Method for treating a disease associated with soluble, oligomeric species of amyloid beta 1-42
Inventors
Goure, William F. • Hefti, Franz F. • Gaspar, Renee C. • Shughrue, Paul J. • Wang, Fubao • Wang, Weirong • Zhang, Ningyan • Zhao, Wei-Qin • McCampbell, Alexander • Xu, Min
Assignees
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Publication Number
US-9320793-B2
Publication Date
2016-04-26
Expiration Date
Abstract
This invention is a method and kit for treating a disease associated with, or resulting from, the accumulation of soluble oligomer amyloid beta 1-42 using an antibody, or antibody fragment thereof, that has a higher affinity for amyloid beta 1-42 oligomers than for amyloid beta 1-42 monomer, amyloid beta 1-40 monomer, plaques and amyloid beta fibrils and, optionally, a tau therapeutic or an inhibitor of amyloid beta production or aggregation.
Core Innovation
Anti-amyloid beta 1-42 soluble oligomer (ADDL) selective antibody immunotherapy is described for treating Alzheimer’s disease (AD)-related disease associated with, or resulting from, the accumulation of soluble oligomer amyloid beta 1-42 (Aβ1-42), including administering an antibody or antibody fragment to a subject in need thereof. The approach emphasizes preferential binding to Aβ1-42 oligomers relative to amyloid beta 1-40 monomers in a competitive binding assay, together with specified antibody variable-region CDR sequence requirements.
A key selectivity requirement is a competitive binding assay affinity ratio of at least 500:1 for binding amyloid beta 1-42 oligomers compared to amyloid beta 1-40 monomers. The antibodies are further characterized by a light chain variable region comprising CDR1, CDR2, and CDR3 with defined sequence patterns and allowable substitutions, together with a heavy chain variable region comprising CDR1, CDR2, and CDR3 defined by specific sequence identifiers.
The document reports functional outcomes associated with the ADDL-selective antibody immunotherapy, including blocking ADDL binding to neurons, preventing ADDL incorporation into growing plaques, reducing acute ADDL-mediated LTP impairment, and producing behavioral improvements in transgenic mouse models. Additional described features include PK and blood-brain barrier penetration and target engagement, including FcRn-related half-life differences and minimal effective dose concepts for elevating brain antibody:ADDL complexes.
Claims Coverage
The provided independent claim sets out a single method of treating a disease associated with accumulation of soluble oligomer amyloid beta 1-42 by administering a specifically defined anti-ADDL antibody at a dose below 10 mg/kg. The claim contains two alternative antibody embodiments that share the same core selectivity and heavy-chain variable region requirements, while differing in the specified light-chain CDR3 specification set in the second alternative.
Low-dose ADDL-selective anti-amyloid beta 1-42 oligomer treatment
Treating a disease associated with or resulting from accumulation of soluble oligomer amyloid beta 1-42 by administering to a subject in need thereof a dose of less than 10 mg/kg body weight of an antibody or antibody fragment.
Competitive binding affinity selectivity for Aβ1-42 oligomers
The antibody has an affinity for amyloid beta 1-42 oligomers compared to amyloid beta 1-40 monomers in a competitive binding assay of at least 500:1.
Specified light-chain variable region CDR1/CDR2 and defined CDR3 (first antibody alternative)
The antibody has a light chain variable region comprising CDR1 with the sequence of SEQ ID NO:1 with specified allowable substitutions, CDR2 with the sequence of SEQ ID NO:2 with specified allowable substitutions, and CDR3 with the sequence of SEQ ID NO:3 with specified allowable substitutions.
Specified heavy-chain variable region CDR1/CDR2/CDR3 (first antibody alternative)
The antibody has a heavy chain variable region comprising CDR1 of SEQ ID NO:4, CDR2 of SEQ ID NO:5, and CDR3 of SEQ ID NO:6.
Specified light-chain variable region CDR3 (second antibody alternative)
The antibody has a light chain variable region comprising CDR1 with the sequence of SEQ ID NO:1 with specified allowable substitutions (restricted to an alternate set), CDR2 with the sequence of SEQ ID NO:2 with specified allowable substitutions, and CDR3 of SEQ ID NO:18.
Specified heavy-chain variable region CDR1/CDR2/CDR3 (second antibody alternative)
The antibody has a heavy chain variable region comprising CDR1 of SEQ ID NO:4, CDR2 of SEQ ID NO:5, and CDR3 of SEQ ID NO:6.
Overall, the claim coverage focuses on an anti-amyloid beta 1-42 oligomer (ADDL) therapeutic antibody administered at less than 10 mg/kg, requiring at least 500:1 competitive binding selectivity for Aβ1-42 oligomers over Aβ1-40 monomers. The antibody embodiments are defined by specified light-chain CDR1 and CDR2 sequences with allowable substitutions, plus defined CDR3 sets, together with heavy-chain variable region CDR1, CDR2, and CDR3 sequence identifiers.
Stated Advantages
Preferential binding to amyloid beta 1-42 oligomers compared to amyloid beta 1-40 monomers in a competitive binding assay of at least 500:1.
Reduction of acute ADDL-mediated LTP impairment.
Blocking ADDL binding to neurons.
Prevention of ADDL incorporation into growing plaques.
Behavioral improvements in transgenic mouse models.
Brain penetration and target engagement, including elevating brain antibody:ADDL complexes at a minimal effective dose concept around 10 mg/kg.
Documented Applications
Treating a disease associated with or resulting from accumulation of soluble oligomer amyloid beta 1-42 (including AD-related disease).
Use in transgenic mouse models to evaluate neuronal ADDL binding/blocking, effects on ADDL-mediated LTP impairment, and behavioral improvements.
Detecting endogenous ADDLs in human CSF using described assays/kits [procedural detail omitted for safety].
Combination approaches are discussed with tau therapeutics and/or inhibitors of Aβ production/aggregation.
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