WO2023194656A1 - Anticorps monoclonaux pd-l1 - Google Patents

Anticorps monoclonaux pd-l1 Download PDF

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WO2023194656A1
WO2023194656A1 PCT/FI2023/050181 FI2023050181W WO2023194656A1 WO 2023194656 A1 WO2023194656 A1 WO 2023194656A1 FI 2023050181 W FI2023050181 W FI 2023050181W WO 2023194656 A1 WO2023194656 A1 WO 2023194656A1
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seq
antibody
sequence
cells
antigen
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PCT/FI2023/050181
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James CLUBB
Tatiana KUDLING
Victor CERVERA-CARRASCON
Akseli Hemminki
João Manuel SANTOS
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Tilt Biotherapeutics Oy
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • C07K16/2827—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against B7 molecules, e.g. CD80, CD86
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/66—Microorganisms or materials therefrom
    • A61K35/76—Viruses; Subviral particles; Bacteriophages
    • A61K35/761—Adenovirus
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • C07K16/2818—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against CD28 or CD152
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
    • C07K2317/565—Complementarity determining region [CDR]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding
    • 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
    • C12N2710/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA dsDNA viruses
    • C12N2710/00011—Details
    • C12N2710/10011—Adenoviridae
    • C12N2710/10311—Mastadenovirus, e.g. human or simian adenoviruses
    • C12N2710/10332—Use of virus as therapeutic agent, other than vaccine, e.g. as cytolytic agent

Definitions

  • the most classically studied mechanism related to the PD-1/PD- L1 signalling is the regulation of peripheral tolerance through transmission of an inhibitory signal on T cells that inhibits TCR-mediated activation of IL-2 production and T cell proliferation (2). Subsequently blockade of the PD-1/PD- L1 interaction has been shown to partially restore T cell function and improve effector function (2). [0003] Consequently, after showing potent antitumor activity in preclinical models, there are now several therapeutic antibodies blocking this interaction available for clinical use for the treatment of various solid cancers and lymphomas (3,4). Such available antibodies have shown significant response rates across a broad spectrum of tumour types (4).
  • Fine needle tumour biopsies were taken on the day before the last treatment for evaluation of mechanism of action.
  • B Percentage change in weight of hamsters after treatments. Data is normalized to day 0.
  • C Individual tumour growth curves with 60 day survival analysis.
  • D Mean percentage change in tumour volume over 28 days.
  • E Phenotypic analysis of intratumoural immune cells in fine needle aspirates by flow cytometry.
  • F Volcano plot for significantly differentially expressed genes between IgG2a and anti-PD-L1 clone 11B12-1. DESeq2 was used to compare gene expression between groups and the Wald test was used to generate p- values and log2 fold changes.
  • FIGURE 7 Cross-reactivity of 11B12-1 and 12F1-1 with human samples.
  • An epitope can be linear, conformational, non-linear or discontinuous epitope.
  • polypeptide antigens it will be appreciated by a person skilled in the art that the presence of an epitope may or may not be dependent on the secondary, tertiary or quaternary structure of the polypeptide.
  • an agent can bind certain amino acid sequence independent of the folding of the said sequence.
  • an agent binds the epitope only if it has a certain three-dimensional structure.
  • fragment includes native polypeptides (either degradation products, synthetically synthesized peptides or recombinant peptides) and modified peptides (i.e.
  • LC-CDR1 is RSSQSIVHNNGNTYLE (SEQ ID NO:14) or RSSQSIVHSNGNTYLE (SEQ ID NO:15).
  • LC-CDR3 is FQGSHVPFT (SEQ ID NO:16) or FQGSHVPPT (SEQ ID NO:17).
  • the antibody or antigen-binding fragment further comprises a heavy chain (HC) variable domain with complementary-determining regions CDR1, CDR2 and CDR3.
