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WO2024148369A1 - Variants de l'il-12 à affinité ciblée - Google Patents

Variants de l'il-12 à affinité ciblée Download PDF

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Publication number
WO2024148369A1
WO2024148369A1 PCT/US2024/010762 US2024010762W WO2024148369A1 WO 2024148369 A1 WO2024148369 A1 WO 2024148369A1 US 2024010762 W US2024010762 W US 2024010762W WO 2024148369 A1 WO2024148369 A1 WO 2024148369A1
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WO
WIPO (PCT)
Prior art keywords
protein
subunit sequence
optionally
cells
seq
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/US2024/010762
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English (en)
Inventor
Bijan A. BOLDAJIPOUR
Scott Edward BOYKEN
Thaddeus M. DAVENPORT
Szu-Han Huang
Marc Joseph LAJOIE
Howell Franklin MOFFETT
Yun Song
Brian D. WEITZNER
Luke CASSEREAU
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Lyell Immunopharma Inc
Outpace Bio Inc
Original Assignee
Lyell Immunopharma Inc
Outpace Bio Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Lyell Immunopharma Inc, Outpace Bio Inc filed Critical Lyell Immunopharma Inc
Publication of WO2024148369A1 publication Critical patent/WO2024148369A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/52—Cytokines; Lymphokines; Interferons
    • C07K14/54—Interleukins [IL]
    • C07K14/5434—IL-12
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
    • C12N5/06—Animal cells or tissues; Human cells or tissues
    • C12N5/0602—Vertebrate cells
    • C12N5/0634—Cells from the blood or the immune system
    • C12N5/0636—T lymphocytes
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2501/00—Active agents used in cell culture processes, e.g. differentation
    • C12N2501/20—Cytokines; Chemokines
    • C12N2501/23—Interleukins [IL]
    • C12N2501/2312—Interleukin-12 (IL-12)

