WO2019204402A1 - Compositions and methods for treatment of cancer - Google Patents

Compositions and methods for treatment of cancer Download PDF

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Publication number
WO2019204402A1
WO2019204402A1 PCT/US2019/027820 US2019027820W WO2019204402A1 WO 2019204402 A1 WO2019204402 A1 WO 2019204402A1 US 2019027820 W US2019027820 W US 2019027820W WO 2019204402 A1 WO2019204402 A1 WO 2019204402A1
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seq
amino acid
abu
lrrf
acid sequence
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PCT/US2019/027820
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French (fr)
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Niranjan B. Pandey
Aleksander S. Popel
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Asclepix Therapeutics, Inc.
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Publication of WO2019204402A1 publication Critical patent/WO2019204402A1/en

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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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/39—Connective tissue peptides, e.g. collagen, elastin, laminin, fibronectin, vitronectin, cold insoluble globulin [CIG]
    • 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
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
    • 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
    • C07K14/575—Hormones
    • C07K14/61—Growth hormone [GH], i.e. somatotropin
    • 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
    • C07K14/78—Connective tissue peptides, e.g. collagen, elastin, laminin, fibronectin, vitronectin or cold insoluble globulin [CIG]

Definitions

  • Cancer immunotherapies have been developed to block these interactions. The objective of these and other cancer immunotherapies is to free immune effector cells from suppression. However, a large number of immune suppressive pathways have been discovered, which limit current responses to first generation immunotherapy agents.
  • the invention provides methods and compositions for treating cancer, including to improve or to potentiate cancer immunotherapy. Aspects of the invention comprise administering a peptide comprising a somatotropin motif amino acid sequence.
  • the peptide comprising a somatotropin motif blocks Neuropilin-l (NRP1) signaling on T regulatory cells, thereby promoting induction and/or proliferation of an effector T cell population.
  • the peptide comprising a somatotropin motif further comprises or is administered along with an amino acid sequence derived from the a5 fibril of type IV collagen.
  • the somatotropin motif amino acid sequence and amino acid sequence derived from the a5 fibril of type IV collagen may be administered as separate peptide agents or as a chimeric protein including both amino acid sequences.
  • the peptide(s) or protein is administered to a cancer patient in connection with an immunotherapy regimen, including but not limited to anti- PD1, anti-PDLl and anti-CTLA4.
  • the peptide or protein agent may improve response to or potentiate the immunotherapy.
  • a somatotropin motif has the general structure L-X(3)-L-L-X(3)-S-X-L, where X is a variable amino acid and the number in parentheses is the number of consecutive variable amino acids; L is leucine, and S is serine.
  • An exemplary peptide comprising a somatotropin motif comprises the amino acid sequence LLRSSLILLQGSWF (SEQ ID NO: 1).
  • Peptides derived from the a5 fibril of type IV collagen include those comprising the amino acid sequence LRRFSTXPXXXXNINNVXNF (SEQ ID NO: 2) or LRRFSTXPXXXXDINDVXNF (SEQ ID NO: 3), where X is a standard amino acid or non-genetically encoded amino acid.
  • Exemplary amino acid sequences derived from the a5 fibril of type IV collagen include LRRFSTAPFAFININNVINF (SEQ ID NO: 4) and LRRFSTAPFAFIDINDVINF (SEQ ID NO: 24).
  • an effective amount of the peptide comprising a somatotropin motif blocks NRP1 signaling on Treg cells, thereby blocking Treg-driven immunosuppression, while an effective amount of the peptide derived from the a5 fibril of type IV collagen normalizes vasculature, increases tumor perfusion, provides anti- angiogenic, and/or activates anti-tumor immunity.
  • These agents can act synergistically, including to improve response to checkpoint inhibitor therapy.
  • the invention provides a chimeric protein or peptide comprising an amino acid sequence comprising a somatotropin motif and an amino acid sequence derived from the a5 fibril of type IV collagen.
  • the chimeric protein is a single fusion protein or peptide, which may optionally comprise a linking sequence.
  • the peptide or chimeric protein is administered to a patient before, during, and/or after cancer immunotherapy.
  • the cancer immunotherapy may be an antibody or antigen-binding portion thereof that blocks an immune checkpoint molecule, e.g., a molecule selected from B7-H3, B7-H4, BTLA, CD 160, CTLA4, KIR, LAG3, PD-l, PD-L1, PD-L2, TIM3, and TIGIT.
  • the peptide or chimeric protein is administered in connection with an immune co-stimulatory molecule or an adoptive cell therapy (e.g., CAR-T).
  • the invention in various embodiments is applicable to hematological cancers as well as solid tumors, including early or late stages cancers.
  • the invention provides methods and compositions for treating cancer. Aspects of the invention comprise administering a peptide comprising a somatotropin motif amino acid sequence.
  • the peptide comprising a somatotropin motif blocks Neuropilin-l (NRP1) signaling on T regulatory cells (Treg; formerly known as “suppressor T cells”), thereby promoting induction and/or proliferation of an effector T cell population.
  • the peptide comprising a somatotropin motif further comprises or is administered along with an amino acid sequence derived from the a5 fibril of type IV collagen.
  • the somatotropin motif amino acid sequence and amino acid sequence derived from the a5 fibril of type IV collagen may be administered as separate peptide agents or as a chimeric protein including both amino acid sequences.
  • the peptide(s) or protein is administered to a cancer patient in connection with an immunotherapy regimen, including but not limited to anti-PDl, anti-PDLl and anti-CTLA4.
  • Peptides comprising a somatotropin motif are described in ETS 8,507,434, which is hereby incorporated by reference in its entirety.
  • the peptide comprising a somatotropin motif also inhibits undesirable or excess angiogenesis and/or lymphangiogenesis.
  • the peptide comprising a somatotropin motif may reduce blood vessel and/or lymph vessel formation, for example, by reducing endothelial cell proliferation, migration, survival, and/or stability and/or by increasing endothelial cell death.
  • a somatotropin motif has the general structure L-X(3)-L-L-X(3)-
  • S-X-L where X is a variable amino acid and the number in parentheses is the number of consecutive variable amino acids; L is leucine, and S is serine.
  • An exemplary peptide comprising a somatotropin motif comprises the amino acid sequence LLRSSLILLQGSWF (SEQ ID NO: 1), or derivatives thereof.
  • Derivatives of the peptide of SEQ ID NO: 1 include peptides having from 1 to 5 amino acid modifications independently selected from substitutions, insertions, or deletions ( e.g ., 1, 2, 3, 4, or 5 amino acid substitutions, insertions, or deletions) with respect to SEQ ID NO: 1.
  • the peptide comprising a somatotropin motif contains about 35 amino acids or less, or about 30 amino acids or less, or about 25 amino acids or less, or about 20 amino acids or less, or about 15 amino acids of less, or is about 10, 11, 12, 13, or 14 amino acids in length.
  • one, two, three, four, or five amino acids of SEQ ID NO: 1 are deleted from its C-terminal end and/or from its N- terminal end (collectively).
  • amino acid substitutions are made at any position of SEQ ID NO: 1, which can be independently selected from conservative or non-conservative substitutions.
  • the peptide includes from 1 to 10 amino acids added to one or both termini (collectively).
  • the N- and/or C-termini may optionally be occupied by another chemical group (other than amine or carboxy, e.g., amide or thiol), and which can be useful for conjugation of other moieties, including PEG or PLGA-PEG co-polymers.
  • amino acid residues involved The 20 genetically encoded amino acids can be grouped into the following six standard amino acid groups:
  • “conservative substitutions” are defined as exchanges of an amino acid by another amino acid listed within the same group of the six standard amino acid groups shown above. For example, the exchange of Asp by Glu retains one negative charge in the so modified polypeptide.
  • glycine and proline may be substituted for one another based on their ability to disrupt a-helices.
  • Some preferred conservative substitutions within the above six groups are exchanges within the following sub-groups: (i) Ala, Val, Leu and Ile; (ii) Ser and Thr; (iii) Asn and Gln; (iv) Lys and Arg; and (v) Tyr and Phe.
  • non-conservative substitutions are defined as exchanges of an amino acid by another amino acid listed in a different group of the six standard amino acid groups (1) to (6) shown above.
  • Peptides derived from the a5 fibril of type IV collagen include those described in US 9,056,923, US 9,802,984, and WO 2017/087825, each of which is hereby incorporated by reference in its entirety.
  • the peptide comprising an amino acid sequence derived from a5 fibril of type IV collagen comprises the amino acid sequence LRRFSTXPXXXXNINNVXNF (SEQ ID NO: 2), where X is a standard amino acid or non-genetically encoded amino acid.
  • the peptide comprising the amino acid sequence derived from a5 fibril of type IV collagen contains about 30 amino acids or less, or about 25 amino acids of less, or about 24 amino acids, or about 23 amino acids, or about 22 amino acids, or about 21 amino acids, or about 20 amino acids.
