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KR-20260062923-A - Anti-VISTA antibody RNA or nucleic acid conjugate (ARC or ANC), compositions containing the same, and therapeutic uses thereof

KR20260062923AKR 20260062923 AKR20260062923 AKR 20260062923AKR-20260062923-A

Abstract

The present invention relates to an anti-VISTA antibody RNA or nucleic acid conjugate (antibody RNA or nucleic acid conjugate, ARC or ANC) that specifically delivers at least one nucleic acid, e.g., RNA, into an immune cell, and to the use of such ARC or ANC as a therapeutic agent for treating, e.g., autoimmune, allergic and inflammatory conditions, or for treating cancer and/or for treating associated inflammatory symptoms caused by a specific type of immune cell expressing VISTA.

Inventors

  • 로스스테인, 제이
  • 칠라마리, 마헤슈웨레디
  • 세레진, 서지
  • 쿠타, 안나
  • 황, 신
  • 벨, 키어스틴
  • 슈워트너, 니콜라스
  • 케리에르, 캐서린
  • 데이, 마리아
  • 우차첸코, 로만

Assignees

  • 리포디 이뮤노테라퓨틱스, 인크.

Dates

Publication Date
20260507
Application Date
20240605
Priority Date
20230605

Claims (20)

  1. As an antibody-RNA or antibody-nucleic acid conjugate ('antibody-RNA conjugate, ARC' or 'antibody-nucleic acid conjugate, ANC'), (i) an antibody or antibody fragment that binds to an antigen specifically or predominantly expressed by one or more immune cell types; and (ii) one or more nucleic acids, preferably RNA or DNA oligonucleotides ('payload' or 'payloads'), which are directly or indirectly conjugated thereto, and which consist of wild-type or modified nucleotides that specifically bind to a target gene expressed by an immune cell, optionally an immunoregulatory gene, or RNA encoded by the oligonucleotide. and optionally comprising (iii) a cleavage-type or non-cleavage-type linker or adapter, e.g., a peptide interposed in (i) the antibody or antibody fragment and (ii) one or more nucleic acids, wherein such ARC or ANC is internalized by the immune cell when in contact with the immune cell expressing the antigen bound by (i) the antibody or antibody fragment, and releases (ii) one or more nucleic acids into the immune cell, thereby optionally modulating the expression and/or function of the targeted immunomodulator.
  2. ARC or ANC according to claim 1 , wherein the one or more payloads comprise one or more modified nucleotides and optionally a peptide linker, additionally optionally a cleavable or non-cleavable linker or adapter, for example, at least one phosphonate and/or ribose modified nucleotide that facilitates the direct or indirect attachment of the one or more payloads to the antibody or antibody fragment through (i) the antibody or antibody fragment and (ii) the peptide interposed in the payload.
  3. In claim 1 or 2 , the payload is directly or indirectly conjugated to the antibody or antibody fragment through a lysine residue on the antibody or antibody fragment and/or through (i) a reactive amine optionally included on a peptide connecting the antibody or antibody fragment to one or more payloads, and/or comprises a 3' sense strand Cy5 label and a 5' amine on the antisense strand, ARC or ANC.
  4. In any one of claims 1 to 3 , the antibody or antibody fragment is an ARC or ANC that binds to VISTA, preferably human VISTA.
  5. In any one of claims 1 to 4 , the antibody or antibody fragment binds to VISTA, preferably human VISTA, and comprises VH and VL CDR identical to any one of the anti-human VISTA antibodies comprising the sequence of FIG. 14 or Appendix 1 or Appendix 3 , ARC or ANC.
  6. In any one of claims 1 to 5 , the antibody or antibody fragment comprises an antibody or antibody fragment that binds to VISTA, preferably human VISTA, and comprises a VH and/or VL region and CDR identical to any one of the anti-human VISTA antibodies comprising the VH and/or VL sequence of FIG . 14 , or a VH and/or VL region having at least 90, 95, or 99% sequence identity with respect to the VH and/or VL region with respect to any one of the anti-human VISTA antibodies comprising the VH and/or VL sequence of FIG. 14; or an antibody or antibody fragment comprising the VH and/or VL sequence of Appendix 1 or Appendix 3 ; and the antibody or antibody fragment comprises an IgG1, IgG2, IgG3, or IgG4 constant domain polypeptide, additionally optionally an IgG1 constant domain polypeptide, and additionally optionally an IgG1 constant domain having a sequence included in Appendix 1 or 3 , ARC or ANC.