  • the said antibody or antigen-binding fragment comprises a heavy chain variable domain having at least 80 % or at least 85 % or at least 90 % or at least 95 % or at least 98 % sequence identity to the amino acid sequence of SEQ ID NO:10 or SEQ ID NO:11 outside said complementary-determining regions, and a light chain variable domain having at least 80 % or at least 85 % or at least 90 % or at least 95 % or at least 98 % sequence identity to the amino acid sequence of SEQ ID NO:12 or SEQ ID NO:13 outside said complementary-determining regions.
  • the said antibody or antigen-binding fragment consists of a heavy chain variable domain having at least 90 % or at least 95 % sequence identity to the amino acid sequence of SEQ ID NO:10 or SEQ ID NO:11 outside said complementary- determining regions and a light chain variable domain having at least 90 % or at least 95 % sequence identity to the amino acid sequence of SEQ ID NO:12 or SEQ ID NO:13 outside said complementary-determining regions.
  • the antibody is a Syrian hamster antibody.
  • the said antibody is a murine antibody.
  • the said antibody is a humanized antibody.
  • the antibody is for use in the treatment of human cancer.
  • the PD-1 and PD-L1 proteins are selected from a group comprising hamster, murine and human PD-1 and PD-L1 proteins.
  • the said preclinical study is preclinical modelling of combination therapies comprising a least one immune checkpoint inhibitor and at least one oncolytic adenovirus.
  • the modelling is conducted in a replication permissive and immune competent setting.
  • the preclinical studies are performed in hamster tissue, preferably in Syrian hamster tissue.
  • the present invention provides also a method for determining the presence of PD-L1 protein in a biological sample obtained from a subject.
  • the PD-L1 protein is detected with the above defined antibody or antigen-binding fragment.
  • the terms “subject,” “individual,” “host,” and “patient,” are used interchangeably herein to refer to an animal being treated with one or more exemplary compounds as taught herein, including, but not limited to, simians, humans, avians, felines, canines, equines, rodents, bovines, porcines, ovines, caprines, mammalian farm animals, mammalian sport animals, and mammalian pets.
  • a suitable subject for various embodiments can be any animal, including a human, that is suspected of having, has been diagnosed as having, or is at risk of developing a disease that can be ameliorated, treated or prevented by administration of one or more exemplary compounds as described herein.
  • the subject refers to Syrian hamster or to human.
  • the term “sample” refers to a sample comprising biological material obtained from a patient or subject. The term encompasses clinical samples, for example, tissue obtained by surgical resection, e.g., by collecting a biological fluid such as blood or saliva, and tissue obtained by biopsy, e.g., a core biopsy or a fine needle biopsy.
  • the antibody or antibody-binding fragment is used for the diagnostics of T-cell dysfunctional diseases, disorders, or conditions.
  • T cell dysfunctional diseases, disorders, and conditions include cancers.
  • the method is used for the diagnostics of cancer.
  • cancers include but are not limited to any cancer wherein the tumor cells or surrounding immune cells express or overexpress PD- L1.
  • PD-L1 expressing tumor cells or surrounding immune cells may help tumor cells escape immune surveillance and clearance (e.g., tumor immunity).
  • the method is used in the diagnostics of cancer selected from a group comprising lung cancer, pancreatic cancer and oral cancer.
  • the adenoviral vector is Ad5/3 comprising an Ad5 nucleic acid backbone and Ad3 fiber knob or Ad5/3 chimeric fiber knob.
  • Ad5/3 vector refers to a chimeric vector having parts of both Ad5 and Ad3 vectors.
  • the capsid modification of the vector is Ad5/3 chimerism.
  • Ad5/3 chimeric fiber knob refers to a chimerism, wherein the knob part of the fiber is from Ad serotype 3, and the rest of the fiber is from Ad serotype 5.
  • the construct has the fiber knob from Ad3 while the remainder of the genome is from Ad5 (SEQ ID NO:44).
