Antibodies against ILT2
Inventors
Mandel, Ilana • PERETZ, Tsuri • HAVES ZIV, Dana • GOLDSHTEIN, Ilana • ALISHEKEVITZ, DROR • FRIDMAN-DROR, Anna • HAKIM, MOTTI • Shulman, Avidor • Sapir, Yair • Ben-Moshe, Tehila
Assignees
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Publication Number
US-11236162-B2
Publication Date
2022-02-01
Expiration Date
Abstract
The present invention provides monoclonal antibodies, or antigen-binding portions thereof, against ILT2, as well as pharmaceutical compositions comprising same and methods of producing same. Also provided are methods of treating cancer comprising administering the antibodies or compositions of the invention. Methods of treating cancer, combination treatments, and patient selection are also provided.
Core Innovation
The invention relates to anti-ILT2 monoclonal antibodies and antigen-binding fragments that antagonize ILT2-mediated immune suppression in cancer. ILT2 is identified as LILRB1/CD85j, and the antibodies are defined by specific heavy chain and light chain complementarity-determining region (CDR) sequences.
The antibodies are described as targeting the ILT2 D1-D2 interdomain interface and directly blocking ILT2 interaction with beta-2-microglobulin (B2M), thereby disrupting ILT2-HLA-G/MHC-I signaling. This ILT2 antagonism is presented as enabling immune activation against cancers characterized by HLA-G or MHC-I signaling.
The invention further discloses that ILT2 antagonism synergizes with PD-1/PD-L1 blockade to produce de novo or greater-than-additive increases in pro-inflammatory cytokines. It is stated that this combination can convert PD-1/PD-L1 refractory cancers to responders, and a patient-selection concept links ILT2 expression, including in circulating CD8+ T cells, to response.
Claims Coverage
The partial claim set includes three independent claims. Across these independent claims, the main inventive features are structurally defined antibodies or antigen-binding fragments specified by particular CDR sequence sets and a specific IgG4 antibody defined by particular heavy- and light-chain SEQ ID NOs.
CDR-defined monoclonal antibody or antigen-binding fragment
A monoclonal antibody or an antigen-binding fragment thereof comprising three heavy chain CDRs and three light chain CDRs, wherein the CDRs are defined by specific SEQ ID NOs, including alternatives with an X residue selected from A, C and S.
IgG4 monoclonal antibody defined by specific heavy- and light-chain SEQ ID NOs
A monoclonal antibody that comprises a heavy chain comprising SEQ ID NO: 28 and a light chain comprising SEQ ID NO: 24, wherein said antibody is an IgG4.
Six CDR-defined monoclonal antibody or antigen-binding fragment
A monoclonal antibody or an antigen-binding fragment thereof comprising three heavy chain CDRs and three light chain CDRs, wherein CDR-H1 comprises SEQ ID NO: 13, CDR-H2 comprises SEQ ID NO: 14, CDR-H3 comprises SEQ ID NO: 25, CDR-L1 comprises SEQ ID NO: 16, CDR-L2 comprises SEQ ID NO: 17, and CDR-L3 comprises SEQ ID NO: 18.
Overall, the claims coverage centers on structurally defined antibodies or antigen-binding fragments specified by particular CDR sequence sets and on a specific IgG4 antibody defined by particular heavy- and light-chain SEQ ID NOs.
Stated Advantages
Antagonizes ILT2-mediated immune suppression in cancer by blocking ILT2 interaction with B2M and disrupting ILT2-HLA-G/MHC-I signaling.
Synergizes with PD-1/PD-L1 blockade to produce de novo or greater-than-additive increases in pro-inflammatory cytokines.
Converts PD-1/PD-L1 refractory cancers to responders in the disclosed context.
Restores or enhances immune functions including NK cytotoxicity and T-cell activity (IFNγ and granzyme B).
Promotes macrophage functional polarization and increases macrophage tumor phagocytosis.
Enhances dendritic-cell functions, including homing to a tumor and activation.
Supports patient selection by linking ILT2 expression, including in circulating CD8+ T cells, to response.
Documented Applications
Treatment/therapeutic use in cancer contexts involving ILT2-mediated immune suppression, including cancers characterized by HLA-G or MHC-I signaling.
Combination immune therapy with PD-1/PD-L1 blockade to increase pro-inflammatory cytokines and to address PD-1/PD-L1 refractory cancers.
Patient-selection use based on ILT2 expression, including circulating CD8+ T cells, to guide response prediction.
Use of ILT2 antagonism to enhance tumor phagocytosis by macrophages.
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