Aβ protofibril binding antibodies
Inventors
NERELIUS, Charlotte • LAUDON, Hanna • SIGVARDSON, Jessica
Assignees
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Publication Number
US-9573994-B2
Publication Date
2017-02-21
Expiration Date
Abstract
The present invention relates to the amyloid beta peptide (Aβ) and more specifically to antibodies binding to Aβ protofibrils and their use in therapy and/or prophylactic treatment of Alzheimer's disease and other disorders associated with Aβ protein aggregation. Further the invention may relate to diagnosis of such diseases as well as monitoring of disease progression by use of the antibodies of the invention. Further, the invention may relate to veterinary use of the antibodies of the invention.
Core Innovation
The invention relates to antibodies or antigen binding fragments having affinity against Aβ protofibrils, including engineered antibodies with specific variable light-chain substitutions and, optionally, specific variable heavy-chain substitutions. The variable light chain is defined by Kabat position selections x1, x2, and x3, and by additional selections y1, y2, y3, and y4, all relative to SEQ ID NO: 8, with an explicit exception excluding the combination x1=A, x2=R, and x3=R.
The document also addresses variants that correspond to BAN2401 and introduce substitutions at the Kabat positions A17/R79/R82 together with optional neighboring variable light-chain substitutions and optional variable heavy-chain substitutions. The background problem addressed is the need for antibodies against Aβ protofibrils for therapeutic and related purposes, while maintaining protofibril affinity and selectivity and improving pharmacokinetic or exposure properties compared with BAN2401.
In addition to engineered variable-region sequence constraints, the document addresses low immunogenicity by deimmunization. It describes ex vivo T-cell assays and epitope mapping that identify immunogenicity risk and peptide deimmunization substitutions that produce deimmunized variants while maintaining protofibril binding.
Claims Coverage
The partial content identifies two independent claims, covering sequence-constrained antibodies or antigen-binding fragments with defined variable light-chain selections and optional variable heavy-chain selections, and sequence-defined antibodies or antigen-binding fragments using specific SEQ ID NO: 12 and SEQ ID NO: 16 variable light and variable heavy chain sequences. The independent and dependent claims also cover therapeutic reduction of Aβ protofibrils, disease-treatment scope tied to Aβ protein aggregation disorders including Alzheimer’s disease, and a measurement approach using contacting tissue or body fluid with a specified antibody or antigen-binding fragment and measuring bound complexes.
Affinity to Aβ protofibrils with sequence-defined variable light-chain selections
An antibody or antigen binding fragment having affinity against Aβ protofibrils, wherein the variable light chain according to SEQ ID NO: 8 has x1 selected from A, D, E and Q, x2 selected from R, T, K, A and G, x3 selected from R, S, C, G and N, and y1 selected from V and A, y2 selected from I and V, y3 selected from S and Q, y4 selected from E and D, with the exception for the combination x1=A, x2=R and x3=R.
Optional variable heavy-chain selections with exception on light-chain combination
Optionally, a variable heavy chain according to SEQ ID NO: 14 with z1 selected from V and I, z2 selected from R and Q, and z3 selected from A, N and T, where the light-chain substitutions obey the stated exception excluding the combination x1=A, x2=R and x3=R.
Aβ protofibril-affinity antibody defined by specific SEQ ID variable light and heavy chains
An antibody or antigen binding fragment having affinity against Aβ protofibrils, comprising a variable light chain comprising the amino acid sequence as set out in SEQ ID NO: 12 and a variable heavy chain comprising the amino acid sequence as set out in SEQ ID NO: 16.
Overall, claim coverage centers on antibodies or antigen-binding fragments with affinity against Aβ protofibrils, defined either by variable light-chain selection rules at Kabat positions relative to SEQ ID NO: 8 with an explicit excluded light-chain substitution combination and optional variable heavy-chain selections relative to SEQ ID NO: 14, or by specific variable light and heavy chain amino-acid sequences defined by SEQ ID NO: 12 and SEQ ID NO: 16. Dependent coverage also ties the defined antibodies to reducing Aβ protofibrils by administration, treating Alzheimer’s disease and related Aβ protein aggregation disorders, and measuring Aβ protofibrils or aggregated Aβ protein via contacting tissue or body fluid with the antibody and measuring bound antibody or antigen-binding fragment.
Stated Advantages
Improved pharmacokinetics and increased serum exposure or half-life relative to BAN2401 for engineered variants.
Preserved protofibril selectivity after introducing the x/y/z variable-region mutations.
Reduced immunogenicity via deimmunization substitutions while maintaining protofibril binding.
Improved predictability of human half-lives over BAN2401 based on cross-species allometric scaling for select deimmunized variants.
Documented Applications
Therapy or prophylaxis for Alzheimer’s disease using an antibody or antigen-binding fragment that binds Aβ protofibrils.
Therapy for other Aβ-aggregation disorders linked to Aβ protein aggregation, including treating a subject with an Aβ protein aggregation disorder associated with Alzheimer’s disease.
Reducing the amount of Aβ protofibrils in a subject by administering a therapeutically effective amount of the specified antibody or antigen-binding fragment.
Diagnosis or monitoring by contacting tissue or body fluid with a labeled antibody and measuring bound complexes.
Veterinary use.
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