Anti-HLA-G antibodies and use thereof
Inventors
Fischer, Jens • Majety, Meher • Dengl, Stefan • Tiefenthaler, Georg • Klostermann, Stefan • KIRSTENPFAD, CLAUDIA • KOENIGSBERGER, Esther • ROS, Francesca
Assignees
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Publication Number
US-11981737-B2
Publication Date
2024-05-14
Expiration Date
Abstract
The present invention relates to anti-HLA-G antibodies and methods of using the same.
Core Innovation
The patent addresses the immunosuppressive function of human leukocyte antigen G (HLA-G), an immunosuppressive MHC class I molecule, and the difficulty of generating truly HLA-G-specific, non-crossreactive antibodies that block receptor binding, including binding to ILT2 and ILT4. The disclosure centers on selecting antibodies directed to HLA-G while avoiding crossreactivity with related MHC I complexes.
The core strategy uses degrafted and engineered chimeric HLA-G/3M MHC complexes as screening antigens and counter-antigens. Antibodies are selected that bind human HLA-G, including SEQ ID NO:25, while not crossreacting with modified HLA-G (SEQ ID NO:26), mouse H2Kd (SEQ ID NO:27), rat RT1A (SEQ ID NO:29), and human HLA-A2 3M MHC I complexes (SEQ ID NO:21/19).
The disclosure further characterizes the resulting antibodies by receptor binding inhibition and cell-based effects. It states inhibition of ILT2 binding across monomeric, dimeric, and trimeric HLA-G complexes and inhibition of ILT4 binding, including effects on JEG3 (HLA-G-expressing) cells. The patent also documents defined antibody sequence sets, including VH/VL frameworks and HVR sets defined by SEQ ID NO:1-6 and SEQ ID NO:7/8, together with IgG1 isotype variants with Kabat EU Fc mutations, formulation, and immunoconjugate/diagnostic use for treating cancer.
Claims Coverage
The partial claims provided include four independent claims that define isolated anti-human HLA-G antibodies using sequence-defined variable-region and HVR constraints. Across the independent claims, inventive features are represented by specified HVR amino-acid sequences for VH and VL, specific VH/VL sequence pairings, and humanized variants defined by the same HVR sets.
Isolated anti-HLA-G antibody with specified HVR sequences
An isolated antibody that binds to human HLA-G, wherein the antibody comprises HVR-H1 (SEQ ID NO:1), HVR-H2 (SEQ ID NO:2), HVR-H3 (SEQ ID NO:3), HVR-L1 (SEQ ID NO:4), HVR-L2 (SEQ ID NO:5), and HVR-L3 (SEQ ID NO:6).
Isolated anti-HLA-G antibody defined by VH and VL HVR sequence sets
An isolated antibody that binds to human HLA-G, wherein the antibody comprises a VH domain comprising HVR-H1 (SEQ ID NO:1), HVR-H2 (SEQ ID NO:2), and HVR-H3 (SEQ ID NO:3), and a VL domain comprising HVR-L1 (SEQ ID NO:4), HVR-L2 (SEQ ID NO:5), and HVR-L3 (SEQ ID NO:6).
Isolated anti-HLA-G antibody with specific VH/VL sequences or humanized variant
An isolated antibody that binds to human HLA-G, wherein the antibody comprises a VH sequence of SEQ ID NO:7 and a VL sequence of SEQ ID NO:8 or a humanized variant of the VH and VL of the antibody thereof, wherein the humanized variant comprises HVR-H1 (SEQ ID NO:1), HVR-H2 (SEQ ID NO:2), HVR-H3 (SEQ ID NO:3), HVR-L1 (SEQ ID NO:4), HVR-L2 (SEQ ID NO:5), and HVR-L3 (SEQ ID NO:6).
Isolated anti-HLA-G antibody with specific VH/VL sequences
An isolated antibody that binds to human HLA-G, wherein the antibody comprises a VH sequence of SEQ ID NO:7 and a VL sequence of SEQ ID NO:8.
Overall, the independent-claim scope is centered on isolated anti-human HLA-G antibodies defined by specific VH/VL sequence identities and specified HVR amino-acid sequence sets (SEQ ID NO:1-6 and SEQ ID NO:7/8).
Stated Advantages
Truly HLA-G-specific antibodies with non-crossreactivity versus related or modified MHC I complexes are targeted.
The antibodies block receptor binding, including inhibition of ILT2 binding and ILT4 binding.
Cell-based inhibition is described for JEG3 (HLA-G-expressing) cells.
The patent states use for treating cancer.
Documented Applications
Treating cancer using anti-HLA-G antibodies.
Use of antibody formats including fragments, humanized/chimeric antibodies, nucleic acids/host cells, pharmaceutical formulations, and immunoconjugate/diagnostic use.
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