WO2020215044A1 - Contrôle à base de petites molécules de l'expression du récepteur de cellules immunitaires - Google Patents

Contrôle à base de petites molécules de l'expression du récepteur de cellules immunitaires Download PDF

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Publication number
WO2020215044A1
WO2020215044A1 PCT/US2020/028894 US2020028894W WO2020215044A1 WO 2020215044 A1 WO2020215044 A1 WO 2020215044A1 US 2020028894 W US2020028894 W US 2020028894W WO 2020215044 A1 WO2020215044 A1 WO 2020215044A1
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cell
protein
small molecule
translation
ribosome
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PCT/US2020/028894
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James H Doudna Cate
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The Regents Of The University Of California
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    • 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
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/63—Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
    • C12N15/67—General methods for enhancing the expression
    • 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
    • A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
    • A61K35/14—Blood; Artificial blood
    • A61K35/17—Lymphocytes; B-cells; T-cells; Natural killer cells; Interferon-activated or cytokine-activated lymphocytes
    • 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
    • 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
    • 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
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide
    • C07K2319/01—Fusion polypeptide containing a localisation/targetting motif
    • C07K2319/02—Fusion polypeptide containing a localisation/targetting motif containing a signal sequence
    • 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

Definitions

  • TCRs engineered T cell receptors
  • CARs chimeric antigen receptors
  • a solution to these problems would be to modulate the level of engineered TCR or CAR expression using a small molecule that either prevents or enhances protein synthesis of the receptor.
  • protein fusions to engineered TCRs and CARs that can allow them to be upregulated or downregulated in response to orally bioavailable small molecules.
  • NK cells natural killer cells expressing CARs.
  • NK cells natural killer cells expressing CARs.
  • protein fusions to engineered CARs in NK cells that can allow them to be upregulated or downregulated in response to orally bioavailable small molecules.
  • T cells T cells or natural killer (NK) cells are genetically modified to express an engineered cell surface receptor that directs these immune cells to tumor cells expressing a target ligand recognized by the receptor, thereby leading to tumor cell destruction.
  • TCRs T cell receptors
  • CARs chimeric antigen receptors
  • ACT can suffer from severe toxic side effects including cytokine release syndrome (CRS), graft-versus-host disease (GvHD), and neurotoxicity, in some cases leading to death of the patient.
  • CRS cytokine release syndrome
  • GvHD graft-versus-host disease
  • neurotoxicity in some cases leading to death of the patient.
  • CRS cytokine release syndrome
  • GvHD graft-versus-host disease
  • neurotoxicity in some cases leading to death of the patient.
  • CRS cytokine release syndrome
  • GvHD graft-versus-host disease
  • neurotoxicity in some cases leading to death of the patient.
  • CRS cytokine release syndrome
  • GvHD graft-versus-host disease
  • neurotoxicity in some cases leading to death of the patient.
  • CRS cytokine release syndrome
  • GvHD graft-versus-host disease
  • neurotoxicity in some cases leading to death of the patient.
  • overactivation of engineered immune cells used in ACT such as CAR T-cells
  • the invention provides systems, such as engineered cells, and methods for small molecule-based control of expression of human proteins like immune cell receptors.
  • the invention provides an isolated, engineered human cell, the cell comprising a gene encoding an engineered fusion protein comprising a functional human protein domain and a ribosome modulation signal peptide, wherein translation of the protein is regulatable by a predetermined small molecule targeting the signal peptide.
  • the cell is configured for adoptive cell transfer
  • the ribosome modulation signal peptide is a ribosome stalling signal peptide of the human protein CDH1, PCSK9 or USOl;
  • the ribosome modulation signal peptide is a ribosome enhancement signal comprising the amino acid sequence alanine-threonine -histidine-phenylalanine (ATHF);
  • the functional domain is a transmembrane receptor and the signal peptide is incorporated into the N-terminal, transmembrane, or C-terminal region of the receptor;
  • the cell is an immune cell for immunotherapy
  • the protein is an immune cell receptor and the functional domain is a T-cell receptor (TCR) or chimeric antigen receptor (CAR) domain, or an enzyme or hormone;
  • TCR T-cell receptor
  • CAR chimeric antigen receptor
  • the fusion protein further comprises a ribosome stalling signal protector domain;
  • the engineered fusion protein also comprises a signal protector domain selected from human protein CDH1, USOl, IFI30, RAB3GAP1, or rat protein Pigw, Pqlc3, Pcyoxll, Slcla3, Naga, Lyar, Steapl, Msln, Tfrc, Prssl2, Msh2, Kif23, Haplnl, Parpl4, Coxl5, or Ndc80.
  • a signal protector domain selected from human protein CDH1, USOl, IFI30, RAB3GAP1, or rat protein Pigw, Pqlc3, Pcyoxll, Slcla3, Naga, Lyar, Steapl, Msln, Tfrc, Prssl2, Msh2, Kif23, Haplnl, Parpl4, Coxl5, or Ndc80.