  7. In any one of claims 1 to 6 , the antibody or antibody fragment comprises a human Fc region, optionally comprises human IgG1, IgG2, IgG3, or IgG4, and is further optionally modified to impair complement and/or FcR binding or to enhance FcRn binding, ARC, or ANC.
  8. An ARC or ANC according to any one of claims 1 to 7, comprising one or more of short interfering RNA (siRNA), short hairpin RNA (shRNA), microRNA (miRNA), double-stranded RNA (dsRNA), transfer RNA (tRNA), ribosomal RNA (rRNA), or heterogeneous nuclear RNA (hnRNA).
  9. In any one of claims 1 to 8, comprising a polynucleic acid molecule having a length of about 10 to about 5000, 10 to about 4000, 10 to about 3000, 10 to about 2000, 10 to about 1000, 10 to about 500, 10 to about 400, 10 to about 300, 10 to about 200, 10 to about 150, 10 to about 100, 10 to about 50, about 10 to about 30, about 15 to about 30, about 18 to about 25, about 18 to about 24, about 19 to about 23, or about 20 to about 22 nucleotides, or having a length of about 50 nucleotides, about 45 nucleotides, about 40 nucleotides, about ARC or ANC comprising a polynucleic acid molecule having 35 nucleotides, about 30 nucleotides, about 25 nucleotides, about 20 nucleotides, about 19 nucleotides, about 18 nucleotides, about 17 nucleotides, about 16 nucleotides, about 15 nucleotides, about 14 nucleotides, about 13 nucleotides, about 12 nucleotides, about 11 nucleotides, or about 10 nucleotides.
  10. ARC or ANC according to any one of claims 1 to 9 , comprising a first polynucleotide and a second polynucleotide, wherein optionally the first polynucleotide is a sense strand or a boarding strand and/or the second polynucleotide is an antisense strand or a guide strand.
  11. In any one of claims 1 to 10 , an ARC or ANC comprising siRNA, tRNA, rRNA, or mRNA.
  12. In any one of claims 1 to 11 , an ARC or ANC comprising, encapsulated in, or conjugated thereto lipid nanoparticles.
  13. In any one of claims 1 to 12 , at least one payload targets a cytokine, chemokine, interleukin, interferon, tumor necrosis factor, or an immunomodulator selected from any of the receptors mentioned above, ARC or ANC.
  14. In any one of claims 1 to 13 , the payload targets an RNA or DNA sequence encoding an immunomodulator selected from IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-11, IL-12, IL-15, IL-17, IL-18, IL-22, IL-37, IL-1β, TGF-β, IFNα, IFNβ, IFNγ, TNF-α, TNF-β, GM-CSF, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA), RAR-related orphan receptor C (RORC), or any molecule having the sequence identified in FIG. 1 or FIG. 2 , ARC or ANC.
  15. ARC or ANC according to any one of claims 1 to 14 , comprising an RNA or DNA encoding GLUT3 or PIK3CA, optionally a siRNA payload targeting a sequence of Table 11 , Appendix 2 or 4 .
  16. In any one of claims 1 to 15 , the antibody or antibody fragment comprises PMBC, T cell, T cell precursor cell, CD4+ T cell, helper T cell, regulatory T cell, CD8+ T cell, unsensitized T cell, effector T cell, memory T cell, stem cell memory T (TSCM) cell, central memory T (TCM) cell, effector memory T (TEM) cell, terminally differentiated effector memory T cell, tumor-infiltrating lymphocyte (TIL), immature T cell, mature T cell, cytotoxic T cell, mucosa-associated invariant T (MAIT) cell, TH1 cell, TH2 cell, TH3 cell, TH17 cell, TH9 cell, TH22 cell, follicular helper T cell and a/b T cell, g/d T cell, natural killer T (NKT) ARC or ANC that binds to at least one immune cell selected from cytokine-induced killer (CIK) cells, lymphokine-activated killer (LAK) cells, perforin-deficient cells, granzyme-deficient cells, B cells, bone marrow cells, monocytes, macrophages, eosinophils, neutrophils, and dendritic cells.