  • D24 24 base pair deletion
  • CR2 constant region 2
  • E1 SEQ ID NO:4
  • CR2 In wild type adenovirus, CR2 is responsible for binding the cellular Rb tumor suppressor/cell cycle regulator protein for induction of the synthesis (S) phase i.e. DNA synthesis or replication phase.
  • S synthesis
  • E1A The interaction between Rb and E1A requires eight amino acids (121 to 127) of the E1A protein conserved region, which are deleted in the present vector.
  • the vector of the present invention comprises a deletion of nucleotides corresponding to amino acids 122-129 of the vector according to Heise C. et al. (15). Viruses with the D24 are known to have a reduced ability to overcome the G1-S checkpoint and replicate efficiently only in cells where this interaction is not necessary, e.g.
  • deletion of gp19k increases tumor selectivity of viruses (virus is cleared faster than wild type virus from normal cells but there is no difference in tumor cells).6.7K proteins are expressed on cellular surfaces and they take part in downregulating TNF-related apoptosis inducing ligand (TRAIL) receptor 2. [0057] Both of these deletions provide an advantage. To regain expression of HLA/MHC for presentation of tumor epitopes, e.g., to adoptively transferred T cells, expression of the gp19k protein is counterproductive and in fact, the upregulation of HLA/MHC requires deletion of gp19k.
  • TRAIL TNF-related apoptosis inducing ligand
  • the cytokine transgene or transgenes are placed into a gp19k/6.7k deleted E3 region, under the E3 promoter. This restricts transgene expression to tumor cells that allow replication of the virus and subsequent activation of the E3 promoter.
  • E3 promoter may be any exogenous (e.g.
  • the adenoviral vector is based on a human adenovirus.
  • E3 Early Region
  • the E3 of the human adenovirus genome contains the highest level of genetic diversity among the six species (A-F) of adenoviruses found in humans. This diversity in genetic content is primarily located between the highly conserved E3-gp19K and E3-RID ⁇ open reading frames (ORFs) where species- specific arrays of genes are encoded.
  • Cytotoxic T-cell mediated killing of viral-infected cells is modulated by E3- gp19K. This is accomplished by blocking transport of MHC class I to the plasma membrane, and inhibiting the TAP-MHC class I complex formation.
  • the important molecule E3-gp19K is comprised in the adenoviral vector to make virus replication stealthier and enable more time for oncolysis and its beneficial effects. Also, retaining E3-gp19K can reduce induction of anti-adenovirus-cytotoxic T cells, resulting in more anti-tumor T cells.
  • Cytokines participate in immune response by acting through various mechanisms including recruitment of T cells towards the tumor.
  • the nucleotide sequence encoding a cytokine transgene may be from any animal such as a human, ape, rat, mouse, hamster, dog or cat, but specifically it is encoded by a human sequence.
  • the nucleotide sequence encoding the transgene may be modified in order to improve its effects, or unmodified i.e. of a wild type.
  • Particular embodiments of the present invention include viral vectors coding for at least one cytokine.
  • the cytokine is IL-2 or TNFalpha, preferably the viral vectors are coding for both cytokines.
  • the virus vector comprises an internal ribosomal entry site (IRES) or optionally a ribosome shunt site 2A between the two transgenes.
  • IRES or a ribosome shunt site 2A may be between any cytokines, such as IL-2 and any other cytokine, preferably selected from the above listed cytokine group.
  • IRES refers to a nucleotide sequence that enables initiation of the translation in the middle of a messenger RNA sequence in protein synthesis.
  • IRES can be from any virus, but in one embodiment of the invention IRES is from encephalomyocarditis virus (EMCV).
  • EMCV encephalomyocarditis virus
  • a ribosome shunt site 2A refers to a translation initiation site in which ribosomes physically bypass parts of the 5' untranslated region to reach the initiation codon. Both the IRES and the A2 enable viruses to produce two transgenes from one promoter (the E3 promoter).
