Nucleic acids encoding and methods of producing proteins comprising antibody chains
Inventors
Chanteux, Stéphanie • Gauthier, Laurent • GOURDIN, Nicolas • Paturel, Carine • Perrot, Ivan • ROSSI, BENJAMIN
Assignees
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Publication Number
US-12202907-B2
Publication Date
2025-01-21
Expiration Date
Abstract
The present invention relates to antigen-binding compounds that inhibit the enzymatic activity of soluble human CD39. The invention also relates to cells producing such compounds; methods of making such compounds, and antibodies, fragments, variants, and derivatives thereof; pharmaceutical compositions comprising the same; methods of using the compounds to diagnose, treat or prevent diseases, e.g., cancer.
Core Innovation
The disclosure concerns anti-CD39 antibodies that inhibit CD39 ATPase activity, directed to soluble human CD39 (sCD39) and membrane-bound CD39 (memCD39). It describes antibodies comprising a heavy chain variable region (VH) and a light chain variable region (VL), including specific VH and/or VL CDR and framework sequences, and identifies inhibitory antibodies by name and potency metrics.
The antibodies include Fc-engineering features intended to reduce or eliminate Fcγ receptor binding and to reduce ADCC for “pure” CD39 blockade. The disclosure also addresses CD39 isoforms, including CD39-L1/L2/L3/L4, and maintains CD39 inhibitory function while binding specificity against CD39 isoforms is described.
The document further describes experimental approaches for identifying CD39 inhibitors, including assays using soluble recombinant CD39 and cell-based systems, with ATP/AMP readouts. Anti-human CD39 monoclonal antibodies are generated and characterized, including BY40, BY12, and I-394, and the disclosure includes downstream humanization/variant optimization, stability assessment, and activity comparison across humanized variants.
Claims Coverage
The independent claim coverage centers on nucleic acids encoding antibody proteins defined by specified heavy-chain and light-chain variable-region amino-acid sequences. The claim set also includes dependent features adding sequence identity constraints and Fc-region engineering that reduces binding to specified human Fcγ receptors. Overall, the inventive features are organized around variable-region sequence identity and, in dependents, specific human Fc-domain modifications and expression/production contexts.
Variable-region sequence-defined antibody nucleic acids
A nucleic acid encoding a protein comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 31 and/or a protein comprising a light chain variable region comprising the amino acid sequence of SEQ ID NOS: 36 or 37.
Sequence-identity constrained heavy and light variable regions
A nucleic acid that encodes an antibody heavy chain with a specified variable-region amino-acid sequence (SEQ ID NO: 31) and at least 95% identity to SEQ ID NO: 38, and that also encodes a light chain whose variable region matches either SEQ ID NOS: 36 or 37 with at least 95% identity to SEQ ID NO: 39 or SEQ ID NO: 40, respectively.
Engineered human IgG1 Fc with modified glycosylation and Kabat-site substitutions
A nucleic acid encoding an antibody or antibody fragment that contains a modified human IgG1 Fc domain with N-linked glycosylation at Kabat residue N297 and amino acid substitutions at Kabat residues 234 and 235.
Fcγ-receptor binding reduction via Fc-domain amino-acid modifications
A nucleic acid is described that encodes an antibody with a human Fc domain containing amino acid modifications that reduce binding to a specified human Fcγ receptor (CD16A, CD16B, CD32A, CD32B, or CD64).
Recombinant host cell expression of the encoded variable regions
A recombinant host cell containing an expression vector with the nucleic acid of claim 1 that enables expression of a protein containing a heavy chain variable region and/or a light chain variable region encoded by that nucleic acid.
Producing and obtaining the variable-region proteins by culturing and recovery/purification
A claim covers producing and obtaining a protein containing a heavy chain variable region and/or a light chain variable region by culturing a cell so the encoded nucleic acids express the protein and then recovering and/or purifying the expressed protein.
The claim coverage provided centers on nucleic acids encoding antibody proteins whose heavy and light variable regions are defined by specified SEQ ID NO amino-acid sequences, with dependent coverage adding sequence-identity constraints and specifying engineered human IgG1 Fc features. Additional dependents specify Fc-domain modifications that reduce binding to selected human Fcγ receptors, and they further cover recombinant expression and recovery/purification of the encoded variable-region-containing proteins.
Stated Advantages
Inhibits ATPase activity of soluble human CD39 (sCD39) and membrane-bound CD39 (memCD39).
Provides “pure” CD39 blockade by reducing or eliminating Fcγ receptor binding and ADCC.
Reduces ATP/AMP generation to relieve immunosuppression.
Restores ATP-driven dendritic cell activation and T-cell responses.
Supports cancer and infectious disease treatment, including combination approaches with CD73 or PD-1/PD-L1 blockade.
Synergizes with anti-CD73 blockade.
Documented Applications
Treatment of cancer.
Treatment of infectious disease.
Combination approaches with CD73.
Combination approaches with PD-1/PD-L1 blockade.
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