  17. In any one of claims 1 to 16 , the antibody or antibody fragment is an ARC or ANC that binds to bone marrow cells and/or T cells.
  18. In any one of claims 1 to 17 , the antibody or antibody fragment is an ARC or ANC that binds to a T cell or T cell precursor cell or NK cell.
  19. In any one of claims 1 to 18 , (1) 17-IA, 4-1BB, 4Dc, 6-keto-PGFla, 8-iso-PGF2a, 8-oxo-dG, Al adenosine receptor, A33, ACE, ACE-2, Activin, Activin A, Activin AB, Activin B, Activin C, Activin RIA, Activin RIA ALK-2, Activin RIB ALK-4, Activin RIIA, Activin RUB, ADAM, ADAM10, ADAM12, ADAM 15, ADAM 17/T ACE, ADAM8, ADAM9, ADAMTS, ADAMTS4, ADAMTS5, Adresin, aFGF, ALCAM, ALK, ALK-1, ALK-7, alpha-l-antitrypsin, alpha-V/beta-1 antagonist, ANG, Ang, APAF-1, APE, APJ, APP, APRIL, AR, ARC, ART, Artemin, Anti-Id, ASPARTIC, Atrial Sodium Diuretic Factor, av/b3 Integrin, Axl, b2M, B7-1, B7-2, B7-H, B-lymphocyte Stimulator (BlyS), BACE, BACE-1, Bad, BAFF, BAFF-R, Bag-1, BAK, Bax, BCA-1, BCAM, Bel, BCMA, BDNF, b-ECGF, bFGF, BID, Bik, BFM, BLC, BL-CAM, BLK, BMP, BMP-2 BMP-2a, BMP-3 Osteogenin, BMP-4 BMP-2b, BMP-5, BMP-6 Vgr-1, BMP-7(OP-1), BMP-8(BMP-8a, OP-2), BMPR, BMPR-IA(ALK-3), BMPR-IB(ALK-6), BRK-2, RPK-1, BMPR-II(BRK-3), BMPs, b-NGF, BOK, Bombesin, Bone-derived neurotrophic factor, BPDE, BPDE-DNA, BTC, Complement factor 3 [complement factor 3, C3], C3a, C4, C5, C5a, CIO, CA125, CAD-8, Calcitonin, cAMP, Carcinoembryonic antigen [CEA]), Carcinoma-associated antigen, Cathepsin A, Cathepsin B, Cathepsin C/DPPI, Cathepsin D, Cathepsin E, Cathepsin H, Cathepsin L, Cathepsin O, Cathepsin S, Cathepsin V, Cathepsin X/Z/P, CBL, CCI, CCK2, CCL, CCL1, CCL11, CCL12, CCL13, CCL 14, CCL15, CCL16, CCL1 7, CCL18, CCL19, CCL2, CCL20, CCL21, CCL22, CCL23, CCL24, CCL25, CCL26, CCL27, CCL28, CCL3, CCL4, CCL5, CCL6, CCL7, CCL8, CCL9/10, CCR, CCR1, CCR10, CCR10, CCR2, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CD1, CD2, CD4, CD5, CD6, CD7, CD8, CD10, CDlla, CD11b, CD11c, CD13, CD14, CD15, CD16, CD18, CD19, CD20, CD21, CD22, CD23, CD25, CD27L, CD28, CD29, CD30, CD30L, CD32, CD33(p67 protein), CD34, CD38, CD40, CD40L, CD44, CD45, CD46, CD49a, CD52, CD54, CD55, CD56, CD61, CD64, CD66e, CD74, CD80(B7-1), CD89, CD95, CD123, CD137, CD138, CD140a, CD146, CD147, CD148, CD152, CD164, CEACAM5, CFTR, cGMP, CINC, Clostridium botulinum toxin, Clostridium perfringens toxin, CKb8-l, CLC, CMV, CMV UL, CNTF, CNTN-1, COX, C-Ret, CRG-2, CT-1, CTACK, CTGF, CTLA-4, CX3CL1, CX3CR1, CXCL, CXCL1, CXCL2, CXCL3, CXCL4, CXCL5, CXCL6, CXCL7, CXCL8, CXCL9, CXCL10, CXCL11, CXCL12, CXCL13, CXCL14, CXCL15, CXCL16, CXCR, CXCR1, CXCR2, CXCR3, CXCR4, CXCR5, CXCR6, Cytokeratin