WO2022056304A1 - Compositions et méthodes pour la reprogrammation de tcr au moyen de protéines de fusion spécifiques de la nectine-4 - Google Patents

Compositions et méthodes pour la reprogrammation de tcr au moyen de protéines de fusion spécifiques de la nectine-4 Download PDF

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WO2022056304A1
WO2022056304A1 PCT/US2021/049935 US2021049935W WO2022056304A1 WO 2022056304 A1 WO2022056304 A1 WO 2022056304A1 US 2021049935 W US2021049935 W US 2021049935W WO 2022056304 A1 WO2022056304 A1 WO 2022056304A1
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domain
nucleic acid
sequence
acid molecule
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Robert Hofmeister
Dario Gutierrez
Andrew Collard
Robert Tighe
Melinda S. HANES
Marat MIRZABEKOV
Vania ASHMINOVA
Michael Lofgren
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TCR2 Therapeutics Inc.
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Publication of WO2022056304A1 publication Critical patent/WO2022056304A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • A61K39/46—Cellular immunotherapy
    • A61K39/461—Cellular immunotherapy characterised by the cell type used
    • A61K39/4611—T-cells, e.g. tumor infiltrating lymphocytes [TIL], lymphokine-activated killer cells [LAK] or regulatory T cells [Treg]
    • 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
    • A61K39/46—Cellular immunotherapy
    • A61K39/463—Cellular immunotherapy characterised by recombinant expression
    • A61K39/4632—T-cell receptors [TCR]; antibody T-cell receptor constructs
    • 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
    • A61K39/46—Cellular immunotherapy
    • A61K39/464—Cellular immunotherapy characterised by the antigen targeted or presented
    • A61K39/4643—Vertebrate antigens
    • A61K39/4644—Cancer antigens
    • A61K39/464466—Adhesion molecules, e.g. NRCAM, EpCAM or cadherins
    • 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
    • A61K39/46—Cellular immunotherapy
    • A61K39/464—Cellular immunotherapy characterised by the antigen targeted or presented
    • A61K39/4643—Vertebrate antigens
    • A61K39/4644—Cancer antigens
    • A61K39/464466—Adhesion molecules, e.g. NRCAM, EpCAM or cadherins
    • A61K39/464468—Mesothelin [MSLN]
    • 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
    • C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
    • C07K14/70503—Immunoglobulin superfamily
    • C07K14/7051—T-cell receptor (TcR)-CD3 complex
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2239/00—Indexing codes associated with cellular immunotherapy of group A61K39/46
    • A61K2239/10—Indexing codes associated with cellular immunotherapy of group A61K39/46 characterized by the structure of the chimeric antigen receptor [CAR]
    • A61K2239/11—Antigen recognition domain
    • A61K2239/13—Antibody-based
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
    • A61K48/005—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy characterised by an aspect of the 'active' part of the composition delivered, i.e. the nucleic acid delivered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide
    • C07K2319/01—Fusion polypeptide containing a localisation/targetting motif
    • C07K2319/03—Fusion polypeptide containing a localisation/targetting motif containing a transmembrane segment
    • 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
    • C12N2510/00—Genetically modified cells

Definitions

  • the present invention is directed to a novel therapeutics and method for treating Nectin- 4-related diseases and disorders.
  • At least two of the TCR extracellular domain, the TCR transmembrane domain, and the TCR intracellular domain are from CD3 epsilon.
  • the sdAb domain comprises a CDR1, a CDR2 and a CDR3 of: (i) SEQ ID NO:2, SEQ ID NO:4, and SEQ ID NO:6, respectively; (ii) SEQ ID NO:2, SEQ ID NO:4, and SEQ ID NO: 10, respectively; (iii) SEQ ID NO: 14, SEQ ID NO: 16, and SEQ ID NO: 18, respectively; (iv) SEQ ID NO:20, SEQ ID NO:22, and SEQ ID NO:24, respectively; (v) SEQ ID NO:26, SEQ ID NO:22, and SEQ ID NO:29, respectively; (vi) SEQ ID NO:31, SEQ ID NO:22, and SEQ ID NO:34, respectively; (vii) SEQ ID NO:37, SEQ ID NO:22, and SEQ ID NO:40, respectively; (viii) SEQ ID NO:43, SEQ ID NO:4, and SEQ ID NO:46, respectively;
  • SEQ ID NO: 176 SEQ ID NO: 180, SEQ ID NO: 185, or SEQ ID NO: 190.