  • one, two, three, four, or five amino acids of SEQ ID NO: 2 are deleted from its C-terminal end and/or from its N-terminal end (collectively).
  • the amino acid sequence derived from the a5 fibril of type IV collagen comprises the amino acid sequence LRRFSTXPXXXXDINDVXNF (SEQ ID NO: 3), where X is a standard amino acid or non-genetically encoded amino acid.
  • the peptide contains about 30 amino acids or less, or about 25 amino acids of less, or about 24 amino acids, or about 23 amino acids, or about 22 amino acids, or about 21 amino acids, or about 20 amino acids.
  • one, two, three, four, or five amino acids of SEQ ID NO: 3 are deleted from its C-terminal end and/or from its N-terminal end (collectively).
  • the amino acid sequence derived from the a5 fibril of type IV collagen comprises the amino acid sequence LRRFSTAPFAFININNVINF (SEQ ID NO: 4) or LRRFSTAPFAFIDINDVINF (SEQ ID NO: 24) or derivatives thereof.
  • Derivatives include peptides having from 1 to 5 amino acid modifications independently selected from substitutions, insertions, or deletions ( e.g ., 1, 2, 3, 4, or 5 amino acid substitutions, insertions, or deletions) with respect to SEQ ID NO: 4 or 24.
  • the peptide comprising about 35 amino acids or less, or about 30 amino acids or less, or about 25 amino acids or less, or about 20 amino acids or less, or about 15 amino acids.
  • one, two, three, four, or five amino acids of SEQ ID NO: 1 are deleted from its C-terminal end and/or from its N-terminal end (collectively).
  • amino acid substitutions are made at any position of SEQ ID NO: 4 or 24, which can be independently selected from conservative or non conservative substitutions.
  • the peptide includes from 1 to 10 amino acids added to one or both termini (collectively).
  • the N- and/or C-termini may optionally be occupied by another chemical group (other than amine or carboxy, e.g., amide or thiol), and which can be useful for conjugation of other moieties, including PEG or PLGA-PEG co-polymers.
  • the peptide derived from the a5 fibril of type IV collagen is a peptide of from about 8 to about 30 amino acids, or from about 10 to about 20 amino acids, and has at least 4, at least 5, or at least 6 contiguous amino acids of SEQ ID NO: 2 or SEQ ID NO: 3.
  • the peptide contains at least one, at least two, or at least three D-amino acids, e.g., dA, dL, and dF.
  • the peptide contains from one to about five (e.g., 1, 2, or 3) non-genetically encoded amino acids, which are optionally selected from 2-Aminobutyric acid (Abu), norleucine (Nle), 4- chlorophenylalanine (4-ClPhe), and Allylglycine (AllylGly).
  • non-genetically encoded amino acids which are optionally selected from 2-Aminobutyric acid (Abu), norleucine (Nle), 4- chlorophenylalanine (4-ClPhe), and Allylglycine (AllylGly).
  • Exemplary peptides derived from the a5 fibril of type IV collagen in accordance with the disclosure include:
  • the peptide derived from the a5 fibril of type IV collagen is a peptide comprising at least one C-terminal amino acid deletion and/or at least one N- terminal amino acid deletion relative to SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO:4, or SEQ ID NO:24, or derivative thereof.
  • Exemplary peptides derived from the a5 fibril of type IV collagen in accordance with the disclosure include:
  • FTNINNVTN SEQ ID NO: 31
  • FIDINDVINF SEQ ID NO: 35
  • an exemplary peptide derived from the a5 fibril of type IV collagen comprises, consists of, or consists essentially of the amino acid sequence LRRFSTAPFAFININNVINF (SEQ ID NO: 4) or LRRFSTAPFAFIDINDVINF (SEQ ID NO: 24).
  • At least one of the amino acid sequences is a retroinverso peptide of any amino acid sequence selected from SEQ ID NOS: l to 39.
  • Retro-inverso peptides are linear peptides whose amino acid sequence is reversed and the a-center chirality of the amino acid subunits is inverted as well. These peptides are designed by including D-amino acids in the reverse sequence to help maintain side chain topology similar to that of the original L-amino acid peptide. Retro-inverso peptides maintain side chain topology similar to that of the original L-amino acid peptide, and also render the peptide more resistant to proteolytic degradation.
  • a retro-inverso peptide has binding characteristics similar to its corresponding L-amino acid peptide; retro-inverso peptides mimic the shape of peptide epitopes, the protein-protein interactions, and/or protein-peptide interfaces of the corresponding L-amino acid peptide.
  • peptides described herein can be chemically synthesized and purified using well-known techniques, such as solid-phase synthesis. See US 9,051,349, which is hereby incorporated by reference in its entirety.
  • an effective amount of the peptide comprising a somatotropin motif blocks NRP1 signaling on Treg cells, e.g., to inhibit an immunosuppressive activity of the Treg.
  • the effective amount of the peptide comprising a somatotropin motif promotes induction and/or proliferation of an effector T cell and/or enhances tumor killing activity by the effector T cell.
  • An effective amount of the peptide derived from the a5 fibril of type IV collagen normalizes vasculature, increases tumor perfusion, provides anti-angiogenic, anti-vascular permeability, anti-tumorigenesis, and/or anti-lymphangiogenic properties and/or activates anti-tumor immunity.
  • These peptide motifs may be administered as separate agents or via a chimeric peptide to provide synergistic therapeutic effects.
  • the invention provides a chimeric protein or peptide comprising an amino acid sequence comprising a somatotropin motif and an amino acid sequence derived from the a5 fibril of type IV collagen.
  • the chimeric protein is a single fusion protein.
  • the chimeric protein or peptide contains one or more amino acid sequences selected from SEQ ID NO: l or a derivative thereof, and one or more amino acid sequences selected from SEQ ID NO: 2 to SEQ ID NO: 39.
  • the chimeric protein or peptide further comprises a linker peptide.
  • the amino acid sequence comprising the somatotropin motif is N-terminal to the linker and the amino acid sequence derived from the a5 fibril of type IV collagen is C-terminal to the linker.
  • the amino acid sequence derived from the a5 fibril of type IV collagen is N-terminal to the linker and the peptide comprising the somatotropin motif is C-terminal to the linker.
  • the size of the linker is not particularly limited, in some embodiments, the linker is about 20 amino acids or less, or about 10 amino acids or less. In some embodiments, the linker is from 1 to 5 amino acids in length.
  • the liner is a flexible linker such as a linker composed predominately of amino acids selected from glycine, serine, threonine, and alanine residues.
  • the linker comprises at least one proline residue.
  • the peptide linker comprises an Fc domain of an antibody (e.g., of IgG, IgA, IgD, and IgE, inclusive of subclasses (e.g., IgGl, IgG2, IgG3, and IgG4, and IgAl and IgA2)).
  • the peptide linker is a hinge region of an antibody (e.g., of IgG, IgA, IgD, and IgE, inclusive of subclasses (e.g., IgGl, IgG2, IgG3, and IgG4, and IgAl and IgA2)).
  • the peptide linker may be functional.
  • the peptide linker may function to improve the folding and/or stability, improve the expression, improve the pharmacokinetics, and/or improve the bioactivity of the present chimeric protein, for example, where recombinant expression of the protein is desired.
  • the peptide linker may function to target the chimeric protein to a particular cell type or location.
  • the linker may be derived from naturally-occurring multi- domain proteins or are empirical linkers as described, for example, in Chichili et ak, (2013), Protein Sci. 22(2): 153-167, Chen et ak, (2013), Adv Drug Deliv Rev. 65(10): 1357- 1369, the entire contents of which are hereby incorporated by reference.
  • the linker may be designed using a linker designing databases and computer programs such as those described in Chen et ak, (2013), Adv Drug Deliv Rev. 65(10): 1357-1369 and Crasto et. ak, (2000), Protein Eng. 13(5):309-312, the entire contents of which are hereby incorporated by reference.
  • the chimeric protein including a peptide linker is a single fusion protein encoded by and translated from a single mRNA.
  • the linker is a non-peptide linker.
  • the linker may be a synthetic linker such as PEG.
  • the peptides disclosed herein, e.g., in an effective amount thereof, may be formulated into pharmaceutical compositions for local or systemic delivery, for example, using a variety of pharmaceutically acceptable carriers, including, but not limited to, water, saline, dextrose solutions, a physiologically-compatible buffers (e.g., Hank's solution, Ringer's solution, or physiological saline buffer), human serum albumin, liposomes, hydrogels, microparticles, nanoparticles, and gels. Techniques and formulations generally may be found in Remington: The Science and Practice of Pharmacy (20th ed.) Lippincott, Williams & Wilkins (2000), which is hereby incorporated by reference in its entirety.
