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JP-7854991-B2 - Novel anti-LILRB2 antibody and derivative products

JP7854991B2JP 7854991 B2JP7854991 B2JP 7854991B2JP-7854991-B2

Inventors

  • コスタ，マリア・ジョゼ
  • スタフォード，ライアン
  • マカッチョン，クリスタ
  • マー，ジン－ティアン
  • ホン，ギュ・ヒー
  • ティアン，ホンギュ
  • ソン，アン
  • リャオ，エックス・シャーリーン

Assignees

  • イミューン－オーエヌシー セラピューティクス，インコーポレーテッド

Dates

Publication Date
20260507
Application Date
20211020
Priority Date
20201021

Claims (20)

  1. An anti-LILRB2 antibody or its antigen-binding fragment comprising a heavy chain variable region and a light chain variable region , (a) The heavy chain variable region has the amino acid sequence of SEQ ID NO: 25, and the light chain variable region has the amino acid sequence of SEQ ID NO: 26; or (b) The heavy chain variable region has the amino acid sequence of SEQ ID NO: 31, and the light chain variable region has the amino acid sequence of SEQ ID NO: 32. Anti-LILRB2 antibody or its antigen-binding fragment.
  2. The antibody or antigen-binding fragment according to claim 1, further comprising an immunoglobulin constant region, optionally an IgG constant region, optionally a human IgG constant region, optionally an IgG4 constant region, or optionally a hinge-stabilized IgG4 constant region.
  3. The antibody or its antigen-binding fragment according to claim 1, wherein the antibody is a diabody, scFv, scFv dimer, BsFv, dsFv, (dsFv) ² , dsFv-dsFv', Fv fragment, Fab, Fab', F(ab') ² , a bispecific antibody, a ds diabody , or a bivalent antibody.
  4. An antibody or antigen-binding fragment according to claim 1, which blocks the binding of LILRB2 to one or more ligands, wherein the ligand is selected from the group consisting of HLA-G, classical MHC-I, ANGPTL, CD1c/d, CSP, and SEMA4A.
  5. An antibody or antigen-binding fragment according to claim 1, which modulates LILRB2 activation, and which suppresses LILRB2 activation or antagonistizes LILRB2 signaling.
  6. A polyspecific antibody or antigen-binding fragment according to claim 1, comprising PD-1, PD-L1, PD-L2, CTLA-4, LAG3, TIM-3, Fc receptor, FCRL (1-6), A2AR, CD160, 2B4, TGF-β, TGF-βR, VISTA, BTLA, TIGIT, LAIR1, LILRB1, LILRB3, LILRB4, LILRB5, LILRA (1-6), OX40, CD2, CD27, CD28, CD30, CD40, CD47, SIRPA, CLEC-1, clever-1/stabilin-1, AD An antibody or its antigen-binding fragment that specifically binds to a second antigen selected from GRE, TREM1, TREM2, CD122, ICAM-1, IDO, NKG2D/C, SLAMF7, MS4A4A, SIGLEC (7-15), NKp80, NKG2A, CD160, CD161, CD300, CD163, B7-H3, B7-H4, LFA-1, ICOS, 4-1BB, GITR, BAFFR, HVEM, CD7, LIGHT, TNFR2, TLR (1-9), IL-2, IL-7, IL-15, IL-21, CD16, and CD83.
  7. An antibody or antigen-binding fragment according to claim 1, which is linked to one or more conjugate portions, wherein the conjugate portions include an immunomodulator, an antitumor agent, a clearance modifier, a toxin, a detectable label, DNA, RNA, a cytokine, or a purified portion.
  8. A pharmaceutical composition comprising an antibody or an antigen-binding fragment thereof according to any one of claims 1 to 7 , and a pharmaceutically acceptable carrier.
  9. An isolated polynucleotide encoding an antibody or an antigen-binding fragment thereof according to any one of claims 1 to 7 .
  10. A vector comprising an isolated polynucleotide as described in claim 9 .
  11. A host cell comprising the vector according to claim 10 .
  12. A method for expressing an antibody or an antigen-binding fragment thereof, comprising the step of culturing the host cells described in claim 11 under conditions in which the antibody or the antigen-binding fragment thereof is expressed.
  13. A chimeric antigen receptor (CAR) protein comprising an antigen-binding fragment according to any one of claims 1 to 7 .
  14. An isolated nucleic acid encoding the CAR protein according to claim 13 .
  15. A vector comprising the isolated nucleic acid described in claim 14 .
  16. A manipulated cell comprising the isolated nucleic acid described in claim 14 , wherein the manipulated cell is a T cell, an NK cell, or a macrophage.
  17. A pharmaceutical composition according to claim 8 for use in a method for treating or improving the effects of cancer in a subject, the method comprising the step of administering to the subject a therapeutically effective amount of the antibody or an antigen-binding fragment thereof.
  18. A composition comprising the antibody or antigen-binding fragment thereof according to claim 1 for use in a method for detecting cancer cells or cancer stem cells in a sample or subject, wherein the method is: (a) The step of bringing a sample of a subject or a sample derived from a subject into contact with the antibody or an antigen-binding fragment thereof; (b) the step of detecting the binding of the antibody in the subject or sample to cancer cells or cancer stem cells, A composition in which the sample is body fluid, biopsy, blood, bone marrow, sputum, tears, saliva, mucus, serum, ascites, urine, or feces.
  19. The composition according to claim 18 , wherein the method further comprises (c) a step of performing steps (a) and (b) at a second time point and determining the change in the detection level compared to the first time point.
  20. A composition comprising an antibody or antigen-binding fragment thereof according to any one of claims 1 to 7 for use in a method for enhancing T cell activation or enhancing dendritic cell maturation and activation in a subject; modulating the phenotype of anti-inflammatory macrophages and tolerogenic DCs; polarizing bone marrow cells derived from solid tumor cancer patients to a pro-inflammatory phenotype; or mitigating the inhibitory effect of patient-derived monocytic MDSCs (M-MDSCs) on autologous T cell proliferation and cytokine release, wherein the method comprises the step of administering the antibody or antigen-binding fragment thereof to a subject .