  • the invention provides methods of making and using the subject engineered cells.
  • the invention provides a method of modulating translation of an engineered fusion protein with a predetermined small molecule, comprising: (a) providing an engineered human cell comprising a gene encoding an engineered fusion protein comprising a functional domain and a ribosome modulation signal peptide wherein translation of the protein is regulatable by a predetermined small molecule targeting the modulation signal peptide; and (b) contacting the cell with the small molecule under conditions wherein the small molecule targets the modulation signal peptide and thereby modulates translation of the protein.
  • the cell is in a host and the contacting step comprises administering the small molecule to the host; [020] - the cell is in a host, the contacting step comprises administering the small molecule to the host, and the method further comprises the step of determining that the host is in need of adoptive cell transfer; and/or
  • the method further comprises the subsequent step of detecting a resultant modulation of translation of the protein.
  • Fig. la Schematic representation of an engineered immune cell surface receptor.
  • Fig. lb Protein sequences from CDH1, PCSK9, and USOl useful for stalling.
  • FIG. 2a Schematic representation of an engineered immune cell surface receptor.
  • Fig. 2b Sequences selected from mRNA libraries that can be used to inhibit engineered immune cell receptor translation.
  • Fig. 2c Sequence motif indicating the range of sequences that can be placed in the last 4 amino acids of the CDH1 sequence defined by the NC box.
  • FIG. 3 a Schematic representation of an engineered immune cell surface receptor.
  • Fig. 3b Sequences selected from mRNA libraries that can be used to increase engineered immune cell receptor translation.
  • Fig. 4 In vitro translation assays of the WT CDH1 stalling sequence, or with the ATHF or SRFD motif near the PTC, in the context of the CDH1 sequence. Reactions were carried out in triplicate, with standard deviation shown.
  • Engineered TCRs and CARs are modular in nature, with an extracellular domain encoded at the N-terminus of the protein, followed by a transmembrane domain, and then followed C-terminally by signaling domains in the cytoplasm of the cell. See for example Figure 1 of (Lee, 2019).
  • Modified receptors comprised of an additional domain encoded in either the N- terminal region (extracellular), as part of the transmembrane domain, or in the C-terminal region (intracellular) enable small-molecule mediated control of receptor expression. The modifications are further described herein, with mechanisms of action described in the cited references.
  • this invention conceptually unites these small molecules with engineered immune cell receptors, incorporating polypeptide sequences, such as described in the above references, into the receptor, including the N-terminal, transmembrane, or C-terminal region of the receptor. Locations for inserting these sequences are informed by the length and composition of different polypeptide hinge and spacer regions described in, for example (Imai, 2005;
  • Additional sequences can be incorporated into the engineered immune cell surface receptor to inhibit its protein synthesis by the action of one of the small molecules referenced above (Lintner, 2017; Londregan, 2018a; Londregan, 2018b; Liaud, 2019; Li, 2018) acting on the human ribosome.
  • other sequences can be incorporated into the engineered immune cell surface receptor to increase its protein synthesis by the action of one of the small molecules referenced above acting on the human ribosome.
  • ribosome display of an mRNA library to identify protein sequences that either inhibit or increase translation of the polypeptide in the presence of one of these compounds; suitable methods are described, inter alia, in PCT/US 18/55262 and Li 2018 and Li 2019. The efficacy of these sequences can be verified using luciferase reporters as described in (Lintner, 2017; Li, 2018; Liaud, 2019).
  • engineered TCRs or CARs comprised of sequences sensitive to the small molecules referenced above, and with representative SMILES forms given below, involves genetically modifying T cells or NK cells with a DNA sequence encoding the engineered TCR or CAR.
  • Many such methods have been described in the literature involving, for example, retroviral vectors (Imai, 2005; Liu, 2018), transposons (Kabriaei, 2016), and more recently the use of CRISPR-Cas9 (Roth, 2018).
  • NK cells NK cells and induced pluripotent stem cells (iPSCs) that are subsequently differentiated into T cells (Nishimura, 2019) or NK cells (Bemareggi, 2019).
  • iPSCs induced pluripotent stem cells
  • T cells Neokimura, 2019
  • NK cells Bemareggi, 2019
  • These modified cells can then be expanded and used for ACT.
  • Patients who receive these modified cells can then be treated with different doses of the compounds referenced above, and with representative SMILES forms given below, in order to decrease or increase the expression of the engineered immune cell surface receptors as needed for optimal therapeutic outcomes.
  • Protein sequences sensitive to the compounds referenced above that can be inserted into engineered immune cell surface receptors include, but are not limited to, the following examples. These sequences require relevant cell surface receptor polypeptide sequences as referenced above located N-terminal and/or C-terminal to those shown. Additionally, one can add polypeptide linkers of various lengths between the compound-sensitive sequences and the N-terminal or C-terminal flanking sequences. These include, for example poly-(GS) sequences.
