WO2013096829A2 - Activation de procédés d'agression cellulaire dans le traitement d'un glioblastome multiforme - Google Patents

Activation de procédés d'agression cellulaire dans le traitement d'un glioblastome multiforme Download PDF

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Publication number
WO2013096829A2
WO2013096829A2 PCT/US2012/071356 US2012071356W WO2013096829A2 WO 2013096829 A2 WO2013096829 A2 WO 2013096829A2 US 2012071356 W US2012071356 W US 2012071356W WO 2013096829 A2 WO2013096829 A2 WO 2013096829A2
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polypeptide
group
amino acid
polypeptides
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WO2013096829A3 (fr
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Laura L. Eggink
James Kenneth HOOBER
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Arizona Biomedical Research Commission
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Arizona Biomedical Research Commission
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/10—Peptides having 12 to 20 amino acids

Definitions

  • FIG. 5 shows bar graphs illustrating, quantitatively, various cytokines released from human peripheral blood mononuclear cells (PBMCs) during a 24-hour incubation of SVL4 in the presence and absence of 1 ng/ml lipopolysaccharide (LPS).
  • FIG. 6 is a bar graph illustrating the stimulation of interleukin-21 (IL-21) release by treatment of PBMCs with 1 nM of interferon-gamma (IFN- ⁇ ) or 50 nM of SVL4 for 16 hours.
  • IFN- ⁇ interferon-gamma
  • FIG. 9 A shows bar graphs illustrating the change in the ratio of microglial cells to macrophages, in the brains of mice with implanted glioma cells, following radiation treatment with SVL4, compared to radiation treatment alone.
  • Additional polypeptides include those having one or more of the active mimetic sequences SEQ ID NOS: 1-33, but with an added C-terminal spacer sequence to move these active mimetic sequences away from the core of a branched polypeptide.
  • a representative spacer sequence is GGGS (SEQ ID NO: 34), and therefore such additional polypeptides include those having the added C-terminal spacer sequence GGGS in sequences (e.g., SEQ ID NO: 3) otherwise lacking such a sequence.
  • branches at least one of which, some portion of which, or all of which, comprise(s) an active mimetic sequence as described above, including sequences having additional C-terminal, N-terminal, and/or spacer sequences.
  • a schematic representation of a polypeptide having four branches, each with an active mimetic sequence 1 and a spacer sequence 2 linking the mimetic sequence 1 to the polypeptide core 3 (e.g., a tri-lysine core) is illustrated in FIG. 1A.
  • the chemical structure of a specific polypeptide with 4 branches, each having the polypeptide sequence of SEQ ID NO. 36, comprising both active mimetic and spacer sequences, is illustrated in FIG. IB. As shown, this polypeptide has a C-terminal amide group.
  • polypeptides useful for the treatment of GBM comprise one or more amino acid sequences selected from the group consisting of SEQ ID NOS: 1-33 and 35-40.
  • D- and L-amino acids may be present in the active amino acid sequences described herein, or may be present elsewhere in the polypeptide.
  • the polypeptides may comprise various "designer" amino acids ⁇ e.g., ⁇ -methyl amino acids, C-a- methyl amino acids, and N-a-methyl amino acids, etc) in the active sequences or elsewhere in the polypeptide to convey special properties.
  • Synthetic amino acids include ornithine for lysine, and norleucine for leucine or isoleucine.
  • polypeptides comprising any of the amino acid sequences described herein can have peptidomimetic bonds, such as ester bonds, to prepare polypeptides with novel properties.
  • polypeptides comprising any of the amino acid sequences described herein may be present in a fusion protein with full length vitamin D-binding protein (DBP), or with variations of Domain III of DBP (including but not limited to polypeptides comprising the amino acid sequence of SEQ. ID NOS: 38 and/or 39), as described herein.
  • DBP full length vitamin D-binding protein
  • variations of Domain III of DBP including but not limited to polypeptides comprising the amino acid sequence of SEQ. ID NOS: 38 and/or 39, as described herein.
  • the polypeptides comprising any of the amino acid sequences described herein can be fused or otherwise linked to therapeutic agents in order to enhance potential therapeutic effects of both agents.