  • the antibody or antibody fragment comprises a light chain variable domain comprising a light chain complementarity determining region 1 (CDR1), a CDR2, and a CDR3.
  • CDR1 light chain complementarity determining region 1
  • CDR2 light chain complementarity determining region 2
  • CDR3 light chain complementarity determining region 3
  • the scFv comprises the sequence of SEQ ID NO: 194.
  • FIG. 7 is an SDS PAGE gel showing expression of Nect-001-Nect-016 in E. coli.
  • FIG. 12 is a series of plots showing the CD4:CD8 T cell distribution of T cells transduced with TC-210, hNec4.11 TFP, Enf TFP, or non-transduced controls.
  • FIG. 21 is a graph showing cytotoxicity of T cells transduced with hNec4.11 TFP, Nect- 001 TFP, Nect-003 TFP, or non-transduced controls, when contacted with T47D target cells.
  • the present disclosure provides a TFP molecule or a TCR complex having the TFP molecule incorporated therein.
  • the present disclosure also provides a vector comprising the recombinant nucleic acid molecule encoding the TFP.
  • the present disclosure also provides a cell (e.g., a T cell) comprising the TFP or the recombinant nucleic acid molecule encoding the TFP.
  • TFPs when expressed in a cell, can target Nectin-4 expressing cells (e.g., tumor cells).
  • the present disclosure also provides a pharmaceutical composition comprising a cell comprising the TFP or the recombinant nucleic acid molecule encoding the TFP and a pharmaceutically acceptable carrier.
  • the present disclosure also provides a method of treating cancer in a subject in need thereof, the method comprising administering to the subject a pharmaceutical composition described herein.
  • affinity refers to the strength of the sum total of non-covalent interactions between a single binding site of a molecule (e.g., an antibody) and its binding partner (e.g., an antigen or epitope).
  • affinity refers to intrinsic binding affinity, which reflects a 1 : 1 interaction between members of a binding pair (e.g., antibody and antigen or epitope).
  • KD dissociation equilibrium constant
  • the kinetic components that contribute to the dissociation equilibrium constant are described in more detail below. Affinity can be measured by common methods known in the art, including those described herein, such as surface plasmon resonance (SPR) technology (e.g., BIACORE®) or biolayer interferometry (e.g., FORTEBIO®).
  • the term “subject” means a mammalian subject. Exemplary subjects include humans, monkeys, dogs, cats, mice, rats, cows, horses, camels, goats, rabbits, and sheep. In certain embodiments, the subject is a human.
  • a “patient” is a subject suffering from or at risk of developing a disease, disorder or condition or otherwise in need of the compositions and methods provided herein. In some embodiments, the subject has cancer, e.g., a cancer described herein.
  • modulate and “modulation” refer to reducing or inhibiting or, alternatively, activating or increasing, a recited variable.
  • CD36 includes any of the recombinant or naturally-occurring forms of CD36 or variants or homologs thereof that have or maintain CD36 activity (e.g., at least 40% 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99% or 100% activity).
  • the variants or homologs have at least 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity across the whole sequence or a portion of the sequence (e.g., a 50, 100, 150 or 200 continuous amino acid portion) compared to a naturally occurring CD3y.
  • CD3y is substantially identical to the protein identified by the UniProt reference number P09693 or a variant or homolog having substantial identity thereto.
  • exogenous refers to any material introduced from or produced outside an organism, cell, tissue or system.