Definitions

  • IL-12RP1 primarily binds the IL-12 p40 subunit, while IL-12RP2 primarily binds the IL-12 p35 subunit (Presky et al., J Immunol. (1998) 160(5):2174-9).
  • IL-12R There is no complete co-crystal structure of IL- 12 bound to IL-12R.
  • Simultaneous binding of IL- 12 to both IL-12RP1 and IL-12RP2 may be required to drive intracellular signaling (Presky et al., PNAS (1996) 93(24): 14002-7; Presky et al., Ann NY Acad Sci. (1996) 795:390-3; Robinson, Cytokine (2015) 71(2):348-59).
  • IL-12 is a key cytokine in the initiation of a Thl response and has been explored as a potential therapy to treat cancer (Lasek et al., Cancer Immunol Immunother. (2014) 63(5):419-35). But due to significant systemic toxicity, the approaches to IL-12-based immunotherapy have been focused on direct injections of IL- 12 to tumor sites and on fusions of IL-12 to tumor-targeting moieties. Some researchers have attempted to use a cell-based approach to deliver IL- 12 in which cells engineered to express IL- 12 are administered in vivo (Wei et al., J Cell Mol Med. (2013) 17(11): 1465-74; Zhang et al., Clin Cancer Res.
  • the mutein comprises a mutation at position 171 of SEQ ID NO: 1, optionally wherein the mutation is 1171 A.
  • FIG. 12 is a schematic diagram depicting an exemplary scIL-12 affinity variant of the disclosure linked to a targeting moiety that specifically and selectively binds to an antigen present in the tumor microenvironment (TME), for example, in the format of a fusion protein.
  • TME tumor microenvironment
  • the targeting moiety directs the exemplary scIL-12 affinity variant of the disclosure to the TME to localize scIL-12 affinity variant: IL- 12R mediated signaling to this biological niche.
  • the targeting moiety may comprise a binder of any format, including, a single chain variable region (scFv) raised against an antigen present in the TME.
  • scFv single chain variable region
  • the p35 mutein comprises a mutation at position 38 of SEQ ID NO: 1.
  • the mutein comprises an amino acid substitution at position 38 of SEQ ID NO: 1, wherein glutamate (E) is substituted with an amino acid other than glutamate (E).
  • the substitute amino acid is glycine (G) or serine (S).
  • the p35 mutein comprises a mutation at position 41 of SEQ ID NO: 1.
  • the mutein comprises an amino acid substitution at position 41 of SEQ ID NO: 1, wherein proline (P) is substituted with an amino acid other than proline (P).
  • the substitute amino acid is glycine (G) or serine (S).
  • the IL-12 affinity variants of the present disclosure are mouse IL-12 affinity variants.
  • An exemplary wildtype mouse IL-12 p35 amino acid sequence (UniProt ID No. P43431) is shown below, where the signal peptide (residues 1-22) is boxed:
  • an IL-12 p40 subunit may comprise an amino acid sequence having at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 97%, 99% or any percentage in between identity to SEQ ID NO:4 or to a sequence comprising SEQ ID NO:4.
  • the mutations in p40 may further reduce the affinity of the IL- 12 variants for IL-12R, such as IL-12RPL [0083]
  • the p40 subunit may contain mutations, such as substitutions, at the interface with IL-2RP1.
  • the p40 subunit contains mutations at, e.g., positions that correspond to residues P39, D40, E81, and F82 of SEQ ID NO:5.
  • the p40 mutein is derived from human p40 and has one or more mutations selected from P39A, D40A, E81A, and F82A in SEQ ID NO:5. See, e.g., Glassman et al., supra.
  • the IL-12 variants are mouse IL-12 variants and comprise a mouse p40 subunit, with or without mutations.
  • An exemplary wildtype mouse p40 amino acid sequence (UniProt ID No. P43432) is shown below, with the signal sequence (amino acids 1-22) in box:
  • the mouse p40 contains mutations that correspond to those described above for human p40 (e.g., E81A and F82A mutations in SEQ ID NO:6).
  • the present IL- 12 affinity variants are single-chain IL- 12 (scIL-12) fusion proteins comprising a p35 mutein sequence fused to a p40 sequence (with or without mutations).
  • the scIL-12 variants comprise a membrane anchor or a transmembrane domain such that they are expressed at the cell surface.
  • membrane anchors are glycolipid anchors such as a glycosylphosphatidylinositol (GPI) anchor, covalent lipid modifications, membrane anchor peptides, and a fusion protein (e.g., derived from a mammalian sequence, a viral sequence, and/or a bacterial sequence).
  • the scIL-12 variant comprises a CLS transmembrane domain, and optionally an N-terminal tag such as a strep tag II (STII).
  • the scIL-12 has the structure STII-pdO ⁇ -GeS-pSS ⁇ -CLS (“GeS” is disclosed as SEQ ID NO: 17), where (*) denotes the possibilities of having or not having mutations, and GeS (SEQ ID NO: 17) denotes a linker having the sequence GGGGGGS (SEQ ID NO: 17).
  • scIL-12 comprises a wildtype sequence of the p35 subunit of IL-12.
  • the scIL-12 variants herein do not contain the mutations listed in Table 4.
  • Table 6 summarizes the effects of exemplary human scIL-12 affinity variants in a TransActTM assay (FIG. 7) or sequential killing assays (FIGs. 9 and 10). Position numbering is based off of SEQ ID NO: 1. Unless otherwise indicated, the IL-12 variants contain a wildtype p40 sequence. Table 6
  • the present disclosure provides IL-12 variants comprising the p35 muteins shown in Tables 5 and 6. II. Targeting Moieties
