Humanised antibodies to toll-like receptor 2 and uses thereof
Inventors
Assignees
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Publication Number
US-8734794-B2
Publication Date
2014-05-27
Expiration Date
Abstract
A fully humanized antibody having binding specificity to Toll-like Receptor 2 comprises a light chain and a heavy chain entirely comprised of amino acid sequence of human origin. The variable region of the light chain comprises an amino acid sequence which is substantially homologous with the sequence of SEQ ID NO:1, while the variable region of the heavy domain comprises an amino acid sequence which is substantially homologous with the sequence of SEQ ID NO:4. Also provided are nucleic acids encoding such antibodies, as well as the use of the antibodies in medicine, in particular for the treatment of inflammatory and autoimmune diseases which are mediated by Toll-like Receptor 2 activation and signalling.
Core Innovation
A neutralising antibody or an antigen binding portion comprises a light chain variable domain comprising the amino acid sequence of SEQ ID NO:1 or at least 90% amino acid sequence identity with SEQ ID NO:1 and a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO:4 or at least 90% amino acid sequence identity with SEQ ID NO:4. The antibody or antigen binding portion specifically binds to Toll-like Receptor 2 (TLR2) and antagonises TLR2 signaling by targeting CDR-defined variable domains comprising CDR1, CDR2 and CDR3 of SEQ ID NO:7, SEQ ID NO:8 and SEQ ID NO:9 for the light chain and CDR1, CDR2 and CDR3 of SEQ ID NO:10, SEQ ID NO:11 and SEQ ID NO:12 for the heavy chain.
The antibody antagonises TLR2 independently of binding of the antibody or antigen binding portion to CD32. The described antibody is exemplified as a fully humanised TLR2 antagonistic monoclonal antibody with an IgG4 constant region and an S241P hinge mutation to prevent Fab-arm exchange, and it binds a specific TLR2 epitope spanning N- and C-terminal extracellular regions.
The description additionally provides nucleic acids encoding the antibody and production-related constructs, including expression vector/host cell and producing embodiments. Therapeutic uses are described for TLR2-mediated inflammatory and autoimmune diseases, including ischemia/reperfusion injury and sepsis, with broad cross-reactivity across human, mouse, and monkey TLR2 and reduced predicted immunogenicity via CD4+ T-cell epitope screening.
Claims Coverage
Two independent claim groups are present. Together they cover specified light- and heavy-chain variable-domain sequences with defined CDRs, TLR2-specific binding, and TLR2 antagonism independent of CD32; and, separately, an isolated monoclonal antibody binding a human TLR2 epitope with a KD threshold and CD32-independent antagonism.
CD32-independent TLR2 antagonism with specified variable domains and CDRs
A neutralising antibody or an antigen binding portion comprising a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 1 or at least 90% amino acid sequence identity with SEQ ID NO: 1 and a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO:4 or at least 90% amino acid sequence identity with SEQ ID NO:4, wherein the antibody specifically binds to TLR2 and antagonises TLR2 independently of binding to CD32, and wherein the light chain variable domain comprises CDR1, CDR2 and CDR3 of SEQ ID NO:7, SEQ ID NO:8 and SEQ ID NO:9 and the heavy chain variable domain comprises CDR1, CDR2 and CDR3 of SEQ ID NO: 10, SEQ ID NO: 11 and SEQ ID NO: 12.
Human TLR2 epitope binding defined by a reference antibody with a KD threshold and CD32-independent antagonism
An isolated monoclonal antibody or antigen binding portion thereof which binds an epitope on human TLR2 with a KD of 3×10−28 M or less and which mediates TLR2 antagonism independently of binding to CD32, wherein the epitope is recognised by a reference antibody, wherein the reference antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:4 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:1.
The claim coverage centers on TLR2-specific neutralising or antagonistic antibodies that bind defined variable-domain sequences and antagonise TLR2 signaling without requiring binding to CD32, with an additional isolated-antibody formulation requiring human TLR2 epitope binding and epitope recognition by a reference antibody having specified light and heavy chain variable-region sequences.
Stated Advantages
Reduced predicted immunogenicity via CD4+ T-cell epitope screening.
Broad cross-reactivity across human, mouse, and monkey TLR2.
TLR2 antagonism independently of CD32.
Documented Applications
Therapeutic treatment of TLR2-mediated inflammatory and autoimmune diseases, including ischemia/reperfusion injury and sepsis, by administering an antibody or antigen-binding portion to a subject in need.
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