  • the peptides are delivered, for example, in a timed- or sustained release form.
  • Techniques for formulation and administration may be found in Remington: The Science and Practice of Pharmacy (20th ed.) Lippincott, Williams & Wilkins (2000).
  • Suitable routes may include parenteral delivery, such as including intramuscular, subcutaneous, intravenous, intralesional, or intratumoral injections or other modes of delivery.
  • Other modes of delivery include oral, buccal, inhalation, sublingual, rectal, transdermal, nasal, intraocular, or intestinal administration.
  • the peptides can be formulated into pharmaceutical compositions suitable for oral administration using pharmaceutically acceptable carriers well known in the art.
  • an effective amount of the peptide comprising a somatotropin motif and an effective amount of the peptide derived from the a5 fibril of type IV collagen may be provided together in a single pharmaceutical composition.
  • a subject in need thereof may be administered the single pharmaceutical composition which includes effective amounts of each peptide.
  • an effective amount of a peptide will be within the range of from about 100 pg to about 10 mg per dose. The exact dosage will depend upon, for example, the route of administration, the form in which the peptide and/or pharmaceutical composition is administered, and the medical condition of the subject.
  • the peptide is administered at least once daily, at least once weekly, or at least once monthly.
  • the peptides and chimeric proteins disclosed herein are delivered in the form of nanoparticle formulation or microparticle formulations as described in US 9,056,923, US 9,802,984, and WO 2017/087825, which are hereby incorporated by reference in their entireties.
  • the peptides or chimeric proteins may be conjugated to the surface of or encapsulated within the nanoparticle or microparticle.
  • the microparticle, nanoparticle, or gel comprises a biodegradable polymer or a blend of polymers selected from the group consisting of poly(lactic-co-glycolic acid) (PLGA), poly(beta-amino ester) (PBAE), polycaprolactone (PCL), polygly colic acid (PGA), polylactic acid (PL A), poly(acrylic acid) (PAA), poly-3 - hydroxybutyrate (P3HB) and poly(hydroxybutyrate-co-hydroxyvalerate).
  • the particles comprise a blend of PLGA and PBAE.
  • the invention provides methods for treating cancer, including for improving or potentiating cancer immunotherapy.
  • the invention comprises administering a peptide comprising a somatotropin motif, optionally along with an amino acid sequence derived from the a5 fibril of type IV collagen.
  • a somatotropin motif peptide and peptide derived from the a5 fibril of type IV collagen may be administered as separate peptide agents or as a chimeric protein including both amino acid sequences.
  • the peptide or chimeric protein is administered to a patient before, during, and/or after cancer immunotherapy regimen.
  • the cancer immunotherapy may be an antibody or antigen-binding portion thereof that blocks an immune checkpoint molecule, e.g., a molecule selected from B7-H3, B7-H4, BTLA, CD 160, CTLA4, KIR, LAG3, PD-l, PD-L1, PD-L2, TIM3, and TIGIT.
  • the cancer immunotherapy comprises an agonist of an immune co-stimulatory molecule, e.g., a molecule selected from 4-1BB, CD27, CD28, CD40L, CD 137, GITR, ICOS, 0X40, TMIGD2, and TNFRSF25.
  • an immune co-stimulatory molecule e.g., a molecule selected from 4-1BB, CD27, CD28, CD40L, CD 137, GITR, ICOS, 0X40, TMIGD2, and TNFRSF25.
  • the agonist is an antibody or a small molecule.
  • the cancer immunotherapy is an adoptive cell therapy, which can include a recombinant T cell that expresses a CAR-T which recognizes and binds a tumor antigen.
  • the peptide(s) or protein is administered to a cancer patient in connection with a regimen of anti-PDl, anti-PDLl and anti-CTLA4.
  • Peptides comprising a somatotropin motif may bind Neuropilin 1 (NRP1).
  • NRP1 complexes with vascular endothelial growth factor receptor 2 (VEGFR2).
  • VEGFR2 vascular endothelial growth factor receptor 2
  • VEGF-VEGFR2 signaling promotes angiogenesis and lymphangiogenesis and suppresses tumor immune responses by stimulating T regulatory cells (Treg).
  • the peptides comprising a somatotropin motif, or chimeric proteins including such peptides block NRP1-VEGFR2 signaling; thereby, simultaneously inhibiting angiogenesis and lymphangiogenesis as well as Treg tumor infiltration and Treg immune suppression.
  • administering blocks NRP1 signaling on Treg cells.
  • the effective amount of the peptide or chimeric protein promotes induction and/or proliferation of an effector T cell population and/or enhances tumor killing activity by the effector T cell population.
  • Peptides derived from the a5 fibril of type IV collagen may target a5b1 and anb3 integrins in some embodiments, and may inhibit signaling through multiple receptors, including vascular endothelial growth factor receptor (VEGFR), hepatocyte growth factor receptor (HGFR), insulin-like growth factor receptor (IGFR), and epidermal growth factor receptor (EGFR).
  • VEGFR vascular endothelial growth factor receptor
  • HGFR hepatocyte growth factor receptor
  • IGFR insulin-like growth factor receptor
  • EGFR epidermal growth factor receptor
  • These collagen IV-derived biomimetic peptides or amino acid sequences may further promote Tie2 agonist activities of Angiopoietin 2, thereby stabilizing vasculature and/or lymphatic vessels.
  • the peptide or amino acid sequence derived from the a5 fibril of type IV collagen normalizes vasculature, increases tumor perfusion, and/or activates anti-tumor immunity, and can act synergistically with a peptide or amino acid sequence comprising a somatotropin motif.
  • the cancer is a hematological cancer selected from leukemia, lymphoma, and multiple myeloma.
  • the leukemia may be Acute lymphoblastic leukemia (ALL), Acute myelogenous leukemia (AML), Chronic lymphocytic leukemia (CLL), Chronic myelogenous leukemia (CML), or Acute monocytic leukemia (AMoL).
  • the cancer is a lymphoma selected from Hodgkin's lymphoma or a Non-Hodgkin's lymphoma.
  • the cancer comprises a sarcoma, carcinoma, or solid tumor cancer selected from adenocarcinoma, adrenocortical carcinoma, astrocytoma, bladder cancer, breast cancer, cancer of the biliary tract, cancer of the larynx, cancer of the parotid, cervical cancer, colon cancer, desmoid tumors, desmoplastic small round cell tumor, endocrine tumor, endometrial cancer, epithelial carcinoma, esophageal cancer, Ewing sarcoma family tumor, germ cell tumor, germ line tumor, glioblastoma, glioma, hepatoblastoma, hepatocellular carcinoma, liver cancer, lung cancer (including non-small cell lung cancer), melanoma (including advanced melanoma), mesothelioma, neuroblastoma, non-rhabdomyosarcome soft tissue sarcoma, osteosarcoma, ovarian cancer, pancreatic cancer,
  • the cancer is non-small cell lung cancer, melanoma, prostate cancer, or metastatic renal cell cancer.
  • the cancer is triple-negative breast cancer (TNBC), small cell lung cancer (SCLC), glioblastoma, or liver cancer.
  • TNBC triple-negative breast cancer
  • SCLC small cell lung cancer
  • glioblastoma glioblastoma
  • liver cancer liver cancer
  • the patient can have either early stage cancer (e.g stage I or II), or be in later stages (stage III or stage IV).
  • Stage I cancers are localized to one part of the body.
  • Stage II cancers are locally advanced, as are Stage III cancers. Whether a cancer is designated as Stage II or Stage III can depend on the specific type of cancer. For example, stage II can indicate affected lymph nodes on only one side of the diaphragm, whereas stage III indicates affected lymph nodes above and below the diaphragm. The specific criteria for stages II and III therefore differ according to diagnosis.
  • Stage IV cancers have often metastasized, or spread to other organs or throughout the body.
  • the active agents or particle formulation thereof can be administered to prevent progression of Stage I or II cancer, or to slow progression or inhibit further progression of Stage III or Stage IV cancers.
  • the cancer is non-resectable, such as non-resectable liver cancer.
  • a non-resectable cancer is a malignancy which cannot be surgically removed, due either to the number of metastatic foci, or because it is in a surgical danger zone.

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Abstract

The invention provides methods and compositions for treating cancer, including to improve or to potentiate cancer immunotherapy. Aspects of the invention comprise administering a peptide comprising a somatotropin motif amino acid sequence. The peptide comprising a somatotropin motif blocks Neuropilin-1 (NRP1) signaling on T regulatory cells, thereby promoting induction and/or proliferation of an effector T cell population. In embodiments, the peptide comprising a somatotropin motif further comprises or is administered along with an amino acid sequence derived from the α5 fibril of type IV collagen. For example, the somatotropin motif amino acid sequence and amino acid sequence derived from the α5 fibril of type IV collagen may be administered as separate peptide agents or as a chimeric protein including both amino acid sequences.

