weekly until end-stage | Increased skeletal muscle mass and strength in early stages, slowed degenerative changes in skeletal muscle | Did not delay onset nor enhance survival | Holzbaur et al., 2006 |
| Effects were not observed in advanced stage of the disease | |||||||
| CD40L | Mab: MR1 | SOD1G93A mice | Pre-symp. (50 days) | IP injections weekly until end-stage | Slowed weight loss, delayed disease onset, extended survival, reduced neuroinflammation and reduced MN loss | Lincecum et al., 2010 | |
| DR-6 | Mab: 5D10 | SOD1G93A mice | Pre-symp. (42 days) | IP injections twice a week, until end stage (140 days) | Decreased gliosis, increases survival of MN and oligodendrocytes, protected NMJ, improved motor function and decreased pNfH levels in serum | Huang et al., 2013 | |
| Motor neurons | In the cell medium after stimuli | Prevent challenger-induced death | |||||
| IFN-γ | MAb: R4-6A2 | SOD1G93A mice | Early-onset (13 weeks) | Continuous ICV infusion | Increase MN survival | Did not increase survival. Therapeutic benefit obtained only during antibody delivery | Otsmane et al., 2014 |
| Motor neurons | In cells medium | Reduced IFN-g-induced death | |||||
| GD1a/GT1b | hAb: rHIgM12 | SOD1G93A, SOD1G86R mice | Pre-symp. (60 days) | Single IP injection | Increased survival, delayed the onset of symptoms preserved MN from death | Multiple doses were ineffective due to anti-human response | Xu et al., 2015 |
| Primary neurons | In cells medium | Promoted cytoskeleton dynamics | |||||
| CTGF | hMAb: FG-3019 | SOD1G93A mice (males) | Pre-symp. (8 weeks) | IP injections trice a week for 2 months | Improved muscle function and locomotor capacity. Reduced pathological events in skeletal muscle. Improved NMJ innervation. | Gonzalez et al., 2018 | |
| HMGB1 | HuMAb: 2G7 | SOD1G93A mice (females) | Pre-onset (35 days) or post-onset (70 days) | IP injections weekly until end-stage | Pre-onset: Transiently improved muscle strength and reduced key pro-inflammatory genes | Overall, had limited efficacy and did not extend survival time | Lee et al., 2019 |
| Post-onset: No effect | |||||||
Ab, antibody; AAV, adenoassociated virus; h, human; Hu, humanized; ICV, intracerebroventricular; IP, intraperitoneal; IT, intrathecal; IV, intravenous; IN, intranasal; m, mouse; MAb, monoclonal antibody; mMAb, mouse monoclonal antobody; MN, motor neurons; mSOD1, misfolded SOD1; NMJ, neuromuscular junction; Pre-symp., presymptomatic; sALS, sporadic ALS; scFv, single-chain variable fragment; Symp., symptomatic.