  • monoclonal antibodies have been generated against a large number of cancers and other pathogenic agents for therapeutic use. Binding of these antibodies to the infectious agent is the first part of the therapy. Phagocytosis of the antibody-bound agent by macrophages and other phagocytic cells must then occur to eliminate the agent from the body. Therefore, a combination of target-directed antibodies with the polypeptides described herein provides an effective combination therapy. Many other such fusions or linkages to other therapeutic agents will be apparent to those of skill in the art, having regard for the teachings herein.
  • fusion proteins can result from the addition of a polypeptide having an amino acid sequence as described herein to the carboxy or amino terminal end of another polypeptide, or can comprise the placement of a polypeptide having an amino sequence as described herein within another polypeptide.
  • a polypeptide having an amino acid sequence as described herein to the carboxy or amino terminal end of another polypeptide, or can comprise the placement of a polypeptide having an amino sequence as described herein within another polypeptide.
  • a pharmaceutical composition comprising the active agent ⁇ e.g., a polypeptide as described herein) in a solid form (including granules, powders, transdermal or transmucosal patches or suppositories) or in a liquid form ⁇ e.g., solutions, suspensions, or emulsions) may be subjected to conventional pharmaceutical operations such as sterilization and/or may contain conventional pharmaceutically acceptable carriers, such as adjuvants as described above, stabilizers, wetting agents, emulsifiers, preservatives, cosolvents, suspending agents, viscosity enhancing agents, ionic strength and osmolality adjustors, and/or buffering agents.
  • conventional pharmaceutically acceptable carriers such as adjuvants as described above, stabilizers, wetting agents, emulsifiers, preservatives, cosolvents, suspending agents, viscosity enhancing agents, ionic strength and osmolality adjustors, and/or buffering agents.
  • the active agent is a polypeptide or a polynucleotide
  • it is administered, according to methods described herein, to a patient in need of treatment for GBM.
  • the patient is a mammal and more preferably a human.
  • Administration may be by any suitable route, including local delivery, parentally, transdermally, inhalation, and topically, in dosage unit formulations containing conventional pharmaceutically acceptable carriers, as described above.
  • Parenteral administration includes subcutaneous, intravenous, intramuscular, intrasternal, intratendinous, intraspinal, intracranial, intrathoracic, intraperitoneal, and infusion techniques.
  • Preferred administration routes are subcutaneous and intravenous injection, as well as buccal and sublingual administration.
  • the therapeutic agent may be administered prior to, at the time of, or shortly after a given round of treatment with a chemotherapy and/or radiation therapy (radiotherapy).
  • Radiation therapy includes external-beam radiation therapy, as well as the use of radiolabeled compounds targeting tumor cells. Any reduction in a chemotherapeutic or a radio therapeutic dose, as a result of administration of a polypeptide as described herein, benefits the patient by decreasing side effects relative to standard chemotherapy and/or radiation therapy treatment.
  • a first radiation dose is administered prior to all radiation doses of the treatment regimen, and this is then followed by a first polypeptide dose, administered prior to all polypeptide doses of the treatment regimen.
  • a second radiation dose is then administered, followed by a second polypeptide dose, and so on. No intervening radiation dose occurs between the first radiation dose and the first polypeptide dose, between the second radiation dose and the second polypeptide dose, and so on.
  • aspects of the invention are directed to methods for the treatment of GBM, including methods for prolonging the survival of patients suffering from this disease.
  • a patient suffering from GBM is administered a pharmaceutical composition comprising a monovalent or multivalent (e.g., tetravalent) polypeptide having the structural and/or functional characteristics described herein, such as the active amino acid sequences described above, exhibiting lectin-binding properties.
  • Administration of the pharmaceutical composition is performed, according to some embodiments, in conjunction with radiotherapy, the administration of other chemotherapeutic agents, and/or surgical procedures.
  • the most difficult blocking groups to remove (and the additional mass provided by a residual blocking group) were tert-butyl (56 Da) and PBF (253 Da).
  • the blocking groups were removed by trifluoroacetic acid (TFA) during cleavage from the resin.
  • TFA trifluoroacetic acid
  • Modifications at the C-terminus consisted of (a) an amide group (no tag) or (b) an extension of the polypeptide by addition of C-terminal ⁇ -biotinyl-lysine-amide or ⁇ -alanine-cysteine-amide.