  • targeting moieties of the disclosure prevent affinity variants of the disclosure or muteins thereof from diffusing out of a TME. [0098] In some embodiments of the disclosure, targeting moieties of the disclosure reduce the systemic exposure to or bioavailability of affinity variants of the disclosure or muteins thereof in a location outside a TME.
  • the targeting moiety selectively and/or specifically binds to an antigen expressed within a TME.
  • a targeting moiety of the disclosure binds to PD-L1.
  • a targeting moiety of the disclosure binds to EpCAM.
  • a targeting moiety of the disclosure binds to HER2.
  • a targeting moiety of the disclosure binds to ROR1.
  • a targeting moiety of the disclosure binds to CBD.
  • a targeting moiety of the disclosure binds to lumican.
  • a targeting moiety of the disclosure binds to VWFA3.
  • a targeting moiety of the disclosure binds to lumican.
  • some or all of the various functional components of the present targeted IL- 12 affinity variants are linked through a peptide linker, such as a flexible peptide linker, e.g., a G/S-rich linker.
  • a G/S-rich linker may contain glycine and/or serine in 50% or more of its residues.
  • viral vectors include, without limitation, vectors derived from lentivirus, retrovirus, adenovirus, adeno-associated virus, herpes simplex virus, Sendai virus, and vaccinia virus.
  • the recombinant virus is pseudotyped with a heterologous envelope protein.
  • the recombinant virus is a lentivirus pseudotyped with an envelope glycoprotein derived from vesicular stomatitis virus (VSV), measles virus, or another virus (see e.g., Cronin et al., Curr Gene Ther.
  • the targeted IL-12 variant herein may be expressed in immune cells such as T cells (e.g., CD4 + T cells and CD8 + T cells) and natural killer (NK) cells.
  • T cells e.g., CD4 + T cells and CD8 + T cells
  • NK natural killer
  • the T cells are engineered T cells.
  • the T cells are tumor-infiltrating T cells (TILs).
  • TILs tumor-infiltrating T cells
  • an abTCR may comprise an engineered TCR in which the antigen-binding domain of a TCR (e.g., an alpha/beta TCR or a gamma/delta TCR) has been replaced by that of an antibody (with or without the antibody’s constant domains); the engineered TCR then becomes specific for the antibody’s antigen while retaining the TCR’s signaling functions.
  • a TCR e.g., an alpha/beta TCR or a gamma/delta TCR
  • Expi293 cells of passage less than 30 were transfected with plasmid DNA encoding CMV promoter and scIL-12 variant at a concentration of 1 pg/mL of culture in 25 or 50 mL cultures. Generally, all complexation reaction amounts are as described in the Expi293 system manual. Feed/Enhancers were added 18-22 hours post transfection, and harvest of cells by centrifugation at 4,000 x g was done 5 or 6 days post transfection. Purification was done by subjecting supernatants to end over end mixing in the presence of Nickel Sepharose excel (GE) using 0.5 mL of resin (1 mL 50% slurry) that had been exchanged into PBS before addition.
  • GE Nickel Sepharose excel
  • IL-12RP2-Fc protein from R&D Biosystems/Bio-Techne was resuspended at 0.2 mg/mL and buffer-exchanged into PBS using ZebaTM desalting columns (Thermo Fisher).
  • the pH of the protein solution was adjusted with 20X borate buffer (Pierce) just prior to the addition of Alexa Fluor 647-NHS (Thermo Fisher) in DMSO, using a 10-fold molar ratio of dye to protein. Labeling was carried out at room temperature for 2 hours before dye removal and buffer-exchange into PBS using ZebaTM columns (Thermo Fisher).
  • SSM site- saturation mutagenesis
  • the transduced Jurkat cells were stained with an anti-STII-FITC antibody to measure surface expression of IL-12 (STII-p40- G6S-p35*-CLS) and stained with IL-12Rp2-Fc-AF647 to measure binding of IL-12RP2.
  • FIG. 12 depicts an exemplary scIL-12 affinity reagent of the disclosure linked to a targeting moiety (“TME Binder”). That targeting moiety specifically and selectively binds to an antigen present in the tumor microenvironment (TME).
  • TME Binder specifically and selectively binds to an antigen present in the tumor microenvironment
  • Exemplary targeted IL-12 affinity reagents can be in the format of a fusion protein, although the IL- 12 affinity variants and targeting moieties can be linked using other known techniques and structures.
  • the targeting moiety directs the exemplary scIL-12 affinity variant of the disclosure to the TME to localize scIL- 12 affinity variant:IL-12R mediated signaling to this biological niche.
  • the right-most graph shows the elevated levels of IL-12R signaling IL- 12 cytokine constructs with and without PD-L1 -targeting in PD-L1 + cells before any washout.
  • the center graph shows that IL-12R signaling after washout only occurred from exposure to PD-L1 -targeted IL-12 constructs in PD-L1 + cells.
  • the PD- Ll-targeted IL-12 affinity variants retain IL-12R signaling ability when bound to target cells, as would occur in the TME.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Genetics & Genomics (AREA)
  • Biomedical Technology (AREA)
  • Zoology (AREA)
  • Biotechnology (AREA)
  • Biochemistry (AREA)
  • Immunology (AREA)
  • Wood Science & Technology (AREA)
  • General Health & Medical Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Hematology (AREA)
  • General Engineering & Computer Science (AREA)
  • Cell Biology (AREA)
  • Microbiology (AREA)
  • Toxicology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Biophysics (AREA)
  • Medicinal Chemistry (AREA)
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  • Proteomics, Peptides & Aminoacids (AREA)
  • Peptides Or Proteins (AREA)
  • Micro-Organisms Or Cultivation Processes Thereof (AREA)

