Targeting α-synuclein by PD03 AFFITOPE® and Anle138b rescues neurodegenerative pathology in a model of multiple system atrophy: clinical relevance

Abstract

Background Misfolded oligomeric α-synuclein plays a pivotal role in the pathogenesis of α-synucleinopathies including Parkinson’s disease and multiple system atrophy, and its detection parallels activation of microglia and a loss of neurons in the substantia nigra pars compacta. Here we aimed to analyze the therapeutic efficacy of PD03, a new AFFITOPE® immunotherapy approach, either alone or in combination with Anle138b, in a PLP-α-syn mouse model. Methods The PLP-α-syn mice were treated with PD03 immunotherapy, Anle138b, or a combination of two. Five months after study initiation, the mice underwent behavioral testing and were sacrificed for neuropathological analysis. The treatment groups were compared to the vehicle group with regard to motor performance, nigral neuronal loss, microglial activation and α-synuclein pathology. Results The PLP-α-syn mice receiving the PD03 or Anle138b single therapy showed improvement of gait deficits and preservation of nigral dopaminergic neurons associated with the reduced α-synuclein oligomer levels and decreased microglial activation. The combined therapy with Anle138b and PD03 resulted in lower IgG binding in the brain as compared to the single immunotherapy with PD03. Conclusions PD03 and Anle138b can selectively target oligomeric α-synuclein, resulting in attenuation of neurodegeneration in the PLP-α-syn mice. Both approaches are potential therapies that should be developed further for disease modification in α-synucleinopathies.

Targeting Microglial α-Synuclein/TLRs/NF-kappaB/NLRP3 Inflammasome Axis in Parkinson’s Disease

“…Both have been evaluated in phase 1 study in patients with early PD and multiple system atrophy. Furthermore, the repeated administration of PD01A has proven safe and well tolerated over an extended period (105,106). PRX002, a humanized monoclonal antibody targeting aggregated a-syn, adopts the principle of active immunity.…”

Therapeutics in the Pipeline Targetingα-Synuclein for Parkinson's Disease

“…Further testing demonstrated that treatment with Anle138b slowed disease progression in the A30P a-Syn transgenic mouse model of PD even when treatment was initiated after disease (Tremblay et al, 2006;Stack et al, 2008;Sun et al, 2010); in addition, overexpression of TG2 exacerbates a-Syn toxicity, whereas knockout of TG2 is protective against a-Syn toxicity in a-Syn transgenic mice, on measures of a-Syn aggregation, neuroinflammation, and motor performance (Grosso et al, 2014;Zhang et al, 2020a) Therapeutics Targeting a-Synuclein onset (Levin et al, 2014). The protective effect of Anle138b extends to the MI2 mouse model of PD, which expresses human, aggregation-prone truncated 1-120 a-Syn under the control of the tyrosine hydroxylase promoter (Wegrzynowicz et al, 2019) as well as to the motor deficits in models of MSA (Fellner et al, 2016;Heras-Garvin et al, 2019;Lemos et al, 2020). Anle138 completed a first-in-human, placebo-controlled, doubleblind, randomized trial to evaluate safety, tolerability, and pharmacokinetics in healthy volunteers in August of 2020 (NCT04208152).…”

Current experimental disease-modifying therapeutics for multiple system atrophy

“…The immunogenic peptide, i.e., AFFITOPE, operates a B cell epitope and is responsible for the specificity of the immune response. Initial studies in PD, DLB, and MSA mouse models demonstrated the efficacy of the AFFITOPE® PD01 and PD03, which triggered specific antibody generation with CNS penetration and lowered α-Syn aggregates and oligomers, leading to neuroprotection and improvement of locomotor behavior in PD and MSA mice, respectively (Mandler et al 2014(Mandler et al , 2015Lemos et al 2020). The first phase I clinical trial with PD patients using PD01 suggested good immunogenicity, safety and tolerability (Volc et al 2020).…”

“…In support of this hypothesis, PD03 immunotherapy in MSA mice showed high binding of IgGs in the brain, suggesting that the PD03-induced antibodies entered the brain and accumulated at the sites of α-Syn pathology. In contrast, if the MSA mice received in parallel to PD03 also Anle138b, a small molecule that modulates the oligomerization of α-Syn, the IgG binding in the brain was significantly decreased (Heras-Garvin et al 2019 ; Lemos et al 2020 ). This phenomenon was accompanied by increase in the measured plasma antibodies to α-Syn in the mice receiving combined therapy, therefore, supporting the hypothesis that the plasma levels of anti-α-Syn antibodies may reflect not simply the immunogenicity of the used vaccine, but also the level of selective binding to a specific α-Syn conformation (Fig.…”

“…PD03 immunization of PLP-α-Syn mice results in significant binding of the specific antibodies in the brain. This antibody binding strongly decreases, while higher levels of free antibodies in the plasma are detected when the specific α-Syn oligomers,—the target of the PD03 antibodies—, are reduced by Anle 138b (Lemos et al 2020 ). The shift between specific antibody binding and free antibodies in the plasma may be relevant to the definition of immunogenicity in clinical trials.…”