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WO2014098649A1 - Compositions et procédés à l'aide du récepteur 5 de type toll et d'un agoniste d'un récepteur de type toll - Google Patents

Compositions et procédés à l'aide du récepteur 5 de type toll et d'un agoniste d'un récepteur de type toll Download PDF

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Publication number
WO2014098649A1
WO2014098649A1 PCT/RU2013/001134 RU2013001134W WO2014098649A1 WO 2014098649 A1 WO2014098649 A1 WO 2014098649A1 RU 2013001134 W RU2013001134 W RU 2013001134W WO 2014098649 A1 WO2014098649 A1 WO 2014098649A1
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Prior art keywords
tlr5
agonist
toll
cells
receptor
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English (en)
Inventor
Andrei Gudkov
Venkatesh Natarajan
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OBSCHESTVO S OGRANICHENNOY OTVETSTVENNOSTYU "PANACELA LABS"
Health Research Inc
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OBSCHESTVO S OGRANICHENNOY OTVETSTVENNOSTYU "PANACELA LABS"
Health Research Inc
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Publication of WO2014098649A1 publication Critical patent/WO2014098649A1/fr
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7088—Compounds having three or more nucleosides or nucleotides
    • 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
    • C07K14/195—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from bacteria
    • C07K14/24—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from bacteria from Enterobacteriaceae (F), e.g. Citrobacter, Serratia, Proteus, Providencia, Morganella, Yersinia
    • C07K14/255—Salmonella (G)
    • 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
    • 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
    • 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
    • C12N15/79—Vectors or expression systems specially adapted for eukaryotic hosts
    • C12N15/85—Vectors or expression systems specially adapted for eukaryotic hosts for animal cells
    • C12N15/86—Viral vectors
    • 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
    • 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
    • C12N2740/00—Reverse transcribing RNA viruses
    • C12N2740/00011—Details
    • C12N2740/10011—Retroviridae
    • C12N2740/16011—Human Immunodeficiency Virus, HIV
    • C12N2740/16041—Use of virus, viral particle or viral elements as a vector
    • C12N2740/16043—Use of virus, viral particle or viral elements as a vector viral genome or elements thereof as genetic vector