  • the dose amount and dosing frequency of each therapeutic agent in the combination depends in part on the particular therapeutic agent, the severity of the cancer being treated, and patient characteristics.
  • a dosage regimen maximizes the amount of each therapeutic agent delivered to the patient consistent with an acceptable level of side effects.
  • the antibody is administered in an amount from about 2 mg/kg to 50 mg/kg, more preferably about 2 mg/kg to 25 mg/kg.
  • the separate administration(s) of (a) an oncolytic adenoviral vector and (b) the antibody to a subject is (are) conducted simultaneously or consecutively, in any order.
  • (a) and (b) may be provided in a single unit dosage form for being taken together or as separate entities (e.g. in separate containers) to be administered simultaneously or with a certain time difference.
  • This time difference may be between 1 hour and 1 week, preferably between 12 hours and 3 days, more preferably up to 24 or 48 hours.
  • the first administration of the adenoviral vector is conducted before the first administration of the antibody.
  • the virus is administered intratumorally and the antibody intravenously.
  • the virus and the antibody are administered as separate compounds.
  • the administration of oncolytic virus is conducted through an intratumoral, intra-arterial, intranasal, intravenous, intrapleural, intravesicular, intracavitary or peritoneal injection, or an oral administration. Any combination of administrations is also possible. The approach can give systemic efficacy despite local injection.
  • Antibodies may be administered intravenously or intratumorally. In one embodiment the administration of the antibody is conducted through an intratumoral, intra-arterial, intravenous, intrapleural, intravesicular, intranasal, intracavitary or peritoneal injection, or an oral administration.
  • the method or use of the invention further comprises administration of concurrent or sequential radiotherapy, chemotherapy, antiangiogenic agents or targeted therapies, such as alkylating agents, nucleoside analogs, cytoskeleton modifiers, cytostatic agents, other monoclonal antibodies such as checkpoint inhibitors, kinase inhibitors or other anti-cancer drugs or interventions (including surgery) to a subject.
  • chemotherapy antiangiogenic agents or targeted therapies, such as alkylating agents, nucleoside analogs, cytoskeleton modifiers, cytostatic agents, other monoclonal antibodies such as checkpoint inhibitors, kinase inhibitors or other anti-cancer drugs or interventions (including surgery) to a subject.
  • antiangiogenic agents or targeted therapies such as alkylating agents, nucleoside analogs, cytoskeleton modifiers, cytostatic agents, other monoclonal antibodies such as checkpoint inhibitors, kinase inhibitors or other anti-cancer drugs or interventions (including surgery) to a subject.
  • targeted therapies such as alkyl
  • the Syrian hamster PD-L1 protein sequence (isoform X1) was extracted from NCBI protein BLAST and can be found using NCBI Reference Sequence: XP_005063766.1.
  • the signal peptide and transmembrane region were removed from the sequence for E.Coli expression and his-tag added for purification (NdeI ⁇ ATG- ⁇ Syrian Hamster PD-L1 ⁇ His tag--Stop codon ⁇ HindIII).
  • the recombinant protein was purified by Ni column. Concentration was determined as 1.45 mg/ml (by BCA) and purity was ⁇ 90% (SDS-PAGE).
  • SOP standard operating procedure
  • RACE rapid amplification of cDNA ends
  • Culture medium consisted of RPMI-1640 supplemented with 20% fetal bovine serum (FBS), 1% penicillin/streptomycin, 1% l-glutamine, 15 mM HEPES, 50 ⁇ M 2-mercaptoethanol, 1 mM Na-pyruvate and 6,000 IU/mL of recombinant human IL-2 (rhIL- 2) (PeproTech). Half of the medium was renewed 5 d after culture initiation and every 2 d after that. On Day 10 of culture, wells with visible TIL growth were collected and pooled for in vitro co-culture experiments.