Description

COMPOSITIONS AND METHODS FOR TREATMENT OF CANCER
BACKGROUND
Tumors often marshal a patient’s immune system by expressing surface molecules that interact with receptors on T-cells to suppress tumor-cell killing activity. Cancer immunotherapies have been developed to block these interactions. The objective of these and other cancer immunotherapies is to free immune effector cells from suppression. However, a large number of immune suppressive pathways have been discovered, which limit current responses to first generation immunotherapy agents.
Thus, there is an unmet need for therapeutics agents to improve and/or potentiate cancer immunotherapy.
SUMMARY OF THE INVENTION
In various aspects and embodiments, the invention provides methods and compositions for treating cancer, including to improve or to potentiate cancer immunotherapy. Aspects of the invention comprise administering a peptide comprising a somatotropin motif amino acid sequence. The peptide comprising a somatotropin motif blocks Neuropilin-l (NRP1) signaling on T regulatory cells, thereby promoting induction and/or proliferation of an effector T cell population. In embodiments, the peptide comprising a somatotropin motif further comprises or is administered along with an amino acid sequence derived from the a5 fibril of type IV collagen. For example, the somatotropin motif amino acid sequence and amino acid sequence derived from the a5 fibril of type IV collagen may be administered as separate peptide agents or as a chimeric protein including both amino acid sequences. In various embodiments, the peptide(s) or protein is administered to a cancer patient in connection with an immunotherapy regimen, including but not limited to anti- PD1, anti-PDLl and anti-CTLA4. The peptide or protein agent may improve response to or potentiate the immunotherapy. A somatotropin motif has the general structure L-X(3)-L-L-X(3)-S-X-L, where X is a variable amino acid and the number in parentheses is the number of consecutive variable amino acids; L is leucine, and S is serine. An exemplary peptide comprising a somatotropin motif comprises the amino acid sequence LLRSSLILLQGSWF (SEQ ID NO: 1).
Peptides derived from the a5 fibril of type IV collagen include those comprising the amino acid sequence LRRFSTXPXXXXNINNVXNF (SEQ ID NO: 2) or LRRFSTXPXXXXDINDVXNF (SEQ ID NO: 3), where X is a standard amino acid or non-genetically encoded amino acid. Exemplary amino acid sequences derived from the a5 fibril of type IV collagen include LRRFSTAPFAFININNVINF (SEQ ID NO: 4) and LRRFSTAPFAFIDINDVINF (SEQ ID NO: 24).
In embodiments, an effective amount of the peptide comprising a somatotropin motif blocks NRP1 signaling on Treg cells, thereby blocking Treg-driven immunosuppression, while an effective amount of the peptide derived from the a5 fibril of type IV collagen normalizes vasculature, increases tumor perfusion, provides anti- angiogenic, and/or activates anti-tumor immunity. These agents can act synergistically, including to improve response to checkpoint inhibitor therapy.
In aspects and embodiments, the invention provides a chimeric protein or peptide comprising an amino acid sequence comprising a somatotropin motif and an amino acid sequence derived from the a5 fibril of type IV collagen. In some embodiments, the chimeric protein is a single fusion protein or peptide, which may optionally comprise a linking sequence.
In various embodiments, the peptide or chimeric protein is administered to a patient before, during, and/or after cancer immunotherapy. For example, the cancer immunotherapy may be an antibody or antigen-binding portion thereof that blocks an immune checkpoint molecule, e.g., a molecule selected from B7-H3, B7-H4, BTLA, CD 160, CTLA4, KIR, LAG3, PD-l, PD-L1, PD-L2, TIM3, and TIGIT. In some embodiments, the peptide or chimeric protein is administered in connection with an immune co-stimulatory molecule or an adoptive cell therapy (e.g., CAR-T). The invention in various embodiments is applicable to hematological cancers as well as solid tumors, including early or late stages cancers.
Other aspects and embodiments of the invention will be apparent from the following detailed description. DETAILED DESCRIPTION
In various aspects and embodiments, the invention provides methods and compositions for treating cancer. Aspects of the invention comprise administering a peptide comprising a somatotropin motif amino acid sequence. In embodiments, the peptide comprising a somatotropin motif blocks Neuropilin-l (NRP1) signaling on T regulatory cells (Treg; formerly known as “suppressor T cells”), thereby promoting induction and/or proliferation of an effector T cell population. In embodiments, the peptide comprising a somatotropin motif further comprises or is administered along with an amino acid sequence derived from the a5 fibril of type IV collagen. For example, the somatotropin motif amino acid sequence and amino acid sequence derived from the a5 fibril of type IV collagen may be administered as separate peptide agents or as a chimeric protein including both amino acid sequences. In various embodiments, the peptide(s) or protein is administered to a cancer patient in connection with an immunotherapy regimen, including but not limited to anti-PDl, anti-PDLl and anti-CTLA4.
Peptides comprising a somatotropin motif are described in ETS 8,507,434, which is hereby incorporated by reference in its entirety. In various embodiments, the peptide comprising a somatotropin motif also inhibits undesirable or excess angiogenesis and/or lymphangiogenesis. The peptide comprising a somatotropin motif may reduce blood vessel and/or lymph vessel formation, for example, by reducing endothelial cell proliferation, migration, survival, and/or stability and/or by increasing endothelial cell death. In embodiments, a somatotropin motif has the general structure L-X(3)-L-L-X(3)-
S-X-L, where X is a variable amino acid and the number in parentheses is the number of consecutive variable amino acids; L is leucine, and S is serine. An exemplary peptide comprising a somatotropin motif comprises the amino acid sequence LLRSSLILLQGSWF (SEQ ID NO: 1), or derivatives thereof. Derivatives of the peptide of SEQ ID NO: 1 include peptides having from 1 to 5 amino acid modifications independently selected from substitutions, insertions, or deletions ( e.g ., 1, 2, 3, 4, or 5 amino acid substitutions, insertions, or deletions) with respect to SEQ ID NO: 1.
In various embodiments, the peptide comprising a somatotropin motif contains about 35 amino acids or less, or about 30 amino acids or less, or about 25 amino acids or less, or about 20 amino acids or less, or about 15 amino acids of less, or is about 10, 11, 12, 13, or 14 amino acids in length. In some embodiments, one, two, three, four, or five amino acids of SEQ ID NO: 1 are deleted from its C-terminal end and/or from its N- terminal end (collectively).
In embodiments, amino acid substitutions are made at any position of SEQ ID NO: 1, which can be independently selected from conservative or non-conservative substitutions. In these or other embodiments, the peptide includes from 1 to 10 amino acids added to one or both termini (collectively). The N- and/or C-termini may optionally be occupied by another chemical group (other than amine or carboxy, e.g., amide or thiol), and which can be useful for conjugation of other moieties, including PEG or PLGA-PEG co-polymers.
Conservative substitutions may be made, for instance, on the basis of similarity in polarity, charge, size, solubility, hydrophobicity, hydrophilicity, and/or the amphipathic nature of the amino acid residues involved. The 20 genetically encoded amino acids can be grouped into the following six standard amino acid groups:
(1) hydrophobic: Met, Ala, Val, Leu, and Ile;
(2) neutral hydrophilic: Cys, Ser, Thr, Asn, and Gln;
(3) acidic: As and Glu;
(4) basic: His, Lys, and Arg;
(5) residues that influence chain orientation: Gly and Pro; and
(6) aromatic: Trp, Tyr, and Phe. As used herein,“conservative substitutions” are defined as exchanges of an amino acid by another amino acid listed within the same group of the six standard amino acid groups shown above. For example, the exchange of Asp by Glu retains one negative charge in the so modified polypeptide. In addition, glycine and proline may be substituted for one another based on their ability to disrupt a-helices. Some preferred conservative substitutions within the above six groups are exchanges within the following sub-groups: (i) Ala, Val, Leu and Ile; (ii) Ser and Thr; (iii) Asn and Gln; (iv) Lys and Arg; and (v) Tyr and Phe.
As used herein,“non-conservative substitutions” are defined as exchanges of an amino acid by another amino acid listed in a different group of the six standard amino acid groups (1) to (6) shown above.