  • Example 1 Sequences that can be used to inhibit engineered immune cell receptor translation.
  • Fig. la is a schematic representation of the engineered immune cell surface receptor comprised of a PF-06446846 sensitive sequence.
  • CDH1 sequence comprised of the CDH1-V domain followed by the small-molecule sensitive sequence. See Uniprot ID: P12830 and PCT/US 18/55262.
  • Fig 1 b shows protein sequences from CDH1, PCSK9, and USOl useful for stalling (sequences in NC box). The arrow indicates the PF-06446846-dependent stalling site predicted from ribosome profiling data in (Lintner, 2017).
  • On can add flexible polypeptide linkers of suitable length N-terminal and C-terminal to sequences defined by the NC box, and the CDH1-V box.
  • Example 2 Additional chimeric polypeptides stalled by PF-06446846. Based on results in (Lintner, 2017), PF-06446846 is highly selective and stalls translation of just 18 polypeptides, of those that could be assayed using ribosome profiling ( Figure 6 of Lintner,
  • CDH1 which in its cellular context stalls at amino acid 729, can be dissected to isolate a single domain that enables robust stalling of RNCs, with engineered N- terminal extensions and alternate stall sequences appended C-terminal to the Cadherin-5 (CDH1-V) domain.
  • CDH1-V Cadherin-5
  • the N-terminal sequence of USOl up to amino acid 298 can be used to stall RNCs, with additional sequences appended N-terminal and C-terminal to this segment of USOl.
  • the N-terminal 92 amino acids of IFI30 can be used to form stalled RNCs, with additional sequences appended N-terminal and C-terminal to this segment of IFI30.
  • Ribosome profiling with these alternative compounds can be used to identify additional proteins that extend beyond the ribosome exit tunnel, i.e. whose stall site resides ⁇ 40 or more amino acids from the N-terminus, and these can then be used to make engineered immune cell surface receptors whose translation is sensitive to the presence of the new compound.
  • Example 3 Sequences selected from mRNA libraries that can be used to inhibit engineered immune cell receptor translation.
  • mRNA libraries encoding randomized codons can be used to select for protein sequences that can be inhibited by compounds like PF- 06446846; see, PCT/US 18/55262 and Li, 2018.
  • Fig. 2a shows the sequence context, and examples selected in the context of the CDH1 stalling peptide are shown in Fig. 2b - sequences in location of the NC box.
  • Flexible polypeptide linkers of suitable length N-terminal and C- terminal can be added to sequences defined by the NC box and the CDH1-V domain.
  • Fig. 2c is a sequence motif indicating the range of sequences that can be placed in the last 4 amino acids of the CDH1 sequence defined by the NC box.
  • Example 4 Sequences selected from mRNA libraries that can be used to increase engineered immune cell receptor translation.
  • mRNA libraries encoding randomized codons can be used to select for protein sequences that can increase translation in the presence of compounds like PF-06446846; see, PCT/US 18/55262 and Li, 2018..
  • Fig. 3a shows the sequence context of PF-06446846 sensitive sequences.
  • Fig. 3b shows example sequences that can be used to increase translation due to the action of PF-06446846, when located in the position of the NC sequence in Fig. 3a.
  • Flexible polypeptide linkers of suitable length N-terminal and C-terminal can be added to sequences defined by the NC box and the CDH1-V domain.
  • Example 5 Sequences sensitive to PF -06446846 and/or compound 71 in rat intestinal cells (Londregan et aL, 2018a).
  • Compound 71 is a next- generation selective translation inhibitor related to PF-06446846 and is described in (Londregan, 2018a). These sequences are readily screened with differing polypeptide start and end points for sensitivity to the compounds with SMILES codes provided below, using luciferase reporters as described in (Lintner, 2017; Li, 2018; Liaud, 2019). Suitable sequences with the main stall position induced by compounds 7f (PF-06446846) and/or 71 located within 40 amino acids (i.e.
  • codons in the table) from the N-terminus can include amino acids 1 to the Dmax position (i.e. amino acids 1- 41 of Car9, amino acids 1-28 of Rpl27, or amino acids 1-40 of Cyp2sl, etc.).
  • sequences whose main stall position occurs in a more C-terminal position, i.e. after the first 40 amino acids, can also be used.
  • the N-terminal boundary of the sensitive sequence may be determined using structure prediction algorithms such as Phyre2 (Kelley, 2015).
  • the Dmax position is a suitable location for the C-terminus of the compound- sensitive sequence. Sequences in this category may be comprised of polypeptides derived from amino acids 1-361 of Pigw, amino acids 1-119 of Pqlc3, etc.
  • SMILES codes for compounds useful for selective stalling or enhancement of translation. Codes taken from (Londregan et al , 2018).
  • Example 6 Amino acid changes in stalled sequences can actually enhance rather that repress translation in a PF846-dependent manner.
  • sequences SFRD and ATHF increase overall translation in a PF846-dependent manner (Fig. 4), with ATHF increasing translation ⁇ 4-fold.
  • PCSK9 Proprotein Convertase Subtilisin Kexin Type 9
  • Wilson DN Beckmann R. The ribosomal tunnel as a functional environment for nascent polypeptide folding and translational stalling. Curr Opin Struct Biol. 2011 Apr;21(2):274-82. doi: 10.1016/j.sbi.2011.01.007. Review. PubMed PMID: 21316217.

