Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
  • C07K7/04—Linear peptides containing only normal peptide links
  • C07K7/23—Luteinising hormone-releasing hormone [LHRH]; Related peptides
• • 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
  • A61K38/08—Peptides having 5 to 11 amino acids
  • A61K38/09—Luteinising hormone-releasing hormone [LHRH], i.e. Gonadotropin-releasing hormone [GnRH]; Related peptides
• • 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
  • A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
  • A61K47/51—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
  • A61K47/62—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
  • A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
  • A61K47/646—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent the entire peptide or protein drug conjugate elicits an immune response, e.g. conjugate vaccines
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P13/00—Drugs for disorders of the urinary system
  • A61P13/08—Drugs for disorders of the urinary system of the prostate
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
  • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
  • C07K14/575—Hormones
  • C07K14/59—Follicle-stimulating hormone [FSH]; Chorionic gonadotropins, e.g.hCG [human chorionic gonadotropin]; Luteinising hormone [LH]; Thyroid-stimulating hormone [TSH]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides
• • 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

Definitions

• the present disclosure describes compositions comprising the GnRH-hC conjugates or GhC oligomers described herein and an excipient.
• the composition is a pharmaceutical composition, which can be used to treat subjects in need thereof.
• the pharmaceutical composition can be an immunogenic composition.
• the subject could be suffering from a disease or condition, for example, prostate cancer.
• the subject may need to have reduced testosterone levels so that prostate tumor cells do not proliferate or metastasize.
• the pharmaceutical compositions or the GnRH-hC conjugates or GhC oligomers can be used as therapeutics for treating prostate cancer.
• FIG. 6 shows mouse anti-GnRH IgG titers and T levels at d42 induced by exemplary GnRH-HhC conjugates and a GHhC oligomer compared to controls.
• the present disclosure describes hapten carrier (hC) for small peptides, such as GnRH.
• GnRH hapten carrier
• GnRH can induce a robust immune response.
• the present disclosure describes a novel method for producing GnRH therapeutics including a GnRH-hC conjugate or a GhC oligomer.
• the method eliminates many of the costliest and time-consuming steps of traditional subunit or protein carrier-based therapeutic development.
• a flexible and modular system where the hC and GnRH components are produced synthetically by solid phase peptide synthesis (SPPS).
• SPPS solid phase peptide synthesis
• the method described herein includes designing a hC component including monomeric peptides that self-assemble into amphipathic alpha-helices to form a carrier complex large enough to induce a robust immune response after one or more GnRH peptides are attached to the hC.
• Z is A, D, H, S, E, R, N, Q, K, or G; and n is an integer greater than 1
• IREISRA SEQ ID NO: 5
• IRSIGKE SEQ ID NO: 15
• VKDVARGIRDIGNSIKDLARGIRDIGRG (SEQ ID NO: 24);
• the peptides described herein include peptides that comprise an amino acid sequence having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NOs: 19, 20, 21 , 22, 23, 24, 25, 26, or 27.
• Sequence identity refers to the degree of correspondence of two sequences in an alignment, often expressed as a percentage. Differences between two sequences may be determined by methods routinely practiced in the art to determine identity, which are designed to give the greatest match between the sequences tested. Methods to determine sequence identity can be determined by using publicly available computer programs. Computer program methods to determine identity between two sequences include BLASTP. The BLAST family of programs is publicly available from NCBI and other sources.
• Vertebrates which are sources of GnRH peptide including the amino acid sequence SEQ ID NO: 29 include primates (including human), rodents, rabbit and hares, placentals, bats, odd-toed ungulates, whales, dolphins, even-toed ungulates, frogs, toads, marsupials, and caecilians.
• the GnRH peptide is a GnRH 1 peptide comprising the following amino acid sequence: QHWSHGWLPG (SEQ ID NO: 30).
• Vertebrates which are sources of GnRH peptide including the amino acid sequence SEQ ID NO: 30 include spiny dogfish, smaller spotted catshark, and coelacanth.