  • polypeptides were synthesized in 5-g batches by CBL Biopharma LLC ("CBL,” Patras, Greece).
  • CBL CBL Biopharma LLC
  • the tri-lysine "core” was synthesized on the solid-phase resin and extended with the GGS sequence.
  • the polypeptide "arms” with C-terminal G were synthesized separately by the standard chemistry method described above and condensed with the core.
  • the polypeptide was purified extensively by HPLC using a gradient of acetonitrile in 0.1% TFA.
  • the data sheet from CBL illustrated the HPLC pattern of the purified polypeptide (99.4% by HPLC) and the ESI mass spectrum.
  • the quality of the synthetic product was assessed by matrix-assisted laser desorption/ionization (MALDI) and electrospray ionization (ESI) mass spectroscopy.
  • MALDI matrix-assisted laser desorption/ionization
  • ESI electrospray ionization
  • Possible impurities remaining in the final product were derivatives of the main polypeptide, which may have included smaller products of incomplete synthesis or molecules with incomplete removal of blocking groups. As shown by the mass spectra, these impurities were present in very low amounts in the purified polypeptide.
  • SVL4 in lyophilized form was prepared as a white fluffy powder using trifluoroacetate (TFA) as a counterion, although other physiologically acceptable counterions ⁇ e.g., acetate) may also be used.
  • Net polypeptide content with and without the counter ion was approximately 88% and 73%, respectively. The remainder was likely water of hydration of the highly polar polypeptide. Solubility of the polypeptide in water was high, meaning that preparation of solutions is limited largely by the bulk of the powder.
  • concentrations of the polypeptide of 25 mM, and possibly somewhat higher can be readily achieved, particularly in aqueous compositions.
  • the polypeptide is administered to a patient suffering from GBM in an aqueous pharmaceutical composition having a polypeptide concentration generally from about 0.05 mM to about 25 mM, typically from about 0.1 mM to about 20 mM, and often from about 0.1 mM to about 10 mM, and a pharmaceutically acceptable carrier.
  • an administration amount from about 0.1 mg/kg body weight per dose to about 1 mg/kg body weight per dose may be optimal.
  • administration may be at least once weekly, at least twice weekly, at least three times weekly, on alternate days, or daily, over a given treatment regimen.
  • FIG. 4 illustrates the binding of the polypeptide SVL4 to specific lectins, with the source of the lectins and their specificities being Griffonia simplicofolia (GS: Gal), Helix pomatia (HP: GalNAc/Gal), and wheat germ agglutinin (WGA: GlcNAc, Neu5Ac).
  • GS Griffonia simplicofolia
  • HP Helix pomatia
  • WGA wheat germ agglutinin
  • C-terminal biotin-tagged, tetravalent SVL4 was bound to streptavidin in wells of a microtiter plate. Binding of lectins was detected by the activity of conjugated peroxidase after extensive washing.
  • polypeptide SVL4 was screened from a phage display library with the GalNAc/Gal-specific lectin HP, even though this polypeptide was bound most strongly in this assay to the G. simplicifolia lectin, specific for Gal.
  • Representative polypeptides, useful in the methods described herein, are therefore polypeptides exhibiting binding to lectins in a solid-phase lectin binding assay.
  • Particular polypeptides of interest exhibit binding to a receptor that is specific for galactose/N- acetylgalactosamine (GalNAc/Gal) ligands in a solid-phase binding assay.
  • An example of a receptor that may be characterized in this manner is recombinant receptor CLEC10a/CD301.
  • FIG. 5 illustrates the results of the quantitative analysis of cytokines released from human PBMCs during the 24-hour incubation in the presence or absence of 1 ng/ml LPS. As shown in FIG. 5, slight antiinflammatory responses were detected by a reduction in release of these cytokines, induced by LPS, at high concentrations of the polypeptide. Of particular interest was induction of selective release of IL-8 but not the inflammatory cytokines, IL- ⁇ , IL-6 or TNF-a by SVL4, at low concentrations, with a maximal response at 3 nM polypeptide.
  • IL-8 is a chemokine released from activated macrophages that attracts neutrophils and plays an important role in host defense by enhancing microbiocidal activity and cytotoxicity.
  • polypeptides as described herein stimulate the immune system, based on increased density of one or more cellular markers on blood monocytes.
  • Particular cellular markers include CD l ib and MHCII protein, with the density increase of one or both of these markers being generally at least about 1.5 times ⁇ e.g., from about 1.5 times to about 9 times), and typically at least about 2 times ⁇ e.g., from about 2 times to about 8 times), compared to a control case in which the polypeptide is not administered.
