Anti-Aβ antibodies
Inventors
SKOV, Michael • Nijjar, Tarlochan S. • Govindarajan, Sridhar • Purcell, Tom • Welch, Mark • Bard, Frédérique • Barbour, Robin • Zago, Wagner
Assignees
Dna Twopointo Inc D/b/a Atum • Othair Prothena Ltd • Neotope Neuroscience Ltd
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Publication Number
US-12435129-B2
Publication Date
2025-10-07
Expiration Date
Abstract
Antibodies that bind human beta-amyloid peptide, methods of detecting, measuring and treating amyloidogenic disorders with said antibodies, pharmaceutical compositions comprising the antibodies and methods of manufacture are provided.
Core Innovation
The invention relates to anti-amyloid beta (Aβ) antibody compositions and methods, including antibodies or fragments thereof that specifically bind to Aβ peptide. A nucleic acid encodes an antibody defined by a heavy chain variable region and a light chain variable region that include specified CDR1, CDR2, and CDR3 sequences. The heavy chain CDR1, CDR2, and CDR3 are SEQ ID NO: 19, SEQ ID NO: 21, and SEQ ID NO: 24, and the light chain CDR1, CDR2, and CDR3 are SEQ ID NO: 29, SEQ ID NO: 34, and SEQ ID NO: 38.
The described antibodies are improved N-terminal Aβ binders and bind to Aβ N-terminal epitopes such as residues 1–6 and related ranges. The invention also specifies that the encoded antibodies can specifically bind an epitope defined by an amino-acid sequence that includes at least three amino-acid positions corresponding to amino acids 1–7 of Aβ. The disclosure links defined antibody variable-region sequences to binding to Aβ-related species in brain tissue and to functional activity in assays evaluating binding, clearance or phagocytosis, and target engagement.
The invention further includes approaches for generating and using the encoded antibodies, including pharmaceutical compositions and uses for therapeutic and detection purposes. Documented activities include binding to amyloid plaque burden, neutralization of soluble toxic oligomers, microglial-mediated phagocytosis and clearance, cognition improvement, and labeled in vivo detection and efficacy measurement. The described work includes comparisons of binding and kinetics against other antibodies and assessment of selectivity across Aβ species, including AβpE3-42.
Claims Coverage
The independent claim set centers on one nucleic acid encoding an Aβ-binding antibody or fragment defined by specified heavy- and light-chain CDR sequence identities, with six SEQ ID-defined CDRs. The partial content also adds epitope definition and framework identity constraints, with dependent production and screening features described in the source items.
CDR-defined Aβ-binding antibody nucleic acid
A nucleic acid encoding a heavy chain variable region and a light chain variable region of an antibody or fragment thereof that specifically binds to Aβ peptide, wherein the heavy chain variable region comprises heavy chain CDR1, CDR2, and CDR3 and the light chain variable region comprises light chain CDR1, CDR2, and CDR3, wherein the heavy chain CDR1, CDR2, and CDR3 are SEQ ID NO: 19, SEQ ID NO: 21, and SEQ ID NO: 24 and the light chain CDR1, CDR2, and CDR3 are SEQ ID NO: 29, SEQ ID NO: 34, and SEQ ID NO: 38.
Variable-region framework identity constraints outside CDRs
The nucleic acid has a heavy chain variable region comprising heavy chain CDR1, CDR2, and CDR3 and wherein the heavy chain variable region excluding CDRs has at least 95% identity to SEQ ID NO: 4, and wherein the light chain variable region excluding CDRs has at least 95% identity to SEQ ID NO: 9.
Specified light chain constant region identity constraint
The nucleic acid further comprises a light chain constant region with an amino acid sequence at least 95% identical to SEQ ID NO: 41.
Epitope defined by Aβ positions 1–7
The nucleic acid whose encoded antibody specifically binds an epitope defined by an amino acid sequence that includes at least three amino-acid positions corresponding to amino acids 1–7 of Aβ.
Production via selection for increased vector copy number and single-cell cloning
A method for producing a cell line by introducing a vector with nucleic acid and a selectable marker into cells, selecting for increased vector copy number, isolating single selected cells, and banking cloned cells chosen based on the yield of secreted antibody or fragment encoded by the nucleic acid.
Screening and selecting cell lines based on a quantitative secretion level
The method further propagates cells under selective conditions and screens for cell lines that naturally express and secrete at least the specified level.
The claim set is directed to Aβ-specific antibody binding defined by predetermined heavy- and light-chain CDR sequences, with additional constraints that narrow framework identity and epitope description, and further includes production and screening features that select cell lines based on vector copy number and antibody secretion levels.
Stated Advantages
Improved N-terminal Aβ binder activity relative to bapineuzumab.
Improved binding and functional activity in AD brain tissue, including measurable soluble oligomer binding and IHC-based plaque staining comparisons versus aducanumab.
Improved binding/kinetic performance versus comparator antibodies, including improved apparent KD and slower off-rate as described.
Plaque reduction and clearance-related effects, including microglial-mediated phagocytosis and reduced plaque binding outcomes as described.
Reduced Aβ1-42 and AβpE3-42 in ex vivo microglia phagocytosis assays with h2731, described as microglia-dependent and dose-dependent.
Blocking of soluble Aβ aggregate binding in hippocampal neuron assays.
Target engagement in vivo for h2731 versus aducanumab in APPxPS1 mice, quantified as plaque binding (%ROI).
Selectivity for Aβ species including AβpE3-42 as described.
Cognition improvement as described.
Clearance or potency evidence described as additional evidence over aducanumab.
Documented Applications
Therapeutic use for amyloidogenic disorders, including Alzheimer’s disease, including reduction of amyloid plaque burden and neutralization/clearance of soluble toxic Aβ oligomers.
Binding and functional testing of humanized anti-Aβ antibodies h2726, h2731, h2831, and h2931 in AD brain tissue, including soluble oligomer binding and IHC-based plaque staining comparisons versus aducanumab.
Ex vivo human AD brain phagocytosis/clearance and plaque binding outcomes as described.
Ex vivo microglia phagocytosis assays evaluating reduction of Aβ1-42 and pyroglutamate-modified Aβ (AβpE3-42), described as microglia-dependent and dose-dependent for h2731.
Hippocampal neuron assays evaluating blocking of soluble Aβ aggregate binding.
Microglial-dependent target engagement after peripheral dosing as described.
In vivo target engagement assessment comparing h2731 versus aducanumab in APPxPS1 mice with quantified plaque binding (%ROI).
Labeled in vivo detection and efficacy measurement as described.
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