Definitions

  • the present invention relates generally to use of Toll-like receptor 5 (TLR5) and agonists thereof for immunological based therapies.
  • TLR5 Toll-like receptor 5
  • TLRs Toll like receptors
  • Fig.l provides a visual representation of construction and structure of secreted flagellin derivative.
  • A. Three dimensional structure of flagellin, location of structural (DO, Dl, D2, and D3) and functional (CI and C2) domains, and design of CBLB502 polypeptide,
  • Fig. 2 provides a map of single-color lentiviral TR vector. Transcription factor-specific transcriptional response elements (TRE) can be cloned into polylinker upstream of mCMV promoter to provide transcriptional factor-dependent expression of GFP reporter.
  • TRE Transcription factor-specific transcriptional response elements
  • Fig.3. provides a summary of data obtained using NFkB-GFP reporter-293 cells, (a) Induction of GFP in Nf-kB reporter clone- 3 by TNF and IL1 Control + CBLB502 +TNF. (b) Lack of GFP induction by CBLB502 in NF-kB reporter clone-3. (c). Selection of TLR5 responding clones: reporter clone- 3 was transduced with lentivirus expressing TLR5 and after 48h of transduction single cell cloning was done by limiting dilution. Several clones were expanded and induced with CBLB502 (5ng/ml). Percentage of GFP positive cells were assessed by flow cytometry. Clone- 14 showed over 50 fold induction of GFP.
  • Fig. 4 provides a map of pBASP lentiviral vector as one embodiment of the invention.
  • Fig. 5 illustrates sequences used for optimization of the secretion signal for the TLR5 agonist.
  • Fig. 6 provides a graphical representation of results obtained from assessment of secretion of CBLB502.
  • HEK-293 NFkB-GFP reporter cells were incubated with indicated dilutions of the conditioned media from cells expressing SEAPCBLB502 or cells expressing empty vector and percentage of GFP expressing cells was assessed by flow cytometry.
  • Fig. 7 shows nucleotide and amino acid sequence for representative flagellin variants that can be used in the invention.
  • the pRSETb leader sequence is shown in Italic (leader includes Met, which is also amino acid 1 of FliC).
  • the N terminal constant domain is underlined.
  • the amino acid linker sequence is in Bold.
  • the C terminal constant domain is underlined. GST, if present, is highlighted.
  • Fig. 8 shows the nucleic acid and amino acid sequence for a human Toll-like receptor 5 protein.
  • Fig. 9 depicts a recombinant adenovirus encoding a TLR5, but not a TLR5 agonist. This embodiment is provided in the context of the pCD515-CMV -hTLR5 expression vector.
  • Fig. 10 depicts a recombinant adenovirus encoding a secretable TLR5 agonist, but not a TLR5. This embodiment is provided in the context of the pCD515-CMV -Sseap-502 expression vector.
  • Fig. 1 1 provides a graphical depiction of the domain structure and approximate boundaries (amino acid coordinates) of selected flagellin derivatives.
  • Fig. 12 provides a graphical summary of results obtained by measuring the ratio of tumor volume in mice over a number of days in tumor cells (A549) transduced with a control vector (without TLR5) or vector expressing TLR5 wherein the mice are treated three days with either CBLB502 or PBS. DESCRIPTION OF THE INVENTION
  • the present invention provides methods for use in immunotherapy, and particularly for immunotherapy of cancer. Certain aspects of the invention are based in part on our discovery that, by conferring tumor cells with the capability to express a Toll-like receptor (TLR), the cells become sensitized to certain TLR agonists such that the immunosuppressive quality of the tumor environment is inhibited and/or reversed. Certain aspects of research related to the invention are described in WO/2011/044246, the entire disclosure of which is incorporated herein by reference.
  • TLR Toll-like receptor
  • the invention provides compositions comprising polynucleotide sequences encoding a TLR5.
  • the polynucleotides are provided in an expression vector that is adapted for use in therapeutic methods.
  • the expression vector encodes a TLR5, but does not encode a TLR5 agonist.
  • the invention provides an expression vector which encodes a secretable agonist of TLR5, but does not encode a TLR5.
  • the expression vector encoding a TLR used in the invention encodes a human Toll-like receptor 5 (TLR5) or a derivative thereof.
  • TLR5 human Toll-like receptor 5
  • a representative nucleic acid and its encoded amino acid sequence for human Toll-like receptor 5 protein is presented in Figure 8. All nucleotide sequences encoding the amino acid sequence presented in Figure 8 are encompassed within the scope of this invention. Further, all modifications to the human TLR5 amino acid sequence which do not materially affect the function of the TLR5 are included within the scope of the invention, as are all nucleotide sequences which encode such modified TLR5 amino acid sequences.
  • Modified TLR5 proteins which can be encoded by expression vectors and used in the method of the invention, and therefore are considered to not have materially altered function, include but are not necessarily limited to TLR5 proteins which recognize bacterial flagellin, or fragments or derivatives thereof. Thus, any TLR5 for which bacterial flagellin can act as an agonist is included within the scope of the present invention.
  • a TLR5 that is suitable for use in the invention can be identified by determining that binding of a known TLR5 agonist to it mobilizes the nuclear factor NF- ⁇ in the cell that expresses the TLR5, and/or stimulates tumor necrosis factor-alpha production by such a cell.