Tumor-Associated Antigen, DAN, DCC, DcR3, DC-SIGN, Disintegration-Promoting Factor, des(l-3)-IGF-I(Brain IGF-1), Dhh, Digoxin, DNAM-1, Dnase, Dpp, DPPIV/CD26, Dtk, ECAD, EDA, EDA-A1, EDA-A2, EDAR, EGF, EGFR(ErbB-1), EMA, EMMPRIN, EN A, Endothelin receptor, Enkephalinase, eNOS, Eot, Eotaxin, EpCAM, Ephrin B2/EphB4, EPO, ERCC, E-selectin, ET-1, Factor IIa, Factor VII, Factor VIIIc, Factor IX, Fibroblast activation protein (FAP), Fas, FcRl, FEN-1, Ferritin, FGF, FGF-19, FGF-2, FGF3, FGF-8, FGFR, FGFR-3, Fibrin, FL, FLIP, Flt-3, Flt-4, Follicle-stimulating hormone, Fractalkine, FZD1, FZD2, FZD3, FZD4, FZD5, FZD6, FZD7, FZD8, FZD9, FZD10, G250, Gas 6, GCP-2, GCSF, GD2, GD3, GDF, GDF-1, GDF-3(Vgr-2), GDF-5(BMP-14, CDMP-1), GDF-6(BMP-13, CDMP-2), GDF-7(BMP-12, CDMP-3), GDF-8(myostatin), GDF-9, GDF-15(MIC-1), GDNF, GFAP, GFRa-1, GFR-alpha-1, GFR-alpha-2, GFR-alpha-3, GITR, Glucagon, Glut 4, Glycoprotein Ilb/IIIa [glycoprotein Ilb/IIIa, GP Ilb/IIIa], GM-CSF, gpl30, gp72, GRO, Growth Hormone-releasing Factor, Hapten (NP-cap or NIP-cap), HB-EGF, HCC, HCMV gB envelope glycoprotein, HCMV gH envelope glycoprotein, HCMV UL, hematopoietic growth factor (HGF), Hep B gpl20, heparase, Her2, Her2/neu(ErbB-2), Her3(ErbB-3), Her4(ErbB-4), herpes simplex virus (HSV) gB glycoprotein, HSV gD glycoprotein, HGFA, High molecular weight melanoma-associated antigen (HMW-MAA), HIV gpl20, HIV IIIB gp 120 V3 loop, HLA, HLA-DR, HM1.24, HMFG PEM, HRG, Hrk, human cardiac myosin, human cytomegalovirus (HCMV), human growth hormone, HGH), HVEM, 1-309, IAP, ICAM, ICAM-1, ICAM-3, ICE, ICOS, IFNg, Ig, IgA receptor, IgE, IGF, IGF binding protein, IGF-1R, IGFBP, IGF-I, IGF-II, IL, IL-1, IL-1R, IL-2, IL-2R, IL-4, IL-4R, IL-5, IL-5R, IL-6, IL-6R, IL-8, IL-9, IL-10, IL-12, IL-13, IL-15, IL-18, IL-18R, IL-23, Interferon (INF)-alpha, INF-beta, INF-gamma, Inhibin, iNOS, Insulin A chain, Insulin B chain, Insulin-like growth factor 1, Integrin alpha2, Integrin alpha3, Integrin alpha4, Integrin Alpha 4/Beta 1, Integrin, Alpha 4/Beta 7, Integrin Alpha 5 (Alpha V), Integrin Alpha 5/Beta 1, Integrin Alpha 5/Beta 3, Integrin Alpha 6, Integrin Beta 1, Integrin Beta 2, Interferon Gamma, IP-10, 1-TAC, JE, Kallikrein 2, Kallikrein 5, Kallikrein 6, Kallikrein 11, Kallikrein 12, Kallikrein 14, Kallikrein 15, Kallikrein LI, Kallikrein L2, Kallikrein L3, Kallikrein L4, KC, KDR, Keratinocyte Growth Factor [KGF], Laminin 5, LAMP, LAP, LAP(TGF-1), Inactive TGF-1, Inactive