Modified J-chain
Inventors
Keyt, Bruce • Presta, Leonard George • Zhang, Fen • Baliga, Ramesh
Assignees
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Publication Number
US-10975147-B2
Publication Date
2021-04-13
Expiration Date
Abstract
The present invention concerns modified recombinant J-chain polypeptides, binding molecules, such as antibodies comprising the same, and their uses.
Core Innovation
A polymeric antibody that specifically binds to an antigen is provided with at least two immunoglobulin monomers and a modified J-chain. The modified J-chain is based on a native J-chain comprising SEQ ID NO: 1 and includes an extraneous binding moiety introduced into the native J-chain at or within 10 residues from the C- or N-terminus of the native J-chain. This architecture is configured so the antibody retains antigen binding while the modified J-chain contributes additional binding capability via the extraneous binding moiety.
The immunoglobulin monomers in the polymeric antibody each comprise either a Cμ4 and an IgM tail-piece (αctp) domain or a Cα13 and an IgA tail-piece (αtp) domain. The modified J-chain with the introduced extraneous binding moiety is incorporated into polymeric antibody formats described for IgM, IgA, and IgG/IgA hybrid assemblies. In this way, the polymeric antibody includes dual binding activities: antigen binding through the immunoglobulin monomers and effector-cell engagement through the modified J-chain moiety.
The document describes effector-cell binding moieties associated with specific immune cell types, including binding to CD3ε on T cells and binding to NK cells via CD16, CD64, or NKG2D. It also describes binding to macrophages via CD14 and to neutrophils via CD16b or CD177. The document further reports that modified J-chain incorporation and bispecific targeting are validated, and it addresses complement-dependent cytotoxicity in connection with the described polymeric antibody context.
Claims Coverage
The independent claim defines a polymeric antigen-binding antibody architecture using at least two immunoglobulin monomers plus a modified J-chain with an extraneous binding moiety introduced within 10 residues of the J-chain N- or C-terminus. The claim specifies two alternative monomer domain/tail-piece compositions, and the dependent claims further refine the extraneous binding moiety format, the method of introduction, effector-cell target, and polymer valency/stoichiometry.
Modified J-chain with terminal-proximal extraneous binding moiety
A polymeric antibody comprises at least two immunoglobulin monomers and a modified J-chain, where the modified J-chain comprises an extraneous binding moiety introduced into a native J-chain comprising SEQ ID NO: 1, introduced at or within 10 residues from the C- or N-terminus of the native J-chain.
Immunoglobulin monomer composition with tail-piece domain pairing
Each immunoglobulin monomer comprises either Cμ4 and an IgM tail-piece (αctp) domain or Cα13 and an IgA tail-piece (αtp) domain.
Overall, the claim set focuses on terminal-proximal insertion of an extraneous binding moiety into a native J-chain (SEQ ID NO: 1) to create a modified J-chain in a polymeric antigen-binding antibody, while constraining monomer tail-piece/constant-domain pairings.
Stated Advantages
Improved potency/avidity and improved ADCC/cell killing.
Validation of J-chain incorporation and bispecific targeting.
Reported lack of deleterious effect on complement-dependent cytotoxicity with enhanced CDC versus corresponding IgG.
Documented Applications
Cancer and viral disease contexts are described, including HBV and HIV.
T-cell dependent B-cell killing and in vivo B-cell depletion are described in a humanized NSG mouse model.
Examples of bispecific IgM targeting include anti-CDIM with CD3 scFv and anti-CD20 with CD3 scFv, including T-ALL-related context.
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