  • tissue-specific promoter refers to a nucleotide sequence which, when operably linked with a polynucleotide encodes or specified by a gene, causes the gene product to be produced in a cell substantially only if the cell is a cell of the tissue type corresponding to the promoter.
  • /// vitro transcribed RNA refers to RNA, preferably mRNA, which has been synthesized in vitro.
  • the in vitro transcribed RNA is generated from an in vitro transcription vector.
  • the in vitro transcription vector comprises a template that is used to generate the in vitro transcribed RNA.
  • the disease is a cancer selected from the group consisting of breast cancer, lung cancer, ovarian cancer, pancreatic cancer, gallbladder cancer, esophageal cancer, head and neck cancer, bladder cancer, and gastric cancer.
  • the disease is a cancer selected from the group consisting of T cell lymphoma, diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), an Epstein-Barr virus (EBV) + cancer, or a human papilloma virus (HPV) + cancer.
  • the cancer is kidney cancer, renal cell carcinoma, nasopharyngeal carcinoma, mesothelioma, glioblastoma, or thymic carcinoma.
  • the antigen binding domain comprises a VL having at least about 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 98%, 99%, 99.5%, 99.7%, 99.9%, or 100% sequence identity to SEQ ID NO: 193 or SEQ ID NO: 197.
  • the antigen binding domain comprises a VH having at least about 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 98%, 99%, 99.5%, 99.7%, 99.9%, or 100% sequence identity to SEQ ID NO: 192 or SEQ ID NO: 196.
  • the TFP comprises a sequence having at least about 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 98%, 99%, 99.5%, 99.7%, 99.9%, or 100% sequence identity to SEQ ID NO:202. In some embodiments, the TFP comprises the sequence of SEQ ID NO:202. [0322] In some embodiments, the TFP comprises a sequence having at least about 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 98%, 99%, 99.5%, 99.7%, 99.9%, or 100% sequence identity to any one of the TFP sequences as listed in Table 2. In some embodiments, the TFP comprises any one of the TFP sequences as listed in Table 2.
  • a non-human antibody is humanized, where specific sequences or regions of the antibody are modified to increase similarity to an antibody naturally produced in a human or fragment thereof.
  • the antigen binding domain is humanized.
  • framework substitutions are identified by methods well-known in the art, e.g., by modeling of the interactions of the CDR and framework residues to identify framework residues important for antigen binding and sequence comparison to identify unusual framework residues at particular positions (see, e.g., Queen et al., U.S. Pat. No. 5,585,089; and Riechmann et al., 1988, Nature, 332:323, which are incorporated herein by reference in their entireties.)
  • the anti-Nectin-4 binding domain e.g., scFv or sdAb, comprises at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 mutations arising from the humanization process such that the mutated antigen binding domain confers improved stability to the anti-Nectin-4 TFP construct.
  • the antigen binding domain of the TFP is engineered by modifying one or more amino acids within one or both variable regions (e.g., VH and/or VL), for example within one or more CDR regions and/or within one or more framework regions.
  • the TFP composition of the present disclosure comprises an antibody fragment.
  • that antibody fragment comprises a scFv or sdAb.
  • sequence comparison typically one sequence acts as a reference sequence, to which test sequences are compared.
  • test and reference sequences are entered into a computer, subsequence coordinates are designated, if necessary, and sequence algorithm program parameters are designated. Default program parameters can be used, or alternative parameters can be designated.
  • sequence comparison algorithm then calculates the percent sequence identities for the test sequences relative to the reference sequence, based on the program parameters. Methods of alignment of sequences for comparison are well known in the art. Optimal alignment of sequences for comparison can be conducted, e.g., by the local homology algorithm of Smith and Waterman, (1970) Adv. Appl. Math.
  • the TCR extracellular domain comprises an extracellular domain or portion thereof of a protein selected from the group consisting of a TCR alpha chain, a TCR beta chain, a TCR gamma chain, a TCR delta chain, a CD3 epsilon TCR subunit, a CD3 gamma TCR subunit, a CD3 delta TCR subunit, functional fragments thereof, and amino acid sequences thereof having at least one but not more than 20 modifications.