TGF-1 bpl, LBP, LDGF, LECT2, Lefty, Lewis-Y Antigen, Lewis-Y Related Antigen, LFA-1, LFA-3, Lfo, LIF, LIGHT, Lipoprotein, LIX, LKN, Lptn, L-Selectin, LT-a, LT-b, LTB4, LTBP-1, Pulmonary surfactant, Luteinizing hormone, Lymphotoxin beta receptor, Mac-1, MAdCAM, MAG, MAP2, MARC, MCAM, MCAM, MCK-2, MCP, M-CSF, MDC, Mer, Metalloproteinase, MGDF receptor, MGMT, MHC(HLA-DR), MIF, MIG, MIP, MIP-1-alpha, MK, MMAC1, MMP, MMP-1, MMP-10, MMP-11, MMP-12, MMP-13, MMP-14, MMP-15, MMP-2, MMP-24, MMP-3, MMP-7, MMP-8, MMP-9, MPIF, Mpo, MSK, MSP, Mucin (Mucl), MUC18, Müllerian duct inhibitor, Mug, MuSK, NAIP, NAP, NCAD, N-cadherin, NCA 90, NCAM, Neprilysin, Neurotrophin-3, -4, or -6, Neuturin, Neuronal growth factor (NGF), NGFR, NGF-beta, nNOS, NO, NOS, Npn, NRG-3, NT, NTN, OB, OGG1, OPG, OPN, OSM, OX40L, OX40R, pl50, p95, PADPr, Parathyroid hormone, PARC, PARP, PBR, PBSF, PCAD, P-cadherin, PCNA, PDGF, PDGF, PDK-1, PECAM, PEM, PF4, PGE, PGF, PGI2, PGJ2, PIN, PLA2, placental alkaline phosphatase (PLAP), PIGF, PLP, PP14, pro-insulin, pro-relaxin, protein C, PS, PSA, PSCA, prostate specific membrane antigen (PSMA), PTEN, PTHrp, Ptk, PTN, R51, RANK, RANKL, RANTES, relaxin chain A, relaxin chain B, renin, respiratory syncytial virus (RSV) F, RSV Fgp, Ret, rheumatoid factor, RLIP76, RPA2, RSK, S100, SCF/KL, SDF-1, SERINE, serum albumin, sFRP-3, Shh, SIGIRR, SK-1, SLAM, SLPI, SMAC, SMDF, SMOH, SOD, SPARC, Stat, STEAP, STEAP-II, TACE, TACI, tumor-associated glycoprotein-72 [TAG-72], TARC, TCA-3, T cell receptor (e.g., T cell receptor alpha/beta), TdT, TECK, TEM1, TEM5, TEM7, TEM8, TERT, testicular PLAP-like alkaline phosphatase, TfR, TGF, TGF-alpha, TGF-beta, TGF-beta pan-specific, TGF-beta RI(ALK-5), TGF-beta RII, TGF-beta RIIb, TGF-beta RIII, TGF-beta1, TGF-beta2, TGF-beta3, TGF-beta4, TGF-beta5, thrombin, thymus Ck-1, thyroid-stimulating hormone, Tie, TIMP, TIQ, TMEFF2, Tmpo, TMPRSS2, TNF, TNF-alpha, TNF-alpha beta, TNF-beta2, TNFc, TNF-RI, TNF-RII, TNFRSF10A (TRAIL Rl Apo-2, DR4), TNFRSFIOB (TRAIL R2 DR5, KILLER, TRICK-2A, TRICK-B), TNFRSF10C (TRAIL R3 DcRl, LIT, TRID), TNFRSF10D (TRAIL R4) DcR2, TRUNDD), TNFRSF11A (RANK ODF R, TRANCE R), TNFRSFllB (OPG OCIF, TR1), TNFRSF12 (TWEAK R FN14), TNFRSF13B (TACI), TNFRSF13C (BAFF R), TNFRSF14 (HVEM ATAR, HveA, LIGHT R, TR2), TNFRSF16 (NGFR p75NTR), TNFRSF17 (BCMA), TNFRSF 18 (GITR AITR), TNFRSF19 (TROY TAJ, TRADE), TNFRSF19L (RELT), TNFRSFIA (TNF RI CD120a, p55-60), TNFRSFIB (TNF RII CD120b, p75-80), TNFRSF26 (TNFRH3), TNFRSF3 (LTbR TNF RIII, TNFC R), TNFRSF4 (OX40 ACT35, TXGP1 