Peptides derived from the a5 fibril of type IV collagen include those described in US 9,056,923, US 9,802,984, and WO 2017/087825, each of which is hereby incorporated by reference in its entirety. In some embodiments, the peptide comprising an amino acid sequence derived from a5 fibril of type IV collagen comprises the amino acid sequence LRRFSTXPXXXXNINNVXNF (SEQ ID NO: 2), where X is a standard amino acid or non-genetically encoded amino acid. In some embodiments, X at position 7 is M, A, or G; X at position 9 is F, A, Y, or G; X at position 10 is M, A, G, D-Alanine (dA), or norleucine (Nle); X at position 11 is F, A, Y, G, or 4-chlorophenylalanine (4-ClPhe); X at position 12 and position 18 are independently selected from 2-Aminobutyric acid (Abu), G, S, A, V, T, I, L, or Allylglycine (AllylGly). In various embodiments, the peptide comprising the amino acid sequence derived from a5 fibril of type IV collagen contains about 30 amino acids or less, or about 25 amino acids of less, or about 24 amino acids, or about 23 amino acids, or about 22 amino acids, or about 21 amino acids, or about 20 amino acids. In still other embodiments, one, two, three, four, or five amino acids of SEQ ID NO: 2 are deleted from its C-terminal end and/or from its N-terminal end (collectively).
In embodiments, the amino acid sequence derived from the a5 fibril of type IV collagen comprises the amino acid sequence LRRFSTXPXXXXDINDVXNF (SEQ ID NO: 3), where X is a standard amino acid or non-genetically encoded amino acid. In some embodiments, X at position 7 is M, A, or G; X at position 9 is F, A, Y, or G; X at position 10 is M, A, G, D-Alanine (dA), or norleucine (Nle); X at position 11 is F, A, Y, G, or 4-chlorophenylalanine (4-ClPhe); X at position 12 and position 18 are independently selected from 2-Aminobutyric acid (Abu), G, S, A, V, T, I, L, or Allylglycine (AllylGly). In various embodiments, the peptide contains about 30 amino acids or less, or about 25 amino acids of less, or about 24 amino acids, or about 23 amino acids, or about 22 amino acids, or about 21 amino acids, or about 20 amino acids. In still other embodiments, one, two, three, four, or five amino acids of SEQ ID NO: 3 are deleted from its C-terminal end and/or from its N-terminal end (collectively).
In some embodiments, the amino acid sequence derived from the a5 fibril of type IV collagen comprises the amino acid sequence LRRFSTAPFAFININNVINF (SEQ ID NO: 4) or LRRFSTAPFAFIDINDVINF (SEQ ID NO: 24) or derivatives thereof. Derivatives include peptides having from 1 to 5 amino acid modifications independently selected from substitutions, insertions, or deletions ( e.g ., 1, 2, 3, 4, or 5 amino acid substitutions, insertions, or deletions) with respect to SEQ ID NO: 4 or 24. In various embodiments, the peptide comprising about 35 amino acids or less, or about 30 amino acids or less, or about 25 amino acids or less, or about 20 amino acids or less, or about 15 amino acids. In some embodiments, one, two, three, four, or five amino acids of SEQ ID NO: 1 are deleted from its C-terminal end and/or from its N-terminal end (collectively).
In certain embodiments, amino acid substitutions are made at any position of SEQ ID NO: 4 or 24, which can be independently selected from conservative or non conservative substitutions. In these or other embodiments, the peptide includes from 1 to 10 amino acids added to one or both termini (collectively). The N- and/or C-termini may optionally be occupied by another chemical group (other than amine or carboxy, e.g., amide or thiol), and which can be useful for conjugation of other moieties, including PEG or PLGA-PEG co-polymers.
In embodiments, the peptide derived from the a5 fibril of type IV collagen is a peptide of from about 8 to about 30 amino acids, or from about 10 to about 20 amino acids, and has at least 4, at least 5, or at least 6 contiguous amino acids of SEQ ID NO: 2 or SEQ ID NO: 3. In some embodiments, the peptide contains at least one, at least two, or at least three D-amino acids, e.g., dA, dL, and dF. In some embodiments, the peptide contains from one to about five (e.g., 1, 2, or 3) non-genetically encoded amino acids, which are optionally selected from 2-Aminobutyric acid (Abu), norleucine (Nle), 4- chlorophenylalanine (4-ClPhe), and Allylglycine (AllylGly). Exemplary peptides derived from the a5 fibril of type IV collagen in accordance with the disclosure include:
LRRFSTAPFAFININNVINF (SEQ ID NO: 4),
LRRF S TMP AMF ( Abu)NINN V ( Abu)NF (SEQ ID NO: 5),
LRRF S TMPF (Nl e)F ( Abu)NINN V ( Abu)NF (SEQ ID NO: 6),
LRRF S TMPF AF ( Abu)NINN V ( Abu)NF (SEQ ID NO: 7),
LRRF STMPF AFININNVINF (SEQ ID NO: 8),
LRRFSTMPF(dA)FININNVINF (SEQ ID NO: 9),
LRRFSTMPFM(4-ClPhe)(Abu)NINNV(Abu)NF (SEQ ID NO: 10),
LRRF S TMPFM A( Abu)NINN V ( Abu)NF (SEQ ID NO: 11),
LRRF S TMPFMF ( Abu)NINN V ( Abu)NF (SEQ ID NO: 12),
LRRF STMPFMF (Ally Gly)NINNV (Ally Gly)NF (SEQ ID NO: 13),
LRRF S TMPFMF ANINN V ANF (SEQ ID NO: 14),
LRRF S TMPFMF GNINN V GNF (SEQ ID NO: 15),
LRRF STMPFMF ININNVINF (SEQ ID NO: 16),
LRRF STMPFMF SNINNVSNF (SEQ ID NO: 17),
LRRF S TMPFMF TNINN VTNF (SEQ ID NO: 18),
LRRF STMPFMF VNINNVVNF (SEQ ID NO: 19),
LRRF S T APF (d A)FIDIND VINF (SEQ ID NO:20),
(dL)RR(dL)RRF S T APF AFIDIND VINF (SEQ ID NO: 21),
LRRF S T APF AFIDIND VIN (dF) (SEQ ID NO: 22),
(dL)RRF S T APF AFIDIND VIN (dF ) (SEQ ID NO: 23), and
LRRF STAPF AFIDIND VINF (SEQ ID NO: 24).
In embodiments, the peptide derived from the a5 fibril of type IV collagen is a peptide comprising at least one C-terminal amino acid deletion and/or at least one N- terminal amino acid deletion relative to SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO:4, or SEQ ID NO:24, or derivative thereof. Exemplary peptides derived from the a5 fibril of type IV collagen in accordance with the disclosure include:
A( Abu)NINN V ( Abu)NF (SEQ ID NO: 25),
F ( Abu)NINN V ( Abu)N (SEQ ID NO: 26),
F (Ally Gly)NINNV( Ally Gly)NF (SEQ ID NO: 27),
FANINNVANF (SEQ ID NO: 28),
FININNVINF (SEQ ID NO: 29),
FSNINNVSNF (SEQ ID NO: 30),
FTNINNVTN (SEQ ID NO: 31),
FVNINNVVNF (SEQ ID NO: 32),
LRRF STMPFMFININN (SEQ ID NO: 33),
LRRF S TMPFMF TNINN (SEQ ID NO: 34),
FIDINDVINF (SEQ ID NO: 35),
FIDINDVINW (SEQ ID NO: 36),
FTDINDVTN (SEQ ID NO: 37),
(4-ClPhe)(Abu)NINNV(Abu)NF (SEQ ID NO: 38), and
LRRFSTAPFAFIDINDVINW (SEQ ID NO: 39).
Thus, an exemplary peptide derived from the a5 fibril of type IV collagen comprises, consists of, or consists essentially of the amino acid sequence LRRFSTAPFAFININNVINF (SEQ ID NO: 4) or LRRFSTAPFAFIDINDVINF (SEQ ID NO: 24).
In certain embodiments, at least one of the amino acid sequences is a retroinverso peptide of any amino acid sequence selected from SEQ ID NOS: l to 39. Retro-inverso peptides are linear peptides whose amino acid sequence is reversed and the a-center chirality of the amino acid subunits is inverted as well. These peptides are designed by including D-amino acids in the reverse sequence to help maintain side chain topology similar to that of the original L-amino acid peptide. Retro-inverso peptides maintain side chain topology similar to that of the original L-amino acid peptide, and also render the peptide more resistant to proteolytic degradation. In embodiments, a retro-inverso peptide has binding characteristics similar to its corresponding L-amino acid peptide; retro-inverso peptides mimic the shape of peptide epitopes, the protein-protein interactions, and/or protein-peptide interfaces of the corresponding L-amino acid peptide.
The peptides described herein can be chemically synthesized and purified using well-known techniques, such as solid-phase synthesis. See US 9,051,349, which is hereby incorporated by reference in its entirety.
In embodiments, an effective amount of the peptide comprising a somatotropin motif blocks NRP1 signaling on Treg cells, e.g., to inhibit an immunosuppressive activity of the Treg. In embodiments, the effective amount of the peptide comprising a somatotropin motif promotes induction and/or proliferation of an effector T cell and/or enhances tumor killing activity by the effector T cell. An effective amount of the peptide derived from the a5 fibril of type IV collagen normalizes vasculature, increases tumor perfusion, provides anti-angiogenic, anti-vascular permeability, anti-tumorigenesis, and/or anti-lymphangiogenic properties and/or activates anti-tumor immunity. These peptide motifs may be administered as separate agents or via a chimeric peptide to provide synergistic therapeutic effects.
