Anti-ILT4 antibodies and antigen-binding fragments
Inventors
Blanusa, Milan • Joyce-Shaikh, Barbara • Schuster, Andrea Claudia • Schultze, Kornelia • Zuniga, Luis A.
Assignees
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Publication Number
US-11897956-B2
Publication Date
2024-02-13
Expiration Date
Abstract
The present invention provides antibodies and antigen-binding fragments thereof that bind to ILT4 (immunoglobulin-like transcript 4) and combinations thereof, e.g., with an anti-PD1 antibody. Also provided are methods of use thereof, for example, for treating or preventing cancer in a subject; and methods of making such antibodies and fragments.
Core Innovation
The invention relates to anti-ILT4 antibodies and antigen-binding fragments that bind human ILT4. The antibodies include defined heavy chain variable domain CDR-H1, CDR-H2, and CDR-H3 amino acid sequences and defined light chain variable domain CDR-L1, CDR-L2, and CDR-L3 amino acid sequences. The document further provides polynucleotides encoding these variable domains, heavy chains, light chains, or both.
The described compositions include anti-ILT4 antibodies and antigen-binding fragments that block ILT4-mediated binding of HLA-G and other HLA ligands. The functional effects include reversing ILT4-mediated suppression, rescuing mast cell degranulation, and enhancing LPS/anti-CD3-induced pro-inflammatory myeloid cytokines. The document also focuses on Fc glycosylation engineering to enhance ADCC, including hypofucosylated/afucosylated glycans and/or increased bisecting GlcNAc glycans.
Beyond the antibody variable domains and Fc glycosylation, the document describes multiple antibody formats and downstream constructs. It covers fucosidase-treated forms, conjugates including polymers/PEGylation and radiolabels/fluorophores, and cytotoxic or drug conjugates. It further includes pharmaceutical compositions, administration concepts, and broad therapeutic and diagnostic uses along with binding and functional characterization involving ILT4 binding and related assays.
Claims Coverage
The independent claim set covers polynucleotides encoding antibodies or antigen-binding fragments that bind human ILT4, with specified heavy-chain and light-chain variable-domain CDR amino acid sequences. The coverage centers on the same ILT4-binding requirement while differing in the recited CDR-H2 and CDR-L2 sequence variants.
Polynucleotides encoding ILT4-binding antibodies with specified heavy and light CDRs
A polynucleotide comprising a nucleotide sequence encoding a VH, a VL, both a VH and a VL, a heavy chain immunoglobulin, a light chain immunoglobulin, or both a heavy chain and a light chain immunoglobulin of an antibody or antigen-binding fragment thereof that binds human ILT4, wherein the antibody comprises a heavy chain variable domain with CDR-H1 (GYYWS), CDR-H2 (EINHSGSTNYNPSLKS or EINHAGSTNYNPSLKS), and CDR-H3 (LPTRWVTTRYFDL), and a light chain variable domain with CDR-L1 (TGSSSNIGAGYDVH), CDR-L2 (GNSNRPS, GQSNRPS, GESNRPS, GDSNRPS, GNANRPS, GQANRPS, GEANRPS, or GDANRPS), and CDR-L3 (QSFDNSLSAYV).
Polynucleotides encoding ILT4-binding antibodies with a specific CDR-H2 and CDR-L2 set
A polynucleotide comprising a nucleotide sequence encoding a VH, a VL, both a VH and a VL, a heavy chain immunoglobulin, a light chain immunoglobulin, or both a heavy chain and a light chain immunoglobulin of an antibody or antigen-binding fragment thereof that binds human ILT4, wherein the antibody comprises a heavy chain variable domain with CDR-H1 (GYYWS), CDR-H2 (EINHAGSTNYNPSLKS), and CDR-H3 (LPTRWVTTRYFDL), and a light chain variable domain with CDR-L1 (TGSSSNIGAGYDVH), CDR-L2 (GDSNRPS), and CDR-L3 (QSFDNSLSAYV).
The claim coverage primarily concerns ILT4-binding antibody polynucleotides defined by specific heavy-chain and light-chain variable-domain CDR amino acid sequences, with independent claim coverage differing in the specific recited CDR-H2 and CDR-L2 sequence variants.
Stated Advantages
Blocking HLA-G/HLA-A/HLA-B/HLA-F binding to ILT4.
Cross-blocking/competition behavior with respect to ILT4 binding partners.
Reversing ILT4-mediated suppression.
Rescuing mast cell degranulation.
Enhancing LPS/anti-CD3-induced pro-inflammatory myeloid cytokines.
Enhances ADCC via Fc glycosylation modifications, including hypofucosylated/afucosylated glycans and/or increased bisecting GlcNAc glycans.
Documented Applications
Cancer treatment or prevention context, including combination with pembrolizumab.
Use in models and assays involving ILT4-related effects, including ILT4-mediated suppression reversal, mast cell degranulation rescue, and cytokine enhancement.
Therapeutic applications for targeting ILT4 using anti-ILT4 antibodies, including antibody constructs and conjugates.
Diagnostic applications and assay applications involving ILT4-binding and functional characterization (e.g., binding assays and cell-based assays).
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