Oral formulations of oligopeptides, and therapeutic uses thereof

Abstract

The present disclosure relates to oral pharmaceutical compositions of oligopeptides that experience minimal oral, gastric, or intestinal digestion. Such pharmaceutical compositions involve encapsulation of the oligopeptides in a cationically polymerized alpha lipoic acid or derivative thereof in the presence of an anionic initiator. Such formulations may be formulated in oral dosage forms, such as tablets and capsules, and are suitable for treating cancer in combination with a chemotherapeutic agent, such as a nonsteroidal antiandrogen agent or a platinum-based chemotherapeutic agent.

Description

Docket No.: 30487-20004.40ORAL FORMULATIONS OF OLIGOPEPTIDES, AND THERAPEUTIC USES THEREOFCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Patent Application Nos.63 / 775,829, filed March 21, 2025, and 63 / 775,834, filed March 21, 2025, each of which is incorporated herein by reference in its entirety.REFERENCE TO AN ELECTRONIC SEQUENCE LISTING

[0002] The content of the electronic sequence listing (304872000440SEQLIST.xml; Size: 22,060 bytes; and Date of Creation: March 20, 2026) is herein incorporated by reference in its entirety.FIELD

[0003] The present disclosure relates to delivery of oligopeptides, including specifically oral delivery formulations of certain oligopeptides and therapeutic uses thereof. The present disclosure also relates to methods and medicaments for inhibiting proliferation of an ovarian cancer cell by contacting the ovarian cancer cell with a suitable chemotherapeutic agent in combination with a formulation comprising an oligopeptide as described herein. The methods and medicaments are suitable for treating ovarian cancer.BACKGROUND

[0004] Commonly utilized routes of administration for therapeutic peptides and proteins include intravenous (IV), intraperitoneal (IP), and intramuscular (IM) injections. However, oral administration is preferred by patients and oral medications are typically less expensive to manufacture, distribute and administer. Unfortunately, development of orally available dosage forms of therapeutic peptides and proteins have been complicated for a variety of reasons, including but not limited to poor stability in physiological conditions, short biological half-life, and low permeability through the epithelial barrier in the small intestine. Thus, in some1MF-366005067Docket No.: 30487-20004.40 embodiments, the formulations of the present disclosure are designed to protect the isolated oligopeptide from the proteolytic enzymes and acidic environment found in the stomach, such that their bioactivity is retained as they are absorbed into the bloodstream (see, e.g., Dan et al., Children, 7:307, 2020). Oral delivery is often viewed as a promising alternative. However, the harsh gastrointestinal environment and defensive intestinal epithelial barriers are challenges that can hinder oral delivery. See e.g., Chen et al, Theranostics. 2022 Jan 1; 12(3): 1419-1439.

[0005] Thus, what is needed in the art are oral delivery formulations that can address these gastrointestinal challenges, so that the proteins and peptides being delivered can serve their therapeutic needs.

[0006] Ovarian cancer is a common type of cancer, and one of the leading causes of cancer deaths among women. Current treatment options for ovarian cancer depend on the type, stage and individual patient factors. The primary treatment options include surgery (e.g., to remove the cancerous ovary, or hysterectomy), chemotherapy, targeted drug therapies, immunotherapies, hormone therapies and radiation therapies. Approximately 70%-80% of patients suffering from ovarian cancer will experience ovarian cancer recurrence. Patients exposed to longer-term treatment often become refractory to existing therapies.

[0007] Thus, there is also a persistent unmet need for more effective therapies for treating ovarian cancer. In addition, combination therapies for enhancing the effect of chemotherapies are desirable.BRIEF SUMMARY

[0008] In some aspects, provided is a composition comprising an oligopeptide or salt thereof, at least partially encapsulated in a polymer that is cationically polymerized alpha lipoic acid or derivatives thereof. In certain aspects, such composition is provided as an oral pharmaceutical composition, and may further comprise one or more pharmaceutically acceptable excipients or carriers.

[0009] In other aspects, provided is also a method of preparing such aforementioned compositions and therapeutic uses thereof.2MF-366005067Docket No.: 30487-20004.40

[0010] In other aspects, the present disclosure relates to methods and medicaments for inhibiting proliferation of an ovarian cancer cell by contacting the ovarian cancer cell with a suitable chemotherapeutic agent (such as a platinum-based chemotherapeutic agent) in combination with a formulation comprising an oligopeptide capable of decreasing cancer cell proliferation. The methods and medicaments are suitable for treating ovarian cancer.