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Abstract

L'invention porte sur la traduction d'une protéine de fusion modifiée qui est effectuée avec une petite molécule prédéfinie. Une cellule humaine modifiée pour le transfert de cellules adoptives comprend un gène codant pour une protéine de fusion modifiée comprenant un domaine fonctionnel, un domaine de protection de signal de blocage de ribosomes et un signal de blocage de ribosomes, la traduction de la protéine pouvant être régulée par une petite molécule prédéfinie ciblant le signal de blocage. La cellule est mise en contact avec la petite molécule pour induire un blocage de traduction et ainsi moduler la traduction de la protéine.
PCT/US2020/028894 2019-04-17 2020-04-19 Contrôle à base de petites molécules de l'expression du récepteur de cellules immunitaires WO2020215044A1 (fr)

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Citations (6)

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US20130143773A1 (en) * 2010-06-23 2013-06-06 Genefrontier Corporation High-speed maturation method for an oligonucleotide library for the purpose of preparing a protein library
US9006393B1 (en) * 2004-08-26 2015-04-14 Patricia L. Clark Molecular constructs and uses thereof in ribosomal translational events
US20180017573A1 (en) * 2010-12-01 2018-01-18 Mitsubishi Tanabe Pharma Corporation Polynucleotide construct capable of displaying fab in a cell-free translation system, and method for manufacturing and screening fab using same
US20180044423A1 (en) * 2014-07-21 2018-02-15 Novartis Ag Treatment of cancer using a cd33 chimeric antigen receptor
WO2019075098A1 (fr) * 2017-10-13 2019-04-18 The Regents Of The University Of California Compositions de blocage de la traduction et leurs procédés d'utilisation

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9006393B1 (en) * 2004-08-26 2015-04-14 Patricia L. Clark Molecular constructs and uses thereof in ribosomal translational events
US20110008774A1 (en) * 2007-06-13 2011-01-13 Cornell Research Foundation Inc Protein discovery using intracellular ribosome display
US20130143773A1 (en) * 2010-06-23 2013-06-06 Genefrontier Corporation High-speed maturation method for an oligonucleotide library for the purpose of preparing a protein library
US20180017573A1 (en) * 2010-12-01 2018-01-18 Mitsubishi Tanabe Pharma Corporation Polynucleotide construct capable of displaying fab in a cell-free translation system, and method for manufacturing and screening fab using same
US20180044423A1 (en) * 2014-07-21 2018-02-15 Novartis Ag Treatment of cancer using a cd33 chimeric antigen receptor
WO2019075098A1 (fr) * 2017-10-13 2019-04-18 The Regents Of The University Of California Compositions de blocage de la traduction et leurs procédés d'utilisation

Non-Patent Citations (3)

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Title
LI ET AL.: "Structural basis for selective stalling of human ribosome nascent chain complexes by a drug-like molecule", NATURE STRUCTURAL & MOLECULAR BIOLOGY, vol. 26, no. 6, 18 December 2019 (2019-12-18), pages 501 - 509, XP036798686, DOI: 10.1038/s41594-019-0236-8 *
LINTNER ET AL.: "Selective stalling of human translation through small-molecule engagement of the ribosome nascent chain", PLOS BIOLOGY, vol. 15, 21 March 2017 (2017-03-21), pages 1 - 36, XP055592997 *
LONDREGAN ET AL.: "Small Molecule Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Inhibitors: Hit to Lead Optimization of Systemic Agents", JOURNAL OF MEDICINAL CHEMISTRY, vol. 61, no. 13, 25 June 2018 (2018-06-25), pages 5704 - 5718, XP055750432 *

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