In aspects and embodiments, the invention provides a chimeric protein or peptide comprising an amino acid sequence comprising a somatotropin motif and an amino acid sequence derived from the a5 fibril of type IV collagen. In some embodiments, the chimeric protein is a single fusion protein. In various embodiments, the chimeric protein or peptide contains one or more amino acid sequences selected from SEQ ID NO: l or a derivative thereof, and one or more amino acid sequences selected from SEQ ID NO: 2 to SEQ ID NO: 39.
In some embodiments, the chimeric protein or peptide further comprises a linker peptide. In some embodiments, the amino acid sequence comprising the somatotropin motif is N-terminal to the linker and the amino acid sequence derived from the a5 fibril of type IV collagen is C-terminal to the linker. In alternate embodiments, the amino acid sequence derived from the a5 fibril of type IV collagen is N-terminal to the linker and the peptide comprising the somatotropin motif is C-terminal to the linker. While the size of the linker is not particularly limited, in some embodiments, the linker is about 20 amino acids or less, or about 10 amino acids or less. In some embodiments, the linker is from 1 to 5 amino acids in length. In some embodiments, the liner is a flexible linker such as a linker composed predominately of amino acids selected from glycine, serine, threonine, and alanine residues. In some embodiments, the linker comprises at least one proline residue.
In various embodiments, the peptide linker comprises an Fc domain of an antibody (e.g., of IgG, IgA, IgD, and IgE, inclusive of subclasses (e.g., IgGl, IgG2, IgG3, and IgG4, and IgAl and IgA2)). In various embodiments, the peptide linker is a hinge region of an antibody (e.g., of IgG, IgA, IgD, and IgE, inclusive of subclasses (e.g., IgGl, IgG2, IgG3, and IgG4, and IgAl and IgA2)).
In various embodiments, the peptide linker may be functional. For example, without limitation, the peptide linker may function to improve the folding and/or stability, improve the expression, improve the pharmacokinetics, and/or improve the bioactivity of the present chimeric protein, for example, where recombinant expression of the protein is desired. In another example, the peptide linker may function to target the chimeric protein to a particular cell type or location.
In various embodiments, the linker may be derived from naturally-occurring multi- domain proteins or are empirical linkers as described, for example, in Chichili et ak, (2013), Protein Sci. 22(2): 153-167, Chen et ak, (2013), Adv Drug Deliv Rev. 65(10): 1357- 1369, the entire contents of which are hereby incorporated by reference. In some embodiments, the linker may be designed using a linker designing databases and computer programs such as those described in Chen et ak, (2013), Adv Drug Deliv Rev. 65(10): 1357-1369 and Crasto et. ak, (2000), Protein Eng. 13(5):309-312, the entire contents of which are hereby incorporated by reference. In embodiments, the chimeric protein including a peptide linker is a single fusion protein encoded by and translated from a single mRNA.
In some embodiments, the linker is a non-peptide linker. For example, the linker may be a synthetic linker such as PEG. The peptides disclosed herein, e.g., in an effective amount thereof, may be formulated into pharmaceutical compositions for local or systemic delivery, for example, using a variety of pharmaceutically acceptable carriers, including, but not limited to, water, saline, dextrose solutions, a physiologically-compatible buffers (e.g., Hank's solution, Ringer's solution, or physiological saline buffer), human serum albumin, liposomes, hydrogels, microparticles, nanoparticles, and gels. Techniques and formulations generally may be found in Remington: The Science and Practice of Pharmacy (20th ed.) Lippincott, Williams & Wilkins (2000), which is hereby incorporated by reference in its entirety.
In embodiments, the peptides are delivered, for example, in a timed- or sustained release form. Techniques for formulation and administration may be found in Remington: The Science and Practice of Pharmacy (20th ed.) Lippincott, Williams & Wilkins (2000).
Suitable routes may include parenteral delivery, such as including intramuscular, subcutaneous, intravenous, intralesional, or intratumoral injections or other modes of delivery. Other modes of delivery include oral, buccal, inhalation, sublingual, rectal, transdermal, nasal, intraocular, or intestinal administration. The peptides can be formulated into pharmaceutical compositions suitable for oral administration using pharmaceutically acceptable carriers well known in the art.
Alternately, an effective amount of the peptide comprising a somatotropin motif and an effective amount of the peptide derived from the a5 fibril of type IV collagen may be provided together in a single pharmaceutical composition. Thus, a subject in need thereof may be administered the single pharmaceutical composition which includes effective amounts of each peptide. In some embodiments, an effective amount of a peptide will be within the range of from about 100 pg to about 10 mg per dose. The exact dosage will depend upon, for example, the route of administration, the form in which the peptide and/or pharmaceutical composition is administered, and the medical condition of the subject. In various embodiments, the peptide is administered at least once daily, at least once weekly, or at least once monthly.
In various aspects and embodiments, the peptides and chimeric proteins disclosed herein are delivered in the form of nanoparticle formulation or microparticle formulations as described in US 9,056,923, US 9,802,984, and WO 2017/087825, which are hereby incorporated by reference in their entireties. For example, the peptides or chimeric proteins may be conjugated to the surface of or encapsulated within the nanoparticle or microparticle. In particular embodiments, the microparticle, nanoparticle, or gel comprises a biodegradable polymer or a blend of polymers selected from the group consisting of poly(lactic-co-glycolic acid) (PLGA), poly(beta-amino ester) (PBAE), polycaprolactone (PCL), polygly colic acid (PGA), polylactic acid (PL A), poly(acrylic acid) (PAA), poly-3 - hydroxybutyrate (P3HB) and poly(hydroxybutyrate-co-hydroxyvalerate). In some embodiments, the particles comprise a blend of PLGA and PBAE.
In some aspects, the invention provides methods for treating cancer, including for improving or potentiating cancer immunotherapy. In accordance with embodiments, the invention comprises administering a peptide comprising a somatotropin motif, optionally along with an amino acid sequence derived from the a5 fibril of type IV collagen. For example, a somatotropin motif peptide and peptide derived from the a5 fibril of type IV collagen may be administered as separate peptide agents or as a chimeric protein including both amino acid sequences.
In various embodiments, the peptide or chimeric protein is administered to a patient before, during, and/or after cancer immunotherapy regimen. For example, the cancer immunotherapy may be an antibody or antigen-binding portion thereof that blocks an immune checkpoint molecule, e.g., a molecule selected from B7-H3, B7-H4, BTLA, CD 160, CTLA4, KIR, LAG3, PD-l, PD-L1, PD-L2, TIM3, and TIGIT.
In some embodiments, the cancer immunotherapy comprises an agonist of an immune co-stimulatory molecule, e.g., a molecule selected from 4-1BB, CD27, CD28, CD40L, CD 137, GITR, ICOS, 0X40, TMIGD2, and TNFRSF25. In embodiments, the agonist is an antibody or a small molecule.
In various embodiments, the cancer immunotherapy is an adoptive cell therapy, which can include a recombinant T cell that expresses a CAR-T which recognizes and binds a tumor antigen. In various embodiments, the peptide(s) or protein is administered to a cancer patient in connection with a regimen of anti-PDl, anti-PDLl and anti-CTLA4.
Peptides comprising a somatotropin motif may bind Neuropilin 1 (NRP1). NRP1 complexes with vascular endothelial growth factor receptor 2 (VEGFR2). When peptides comprising a somatotropin motif bind NRP1, the complexes of NRP1 and VEGFR2 can be disrupted, resulting in inhibition of VEGFA-dependent signaling of the VEGFR2 pathway. VEGF-VEGFR2 signaling promotes angiogenesis and lymphangiogenesis and suppresses tumor immune responses by stimulating T regulatory cells (Treg). Without wishing to be bound by theory, the peptides comprising a somatotropin motif, or chimeric proteins including such peptides, block NRP1-VEGFR2 signaling; thereby, simultaneously inhibiting angiogenesis and lymphangiogenesis as well as Treg tumor infiltration and Treg immune suppression.
In embodiments, administration of an effective amount of a peptide comprising a somatotropin motif or a chimeric protein including the peptide blocks NRP1 signaling on Treg cells. Thus, the effective amount of the peptide or chimeric protein promotes induction and/or proliferation of an effector T cell population and/or enhances tumor killing activity by the effector T cell population.