  • the TLR5 agonist used in the invention can comprise or consist of the sequences described in Figure 1 or Figure 7.
  • the nucleic acids provided by the invention and which encode a TLR5 or a secreatable TLR5 agonist are present in viral vectors which are suitable for insertion into mammalian cells.
  • the viral vectors are suitable for direct injection into an area of tissue where a localized therapeutic or prophylactic effect is desired.
  • suitable vectors include but are not limited to vectors derived from adenovirus, adeno-associated virus, retroviruses (e.g, lentiviruses, Rhabdoviruses, murine leukemia virus), herpes virus, and the like.
  • the tropism of the viral vectors can be modified by pseudotyping the vectors with envelope proteins or other surface antigens from other viruses, or by modifying the virus to include any other component that is desirable for targeted expression of the TLR5 or the secreted TLR5 agonist.
  • compositions comprising DNA polynucleotides which encode a TLR5 or an agonist of it can be prepared using any acceptable technique, such as by amplification using appropriate primers and inserting the amplification products into expression vectors.
  • Suitable expression vectors for using the DNA polynucleotides which encode the TLR5 or an agonist of it can comprise appropriate eukaryotic and/or vial transcription and translation signals, and may contain additional elements, such as polyadenylation sites, internal ribosome entry sites, etc.
  • the polynucleotide sequence encoding the TLR5 is not present in a bicistronic region of a polynucleotide.
  • the polynucleotide sequence encoding the TLR5 agonist is not present in a bicistronic region of a polynucleotide.
  • an expression vector encoding a TLR5 or a TLR5 agonist is provided in a recombinant adenovirus context.
  • a particular embodiment of a recombinant adenovirus encoding a TLR5 suitable for use in the method of the invention is depicted in Figure 9, which provides a graphical representation of the pCD515-CMV -hTLR5 expression vector.
  • This recombinant adenovirus construct expresses human TLR5 comprising the sequence presented in Figure 8.
  • the adenovirus construct comprises a strong cytomegalovirus (CMV) promoter cloned upstream of the human TLR5 (hTLR5) cassette and thus is suitable for facilitating constitutively high expression of TLR5 in cells into which this representative construct is introduced.
  • CMV cytomegalovirus
  • hTLR5 human TLR5
  • CBLB502 cytomegalovirus
  • This vector is termed pCD515- CMV -Sseap-502.
  • Expression vectors encoding the TLR5 or the TLR5 agonist can be formulated in any pharmaceutically acceptable preparation for administration to individuals in need of prophylaxis or therapy of any disease or disorder, infection, etc., wherein localized expression of TLR5 or a secreted form of TLR5 agonist is desired.
  • the DNA polynucleotides of the present invention can be administered by any means known in the art.
  • a preferred route is intratumoral injection.
  • other delivery techniques or any reagent or composition that can assist in targeting delivery of the nucleic acids to a site where expression of TLR5 or a TLR5 agonist is desired can be used.
  • suitable delivery reagents for administration of the compositions in the invention include but are not limited to the Minis Transit TKO lipophilic reagent; lipofectin; lipofectamine; cellfectin; or polycations (e.g., polylysine), liposomes and microsomes or expression vectors based on retroviruses, lentiviruses, adenoviruses and adenoassociated viruses.
  • the invention can be used for prophylactic purposes (i.e., vaccination) or therapeutic (i.e., treatment of disease and/or infection or other disorders).
  • the invention provides methods for enhancing cancer vaccines.
  • the invention is used to inhibit or treat ischemia-reperfusion injury.
  • the invention involves introducing a recombinant polynucleotide encoding a TLR5 to one or more tumor cells in an individual in need of cancer prophylaxis and/or therapy and, concurrently or subsequently administering to the individual a TLR5 agonist.
  • the design and use of the representative expression vectors disclosed herein demonstrates that recombinant expression of a TLR5 can sensitize cells to a TLR5 agonist. (See, for example, Figure 12).
  • the tumor cells are sensitized to a TLR5 agonist, and this aspect of the invention along with data summarized in Figure 12 support the feasibility of therapeutic approaches that utilize exogenously provided TLR5 agonist polypeptides as an immunotherapeutic modality.
  • the TLR5 agonist is provided as a polypeptide component of a pharmaceutical preparation.
  • the TLR5 agonist can comprise or consist of a flagellin protein or a fragment or derivative thereof.
  • flagellin proteins and derivatives thereof are known in the art.
  • suitable flagellin proteins and derivatives thereof are described in U.S. Patent No. 7,638,485, the entire disclosure of which is incorporated herein by reference.
  • the flagellin protein derivative that is used in the invention is the Salmonella flagellin derivative known in the art as CBLB502, which is also described in U.S. Patent No. 7,638,485 and is presented here in Figure 1.
  • the invention provides for administering to cancer cells an expression vector which encodes a secretable form of a TLR5 agonist.
  • the invention provides for conferring the capability of tumor cells, and/or cells proximal to tumor cells, to express a secreted form of a TLR agonist, thereby facilitating activation of TLRs via local TLR-stimulation, which will result in inhibition and/or reversal of the immunosuppressive tumor environment.