[0011] In certain aspects, provided is a method for inhibiting proliferation of an ovarian cancer cell, comprising contacting the ovarian cancer cell with an effective amount of a chemotherapeutic agent, and an effective amount of a formulation comprising an oligopeptide consisting of the amino acid sequence of Xm(R / D)EES(G / D)(E / K)Xn (Consensus No. 1), in which m and n are integers independently selected from the range of from 0-10, and each X, if present, is independently selected from any amino acid.

[0012] In another aspect, provided is a method for inhibiting proliferation of an ovarian cancer cell, comprising contacting the ovarian cancer cell with an effective amount of a chemotherapeutic agent and an effective amount of a formulation comprising an oligopeptide consisting of the amino acid sequence of Xp(R / D)EESGEPXq (SEQ ID NO: 10), in which p is an integer selected from the range of from 0-10, q is an integer selected from the range of from 0-9, and each X, if present, is independently selected from any amino acid.

[0013] In certain aspects, provided is a method for treating ovarian cancer in a mammalian subject in need thereof, comprising: administering to the subject i) an effective amount of a chemotherapeutic agent and ii) an effective amount of a formulation comprising an oligopeptide consisting of the amino acid sequence of Xm(R / D)EES(G / D)(E / K)Xn (Consensus No. 1), in which m and n are integers independently selected from the range of from 0-10, and each X, if present, is independently selected from any amino acid.BRIEF DESCRIPTION OF THE DRAWINGS

[0014] The present application can be understood by reference to the following description taken in conjunction with the accompanying figures.3MF-366005067Docket No.: 30487-20004.40

[0015] FIGs. 1A-1D are graphs showing viability data in the epithelial fraction (Epi) of MDTs treated with vehicle, chemotherapeutic agents, or combination with the oligopeptides tested. For Pan-CK (FIG. 1A) and Cell Nuclei (FIG. IB), IF score is calculated using the positive biomarker area in either the total tissue area (core) or the epithelial fraction (Pan-CK+), respectively. For CC3 (FIG. 1C) and Ki-67 (FIG. ID), the positive biomarker area is detected in the epithelial fraction and normalized on the epithelial nuclei area. (Veh: vehicle, LD: low dose, HD: high dose).

[0016] FIG. 2 shows cell density per compartment in vehicle-treated microdissected tissue (MDT) from three different cancer patients. MI25S029 is a sample from a colonic metastasis from a BRCA 1 / 2-negative, high-grade serous carcinoma of a patient who had received neoadjuvant docetaxel, cyclophosphamide and trastuzumab. MI26S001 is a sample from a stage pT3b high-grade serous ovarian carcinoma from a treatment-naive patient. MI26S005 is a sample from a pT3a ovarian clear cell carcinoma from a treatment-naive patient.

[0017] FIG. 3 shows cell density, proliferative index (Ki67+) and apoptotic index (CC3+) of MI25S029 MDT treated under the indicated conditions.

[0018] FIG. 4 shows cell density, proliferative index (Ki67+) and apoptotic index (CC3+) of MI25S001 MDT treated under the indicated conditions.

[0019] FIG. 5A shows cell density, proliferative index (Ki67+) and apoptotic index (CC3+) of the epithelial compartment of MI25S005 MDT treated under the indicated conditions.FIG. 5B shows cell density, proliferative index (Ki67+) and apoptotic index (CC3+) of the stromal compartment of MI25S005 MDT treated under the indicated conditions.DETAIEED DESCRIPTION

[0020] The following description sets forth exemplary compositions, methods, parameters and the like. It should be recognized, however, that such description is not intended as a limitation on the scope of the present disclosure but is instead provided as a description of exemplary embodiments.4MF-366005067Docket No.: 30487-20004.40

[0021] In some aspects, the present disclosure relates to pharmaceutical compositions comprising certain oligopeptides formulated for oral delivery. In some embodiments, provided are oral pharmaceutical compositions comprising: an oligopeptide or a salt thereof; and cationically polymerized alpha lipoic acid or derivatives thereof, wherein the polymer at least partially encapsulates the oligopeptide or a salt thereof. In certain embodiments, the oral pharmaceutical compositions further comprise one or more pharmaceutically acceptable excipients or carriers.

