General amyloid interaction motif (GAIM)
Inventors
Krishnan, Rajaraman • Asp, Eva • Proschitsky, Ming • Fisher, Richard
Assignees
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Publication Number
US-12247055-B2
Publication Date
2025-03-11
Expiration Date
Abstract
The present invention relates to variants of the general amyloid interaction motif (GAIM) of bacteriophage gene 3 protein (g3p) and fusion proteins thereof. The GAIM variants and fusion proteins of the invention are partially or fully deimmunized and demonstrate superior binding and specificity to a diverse array of amyloid proteins, and exhibit enhanced amyloid remodeling and inhibition of amyloid aggregation. The present invention further relates to nucleic acids, vectors, host cells, and methods of making the GAIM variants and fusion proteins thereof. The present invention also relates to pharmaceutical compositions and methods of increasing bacteriophage infectivity, methods of detecting amyloid aggregates, and methods of diagnosing and/or treating a disease associated with misfolded and/or aggregated amyloid protein.
Core Innovation
The invention relates to GAIM (general amyloid interaction motif) variants derived from filamentous bacteriophage g3p and GAIM-Ig fusion proteins. The GAIM variants are partially or fully deimmunized and engineered for an open-stabilized conformation, with defined amino acid change sets relative to SEQ ID NO: 16.
The invention addresses treating diseases associated with misfolded and/or aggregated amyloid protein by administering a polypeptide variant comprising the specified amino acid changes. It describes open-stabilized conformation logic and enumerated mutation sets affecting T-cell epitopes and glycosylation removal, together with stabilization at N2, and also describes optional additional amino acid changes, including AM1 or deletion sets such as ΔM1 and ΔA2, and substitution rules for N38 and G40.
The invention further describes improved amyloid-binding specificity and potency across diverse amyloid proteins, including Aβ aggregates, tau fibers, transthyretin, and immunoglobulin light-chain aggregates. It also describes enhanced amyloid remodeling/disaggregation and reduced off-target binding, including reduced collagen off-target binding, and states that the open-stabilized engineered variants provide improved stability compared with prior super-stabilized variants.
Claims Coverage
The independent claim coverage centers on administering a specifically defined polypeptide variant of SEQ ID NO: 16, with differences restricted to selected amino acid change sets, to a subject in need thereof for a disease associated with misfolded and/or aggregated amyloid protein. Related claim features also cover labeled polypeptide detection of amyloid aggregates.
Treating amyloid-associated misfolded and/or aggregated disease with a defined SEQ ID NO: 16 variant
A method of treating a disease associated with misfolded and/or aggregated amyloid protein by administering to a subject a polypeptide comprising a variant of starting amino acid sequence SEQ ID NO: 16, where the variant differs from SEQ ID NO: 16 by one or more sets of amino acid changes selected from the enumerated substitution and deletion sets, including optional additional changes from AM1 or ΔM1 and ΔA2, and substitution rules for N38 and G40.
Labeled variant polypeptide detection of amyloid aggregates
A method of detecting amyloid aggregates in a subject by contacting the subject with a labeled polypeptide and detecting the resulting presence of amyloid aggregates.
Overall, the claim coverage centers on administering a GAIM-derived polypeptide variant of SEQ ID NO: 16 whose amino acid differences are restricted to specific allowed sets of changes, together with a detection embodiment using a labeled polypeptide for amyloid aggregates.
Stated Advantages
Improved amyloid-binding specificity and potency across diverse amyloid proteins, including Aβ aggregates, tau fibers, transthyretin, and immunoglobulin light-chain aggregates.
Enhanced amyloid remodeling/disaggregation.
Reduced off-target binding, including reduced collagen off-target binding.
Improved stability versus prior super-stabilized variants.
Documented Applications
Diagnostic imaging to detect amyloid aggregates in the CNS using GAIM-variant/GAIM-Ig polypeptides and compositions.
Combined imaging using a β-amyloid-specific tracer (e.g., F18-AV-45) to enable differential detection of non-β-amyloid aggregates.
Detection of amyloid aggregates in a subject by contacting the subject with a labeled polypeptide and detecting the resulting presence of amyloid aggregates.
Treating a subject having misfolded and/or aggregated amyloid protein associated diseases, including Alzheimer’s disease, AL amyloidosis, and familial amyloidosis variants.
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