Abstract

La présente divulgation concerne des variants de l'IL-12 à affinité ciblée, des compositions pharmaceutiques comprenant les variants, des cellules thérapeutiques exprimant les variants, et des méthodes ou des utilisations de ceux-ci pour le traitement ou la prévention d'une maladie ou d'un trouble.
PCT/US2024/010762 2023-01-07 2024-01-08 Variants de l'il-12 à affinité ciblée Ceased WO2024148369A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US202363478935P 2023-01-07 2023-01-07
US63/478,935 2023-01-07
US202363526405P 2023-07-12 2023-07-12
US63/526,405 2023-07-12

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Citations (12)

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WO2017070608A1 (fr) 2015-10-23 2017-04-27 Eureka Therapeutics, Inc. Constructions chimériques d'anticorps/récepteurs des lymphocytes t et leurs utilisations
WO2018200583A1 (fr) 2017-04-26 2018-11-01 Eureka Therapeutics, Inc. Cellules exprimant des récepteurs d'activation chimériques et des récepteurs de stimulation chimériques et utilisations associées
WO2021067863A2 (fr) * 2019-10-03 2021-04-08 Xencor, Inc. Protéines de fusion fc hétérodimères d'il-12 ciblées
WO2021189139A1 (fr) * 2020-03-23 2021-09-30 Blackler Ryan Protéines de fusion il12 masqués et leurs procédés d'utilisation
WO2022094046A1 (fr) * 2020-10-29 2022-05-05 Proviva Therapeutics (Hong Kong) Limited Compositions d'il-12 et leurs procédés d'utilisation
WO2022155263A2 (fr) * 2021-01-12 2022-07-21 Askgene Pharma Inc. Molécules chimériques comprenant un polypeptide agoniste d'il-12
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WO2023133540A1 (fr) * 2022-01-07 2023-07-13 Lyell Immunopharma, Inc. Variants de l'il-12 à affinité modifiée
WO2023141601A1 (fr) * 2022-01-20 2023-07-27 Repertoire Immune Medicines, Inc. Protéines de fusion il-12 ciblant cd8
WO2023242769A1 (fr) * 2022-06-17 2023-12-21 Pfizer Inc. Variants d'il-12, anticorps anti-pd1, protéines de fusion et leurs utilisations
WO2024018369A1 (fr) * 2022-07-18 2024-01-25 Onko-Innate Pty Ltd Protéines de fusion fc d'il-12 et leurs utilisations

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WO2017070608A1 (fr) 2015-10-23 2017-04-27 Eureka Therapeutics, Inc. Constructions chimériques d'anticorps/récepteurs des lymphocytes t et leurs utilisations
WO2018200583A1 (fr) 2017-04-26 2018-11-01 Eureka Therapeutics, Inc. Cellules exprimant des récepteurs d'activation chimériques et des récepteurs de stimulation chimériques et utilisations associées
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WO2021067863A2 (fr) * 2019-10-03 2021-04-08 Xencor, Inc. Protéines de fusion fc hétérodimères d'il-12 ciblées
WO2021189139A1 (fr) * 2020-03-23 2021-09-30 Blackler Ryan Protéines de fusion il12 masqués et leurs procédés d'utilisation
WO2022094046A1 (fr) * 2020-10-29 2022-05-05 Proviva Therapeutics (Hong Kong) Limited Compositions d'il-12 et leurs procédés d'utilisation
WO2022155263A2 (fr) * 2021-01-12 2022-07-21 Askgene Pharma Inc. Molécules chimériques comprenant un polypeptide agoniste d'il-12
WO2022214653A1 (fr) * 2021-04-09 2022-10-13 Ose Immunotherapeutics Nouvel échafaudage pour molécules bifonctionnelles présentant des propriétés améliorées
WO2023133540A1 (fr) * 2022-01-07 2023-07-13 Lyell Immunopharma, Inc. Variants de l'il-12 à affinité modifiée
WO2023141601A1 (fr) * 2022-01-20 2023-07-27 Repertoire Immune Medicines, Inc. Protéines de fusion il-12 ciblant cd8
WO2023242769A1 (fr) * 2022-06-17 2023-12-21 Pfizer Inc. Variants d'il-12, anticorps anti-pd1, protéines de fusion et leurs utilisations
WO2024018369A1 (fr) * 2022-07-18 2024-01-25 Onko-Innate Pty Ltd Protéines de fusion fc d'il-12 et leurs utilisations

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