[0022] As described in further detail herein, such oral pharmaceutical compositions may be prepared with cationically polymerized alpha lipoic acid or derivatives thereof, and in some instances, together with a suitable anionic initiator. Such oral pharmaceutical compositions were surprisingly observed to demonstrate gastric and intestinal medium stability, including minimal oral, gastric, or intestinal digestion.

[0023] The oligopeptides suitable for use in pharmaceutical compositions formulated for oral delivery, along with the components of such formulations, their methods of preparations and therapeutic uses thereof are described in further detail below.

[0024] In other aspects, the present disclosure relates to methods and medicaments for inhibiting proliferation of an ovarian cancer cell by contacting the ovarian cancer cell with a suitable chemotherapeutic agent (such as a platinum-based chemotherapeutic agent) in combination with a formulation comprising an oligopeptide as described herein. The methods and medicaments are suitable for treating ovarian cancer.Oligopeptides

[0025] In some embodiments, the oligopeptide consists of the amino acid sequence of Xm(R / D)EES(G / D)(E / K)Xn (Consensus No. 1), in which m and n are each independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, and each X, if present, is independently selected from any amino acid. Thus, in some embodiments, the oligopeptides are from 6 to 26 residues in length. In some embodiments, the oligopeptide is no less than 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 residues in length, and / or the oligopeptide is no more than 26, 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, or 7 residues in length, in which the lower5MF-366005067Docket No.: 30487-20004.40 limit is less than the upper limit. In some embodiments, the oligopeptide comprises the amino acid sequence of REESGE (SEQ ID NO:1). In some embodiments, the oligopeptide comprises the amino acid sequence of REESGEP (SEQ ID NOG). In some embodiments, the oligopeptide comprises the amino acid sequence of KEEDEESGE (SEQ ID NOG). In some embodiments, the oligopeptide comprises the amino acid sequence of KPREESGE (SEQ ID NO:4). In some embodiments the oligopeptide comprises the amino acid sequence of LDEESGEP (SEQ ID NOG). In some embodiments, the oligopeptide comprises the amino acid sequence of REESDKPMY (SEQ ID NOG). In some embodiments, the oligopeptide comprises the amino acid sequence of PREESDKP (SEQ ID NOG). In some embodiments, the oligopeptide comprises the amino acid sequence of REESGEL (SEQ ID NOG). In some embodiments, the oligopeptide comprises the amino acid sequence of LREESGEP (SEQ ID NOG). In some embodiments, such as when the oligopeptides comprises the amino acid sequence of REESGEP (SEQ ID NOG), the oligopeptides are from 7 to 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 amino acids in length, optionally from 7 to 8, 9, 10, 11, 12, 13, 14 or 15 amino acids in length, or further optionally from 7 to 8, 9 or 10 amino acids in length. In some embodiments, such as when the oligopeptides comprises the amino acid sequence of LREESGEP (SEQ ID NOG), the oligopeptides are from 8 to 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 amino acids in length, optionally from 8 to 9, 10, 11, 12, 13, 14 or 15 amino acids in length, or further optionally from 8 to 9 or 10 amino acids in length. In some embodiments, the oligopeptide comprises an amino acid sequence having at least 90% (e.g., at least 91%, 92 %, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) amino acid sequence identity to Consensus No. 1 or any one of SEQ ID NOS:1-9.

[0026] In some embodiments, the oligopeptide consists of the amino acid sequence of Xp(R / D)EESGEPXq (Consensus No. 2 / SEQ ID NO: 10), in which p is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, q is 0, 1, 2, 3, 4, 5, 6, 7, 8, or 9, and each X, if present, is independently selected from any amino acid. Thus, in some embodiments, the claimed oligopeptides are from 7 to 26 residues in length. In some embodiments, the oligopeptide is no less than 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 residues in length, and / or the oligopeptide is no more than 26, 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, or 8 residues in length, in which the lower limit is less than the upper limit. In some embodiments, the oligopeptide6MF-366005067Docket No.: 30487-20004.40 comprises the amino acid sequence of REESGEP (SEQ ID NO:2). In some embodiments the oligopeptide comprises the amino acid sequence of LDEESGEP (SEQ ID NO:5), referred to herein as FT-005. In some embodiments, the oligopeptide comprises the amino acid sequence of LREESGEP, (SEQ ID NO:9), referred to herein as FT-002a.