Peptides derived from the a5 fibril of type IV collagen may target a5b1 and anb3 integrins in some embodiments, and may inhibit signaling through multiple receptors, including vascular endothelial growth factor receptor (VEGFR), hepatocyte growth factor receptor (HGFR), insulin-like growth factor receptor (IGFR), and epidermal growth factor receptor (EGFR). These collagen IV-derived biomimetic peptides or amino acid sequences may further promote Tie2 agonist activities of Angiopoietin 2, thereby stabilizing vasculature and/or lymphatic vessels. Thus, the peptide or amino acid sequence derived from the a5 fibril of type IV collagen normalizes vasculature, increases tumor perfusion, and/or activates anti-tumor immunity, and can act synergistically with a peptide or amino acid sequence comprising a somatotropin motif.
In various embodiments, the cancer is a hematological cancer selected from leukemia, lymphoma, and multiple myeloma. As examples, the leukemia may be Acute lymphoblastic leukemia (ALL), Acute myelogenous leukemia (AML), Chronic lymphocytic leukemia (CLL), Chronic myelogenous leukemia (CML), or Acute monocytic leukemia (AMoL). In some embodiments, the cancer is a lymphoma selected from Hodgkin's lymphoma or a Non-Hodgkin's lymphoma.
In some embodiments, the cancer comprises a sarcoma, carcinoma, or solid tumor cancer selected from adenocarcinoma, adrenocortical carcinoma, astrocytoma, bladder cancer, breast cancer, cancer of the biliary tract, cancer of the larynx, cancer of the parotid, cervical cancer, colon cancer, desmoid tumors, desmoplastic small round cell tumor, endocrine tumor, endometrial cancer, epithelial carcinoma, esophageal cancer, Ewing sarcoma family tumor, germ cell tumor, germ line tumor, glioblastoma, glioma, hepatoblastoma, hepatocellular carcinoma, liver cancer, lung cancer (including non-small cell lung cancer), melanoma (including advanced melanoma), mesothelioma, neuroblastoma, non-rhabdomyosarcome soft tissue sarcoma, osteosarcoma, ovarian cancer, pancreatic cancer, peripheral primative neuroectodermal tumor, prostate cancer, rectal cancer, renal cancer (including metastatic renal cell cancer), retinoblastoma, rhabdomyosarcoma, small cell carcinoma, squamous cell carcinoma, stomach cancer, testicular cancer, thyroid cancer, tumors of the central nervous system, uterine cancer, and Wilms’ tumor.
In some embodiments, the cancer is non-small cell lung cancer, melanoma, prostate cancer, or metastatic renal cell cancer.
In some embodiments, the cancer is triple-negative breast cancer (TNBC), small cell lung cancer (SCLC), glioblastoma, or liver cancer.
In various embodiments, the patient can have either early stage cancer ( e.g stage I or II), or be in later stages (stage III or stage IV). Stage I cancers are localized to one part of the body. Stage II cancers are locally advanced, as are Stage III cancers. Whether a cancer is designated as Stage II or Stage III can depend on the specific type of cancer. For example, stage II can indicate affected lymph nodes on only one side of the diaphragm, whereas stage III indicates affected lymph nodes above and below the diaphragm. The specific criteria for stages II and III therefore differ according to diagnosis. Stage IV cancers have often metastasized, or spread to other organs or throughout the body. The active agents or particle formulation thereof can be administered to prevent progression of Stage I or II cancer, or to slow progression or inhibit further progression of Stage III or Stage IV cancers.
In some embodiments, the cancer is non-resectable, such as non-resectable liver cancer. A non-resectable cancer is a malignancy which cannot be surgically removed, due either to the number of metastatic foci, or because it is in a surgical danger zone.
As used in this Specification and the appended claims, the singular forms“a,”“an” and“the” include plural referents unless the context clearly dictates otherwise.
ETnless specifically stated or obvious from context, as used herein, the term“or” is understood to be inclusive and covers both“or” and“and”.
ETnless specifically stated or obvious from context, as used herein, the term“about” is understood as within a range of normal tolerance in the art, for example, within plus or minus 10%.
REFERENCES
Hansen “Neuropilin 1 guides regulatory T cells into VEGF-producing melanoma” Oncoimmunology . 2011; 2(2): e23039.
Lee, et al.,“Inhibition of lymphangiogenesis and angiogenesis in breast tumor xenografts and lymph nodes by a peptide derived from transmembrane protein 45A.” Neoplasia. 2013;15(2): 112-24.
Lee, et al., “Small Peptides Derived from Somatotropin Domain-Containing Proteins Inhibit Blood and Lymphatic Endothelial Cell Proliferation, Migration, Adhesion and Tube Formation” The International Journal of Biochemistry & Cell Biology. 20l l;43., 1812- 1821.
Rosea et al.,“Structure-activity relationship study of collagen derived anti-angiogenic biomimetic peptides”, Chem. Biol. Drug Des. 2012; 80(l):27-37.

Claims

1. A method for treating cancer in a subject undergoing a cancer immunotherapy, comprising administering to the subject a pharmaceutical composition comprising an effective amount of a peptide comprising a somatotropin motif.
2. The method of claim 1, wherein the somatotropin motif comprises the amino acid sequence LLRSSLILLQGSWF (SEQ ID NO: 1), optionally having from 1 to 5 amino acid modifications, independently selected from substitutions, insertions, and deletions.
3. The method of claim 1 or claim 2, wherein the composition is administered as a regimen to the subject prior to the cancer immunotherapy, coincidental with the cancer immunotherapy, and/or after the cancer immunotherapy.
4. The method of any one of claims 1 to 3, wherein the effective amount blocks NRP1 signaling on Treg cells.
5. The method of claim 4, wherein the effective amount promotes induction and/or proliferation of an effector T cell population and/or enhances tumor killing activity by the effector T cell population.
6. The method of any one of claims 1 to 5, wherein the subject is a human.
7. The method of any one of claims 1 to 6, wherein the cancer immunotherapy is an antibody that blocks an immune checkpoint molecule.
8. The method of any one of claims 7, wherein the immune checkpoint molecule is selected from B7-H3, B7-H4, BTLA, CD160, CTLA4, KIR, LAG3, PD-l, PD-L1, PD-L2, TIM3, and TIGIT.
9. The method of any one of claims 1 to 6, wherein the cancer immunotherapy comprises an agonist of an immune co-stimulatory molecule.
10. The method of any claim 9, wherein the immune co- stimulatory molecule is selected from 4-1BB, CD27, CD28, CD40L, CD137, GITR, ICOS, 0X40, TMIGD2, and TNFRSF25.
11. The method of any one of claims 1 to 10, further comprising, administering an effective amount of a peptide derived from the a5 fibril of type IV collagen, or a derivative thereof.
12. The method of claim 11, wherein the peptide is administered in the same pharmaceutical composition or in a separate composition as the peptide comprising the somatotropin motif.
13. The method of claim 11 or claim 12, wherein the peptide derived from the a5 fibril of type IV collagen or a derivative thereof forms a chimeric peptide with the peptide comprising the somatotropin motif.
14. The method of any one of claims 11 to 13, wherein the peptide derived from the a5 fibril of type IV collagen comprises the amino acid sequence LRRF S TXPXXXXNINN VXNF (SEQ ID NO: 2) or LRRFSTXPXXXXDINDVXNF (SEQ ID NO: 3), where X is a genetically-encoded or non-genetically-encoded amino acid.
15. The method of claim 14, wherein the peptide derived from the a5 fibril of type IV collagen comprises the amino acid sequence LRRF S TXPXXXXNINN VXNF (SEQ ID
NO: 2), wherein X at position 7 is M, A, or G; X at position 9 is F, A, Y, or G; X at position 10 is M, A, G, dA, or Nle; X at position 11 is F, A, Y, G, or 4-ClPhe; X at position 12 and position 18 are independently Abu, G, S, A, V, T, I, L, or AllyGly.
16. The method of any one of claims 11 to 15, wherein the peptide derived from the a5 fibril of type IV collagen comprises an amino acid sequence selected from:
LRRFSTAPFAFININNVINF (SEQ ID NO: 4),
LRRF S TMP AMF ( Abu)NINN V ( Abu)NF (SEQ ID NO: 5),
LRRF S TMPF (Nl e)F ( Abu)NINN V ( Abu)NF (SEQ ID NO: 6),
LRRF S TMPF AF ( Abu)NINN V ( Abu)NF (SEQ ID NO: 7),
LRRF STMPF AFININNVINF (SEQ ID NO: 8),
LRRFSTMPF(dA)FININNVINF (SEQ ID NO: 9),
LRRFSTMPFM(4-ClPhe)(Abu)NINNV(Abu)NF (SEQ ID NO: 10),
LRRF S TMPFM A( Abu)NINN V ( Abu)NF (SEQ ID NO: 11), LRRF S TMPFMF ( Abu)NINN V ( Abu)NF (SEQ ID NO: 12),
LRRF STMPFMF (Ally Gly)NINNV (Ally Gly)NF (SEQ ID NO: 13),
LRRF S TMPFMF ANINN V ANF (SEQ ID NO: 14),
LRRF S TMPFMF GNINN V GNF (SEQ ID NO: 15),
LRRF STMPFMF ININNVINF (SEQ ID NO : 16),
LRRF STMPFMF SNINNVSNF (SEQ ID NO: 17),
LRRF S TMPFMF TNINN VTNF (SEQ ID NO: 18), and
LRRF STMPFMF VNINNVVNF (SEQ ID NO: 19).