  • the extracellular domain comprises, or comprises at least 5, 6, 7,
  • a costimulatory molecule is a cell surface molecule other than an antigen receptor or its ligands that is required for an efficient response of lymphocytes to an antigen.
  • examples of such molecules include CD27, CD28, 4-1BB (CD137), 0X40, CD30, CD40, PD1, ICOS, lymphocyte function-associated antigen-1 (LFA-1), CD2, CD7, LIGHT, NKG2C, B7-H3, and a ligand that specifically binds with CD83, and the like.
  • CD27 costimulation has been demonstrated to enhance expansion, effector function, and survival of human TFP-T cells in vitro and augments human T cell persistence and antitumor activity in vivo (Song et al., Blood. 2012; 119(3):696-706).
  • the agent comprises the extracellular domain (ECD) of an inhibitory molecule, e.g., Programmed Death 1 (PD1) can be fused to a transmembrane domain and optionally an intracellular signaling domain such as 4 IBB and CD3 zeta (also referred to herein as a PD1 TFP).
  • the PD1 TFP when used in combinations with an anti- Nectin-4 TFP described herein, improves the persistence of the T cell.
  • the TFP is a PD1 TFP comprising the extracellular domain of PD-1.
  • TFPs containing an antibody or antibody fragment such as a scFv that specifically binds to the Programmed Death-Ligand 1 (PD-L1) or Programmed Death-Ligand 2 (PD-L2).
  • Upstream is used herein to refer to a location 5, to the DNA sequence to be amplified relative to the coding strand.
  • reverse primers are primers that contain a region of nucleotides that are substantially complementary to a double-stranded DNA template that are downstream of the DNA sequence that is to be amplified.
  • Downstream is used herein to refer to a location 3’ to the DNA sequence to be amplified relative to the coding strand.
  • the RNA preferably has 5’ and 3’ UTRs.
  • the 5’ UTR is between one and 3,000 nucleotides in length.
  • the length of 5’ and 3’ UTR sequences to be added to the coding region can be altered by different methods, including, but not limited to, designing primers for PCR that anneal to different regions of the UTRs. Using this approach, one of ordinary skill in the art can modify the 5’ and 3’ UTR lengths that can be used to achieve optimal translation efficiency following transfection of the transcribed RNA.
  • the 5’ UTR can contain the Kozak sequence of the endogenous nucleic acid.
  • a consensus Kozak sequence can be redesigned by adding the 5’ UTR sequence.
  • Kozak sequences can increase the efficiency of translation of some RNA transcripts, but does not appear to be required for all RNAs to enable efficient translation.
  • the 5’ UTR can be 5 ’UTR of an RNA virus whose RNA genome is stable in cells.
  • various nucleotide analogues can be used in the 3’ or 5’ UTR to impede exonuclease degradation of the mRNA.
  • the constant domain can comprise a sequence or fragment thereof of SEQ ID NO:711, SEQ ID NO:715, SEQ ID NO:211, SEQ ID NO:721, SEQ ID NO:725, SEQ ID NO:212, SEQ ID NO:213, SEQ ID NO:214, or SEQ ID NO:215.
  • the constant domain can comprise at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more modifications, mutations or deletions of the sequence of SEQ ID NO:711, SEQ ID NO:715, SEQ ID NO:211, SEQ ID NO:721, SEQ ID NO:725, SEQ ID NO:212, SEQ ID NO:213, SEQ ID NO:214, or SEQ ID NO:215.
  • the constant domain described herein can be a murine TCR alpha constant domain.
  • the murine TCR alpha constant domain can comprise a sequence of SEQ ID NO:212 or SEQ ID NO:213.
  • the murine TCR alpha constant domain can comprise truncations, additions, or substitutions of a sequence of a constant domain described herein.
  • the constant domain can comprise a truncated version of a constant domain described herein having at least about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 150 or more amino acid residues of SEQ ID NO:212 or SEQ ID NO:213.