R), TNFRSF 5 (CD40 p50), TNFRSF6 (Fas Apo-1, APT1, CD95), TNFRSF6B (DcR3 M68, TR6), TNFRSF7 (CD27), TNFRSF8 (CD30), TNFRSF9 (4-1BB CD137, ILA), TNFRSF21(DR6), TNFRSF22(DcTRAIL R2 TNFRH2), TNFRST23(DcTRAIL R1 TNFRH1), TNFRSF25(DR3 Apo-3, LARD, TR-3, TRAMP, WSL-1), TNFSF10(TRAIL Apo-2 ligand, TL2), TNFSF11(TRANCE/RANK ligand ODF, OPG ligand), TNFSF12(TWEAK Apo-3 ligand, DR3 ligand), TNFSF13(APRIL TALL2), TNFSF13B(BAFF BLYS, TALL1, THANK, TNFSF20), TNFSF14(LIGHT HVEM ligand, LTg), TNFSF15(TLIA/VEGI), TNFSF18(GITR ligand AITR ligand, TL6), TNFSFIA(TNF-α Connectin, DIF, TNFSF2), TNFSF1B (TNF-β LTa, TNFSF1), TNFSF3 (LTb TNFC, p33), TNFSF4 (OX40 ligand gp34, TXGP1), TNFSF5 (CD40 ligand CD154, gp39, HIGM1, IMD3, TRAP), TNFSF6 (Fas ligand Apo-1 ligand, APT1 ligand), TNFSF7 (CD27 ligand CD70), TNFSF8 (CD30 ligand CD153), TNFSF9 (4-1BB ligand CD137 ligand), TP-1, t-PA, Tpo, TRAIL, TRAIL R, TRAIL-R1, TRAIL-R2, TRANCE, transporter receptor, TRF, Trk, TROP-2, TSG, TSLP, tumor-associated antigen CA 125, tumor-associated Antigen expression Lewis Y-associated carbohydrate, TWEAK, TXB2, Ung, uPAR, uPAR-1, urokinase, VCAM, VCAM-1, VECAD, VE-cadherin, VE-cadherin-2, VEFGR-1(flt-1), VEGF, VEGFR, VEGFR-3(flt-4), VEGI, VFM, viral antigen, VLA, VLA-1, VLA-4, VNR integrin, von Willebrand factor, WIF-1, WNT1, WNT2, WNT2B/13, WNT3, WNT3A, WNT4, WNT5A, WNT5B, WNT6, WNT7A, WNT7B, WNT8A, WNT8B, WNT9A, WNT9A, WNT9B, WNT10A, WNT10B, WNT11, WNT16, XCL1, XCL2, XCR1, XCR1, XEDAR, XIAP, XPD, cytotoxic T lymphocyte antigen-4 (CTLA4), programmed cell death protein 1 (PD1), programmed cell death ligand 1 (PD-L1), lymphocyte activation gene-3 (LAG-3), T cell immunoglobulin and mucin protein-3 (TIM-3) and hormone receptor; or (2) an antigen selected from the group consisting of BCMA, cytotoxic T lymphocyte antigen-4 (CTLA4), programmed cell death protein 1 [PD1], programmed cell death ligand 1 (PD-L1), lymphocyte activation gene-3 (LAG-3), TIM-3, CD20, CD2, CD19, Her2, EGFR, EpCAM, FcyRIIIa (CD16), FcyRIIa (CD32a), FcyRIIb (CD32b), FcyRI (CD64), Toll-like receptor (TLR), TLR4, TLR9, cytokine, IL-2, IL-5, IL-13, IL-6, IL-17, IL-12, IL-23, TNFa, TGFβ, cytokine receptor, IL-2R, chemokine, chemokine receptor, growth factor, VEGF and HGF; or (3) CD1a, b, c, d; CD2, CD3, CD4, Cd5, CD6, CD7, CD8, CD9, CD10, CD11a, b, c, d; CDw12, CD13, CD14, oCD15, CD15s, CD15u, CD16, CDw17, CD18, CD19, CD20, CD21, CD22, CD23, CD24, CD25, CD26, CD27, CD28, CD29, CD30, CD31, CD32, CD33, CD34, CD35, CD36, CD37, CD38, CD39, CD40, CD41, CD42a,b,c,d; CD43, CD44, CD45, CD45RO, CD45RA, CD45RB, CD46, CD47, CD48, CD49a, CD49b, CD49c, CD49d, CD49e, CD49f, CD50, CD51, CD52, CD53, CD54, CD55m