  • Figure 10 provides a representation of an illustrative expression vector that is suitable for such use.
  • any peptide signal that facilitates secretion of a protein can be operably linked to the TLR5 agonist to arrive at biologically active secreted (extracellular) peptides (BASP) that would be suitable for use in the invention.
  • BASP biologically active secreted
  • secretion signals include the IL-1 -signal sequence and derivatives thereof, the CD 14 signal sequence and derivatives thereof, and secreted placental alkaline phosphatase (SEAP).
  • SEAP secreted placental alkaline phosphatase
  • the secretion signal is a truncated form of SEAP, whereby removal of the transmembrane domain of the protein allows it to be secreted from the cells into the surrounding environment.
  • TLR5 agonist CBLB502 With respect to the TLR5 agonist CBLB502, it is currently in Phase I human trials and is being developed as radiomitigator and radioprotector for biodefense applications. Without intending to be constrained by theory, our work shows that CBLB502, binds to TLR5 and activates the NF- ⁇ pro-survival pathway, which protects from IR damage. Signal transduction by TLR5 involves interaction of its cytoplasmic TIR (Toll IL-1 -receptor homology) domain with the TIR domain of the cytoplasmic adaptor protein MyD88.
  • TIR cytoplasmic TIR
  • MyD88 signals through other adaptor molecules, such as IRAK and TRAF6, and causes activation of ⁇ kinase (IKK), which in turn leads to NF-kB activation and transcriptional upregulation of pro-survival and inflammatory effector genes.
  • IKK ⁇ kinase
  • the p65 (RelA)/p50 heterodimer is sequestered in the cytoplasm by ⁇ . Phosphorylation of ⁇ by IKK and the subsequent degradation of ⁇ leads to NF- ⁇ nuclear translocation and transcriptional activation of NF- ⁇ controlled genes.
  • NF- ⁇ The protective role of NF- ⁇ is mediated by transcriptional activation of multiple genes coding for: a) anti-apoptotic proteins that block major apoptotic pathways, b) cytokines and growth factors that induce proliferation and survival of BP and other stem cells, and c) potent ROS-scavenging antioxidant proteins, such as MnSOD (SOD-2).
  • compositions of the invention can be combined with standard pharmaceutical carriers.
  • Acceptable pharmaceutical carriers for use with proteins are described in Remington's Pharmaceutical Sciences (18th Edition, A. R. Gennaro et al. Eds., Mack Publishing Co., Easton, Pa., 1990.
  • compositions can be mixed with chemotherapeutic agents, adjuvants, and/or combined with other compositions and used with other techniques, such as surgical or radiological interventions for treatment of a variety of disease, including cancers.
  • Salmonella flagellin is a strong activator of antiapoptotic NF- ⁇ pathway. Based on the analysis of the crystal structure of the F41 proteolytic fragment, Salmonella flagellin is a boomerang-shaped protein with four major domains: DO, Dl, D2 and D3.
  • DO random coil
  • Dl a helix domains located at the N- and C-terminus are mainly responsible for motility and signaling, and are comprised of highly conserved stretches of amino acids (CI and C2 domain in Fig. la).
  • the central D2 and D3 domains are highly hypervariable and can be removed without any significant effect on proinflammatory activity induced by flagellin.
  • the D0-D1 domains are conformationally flexible structures that are stabilized by extended interactions between three a-helices in the Dl domain.
  • the TLR5 extracellular domain contains 19-25 copies of a leucine-rich repeat motif (LRR).
  • LRR leucine-rich repeat motif
  • Nf-kB transcriptional reporter cell line In order to develop a readout system for assessment of functional activity of CBLB502 and to facilitate functional screening of new TLR5 agonists, we developed NF-kB transcriptional reporter cell line. First, we have developed a basic, single-color lentiviral transcriptional reporter (TR) vector with destabilized copGFP reporter gene under the control of minimum CMV (mCMV) promoter (Fig.2 ), and utilized this vector for the construction of stable TR cell lines.
  • TR lentiviral transcriptional reporter
  • the lentiviral TR vector is based on third generation, self-inactivated HIV -based vectors, and comprises all necessary functional elements (GAG, RRE, cPPT) necessary for transcription of viral RNA, and packaging of TR constructs in the form of viral genomic RNA into pseudoviral particles. After transduction of these particles into target cells, the viral genomic RNA TR construct is reverse-transcribed into double-stranded DNA, and integrated into host cell genomic DNA, providing long-term expression of the reporter construct in the host cell.
  • CBLB502 can be expressed in the tumor microenvironment such that it is accessible to TLR5 receptors on cell surface. This can be achieved by fusion of a secretion signal to CBLB502.
  • NF-kB activation in 293-NFkB-GFP by the control proteins (TNF, IL-1, and CBLB502) secreted by HEK293 cells was analyzed by fluorescence microscopy (GFP induction).
  • the pR- CMV-S3 vector with the secreted alkaline phosphatase signal sequence (SEAP) provided the most efficient secretion of all three proteins.
  • SEAP secreted alkaline phosphatase signal sequence
  • SEAP-CBLB502 stimulated NFkB-GFP -reporter cells in a dose dependent manner, while supernatant from cells transduced in parallel with control secretary vector did not induce GFP.
  • TLR5 agonists for cancer immunotherapy, we have also constructed adenoviral vectors that express secreted form for CBLB502 for in vivo experiments.