  • the constant domain can comprise at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more modifications, mutations or deletions of the sequence of SEQ ID NO:212 or SEQ ID NO:213.
  • the constant domain can comprise at most 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1 modification, mutations or deletions of the sequence of SEQ ID NO:212 or SEQ ID NO:213.
  • the constant domain can comprise a sequence having a sequence identity of at least about 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99% or 100% to the sequence of SEQ ID NO:212 or SEQ ID NO:213.
  • the nucleic acid can be cloned into a number of types of vectors.
  • the nucleic acid can be cloned into a vector including, but not limited to a plasmid, a phagemid, a phage derivative, an animal virus, and a cosmid.
  • Vectors of particular interest include expression vectors, replication vectors, probe generation vectors, and sequencing vectors.
  • the IL-15Ra polypeptide or a fragment thereof may comprise IL- 15Ra Sushi domain, transmembrane domain, and intracellular domain. In some embodiments, the IL-15Ra polypeptide or a fragment thereof may comprise amino acids 31-267 of IL-15Ra. In some embodiments, the IL-15Ra polypeptide or a fragment thereof may comprise amino acids 31-267 of SEQ ID NO:258. In some embodiments, the IL-15Ra polypeptide or a fragment thereof may comprise a sequence of SEQ ID NO:260. In some embodiments, the IL-15Ra polypeptide or a fragment thereof may comprise a sequence of SEQ ID NO:261.
  • the first and the second nucleic acid molecules are expressed in the same operon.
  • the first nucleic acid sequence and the second nucleic acid sequence are operatively linked by a sequence encoding a linker.
  • the linker comprises a protease cleavage site.
  • the protease cleavage site is a 2A cleavage site.
  • the 2A cleavage site is a T2A cleavage site or a P2A cleavage site.
  • the first nucleic acid sequence and the second nucleic acid sequence are present on different nucleic acid molecules.
  • the CXCR6 or functional fragment thereof comprises a transmembrane region comprising a sequence with at least 80% sequence identity to SEQ ID NO:273. In some embodiments, the CXCR6 or functional fragment thereof comprises a transmembrane region comprising the sequence of SEQ ID NO:273. In some embodiments, the CXCR6 or functional fragment thereof comprises at least one, two, three, or four cytoplasmic domains. In some embodiments, the CXCR6 or functional fragment thereof comprises four cytoplasmic domains. In some embodiments, the CXCR6 or functional fragment thereof comprises a C-terminal cytoplasmic domain comprising a sequence with at least 80% sequence identity to SEQ ID NO:284.
  • the aforementioned culture is maintained for about seven days prior to subculture in soluble anti-CD3, and IL-2.
  • T cells that have been exposed to varied stimulation times may exhibit different characteristics.
  • typical blood or apheresed peripheral blood mononuclear cell products have a helper T cell population (TH, CD4+) that is greater than the cytotoxic or suppressor T cell population (TC, CD8+).
  • TH, CD4+ helper T cell population
  • TC cytotoxic or suppressor T cell population
  • Ex vivo expansion of T cells by stimulating CD3 and CD28 receptors produces a population of T cells that prior to about days 8-9 consists predominately of TH cells, while after about days 8-9, the population of T cells comprises an increasingly greater population of TC cells.
  • the TFP T cells provided herein may be useful for the treatment of any disease or condition involving Nectin-4 (e.g., Nectin-4-expressing cancers).
  • the disease or condition is a disease or condition that can benefit from treatment with adoptive cell therapy.
  • the disease or condition is a cell proliferative disorder.
  • the disease or condition is a cancer.
  • the disease or condition is a blood cancer.
  • the disease or condition is a tumor.
  • the disease or condition is a viral infection.
  • the anti-tumor immunity response elicited by the TFP-expressing T cells may be an active or a passive immune response, or alternatively may be due to a direct vs indirect immune response.
