Molecules for therapy and diagnosis
Inventors
Tsika, Elpida • Warner, John • Stöhr, Jan Peter Henning
Assignees
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Publication Number
US-12534519-B2
Publication Date
2026-01-27
Expiration Date
Abstract
The present invention relates to novel molecules that can be employed for the prevention, alleviation, treatment and/or diagnosis of diseases, disorders and abnormalities associated with alpha-synuclein (a-synuclein, A-synuclein, aSynuclein, A-syn, α-syn, aSyn, a-syn) aggregates, including, but not limited to, Lewy bodies and/or Lewy neurites, such as Parkinson's disease, Multiple System Atrophy, Lewy Body dementia (LBD; dementia with Lewy bodies (DLB) (“pure” Lewy body dementia), Parkinson's disease dementia (FDD)) or Diffuse Lewy Body Disease. The invention relates to alpha-synuclein binding molecules, in particular to alpha-synuclein antibodies or an antigen-binding fragment or a derivative thereof and uses thereof. The present molecules can also be used for determining a predisposition to such a disorder, disease or abnormality, monitoring residual disorder, disease or abnormality, or predicting the responsiveness of a patient who is suffering from such a disorder, disease or abnormality to treatment with a certain medicament.
Core Innovation
The invention relates to alpha-synuclein binding molecules that are monoclonal antibodies or antigen-binding fragments thereof. The molecule comprises specified VH-CDR1, VH-CDR2, and VH-CDR3 amino acid sequences together with specified VL-CDR1, VL-CDR2, and VL-CDR3 amino acid sequences, with multiple alternative CDR combinations provided by SEQ ID NO references. The disclosed embodiments also define alpha-synuclein binding molecules by sequence identity to reference VH and VL sequences.
The invention further describes humanized antibody exemplars and variants comprising sequences corresponding to ACI-7067/7079/7087/7088/7089/8033 and hACI-7067 variants, with improved affinity and delayed seeded aggregation. It also provides isolated antibodies defined by binding to specific human alpha-synuclein epitopes, including linear and non-linear epitopes, with residue ranges and epitope mapping and critical residues. Allowed combinations of VH-CDR and VL-CDR amino acid sequences include embodiments containing 1 to 6 CDRs selected from enumerated VH-CDR1/2/3 and VL-CDR1/2/3 sequences.
The document also encompasses alpha-synuclein aggregate-associated disease targets and therapeutic and diagnostic or monitoring uses connected to alpha-synuclein aggregation. It describes inhibiting or delaying seeded and spontaneous aggregation, reducing pathological and phosphorylated alpha-synuclein, reducing alpha-synuclein spreading and cellular uptake of aggregated alpha-synuclein, and enabling prediction of drug responsiveness and predisposition.
Claims Coverage
The provided independent claim coverage centers on one alpha-synuclein binding molecule claim defined by specific VH-CDR and VL-CDR amino acid sequences in multiple alternative configurations. Additional claim content also covers evaluation of aggregation inhibition or delay using detectable-dye half-maximum signal timing and therapeutic disease-addressing coverage for alpha-synuclein aggregate-associated disorders.
CDR-defined alpha-synuclein binding molecule
An alpha-synuclein binding molecule that is a monoclonal antibody or an antigen-binding fragment thereof comprising VH-CDR1, VH-CDR2, VH-CDR3, VL-CDR1, VL-CDR2, and VL-CDR3, where each CDR is defined by amino acid sequence of the corresponding SEQ ID NO, provided in multiple alternative configurations.
Evaluation of aggregation inhibition or delay by time to half-maximum detectable-dye signal
A method of evaluating an alpha-synuclein binding molecule by contacting alpha-synuclein seed aggregates to form an immunological complex, adding alpha-synuclein monomeric protein and a detectable dye, and determining the time to reach half-maximum detectable-dye signal relative to seeded aggregation without the binding molecule to assess inhibition or delay.
Disease-addressing therapeutic coverage for alpha-synuclein aggregate-associated disorders
A method applicable to treating or addressing synucleinopathies such as Parkinson’s disease, Lewy body dementia, and multiple system atrophy, and further including additional enumerated neurodegenerative and lysosomal storage disorders and REM sleep behavior disorder.
Coverage is centered on structural definition of alpha-synuclein binding molecules by specific VH and VL CDR amino acid sequences, with additional functional coverage for detectable-dye aggregation assay timing and therapeutic disease/disorder addressing.
Stated Advantages
Improved affinity.
Delayed seeded aggregation.
Inhibits or delays seeded alpha-synuclein aggregation.
Inhibits or delays spontaneous alpha-synuclein aggregation.
Reduces pathological and/or phosphorylated alpha-synuclein.
Reduces alpha-synuclein spreading.
Reduces cellular uptake of aggregated alpha-synuclein.
Enables therapeutic treatment.
Enables diagnostic or monitoring uses, including predisposition and drug responsiveness prediction.
Inhibits or delays seeded alpha-synuclein aggregation, as indicated by increased aggregation half-time (T1/2) relative to controls.
Reduces or delays pathological phosphorylated alpha-synuclein spread.
Demonstrates preferential binding to fibrillar over monomeric alpha-synuclein with slower dissociation, as characterized by SPR.
Enables target engagement in human PD and MSA brain tissue for antibodies binding pathological pSyn aggregates (Lewy bodies, neurites, and glial cytoplasmic inclusions).
Changes in body-weight loss and NeuN-based neuronal density/loss recovery in the M83 transgenic mouse model.
Documented Applications
Diagnostic and therapeutic uses for synucleinopathies including Parkinson’s disease, Lewy body dementia, multiple system atrophy, and REM sleep behavior disorder.
Therapeutic treatment for alpha-synuclein aggregate-associated synucleinopathies including Parkinson’s disease, multiple system atrophy, and Lewy body dementias.
Diagnostic/monitoring uses related to alpha-synuclein aggregation, including prediction of predisposition and drug responsiveness.
Evaluation/screening of alpha-synuclein binding molecules using detectable dye aggregation assays with thioflavin T and determination of time to reach half-maximum signal relative to no-binding-molecule controls.
Treatment or addressing of synucleinopathies and other listed diseases/disorders, including Parkinson’s disease, Lewy body dementia, multiple system atrophy, and REM sleep behavior disorder.
In vitro and ex vivo evaluation of monoclonal anti-alpha-synuclein antibodies for inhibiting or delaying seeded alpha-synuclein aggregation using Thioflavin T kinetics.
In vivo assessment of alpha-synuclein pathology in an M83 transgenic mouse model, reporting reduced or delayed pathological phosphorylated alpha-synuclein spread and related readouts.
SPR-based affinity characterization of antibody binding to alpha-synuclein with kinetic parameters and preferential binding to fibrillar over monomeric alpha-synuclein.
Human brain tissue immunohistochemistry in Parkinson’s disease and multiple system atrophy to assess target engagement of selected antibodies binding pathological pSyn aggregates.
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