  • FBS fetal bovine serum
  • penicillin/streptomycin 1% l-glutamine
  • 15 mM HEPES 15 mM HEPES
  • 50 ⁇ M 2-mercaptoethanol 1 mM Na-pyruvate
  • rhIL-2 recombinant human IL-2
  • Resulting cDNA was used for quantitative real- time PCR. Following genes expression level was measured: granzyme B (forward primer 5’- CACTGTTCAGGGAGCTCAATAA-3’, SEQ ID NO:19, reverse primer 5’- TGGAGTAGTCCTTGGGATTATAGTC-3’, SEQ ID NO:20, probe 5’-Fam- CCTCCTTTTCTTTGATGTTGTGGGC-BBQ-3’, SEQ ID NO:21, Perforin (forward primer 5’- TGAGTGCCCTTCTGAAATCG-3’, SEQ ID NO:22, reverse primer 5’- TGTCGCCTGTACAGTTTTCG-3’, SEQ ID NO:23, probe 5’-Fam- CTGGTACAGAGACCCCCACTGCAC-BBQ-3’, SEQ ID NO:24), CD25 (forward primer 5’- TCATCAGTTTCCAGCCAGTG-3’, SEQ ID NO:25, reverse primer 5’- GTATAAATGTCTCCATAGTTGTAGCTGC-3’, S
  • PBMCs For analysis of PD-L1 on Syrian Hamster adherent PBMCs, freshly isolated PBMCs were cultured in flat bottom 6 well plates and adherent cells were allowed to attach overnight. The next day adherent cells were collected and stained with parental hybridoma culture supernatants followed by secondary antibody staining (secondary antibody (Anti-Mouse Ig (Fab specific) F(ab′)2 fragment–FITC antibody produced in goat, F2653; Sigma-Aldrich).
  • secondary antibody Anti-Mouse Ig (Fab specific) F(ab′)2 fragment–FITC antibody produced in goat, F2653; Sigma-Aldrich
  • Animals were randomized into five treatment groups and intraperitoneally injected with PBS, 11B12-1 (300 ⁇ g) or mouse IgG2a (300 ⁇ g) and with or without intratumoural injection of 1x108 VPs of Ad5/3- E2F-D24-hTNF ⁇ -IRES-hIL-2 or PBS. Treatments were given every three days for a total of 8 treatments. A digital calliper was used to measure the tumour progression across the experimental days. Tumour volumes were calculated as (length x width2)/2. The tumour volume in percentage was obtained through normalization of daily tumour volumes to their respective day 0 volume.11B12-1 was sterile filtered, and endotoxins removed for use in vivo. Animals were euthanized at day 60.
  • IL-25, IL-34, IL-13, IL-5, IL-19, IL-11, IL-7, IL-6, IL-23a, Tgfb2, Cxcl12, Cxcl14, Cx3cr1, Ccr9 were all significantly downregulated cytokines or chemokines associated genes.
  • Syngeneic syrian hamster tumors feature tumor-infiltrating lymphocytes allowing adoptive cell therapy enhanced by oncolytic adenovirus in a replication permissive setting.
  • Oncoimmunology 5(5), p.e1136046. 11. Van Duijn, A., Willemsen, K.J., Van Uden, N.O., Hoyng, L., Erades, S., Koster, J., Luiten, R.M. and Bakker, W.J., 2022.

Abstract

Selon un aspect donné à titre d'exemple de la présente invention, l'invention concerne un anticorps, ou un fragment de liaison à l'antigène de celui-ci, qui se lie spécifiquement à une protéine PD-L1. De plus, l'invention concerne l'utilisation ex vivo préclinique dudit anticorps ou fragment de liaison à l'antigène. L'invention concerne également ledit anticorps destiné à être utilisé dans le traitement du cancer, de préférence en combinaison avec un vecteur oncolytique.
PCT/FI2023/050181 2022-04-08 2023-03-31 Anticorps monoclonaux pd-l1 WO2023194656A1 (fr)

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