[0027] In some embodiments, the oligopeptide comprises the amino acid sequence of Xr(R / D)EESGEP (Consensus No. 3 / SEQ ID NO: 11), in which Xr is leucine or absent, and the oligopeptide is no more than 14, 13, 12, 11, 10, 9, or 8 residues in length. In some embodiments, the oligopeptide comprises or consists of the amino acid sequence of LREESGEP (SEQ ID NO:9), referred to herein as FT-002a. In some embodiments, the oligopeptide comprises or consists of the amino acid sequence of LDEESGEP (SEQ ID NO:5). In some embodiments, the oligopeptide comprises or consists of the amino acid sequence of REESGEP (SEQ ID NO:2).

[0028] In some embodiments, the isolated oligopeptides of the present disclosure consist of the amino acid sequence of XjREESDKPXk (Consensus No. 4 / SEQ ID NO: 12), in which j is an integer selected from the range of from 0-10, k is an integer selected from the range of from 0-9, and each X, if present, is independently selected from any amino acid. Thus, in some embodiments, the claimed oligopeptides are from 7 to 26 residues in length. In some embodiments, the oligopeptide is no less than 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24 or 25 residues in length, and / or the oligopeptide is no more than 26, 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, or 8 residues in length, in which the lower limit is less than the upper limit. In some embodiments, the oligopeptides comprise the amino acid sequence of XgREESDKP(XhXi) (Consensus No. 5 / SEQ ID NO: 13), in which Xg is proline (P) or absent, XhXi is methionine and tyrosine (MY) or absent. In some embodiments, the isolated oligopeptide comprises the amino acid sequence of REESDKPMY (SEQ ID NO:6) or the amino acid sequence of PREESDKP (SEQ ID NO:7).

[0029] In some variations, the oligopeptide suitable for use in the pharmaceutical compositions described herein has an overall negative charge at pH 7 as determined by pKa values of side chain groups, or the peptide has an isoelectric point of less than about 7.5.

[0030] In other variations, the oligopeptide has an overall negative charge of -2, -3, or -4 at pH 7 as determined by pKa values of side chain groups.7MF-366005067Docket No.: 30487-20004.40

[0031] In certain variations, the oligopeptide comprises at least 4 amino acid residues; between 4 and 50 amino acid residues; between 4 and 35 amino acid residues.

[0032] In one variation, the oligopeptide has an amino acid sequence of Xm(R / D)EES(G / D)(E / K)Xn (Consensus No. 1), wherein m and n are integers independently selected from the range of from 0-10, and each X, if present, is independently selected from any amino acid. In another variation, the oligopeptide comprises an amino acid sequence of LREESGEP (SEQ ID NO:9).

[0033] In some embodiments, the oligopeptide used herein is provided as a solid powder or a stable gel. In certain embodiments, the oligopeptide used herein is provided as a solid, crystalline powder.

[0034] In some embodiments, the oligopeptide is produced synthetically. In exemplary embodiments, the oligopeptide is produced by solid phase synthesis and purified by high performance liquid chromatography as known in the art.Oligopeptide Formulations

[0035] The oligopeptide formulations used in the methods and medicaments of the present disclosure comprise at least one oligopeptide of the preceding section formulated for suitable delivery to a subject, e.g., a human. In some variations, the oligopeptides herein are formulated for administration by infusion, including e.g., intravenous infusion. In other variations, the oligopeptides herein are formulated for subcutaneous administration. In certain variations, the oligopeptides herein are formulated in a saline solution. In certain variations, both the chemotherapeutic agent (e.g., platinum-based chemotherapeutic agent) and the oligopeptide formulations herein are administered by infusion, including e.g., intravenous infusion, or by subcutaneous administration.

[0036] In other variations, the oligopeptides herein are formulated for oral delivery. In certain variations, the oligopeptide formulations used in the methods and medicaments of the present disclosure comprise at least one oligopeptide of the preceding section and at least one pharmaceutically acceptable excipient and / or an oral delivery agent. In some embodiments, the formulations may further comprise an enteric coating, liposomes, microspheres, or micro- / nano-8MF-366005067Docket No.: 30487-20004.40 particles. For instance, in some embodiments, the oligopeptide is encapsulated within an enteric coating, liposomes, microspheres, or micro- / nano-particles. In certain variations, the chemotherapeutic agent (e.g., platinum-based chemotherapeutic agent) is administered by infusion, including e.g., intravenous infusion, while the oligopeptide formulations herein is administered orally.