  • FIGS. 9A-9D illustrate the increase in immune markers on phagocytic cells in the brains of mice with implanted glioma cells. Radiation treatment (4 Gy) was administered on days 7 and 9 after implantation, and SVL4 polypeptide was administered subcutaneous ly beginning on day 7 at 1 nanomole/gram body weight (1 ⁇ ⁇ body weight).
  • 9D illustrates the increases, compared to radiation treatment alone, in immune markers, MHCII and CDl lc on phagocytic cells and the immune markers CDl 15, CDl lb, and MHCII on microglial cells, in the brains of mice with implanted glioma cells, following radiation treatment (4 Gy) in combination with SVL4 treatment.
  • Tissues for examination of cells by flow cytometry were obtained from the brain hemisphere containing the tumor. Fluorescently tagged antibodies were used to detect cell surface markers, as discussed above with respect to the increased expression of activation markers in healthy mice.
  • mice with implanted glioma cells (murine GL261 cell line) was determined following (i) treatment with radiation (4 Gy on day 7 and 9 following implantation) alone, (ii) administration of polypeptide SVL4 (1 nanomole/gram body weight) alone on alternate days beginning on day 7 following implantation, and (iii) the combination of (i) and (ii), i.e., radiation treatment in combination with polypeptide administration.
  • the animals were imaged to obtain randomized groups with the same average tumor size. As shown in FIGS. 10A and 10B, the size of the tumor was slightly reduced in polypeptide-treated animals, following treatment regimen (ii), but the life of the animals was not significantly extended.
  • the tri-lysine core of tetravalent polypeptides is immunologically silent. Examination of the amino acid sequence of SVL4 using MHC binding prediction databases indicated that they are not likely to be presented by MHC class I or MHC class II molecules in humans. In a direct test of antibody generation against SVL4, a large dose (5 nanomole/g body weight) of the polypeptide was injected into mice. Negligible antibodies were detected 3 weeks after injection, whether the polypeptide was given with or without alum as an adjuvant. In contrast, alum strongly increased antibody production against ovalbumin as a positive control. A test of SVL4 as an adjuvant with ovalbumin was negative.
  • Toxicity of SVL4 was evaluated after two bolus intravenous injections into rats with a dose of 12.5 ⁇ ⁇ body weight (85 mg/kg body weight), one week apart.
  • Sterile solutions of polypeptide were prepared by Susavion, with concentration of polypeptide determined by the bicinchoninic acid assay (Pierce, Rockland, IL), and delivered to an independent laboratory to perform a preliminary toxicity study designed to demonstrate a margin of safety. Because of the lower bioavailability of polypeptide administered subcutaneously, this study should have provided a margin of safety of at least 1000-fold over a proposed standard therapeutic dose. Results of the study indicated that the polypeptide was well tolerated and that no changes were noted in behavior, weight, or food intake.
  • compositions of the polypeptide SVL4 exhibit no cytotoxicity at effective concentrations in vivo.
  • the amino acids of the polypeptide are normal constituents of the body and of the diet, and representative polypeptides such as SVL4 include sites for proteolytic cleavage for degradation.
  • SVL4 itself is not predicted to be antigenic, as indicated by RANKPEP software, and other polypeptides of this design have been shown to be non-antigenic in animals. Release of anti-viral and anti-tumor cytokines in PBMC cultures is stimulated but that of inflammatory cytokines is below detection.
  • the polypeptide SVL4 was found to exhibit a number of biological activities that are believed to correlate with its demonstrated effectiveness in prolonging the survival of mice implanted with glioma cells.
  • the in vitro studies with this polypeptide showed that it (i) activated macrophages, with the selective induction of the release of IL-8, (ii) activated T cells, with the induction of the release of IL-21, which activates CD8 + T cells, and (iii) activated phagocytosis.
  • SVL4 activates T cells, CD8 + T cells and phagocytic cells such as macrophages, microglia and dendritic cells. Activation of these cells is expected to lead to presentation of antigens and generation of antibodies against tumor cells.
  • the synthetic polypeptide SVL4 therefore activates a multicellular assault against the tumor.
  • the biological processes exhibited by SVL4 were found to be critical in mice immunized with radiation-killed glioma cells, which effectively prevented growth of tumors after implantation of glioma cells.