• one or more residues can increase the in vivo half-life of the GnRH peptide more than 5 times, 10 times, 15 times, 20 times, 25 times, 30 times, 35 times, 40 times, 45 times, 50 times, 60 times, 70 times, 80 times, 90 times, 100 times, 110 times, or 120 times longer than the in vivo half-life of a GnRH peptide without an added residue at its N- or C- terminus.
• residues such as G (glycine), V (valine), M (methionine), or A (alanine), or a combination thereof can be added to the N- or C-terminus of the GnRH peptide for stability.
• Haptens which can enhance the immunogenicity of GnRH or enhance the duration or breadth of the immune response of GnRH can be conjugated to the hC along with GnRH.
• a conjugated peptide that functions to bind a TLR can comprise an adjuvant function and enhance the immunogenicity of GnRH.
• the GnRH-hC conjugates can include other haptens or peptides in addition to one or more different or the same GnRH peptides.
• excipient refers to a diluent, adjuvant, or vehicle with which the hC is administered.
• adjuvants include complete and incomplete Freund’s adjuvant, which are used with animals, particularly research animals.
• Pharmaceutically acceptable excipients can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. Water is a preferred excipient when the pharmaceutical composition is administered intravenously. Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid excipients, particularly for injectable solutions.
• the monomeric peptide is synthesized with a T-cell and/or B-cell epitope present at the N- and/or C-terminus.
• the increase in immunogenicity of GnRH is compared with the immunogenicity of GnRH by itself, for example, not linked to or associated with the hC or an excipient.
• the methods described herein also include conjugating one or more other haptens or immunomodulators, in addition to GnRH, to increase the immunogenicity of GnRH. Examples of such haptens and immunomodulators include small molecules, lipids, lipoproteins, and TLR-4 agonists.
• the present disclosure describes immunogenic compositions comprising the GnRH-hC conjugate as described above.
• the GnRH-hC conjugate optionally includes one or more T-cell and/or B-cell epitopes and/or one or more additional haptens or immunomodulators, other than GnRH.
• the hC is a HhC.
• the immunogenic composition includes one or more pharmaceutically acceptable excipients.
• the excipient may be an adjuvant which is used to improve or enhance the immune response to the GnRH-hC conjugate in a therapeutically effective manner.
• the immunogenic composition can be administered to a subject in need thereof by any route described herein for delivering a GnRH immunogenic therapeutic in an effective amount to a cancer patient, or any subject whose testosterone levels need to be reduced.
• T- cell epitopes from many different species can be acquired from the IEDB database and are chosen based on positive T- and B-cell assays including MHC ligand binding assays, ability to recruit T-cell help, and induction of B-cell proliferation.
• MHC ligand binding assays including MHC ligand binding assays, ability to recruit T-cell help, and induction of B-cell proliferation.
• the modular nature of the therapeutic technology described herein simplifies transferring therapeutic constructs between species, as it is a simple matter of replacing the T-cell epitopes and modifying the B-cell epitope if a different disease or condition is targeted.
• a GnRH conjugate (GnRH-hC) or a GnRH oligomer (GhC) including one or more Gonadotropin releasing hormone (GnRH) peptides covalently attached to a hapten carrier (hC), the hC including an oligomer which includes a monomeric peptide comprising the following amino acid sequence:
• a peptide immunogen including amino acid SEQ ID NO: 70 or SEQ ID NO: 71.
• B-cell function Standard ELISA was used to measure therapeutic efficacy by GnRH-specific antibody titer in the collected mouse sera. ELISA plates were coated with GnRH-
• BSA conjugate and 8 sequential 10-fold dilutions (from 1 :10° to 1 :10 l u ) of sera in blocking buffer were made and added to the ELISA plate wells.
• An HRP-labeled anti-mouse secondary antibody was added and the plates developed with a colorimetric substrate and measured in an ELISA plate reader. Data were plotted, curve fitted, and statistically analyzed using Prism Graph Pad software for calculating mid- and end- point titers.

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• 2020
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