Polynucleotides encoding death domain-containing receptor-5 (DR5) binding molecules
Inventors
WANG, Beatrice • Schwarzer, Max Allen • Keyt, Bruce Alan • Baliga, Ramesh
Assignees
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Publication Number
US-11578131-B2
Publication Date
2023-02-14
Expiration Date
Abstract
This disclosure provides dimeric, pentameric, and hexameric Tumor Necrosis Factor (TNF) superfamily receptor protein binding molecules and methods of using such binding molecules to direct apoptosis-mediated killing of TNF receptor-expressing cells.
Core Innovation
The invention relates to multimeric IgM antibody polynucleotides and encoded polypeptides in formats having five or six bivalent binding units. Each binding unit comprises two IgM heavy chain constant regions associated with an antigen-binding domain, and at least three antigen-binding domains specifically and agonistically bind death domain-containing receptor-5 (DR5).
The IgM antibody can cross-link at least three DR5 proteins expressed on the surface of a cell, thereby inducing apoptosis of the cell. The DR5-mediated apoptosis is activated at a higher potency than an equivalent amount of a bivalent IgG antibody or fragment thereof that specifically binds to and agonizes the same TNF superfamily receptor protein.
The encoded polypeptides are organized as a first polypeptide subunit and a second polypeptide subunit. The first polypeptide subunit comprises an IgM heavy chain constant region and at least an antibody VH portion of the antigen-binding domain, while the second polypeptide subunit comprises a light chain constant region and an antibody VL portion of the antigen-binding domain.
Claims Coverage
The provided material identifies one independent claim covering a polynucleotide encoding a specific multimeric IgM antibody with DR5-specific agonistic cross-linking and higher-potency DR5-mediated apoptosis relative to an equivalent bivalent IgG binder.
Multimeric IgM polynucleotide encoding five or six bivalent binding units targeting DR5
A polynucleotide comprising a first nucleic acid sequence encoding a first polypeptide subunit of an IgM antibody and a second nucleic acid sequence encoding a second polypeptide subunit of the IgM antibody, wherein the IgM antibody comprises five or six bivalent binding units, wherein each binding unit comprises two IgM heavy chain constant regions associated with an antigen-binding domain, and wherein at least three of the antigen-binding domains specifically and agonistically bind death domain-containing receptor-5 (DR5).
DR5 cross-linking and DR5-mediated apoptosis at higher potency than equivalent bivalent IgG
The IgM antibody can cross-link at least three DR5 proteins expressed on the surface of a cell, thereby inducing apoptosis of the cell, and can activate DR5-mediated apoptosis in a DR5-expressing cell at a higher potency than an equivalent amount of a bivalent IgG antibody or fragment thereof that specifically binds to and agonizes the same TNF superfamily receptor protein.
Two-subunit IgM architecture with VH and VL portions
The first polypeptide subunit comprises an IgM heavy chain constant region and at least an antibody VH portion of the antigen-binding domain, and the second polypeptide subunit comprises a light chain constant region and an antibody VL portion of the antigen-binding domain of the IgM antibody.
Across the identified inventive features, the independent claim centers on an IgM polynucleotide encoding five or six bivalent binding units with at least three DR5-specific agonistic binding domains, where the antibody cross-links multiple DR5 proteins to induce apoptosis and does so at higher potency than an equivalent bivalent IgG that binds and agonizes the same TNF superfamily receptor, using a two-subunit VH/VL architecture.
Stated Advantages
Higher potency DR5-mediated apoptosis than an equivalent amount of a bivalent IgG antibody or fragment thereof that specifically binds to and agonizes the same TNF superfamily receptor protein.
Documented Applications
Therapeutic methods for treating DR5-expressing cancers using the described DR5-binding multimeric IgA/IgM TNF superfamily receptor binding molecules (including multimeric IgM formats).
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