17. The method of any one of claims 11 to 13, wherein the peptide derived from the a5 fibril of type IV collagen comprises at least one C-terminal amino acid deletion and/or at least one N-terminal amino acid deletion relative to SEQ ID NO: 2, and wherein the peptide comprises at least one of the following amino acid sequences:
A( Abu)NINN V ( Abu)NF (SEQ ID NO: 25),
F ( Abu)NINN V ( Abu)N (SEQ ID NO: 26),
F (Ally Gly)NINNV( Ally Gly)NF (SEQ ID NO: 27),
F ANINN V ANF (SEQ ID NO: 28),
F ININNVINF (SEQ ID NO: 29),
F SNINNVSNF (SEQ ID NO: 30),
FTNINNVTN (SEQ ID NO: 31),
F VNINNVVNF (SEQ ID NO: 32),
LRRF STMPFMF ININN (SEQ ID NO: 33), and
LRRF S TMPFMF TNINN (SEQ ID NO: 34).
18. The method of claim 14, wherein the peptide derived from the a5 fibril of type IV collagen comprises the amino acid sequence LRRFSTXPXXXXDINDVXNF (SEQ ID NO: 3), wherein X at position 7 is M, A, or G; X at position 9 is F, A, Y, or G; X at position 10 is M, A, G, dA, or Nle; X at position 11 is F, A, Y, G, or 4-ClPhe; and X at position 12 and position 18 are independently Abu, G, S, A, V, T, I, L, or AllyGly.
19. The method of claim 18, wherein the peptide derived from the a5 fibril of type IV collagen comprises an amino acid sequence selected from: (clL)RR(dL)RRFSTAPFAFIDINDVINF (SEQ ID NO: 21),
FRRFSTAPFAFIDINDVIN(dF) (SEQ ID NO: 22),
(dL)RRF S T APF FIDIND VIN (dF ) (SEQ ID NO: 23), or
FRRFSTAPFAFIDINDVINF (SEQ ID NO: 24).
20. The method of any one of claims 11 to 13, wherein the peptide derived from the a5 fibril of type IV collagen comprises at least one C-terminal amino acid deletion and/or at least one N-terminal amino acid deletion relative to SEQ ID NO: 3, and wherein the peptide comprises at least one of the following amino acid sequences:
FIDINDVINF (SEQ ID NO: 35),
FIDIND VINW (SEQ ID NO : 36),
FTDINDVTN (SEQ ID NO: 37),
(4-ClPhe)(Abu)NINNV(Abu)NF (SEQ ID NO: 38), and
LRRFSTAPF AFIDIND VINW (SEQ ID NO: 39).
21. The method of any one of claims 11 to 20, wherein the effective amount of the peptide derived from the a5 fibril of type IV collagen normalizes vasculature, increases tumor perfusion, and/or activates anti-tumor immunity.
22. The method of any one of claims 1 to 21, wherein the cancer immunotherapy is an adoptive cell therapy.
23. The method of claim 22, wherein the adoptive cell therapy is a recombinant T cell that expresses a CAR-T which recognizes and binds a tumor antigen.
24. The method of any one of claims 1 to 23, wherein the cancer is a hematological cancer selected from leukemia, lymphoma, and multiple myeloma.
25. The method of any one of claims 1 to 23, wherein the cancer comprises a sarcoma, carcinoma, or solid tumor cancer.
26. A chimeric protein comprising:
(a) a first amino acid sequence comprising a somatotropin motif, and
(b) a second amino acid derived from a5 fibril of type IV collagen.
27. The chimeric protein of claim 26 further comprising: a linker linking the first amino acid sequence and the second amino acid sequence.
28. The chimeric protein of claim 27, wherein the first amino acid sequence is N-terminal to the linker and the second amino acid sequence is C-terminal to the linker.
29. The chimeric protein of claim 27, wherein the second amino acid sequence is N- terminal to the linker and the first amino acid sequence is C-terminal to the linker.
30. The chimeric protein of any one of claims 26 to 29, wherein the somatotropin motif comprises the amino acid sequence LLRSSLILLQGSWF (SEQ ID NO: 1), optionally having from 1 to 5 amino acid modifications independently selected from substitutions, insertions, or deletions.
31. The chimeric protein of any one of claims 26 to 30, wherein the second amino acid sequence comprises LRRFSTXPXXXXNINNVXNF (SEQ ID NO: 2) or LRRF S TXPXXXXDIND VXNF (SEQ ID NO: 3), where X is a genetically-encoded or non-genetically-encoded amino acid.
32. The chimeric protein of any one of claims 26 to 30, wherein the second amino acid sequence comprises LRRFSTXPXXXXNINNVXNF (SEQ ID NO: 2), wherein X at position 7 is M, A, or G; X at position 9 is F, A, Y, or G; X at position 10 is M, A, G, dA, or Nle; X at position 11 is F, A, Y, G, or 4-ClPhe; X at position 12 and position 18 are independently Abu, G, S, A, V, T, I, L, or AllyGly.
33. The chimeric protein of any one of claims 26 to 30, wherein the second amino acid sequence comprises an amino acid sequence selected from:
LRRFSTAPFAFININNVINF (SEQ ID NO: 4),
LRRF S TMP AMF ( Abu)NINN V ( Abu)NF (SEQ ID NO: 5),
LRRF S TMPF (Nl e)F ( Abu)NINN V ( Abu)NF (SEQ ID NO: 6),
LRRF S TMPF AF ( Abu)NINN V ( Abu)NF (SEQ ID NO: 7),
LRRF STMPF AFININNVINF (SEQ ID NO: 8),
LRRFSTMPF(dA)FININNVINF (SEQ ID NO: 9),
LRRFSTMPFM(4-ClPhe)(Abu)NINNV(Abu)NF (SEQ ID NO: 10), LRRF S TMPFM A( Abu)NINN V ( Abu)NF (SEQ ID NO: 11),
LRRF S TMPFMF ( Abu)NINN V ( Abu)NF (SEQ ID NO: 12),
LRRF STMPFMF (Ally Gly)NINNV (Ally Gly)NF (SEQ ID NO: 13),
LRRF S TMPFMF ANINN V ANF (SEQ ID NO: 14),
LRRF S TMPFMF GNINN V GNF (SEQ ID NO: 15),
LRRF STMPFMF ININNVINF (SEQ ID NO: 16),
LRRF STMPFMF SNINNVSNF (SEQ ID NO: 17),
LRRF S TMPFMF TNINN VTNF (SEQ ID NO: 18), and
LRRF STMPFMF VNINNVVNF (SEQ ID NO: 19).
34. The chimeric protein of any one of claims 26 to 30, wherein the second amino acid sequence comprises at least one C-terminal amino acid deletion and/or at least one N- terminal amino acid deletion relative to SEQ ID NO: 2.
35. The chimeric protein of any one of claims 26 to 30, wherein the second amino acid sequence comprises LRRFSTXPXXXXDINDVXNF (SEQ ID NO: 3), wherein X at position 7 is M, A, or G; X at position 9 is F, A, Y, or G; X at position 10 is M, A, G, dA, or Nle; X at position 11 is F, A, Y, G, or 4-ClPhe; and X at position 12 and position 18 are independently Abu, G, S, A, V, T, I, L, or AllyGly.
36. The chimeric protein of claim 35, wherein the second amino acid sequence comprises an amino acid sequence selected from:
(dL)RR(dL)RRF S T APF AFIDIND VINF (SEQ ID NO: 21),
LRRF S T APF AFIDIND VIN (dF) (SEQ ID NO: 22),
(dL)RRFSTAPF AFIDIND VIN(dF) (SEQ ID NO: 23), or
LRRF STAPF AFIDIND VINF (SEQ ID NO: 24).
37. A pharmaceutical composition comprising an effective amount of a peptide comprising a somatotropin motif and an effective amount of a peptide derived from the a5 fibril of type IV collagen, and which is optionally a chimeric protein of any one of claims 26 to 36, and a pharmacologically-acceptable excipient.
38. A method for treating a cancer in a subject comprising administering to the subject an effective amount of the chimeric protein of any one of claims 28 to 41 or the pharmaceutical composition of claim 37.
39. The method of claim 38, wherein the subject is undergoing a cancer immunotherapy.
PCT/US2019/027820 2018-04-17 2019-04-17 Compositions and methods for treatment of cancer WO2019204402A1 (en)

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