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Abstract

La présente invention concerne en général l'utilisation du récepteur 5 de type Toll (TLR5) et des agonistes de celui-ci pour des thérapies immunologiques et, en particulier, pour l'immunothérapie du cancer. Certains aspects de l'invention reposent en partie sur la découverte que, en conférant aux cellules tumorales la capacité d'exprimer un récepteur de type Toll (TLR), les cellules deviennent sensibles à certains agonistes de TLR de telle sorte que la qualité immunosuppressive de l'environnement tumoral est inhibée et/ou inversée.
PCT/RU2013/001134 2012-12-18 2013-12-18 Compositions et procédés à l'aide du récepteur 5 de type toll et d'un agoniste d'un récepteur de type toll Ceased WO2014098649A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3206708A4 (fr) * 2014-10-16 2018-05-30 Cleveland Biolabs, Inc. Méthodes et compositions pour le traitement de troubles liés à l'irradiation

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090246303A1 (en) * 2003-12-02 2009-10-01 Gudkov Andrei V Method for Reducing The Effects of Chemotherapy Using Flagellin Related Polypeptides
WO2012097012A1 (fr) * 2011-01-10 2012-07-19 Cleveland Biolabs, Inc. Utilisation d'un agoniste de récepteur de type toll pour le traitement du cancer
EA201290140A1 (ru) * 2009-10-06 2012-11-30 Общество С Ограниченной Ответственностью "Панацела Лабс" Применение toll-подобного рецептора и агониста для лечения рака

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090246303A1 (en) * 2003-12-02 2009-10-01 Gudkov Andrei V Method for Reducing The Effects of Chemotherapy Using Flagellin Related Polypeptides
EA201290140A1 (ru) * 2009-10-06 2012-11-30 Общество С Ограниченной Ответственностью "Панацела Лабс" Применение toll-подобного рецептора и агониста для лечения рака
WO2012097012A1 (fr) * 2011-01-10 2012-07-19 Cleveland Biolabs, Inc. Utilisation d'un agoniste de récepteur de type toll pour le traitement du cancer

Non-Patent Citations (1)

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Title
ALYSSA GOLDBERG ET AL.: "Toll-like receptor 4 suppression leads to islet allograft survival.", THE FASEB JOURNAL, vol. 21, 2007, pages 1 - 10 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3206708A4 (fr) * 2014-10-16 2018-05-30 Cleveland Biolabs, Inc. Méthodes et compositions pour le traitement de troubles liés à l'irradiation
US10183056B2 (en) 2014-10-16 2019-01-22 Cleveland Biolabs, Inc. Methods and compositions for the treatment of radiation-related disorders
US10857200B2 (en) 2014-10-16 2020-12-08 Cleveland Biolabs, Inc. Methods and compositions for the treatment of radiation-related disorders

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