[0037] In one variation, the chemotherapeutic agent and the oligopeptide formulations herein are simultaneously administered. In another variation, the chemotherapeutic agent and the oligopeptide formulations herein are sequentially administered.

[0038] The amount of an oligopeptide present in the pharmaceutical compositions herein will vary so as to be effective in the treatment of a particular disorder or condition disclosed herein and depends on the nature of the disorder or condition. The effective amount can be determined by standard clinical techniques. In addition, in vitro or in vivo assays may optionally be employed to help identify optimal dosage ranges. In some embodiments, the dose of the oligopeptide of the present disclosure is from about 0.1 mg / kg to about 1000 mg / kg, about 1.0 mg / kg to about 100 mg / kg, or about 10 mg / kg body weight of the subject to be treated. In some embodiments, the dose of oligopeptide is no less than 0.1, 0.5, 1.0, 5.0, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, or 500 mg / kg, and / or the dose of the oligopeptide is no more than 1000, 500, 100, 90, 80, 70, 60, 50, 40, 30, 20, 10, 5.0, 1.0, or 0.5 mg / kg, in which the lower limit is less than the upper limit.

[0039] In certain embodiments, the oral daily dose of the oligopeptide of the present disclosure is between about 100 mg and about 1000 mg, or between about 100 mg and about 750 mg, or between about 100 mg and about 500 mg. In certain embodiments, the daily dose of the oligopeptide of the present disclosure intravenously or subcutaneously administered is between about 1 mg and about 100 mg, or between about 10 mg and about 100 mg, or between about 10 mg and about 50 mg.Cationically polymerized alpha lipoic acid or derivatives thereof

[0040] The pharmaceutical compositions comprising the oligopeptides described herein further comprise cationically polymerized alpha lipoic acid or derivatives thereof.9MF-366005067Docket No.: 30487-20004.40 Polymer

[0041] In some embodiments, such polymer comprising repeating units of formula (U):(U),or a salt thereof, wherein R is H, alkyl or benzyl.

[0042] In other embodiments, the polymer has a structure of formula (P):or a salt thereof, wherein R is H, alkyl or benzyl; and n represents the average number of repeating units to achieve the average molecular weight of the polymer described herein.

[0043] In some variations of the foregoing, polymer has an average molecular weight between 800 Da and 5000 Da, between 1500 Da and 2000 Da, or between 800 Da and 4000 Da.

[0044] In some variations, R is H. In other variations, R is alkyl. In certain variations, R is Ci-4 alkyl. In certain variations, R is methyl or ethyl. In other variations, R is benzyl.

[0045] In one embodiment, the repeating unit of formula (U) is a repeating unit formed from polymerizing alpha lipoic acid; or the polymer is polymerized alpha lipoic acid, in which R is H.Methods of Preparing Oligopeptides Formulated for Oral Delivery

[0046] In certain aspects, provided are methods of preparing the pharmaceutical compositions described herein, including preparing the oligopeptides formulated for oral delivery.10MF-366005067Docket No.: 30487-20004.40

[0047] In some embodiments, provided is a method comprising: combining (i) an oligopeptide mixture comprising the oligopeptides as described herein; and (ii) a monomeric mixture comprising the monomer of formula (M) and an anionic initiator, over a suitable period of time to cationically polymerize the monomer and produce the oligopeptide at least partially encapsulated in the resulting polymer. Such oligopeptide at least partially encapsulated in the resulting polymer can be further formulated to form the oral dosage forms described herein.

[0048] In some variations, the monomer of formula (M) has the structure:ORor a salt thereof, wherein R is as defined herein for formula (U) and (P),.Anionic Initiator

[0049] In certain variations, suitable anionic initiators comprise phosphates. In certain variations, the anionic initiator comprises an ammonium phosphate. In one variation, the anionic initiator comprises ammonium hexafluorophosphate.Additional Acid Present in the Oligopeptide Mixture

[0050] Depending on the nature of the oligopeptides being formulated for oral delivery, the preparation methods described herein may further employ the use of an acid. In some variations, a catalytic amount of such acid is used.