CD56, CD57, CD58, CD59, CD60a, CD60b, CD61, CD61E, CD62L, CD62P, CD63, CD64, CD65, CD66a, CD66b, CD66c, CD66d, CD66e, CD68, CD69, CD70, CD71, CD72, CD73, CD74, CD75, CD75s, CD77, CD78, CD79α,β, CD80, CD81, CD82, CD83, CDw84, CD85, CD86, CD87, CD88, CD89, CD90, CD91, CD92, Cd92, CD93, CD94, CD95, CD96, CD97, CD98, CD99, CD100, CD101, CD102, CD103, CD104, CD105, CD106, CD107a, CD108, CD109, CD110, CD111, CD112, CD114, CD115, CD116, CD117, CD118, CD119, CD120a, CD120b, CD121a, CDw121b, CD122, CD123, CD124, CD125, CD126, CD127, CDw128, CD129, CD130, CDw131, CD132, CD133, CD134, CD135, CDw136, CDw137, CD138, CD139, CD140a,b, CD141, CD142, CD143, CD144, CD145, CD146, CD147, CD148, CD149, CD150, CD151, CD152, CD153, CD154, CD155, CD156b, CD157, CD158, CD158a, CD159a, CD160, CD161, CD162, CD162R, CD163, CD164, CD165, CD166, CD167a, CD168, CD169, CD170, CD171, CD172a, CD173, CD174, CD175, CD175s, CD176, CD177, CD178, CD179a, CD179b, CD180, CD183, CD184, CD195, CDw197, CD200, CD201, CD202b, CD203c, CD204, CD205, CD206, CD207, CD208, CD209, CDw210, CD212, CD213a1, CD213a2, CDw217, CD220, CD221, CD222, CD223,CD224, CD225, CD226, CD227, CD228, CD229. Antigen selected from CD230, CD231, CD232, CD233, CD234, CD235a, CD235b, CD236, CD236R, CD238, CD239, CD240CE, CD240D, CD241, CD242, CD243, CD244, CD245, CD246, CD247, etc.; or (4) IL4ra, TNFa, BTK, RORgt, PIK3CA, JAK1, JAK3, TYK2, Glut1, Glut3, TAP1, CIITA, cGAS, IRF5, STAT3, STAT6, TAK1(MAP3K7), HPK1; or any of SOCS1, CD39, Cbl, or PTPN22; or (5) Glut1, PI3K, BTK, TNF, RORC, CD45, or CD39; or (6) a gene or nucleic acid encoding an antigen selected from the group consisting of any of PD-1, PD-L1, PD-L2, CTLA-4, B7-1, B7-2, LAG-3, HHLA2, TNFRSF12A, HLA-G, NECTIN2, TNFRSF25, TNFSF14, LAIR1, TNFSF15, TNFSF4, KIR2DL4, PDCD1, LGALS9, and PVR, at least one nucleic acid payload that binds to RNA or DNA, optionally RNA, additionally optionally siRNA or antisense RNA comprising an ARC or ANC.
  20. In any one of claims 1 to 19 , a nucleic acid payload having a payload sequence selected from nucleic acid payloads having sequences listed in Table 11 , Appendix 2 , or Appendix 4 , optionally comprising RNA, additionally optionally siRNA or antisense RNA, or comprising an INX201 ARC having an amino acid sequence and payload sequence listed in Appendix 2 , or an ARC or ANC having an INX201 ARC having an amino acid sequence and payload sequence listed in Appendix 4 .