  • the TFP transduced T cells exhibit specific proinflammatory cytokine secretion and potent cytolytic activity in response to human cancer cells expressing the tumor-associated antigen, resist soluble tumor-associated antigen inhibition, mediate bystander killing and/or mediate regression of an established human tumor.
  • antigen-less tumor cells within a heterogeneous field of tumor-associated antigen-expressing tumor may be susceptible to indirect destruction by tumor- associated antigen-redirected T cells that has previously reacted against adjacent antigenpositive cancer cells.
  • the agent that inhibits the interaction between PD-1 and PD-L1 is administered prior to administration of an antibody provided herein. In some embodiments, the agent that inhibits the interaction between PD-1 and PD-L1 is administered after administration of an antibody provided herein. In some embodiments, the agent that inhibits the interaction between PD-1 and PD-L1 is administered contemporaneously with an antibody provided herein, but the agent and antibody are administered in separate pharmaceutical compositions.
  • compositions of the present invention may comprise a TFP-expressing cell, e.g., a plurality of TFP-expressing cells, as described herein, in combination with one or more pharmaceutically or physiologically acceptable carriers, diluents or excipients.
  • Such compositions may comprise buffers such as neutral buffered saline, phosphate buffered saline and the like; carbohydrates such as glucose, mannose, sucrose or dextrans, mannitol; proteins; polypeptides or amino acids such as glycine; antioxidants; chelating agents such as EDTA or glutathione; adjuvants (e.g., aluminum hydroxide); and preservatives.
  • Compositions of the present invention are in one aspect formulated for intravenous administration.
  • the anti-Nectin-4 binding domain is any of the anti-VHH antibody domains of Table 1 Nect-001-0037). In some embodiments, the Nectin-4 binding domain is selected from Nect-001 or 003. In some embodiments, the anti-Nectin-4 binding domain is hNec4.11. In some embodiments, the anti-Nectin-4 binding domain is Enf.
  • the intracellular domain of the human TCR delta chain is:
  • TFP-encoding nucleic acid construct was cloned into the lentiviral expression vector as is described above.
  • the anti-Nectin-4.TFP lentiviral transfer vector was used to produce the genomic material packaged into VSV-G pseudotyped lentiviral particles.
  • the virus stock preparation was either used for infection immediately or aliquoted and stored at -80°C for future use.

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Abstract

La présente invention concerne des protéines de fusion (TFP) du récepteur des lymphocytes T (TCR) comprenant des domaines de liaison de la nectine-4, des lymphocytes T modifiés pour exprimer une ou plusieurs TFP, ainsi que des méthodes d'utilisation de celles-ci pour le traitement de maladies, notamment du cancer.
PCT/US2021/049935 2020-09-10 2021-09-10 Compositions et méthodes pour la reprogrammation de tcr au moyen de protéines de fusion spécifiques de la nectine-4 WO2022056304A1 (fr)

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* Cited by examiner, † Cited by third party
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WO2024062476A1 (fr) * 2022-09-20 2024-03-28 Nectin Therapeutics Ltd. Anticorps humanisés dirigés contre la nectine-4 et conjugués médicamenteux associés
WO2024200573A1 (fr) * 2023-03-27 2024-10-03 LAVA Therapeutics N.V. Agents de liaison à la nectine-4 et méthodes d'utilisation

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Cited By (4)

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Publication number Priority date Publication date Assignee Title
CN112088167A (zh) * 2018-05-09 2020-12-15 耶路撒冷希伯来大学伊森姆研究发展有限公司 特异性针对人类连接蛋白4的抗体
US12077583B2 (en) 2018-05-09 2024-09-03 Nectin Therapeutics Ltd. Antibodies specific to human NECTIN4
WO2024062476A1 (fr) * 2022-09-20 2024-03-28 Nectin Therapeutics Ltd. Anticorps humanisés dirigés contre la nectine-4 et conjugués médicamenteux associés
WO2024200573A1 (fr) * 2023-03-27 2024-10-03 LAVA Therapeutics N.V. Agents de liaison à la nectine-4 et méthodes d'utilisation

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