Description

Cross-reference of related applications [0001] This application claims priority to U.S. Provisional Patent Application No. 63/094,354, filed on 21 October 2020, and U.S. Provisional Patent Application No. 63/110,317, filed on 5 November 2021, the disclosures thereof being incorporated herein by reference. Sequence List [0002] The sequence listing, named "066564-8014WO01_ST25", is 154 KB (measured by Microsoft Windows), and is contained in a file created on October 20, 2021, which was filed electronically together with this specification and is incorporated herein by reference. background [0003] I. Field [0004] This disclosure generally relates to the fields of medicine, oncology, and immunology. More specifically, this disclosure relates to antibodies that bind to LILRB2. [0005] II. Description of related technologies [0006] Myeloid-derived suppressor cells and tumor-associated macrophages inhibit the anti-cancer immune response systemically and in the tumor microenvironment, respectively, thereby limiting the effectiveness of immune checkpoint blockers. On the other hand, myeloid cell plasticity can enable therapeutic intervention. Leukocyte immunoglobulin-like receptor subfamily B member 2 (LILRB2), also known as immunoglobulin-like transcript 4 (ILT4 or ILT-4), leukocyte immunoglobulin-like receptor 2 (LIR2 or LIR-2), and CD85d or CD85D, is a type I membrane protein that is primarily expressed by myeloid cells (monocytes, macrophages, dendritic cells, and neutrophils) and has emerged as a key immune checkpoint that mediates cancer-associated tolerogenic activity in myeloid cells. LILRB2 contains a cytoplasmic immune receptor inhibitory tyrosine motif (ITIM) and is involved in the negative regulation of immune cell activation. LILRB2 possesses several ligands (classical and non-classical MHC-I, ANGPTL2/5, SEMA4A, complement degradation products [CSP], and CD1c/d) that can play a role in cancer, most of which are known to contribute to immunosuppression in the solid tumor microenvironment. Binding of LILRB2 to its ligands results in inhibitory signals that counteract the stimulation of the immune response. Physiologically, its activity is thought to regulate inflammatory responses and immunocytotoxicity to help focus the immune response and limit autoreactivity. Therefore, LILRB2 is a promising target for modulating the immune response in the treatment of a variety of diseases and conditions, including cancer, chronic viral infections, and autoimmune diseases. Novel anti-LILRB2 antibodies are urgently needed. [0007] This disclosure provides anti-LILRB2 antibodies and their antigen-binding fragments, their amino acid and nucleotide sequences, anti-LILRB2 chimeric antigen receptors, and uses thereof. [0008] In one embodiment, the present disclosure provides a monoclonal antibody or an antigen-binding fragment thereof that specifically binds to LILRB2. In certain embodiments, the antibody or antigen-binding fragment, upon binding to LILRB2, modulates the activation of LILRB2. In certain embodiments, the antibody or antigen-binding fragment, upon binding to LILRB2, inhibits the activation of LILRB2. In certain embodiments, the antibody or antigen-binding fragment, upon binding to LILRB2, specifically blocks the binding of MHC and other ligands (e.g., ANGPTL, SEMA4A, etc.) to LILRB2. [0009] In some embodiments, the anti-LILRB2 antibody or its antigen-binding fragment includes a clone-paired heavy-chain variable region and a light-chain variable region, as shown in Figure 1. In some embodiments, the antibody or its antigen-binding fragment includes (a) a heavy-chain variable region having the amino acid sequence of SEQ ID NO: 25 and a light-chain variable region having the amino acid sequence of SEQ ID NO: 26; or (b) a heavy-chain variable region having the amino acid sequence of SEQ ID NO: 31 and a light-chain variable region having the amino acid sequence of SEQ ID NO: 32. [00010] In certain embodiments, the antibody described herein is a recombinant fully human antibody. In certain embodiments, the antibody described herein is a human IgG1, human IgG2, human IgG3, or human IgG4 antibody. In certain embodiments, the antigen-binding fragment described herein is a recombinant scFv (single chain fragment variable) antibody, a Fab fragment, an F(ab')2 fragment, or an Fv fragment. [00011] In certain embodiments, an isolated recombinant fully human antibody described herein is ligated to one or more conjugate moieties. In some embodiments, the conjugate moieties include antitumor agents, STING (Stimulator of Interferon Genes) agonists, cytokines, clearance modifiers, toxins (e.g., chemotherapeutic agents), immunostimulators (e.g., TLR agonists), detectable labels (e.g., radioisotopes, lantanides, luminescence labels, fluorescent labels, or enzyme-substrate labels), DNA, RNA, or purified moieties. [00012] In another embodiment, an isolated nucleic acid encoding an isolated recombinant fully human antibody or an antig