PMN442

Overcoming Hurdles Associated with Achieving α-Syn Molecular Selectivity

α-Syn proteins pose a difficult challenge for molecular species selectivity. There are six molecular species of α-Syn in total, two of which are physiologically important and should be avoided, and two that are toxic and should be targeted.

Only α-Syn antibodies generated using our proprietary discovery platform can selectively target the toxic oligomers and inhibit α-Syn propagation while leaving healthy, physiologic oligomers unaffected. Thanks to our unique platform, we have achieved these results with multiple antibodies, created with different conformational epitope predictions, thereby demonstrating the unrivaled power of our technology.

Using the ProMIS platform, several conformational epitopes were identified as likely to become exposed on misfolded, pathogenic forms of a-syn (toxic oligomers and soluble seeding fibrils). Monoclonal antibodies (mAbs) were raised against these epitopes and were tested for the desired binding profile and ability to protect neurons against toxic a-syn species in vitro. Multiple mAbs were screened and PMN442 emerged as the lead candidate for this program with the desired characteristics. PMN442 showed robust binding to a-syn oligomers and seeding fibrils, with negligible binding to a-syn monomers and physiologic tetramers which are required for normal neuronal function. PMN442 also reacted with native toxic a-syn present in brain homogenates from individuals with MSA and dementia with Lewy bodies (DLB). In activity assays, PMN442 protected rat dopaminergic neurons against killing by a-syn toxic oligomers.

α-Syn Program Key Features

Our technology platform has created antibodies with potentially greater selectivity for only toxic misfolded of α-Syn.

No binding to monomers
No binding to physiological tetramers
Binding to pathogenic oligomers/small soluble fibrils
Binding to native toxic α-Syn in PD/DLB brain extract
Little or no binding to insoluble fibrils (Lewy bodies)

Targeting Alpha-synuclein, the Major Driver of Parkinson’s Disease

Research gathered from numerous genomic analyses, cell cultures, and in vivo studies indicates that alpha-synuclein (α-Syn) plays a major role in the development of Parkinson’s disease (PD) and other neurodegenerative disorders. In particular, soluble aggregates such as oligomers and soluble fibrils represent the most pathogenic forms of α-Syn.

About Parkinson’s

Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by loss of dopaminergic neurons located in the midbrain and the presence of intraneuronal inclusions (Lewy bodies/Lewy neurites) consisting mainly of aggregates of α-Syn. Accumulation of insoluble α-Syn fibrils in the brain has also been observed in dementia with Lewy bodies (DLB). Progression of PD is likely facilitated by misfolded oligomers and small soluble fibrils of α-Syn that have been shown to propagate from cell to cell in a prion-like manner in both in vitro and in vivo studies.

Screening and Validation for PD Candidates

Identifying Highly Selective α-Syn Antibodies

Our proprietary computational platform was used to identify epitopes that are exclusively exposed on the surface of toxic misfolded species of α-Syn, in a shape (conformation) distinguishable from that of monomers, physiological tetramers, and insoluble fibrils (Lewy body/Lewy neurites).

These conformational epitopes were then used for immunization and generation of monoclonal antibodies that exhibit selective binding to the toxic forms of α-Syn, as demonstrated via several methods, including surface plasmon resonance, immunohistochemistry, and dot blot analysis.

Multiple System Atrophy (MSA) Overview

MSA is a rare neurodegenerative disease with an estimated prevalence of 3.4-4.9 cases per 100,000. There is no effective treatment and the mean survival from the onset of symptoms is 6-10 years. The causative role of a-syn aggregates in MSA pathogenesis is supported by experimental evidence showing that a-syn aggregates from MSA brain homogenates propagate in a prion-like manner in vitro and in vivo, and cause MSA-like neurodegeneration in mice.

Posters & Publications

Our scientific expertise is backed by decades of research on protein misfolding diseases such as AD, ALS, and PD. We encourage you to visit our scientific library to learn more about our programs.

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