Protofibril selective antibodies and the use thereof
Inventors
GELLERFORS PAER, null • Gellerfors, Pär • Lannfelt, Lars • Sehlin, Dag • Ekholm Pettersson, Frida • Englund, Hillevi
Assignees
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Publication Number
US-8025878-B2
Publication Date
2011-09-27
Expiration Date
Abstract
The present invention pertains to the prevention, treatment and diagnosis of neurodegenerative diseases, in particular Alzheimer's disease, and other similar disease. More specifically to high affinity antibodies selective for amyloid beta protein (Aβ) in its protofibril conformation and of IgG class and IgG1 or IgG4 subclass or combinations thereof or mutations thereof, retaining high Fc receptor binding and low C1(C1q) binding, effective in clearance of Aβ protofibrils and with reduce risk of inflammation.
Core Innovation
The invention relates to an isolated antibody or fragment thereof that is selective and has high affinity for human Aβ protofibrils. The antibody or fragment is defined by six CDR regions comprising consensus sequences for VH-CDR1, VH-CDR2, VH-CDR3, VL-CDR1, VL-CDR2, and VL-CDR3, while maintaining selectivity against non-protofibril Aβ conformations.
The disclosure also includes engineered IgG/IgG1 or IgG4 antibody constructs and Fc engineering options intended to preserve FcγR binding and reduce C1q/complement activation. It further provides DNA and protein sequence definitions, including 158RKAss and 158RKA, with annotated framework and CDR region information, and related humanized heavy-chain variants 158RHB, 158RHC, 158RHD and light-chain variants 158RKB and 158RKC.
The document further presents diagnostic and biomarker use cases for measuring Aβ protofibrils, including detection at pM levels using sandwich ELISA and proximity ligation approaches, and imaging with labeled antibodies.
Claims Coverage
The provided claim coverage centers on protofibril-selective antibodies defined by either six CDR consensus sequences or specific heavy- and light-chain amino-acid sequences. Across the independent claims and refinements, the inventive features include sequence-defined protofibril binding, quantified selectivity, reduced complement activation, defined heavy/light chain sequence configurations, and freeze-dried stability formulation.
Selective high-affinity protofibril-binding antibody defined by six cdr consensus sequences
An isolated antibody or fragment thereof that is selective and has high affinity for human Aβ protofibrils, wherein the six CDR regions comprise specified consensus sequences for VH-CDR1, VH-CDR2, VH-CDR3, VL-CDR1, VL-CDR2, and VL-CDR3 (SEQ ID NOs 1–6).
Quantified protofibril selectivity ratio versus monomers
An antibody or fragment having a specificity ratio between Aβ monomers and protofibrils of at least 1:200 as measured by competitive ELISA.
Reduced complement activation activity
An antibody or fragment specified to have reduced complement activation activity.
Complete heavy and light chain sequences for a defined antibody
An antibody or fragment containing the complete light-chain sequence 158 VK (Table 20, SEQ ID NO: 116) and the complete heavy-chain sequence 158 VH (Table 20, SEQ ID NO: 115).
Freeze-dried antibody composition with a stability excipient
A freeze-dried antibody or antibody fragment composition formulated with an excipient to increase stability during and after freeze-drying.
Human Aβ protofibril binding isolated antibody
An isolated antibody or fragment thereof that binds to human Aβ protofibrils, wherein the antibody or fragment comprises a heavy chain and a light chain.
Heavy chain sequence 158RHA (Table 27)
The heavy chain comprises the amino acid sequence 158RHA in Table 27 (SEQ ID NO:158).
Light chain sequence 158RKA (Table 38)
The light chain comprises the amino acid sequence 158RKA in Table 38 (SEQ ID NO:244).
Overall, the claim set centers on protofibril-selective antibodies defined by either six CDR consensus sequences or specific heavy- and light-chain amino-acid sequences, with additional features including quantified selectivity, reduced complement activation, defined sequence variants, and freeze-dried stability formulation.
Stated Advantages
Selectivity and high affinity for human Aβ protofibrils.
Reduced complement activation activity.
A quantitative specificity ratio between Aβ monomers and protofibrils of at least 1:200 (competitive ELISA).
Low risk of inflammatory side effects by reducing C1q/complement activation while retaining FcγR binding.
Clearance of protofibrils by selectively binding human Aβ protofibrils.
Improved CNS availability.
Reduced cross-reactivity to monomers/fibrils and other amyloids (selectivity).
Improved ability to detect protofibrils, including pM-level detection.
Documented Applications
Alzheimer’s disease treatment and use of protofibril-selective antibodies in neurodegenerative disease contexts.
Biomarker and diagnostic detection of Aβ protofibrils in samples using sandwich ELISA and proximity ligation approaches.
Imaging using labeled antibodies.
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