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Abstract

L'invention concerne des polypeptides, tels qu'un polypeptide multivalent appelé SVL4, utiles dans des compositions pharmaceutiques pour le traitement d'un glioblastome multiforme. SVL4 a été démontré comme ayant une activité in vivo contre un modèle murin syngénique de cet état. SVL4 et d'autres polypeptides décrits présentement sont des mimétiques d'un ligand naturel de glycane qui se lie à des récepteurs d'activation sur des cellules immunitaires. Ces polypeptides se lient à des lectines spécifiques pour le galactose avec une avidité élevée. SVL4, par exemple, est biologiquement actif à des concentrations nanomolaires et a une durée de vie relativement longue dans le sang. On croit que ces propriétés sont le résultat d'une conséquence de la capacité de SVL4 et d'autres polypeptides décrits présentement à réticuler des récepteurs de surface cellulaire.
PCT/US2012/071356 2011-12-22 2012-12-21 Activation de procédés d'agression cellulaire dans le traitement d'un glioblastome multiforme Ceased WO2013096829A2 (fr)

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015196086A1 (fr) * 2014-06-20 2015-12-23 The University of Montana, Missoula, MT Nouveaux inhibiteurs du système xc(-)
WO2016033602A1 (fr) * 2014-08-30 2016-03-03 Susavion Biosciences, Inc. Activation de processus immunitaires adaptatifs pour le traitement de cancers et de maladies infectieuses
WO2016100679A1 (fr) 2014-12-19 2016-06-23 Susavion Biosciences, Inc. Traitements et compositions d'immunothérapie
WO2019136185A1 (fr) * 2018-01-08 2019-07-11 Susavion Biosciences, Inc. Compositions et méthodes de traitement du cancer à l'aide de peptides glycomimétiques
US10350260B2 (en) * 2015-04-27 2019-07-16 Susavion Biosciences, Inc. Compositions and methods for treating cancer and persistent viral infections
US11208497B2 (en) 2013-12-23 2021-12-28 Zymeworks Inc. Antibodies comprising C-terminal light chain polypeptide extensions and conjugates and methods of use thereof
EP4181942A4 (fr) * 2020-07-28 2024-10-02 Susavion Biosciences, Inc. Méthode de traitement de pathologies inflammatoires entraînées par neutrophiles

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7811995B2 (en) * 2006-12-13 2010-10-12 Susavion Biosciences, Inc. Therapeutic and diagnostic peptides
US8496942B2 (en) * 2006-12-13 2013-07-30 Susavion Biosciences, Inc. Therapeutic peptides and uses thereof

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11208497B2 (en) 2013-12-23 2021-12-28 Zymeworks Inc. Antibodies comprising C-terminal light chain polypeptide extensions and conjugates and methods of use thereof
WO2015196086A1 (fr) * 2014-06-20 2015-12-23 The University of Montana, Missoula, MT Nouveaux inhibiteurs du système xc(-)
WO2016033602A1 (fr) * 2014-08-30 2016-03-03 Susavion Biosciences, Inc. Activation de processus immunitaires adaptatifs pour le traitement de cancers et de maladies infectieuses
US9981044B2 (en) 2014-08-30 2018-05-29 Susavion Biosciences, Inc. Activation of adaptive immune processes for the treatment of cancers and infectious diseases
WO2016100679A1 (fr) 2014-12-19 2016-06-23 Susavion Biosciences, Inc. Traitements et compositions d'immunothérapie
JP2018501247A (ja) * 2014-12-19 2018-01-18 スサヴィオン バイオサイエンシーズ インコーポレイテッド 免疫療法による治療および組成物
US10624965B2 (en) 2014-12-19 2020-04-21 Susavion Biosciences, Inc. Immunotherapy treatments and compositions
US10350260B2 (en) * 2015-04-27 2019-07-16 Susavion Biosciences, Inc. Compositions and methods for treating cancer and persistent viral infections
WO2019136185A1 (fr) * 2018-01-08 2019-07-11 Susavion Biosciences, Inc. Compositions et méthodes de traitement du cancer à l'aide de peptides glycomimétiques
US11376307B2 (en) 2018-01-08 2022-07-05 Susavion Biosciences, Inc. Compositions and methods of treating cancer with glycomimetic peptides
US20220331394A1 (en) * 2018-01-08 2022-10-20 Susavion Biosciences, Inc. Compositions and methods of treating cancer with glycomimetic peptides
EP4181942A4 (fr) * 2020-07-28 2024-10-02 Susavion Biosciences, Inc. Méthode de traitement de pathologies inflammatoires entraînées par neutrophiles

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