Description

Anti-VISTA antibody RNA or nucleic acid conjugate (ARC or ANC), compositions containing the same, and therapeutic uses thereof Related applications This PCT application claims the benefit of priority to U.S. Provisional Application No. 63/506,177 filed June 5, 2023 and U.S. Provisional Application No. 63/611,302 filed December 18, 2023, the entire contents of both provisional applications are incorporated herein by reference. Opening of sequence list The contents of the electronic sequence list (1143260_008613_SL.xml, size: 707,682 bytes and creation date: June 3, 2024) are incorporated herein by reference in their entirety. Technology field The present invention disclosed herein relates to an anti-VISTA antibody RNA or nucleic acid conjugate (antibody RNA or antibody nucleic acid conjugate, ARC or ANC) that specifically delivers at least one nucleic acid, e.g., RNA or DNA or a nucleic acid/protein complex, into an immune cell, and to the use of such ARC or ANC as a therapeutic agent, e.g., for treating autoimmune and inflammatory conditions, or for treating cancer and/or for treating associated symptoms caused by a specific type of immune cell. The regulation of RNA function is a field of growing therapeutic interest. Drugs that affect mRNA stability, such as antisense oligonucleotides and short interfering RNA, are one method of regulating RNA function. Another group of oligonucleotides can regulate RNA function by altering the processing of precursor mRNA to include or exclude specific regions of the precursor mRNA in the final gene product, the encoded protein. Therefore, oligonucleotide therapeutics are useful as treatments because they serve as a means to regulate protein expression in disease states. In addition, methods for delivering RNA to target cells by incorporating it into ANCs or ARCs are also known. However, existing ANCs or ARCs do not target immune cell types. In one embodiment, the present invention relates to an anti-VISTA antibody RNA conjugate (ARC) that can be used to specifically deliver nucleic acids, e.g., RNA or DNA or nucleic acid/protein complexes into immune cells. In another aspect, the present invention relates to the use of such ARC as a therapeutic agent for treating, for example, autoimmune, inflammatory, and cancerous conditions. In a specific embodiment, the present invention comprises (i) an antibody or antibody fragment that binds to an antigen specifically or predominantly expressed by one or more immune cell types; and (ii) one or more nucleic acids, preferably RNA or DNA oligonucleotides ('payload' or 'payloads'), which are directly or indirectly conjugated thereto, and which consist of wild-type or modified nucleotides that specifically bind to a target gene expressed by an immune cell, optionally an immunoregulatory gene, or RNA encoded by the oligonucleotide. and optionally provide (iii) an antibody-RNA or antibody-nucleic acid conjugate ('ARC' or 'antibody-nucleic acid conjugate, ANC') comprising a cleavable or non-cleavable linker or adapter, for example, the (i) antibody or antibody fragment and a peptide interposed in the (ii) one or more nucleic acids, wherein the ARC or ANC is internalized by the immune cell when it comes into contact with the immune cell expressing the antigen bound by the (i) antibody or antibody fragment, and releases the (ii) one or more nucleic acids into the immune cell, thereby optionally regulating the expression and/or function of the targeted immunomodulator. In some specific embodiments, any of the aforementioned ARC or ANC comprises one or more modified nucleotides and optionally one or more payloads comprising at least one phosphonate and/or ribose modified nucleotide that facilitates the direct or indirect attachment of one or more payloads to the antibody or antibody fragment through a peptide linker, additionally optionally a cleavable or non-cleavable linker or adapter, for example, through the (i) antibody or antibody fragment and (ii) peptide interposed in the payload. In some specific embodiments, any of the foregoing ARC or ANC comprises a payload that is directly or indirectly conjugated to an antibody or antibody fragment through a lysine residue on the antibody or antibody fragment and/or a reactive amine optionally included on a peptide that links (i) the antibody or antibody fragment to (ii) one or more payloads. In some specific embodiments, any of the aforementioned ARC or ANC comprises an antibody or antibody fragment that binds to VISTA, preferably human VISTA. In some specific embodiments, any of the aforementioned ARC or ANC binds to VISTA, preferably human VISTA, and comprises an antibody or antibody fragment comprising VH and VL CDR identical to any one of the anti-human VISTA antibodies comprising the sequence of FIG. 14 or Appendix 1 or Appendix 3 . In any of the foregoing embodiments in some specific aspects, the antibody or antibody fragment of the ARC or ANC binds to VISTA, preferably human VISTA, and