[0051] In some embodiments where the oligopeptide has an overall negative charge at pH 7 as determined by pKa values of side chain groups, no acid is added to the oligopeptide mixture to at least partially encapsulate the oligopeptide with the polymer formed in situ.

[0052] In other embodiments wherein the oligopeptide has an overall neutral or positive charge at pH 7 as determined by pKa values of side chain groups, additional acid is present in the oligopeptide mixture to at least partially encapsulate the oligopeptide with the polymer formed in11MF-366005067Docket No.: 30487-20004.40 situ. In some variations of the foregoing, suitable acids have a pKa between about 1.5 and about 0.1. In one variation, trifluoroacetic acid (TFA) is example of a suitable acid added to the reaction mixture to at least partially encapsulate the oligopeptide with the polymer formed in situ.Encapsulation Efficiency

[0053] In some embodiments of the foregoing, the oligopeptide and the polymer as described herein are present in a ratio of between about 1% and 80%, between about 1% and 70%, or between about 5% and 65%, or up to 90%, 85%, 80%, 75%, 70%, 65%, 60%, 50% by weight.

[0054] In such pharmaceutical compositions, the oligopeptide is at least partially encapsulated in the polymer. The resulting composition may be characterized by its “encapsulation efficiency”, which refers to the percentage of the oligopeptide that is successfully trapped inside the polymer. The encapsulation efficiency may be calculated as EE% = (total oligopeptide added - free non-entrapped oligopeptide) / total oligopeptide added. In some variations, the pharmaceutical composition has an encapsulation efficiency of between about 1% and 80%, between about 1% and 70%, or between about 5% and 65%, or up to 90%, 85%, 80%, 75%, 70%, 65%, 60%, 50% by weight.Oral Dosage Forms

[0055] The pharmaceutical compositions described herein are formulated for oral delivery, and the pharmaceutical compositions are oral solid dosages. In some embodiments, oral solid dosage refers to pharmaceutical formulations that are taken by mouth in solid form, such as tablets, capsules, powders, gel or syrup.Excipients or carriers

[0056] In some embodiments, the formulations described herein may further comprise one or more pharmaceutically acceptable excipients or carriers.

[0057] Pharmaceutically acceptable excipients or carriers of the present disclosure include, for instance, solvents, bulking agents, buffering agents, tonicity adjusting agents, and12MF-366005067Docket No.: 30487-20004.40 preservatives (Pramanick et al., Pharma Times, 45:65-77, 2013). In some embodiments the formulations may comprise an excipient that functions as one or more of a solvent, a bulking agent, a buffering agent, and a tonicity adjusting agent (e.g., sodium chloride in saline may serve as both an aqueous vehicle and a tonicity adjusting agent).

[0058] In some embodiments, the formulations comprise an aqueous vehicle as a solvent. Suitable vehicles include for instance sterile water, saline solution, phosphate buffered saline, and Ringer’s solution. In some embodiments, the formulation is isotonic.

[0059] The formulations may comprise a bulking agent. Bulking agents are particularly useful when the pharmaceutical formulation is to be lyophilized before administration. In some embodiments, the bulking agent is a protectant that aids in the stabilization and prevention of degradation of the active agents during freeze or spray drying and / or during storage. Suitable bulking agents are sugars (mono-, di- and polysaccharides) such as sucrose, lactose, trehalose, mannitol, sorbital, glucose and raffinose.

[0060] The formulations may comprise a preservative. Suitable preservatives include for instance antioxidants and antimicrobial agents. However, in preferred embodiments, the formulation is prepared under sterile conditions and is in a single use container, and thus does not necessitate inclusion of a preservative.Oral Delivery Agents

[0061] In some embodiments, the formulations described herein may further comprise one or more oral delivery agents. Oral delivery agents of the present disclosure include, for instance, absorption enhancers, fatty acids, enzyme inhibitors, polyethylene glycol, mucoadhesive polymers, and cell penetrating peptides (Dan et al., Children, 7:307, 2020).Chemotherapeutic Agents

[0062] Chemotherapeutic agent may include a hormone agonist / antagonist, chemotherapy, a chemotherapeutic agent, or radiotherapy. In some embodiments, chemotherapeutic agents for use with the treatment methods described herein include platinum-based chemotherapeutic agents. In some embodiments, the platinum based chemotherapeutic agent is selected from13MF-366005067Docket No.: 30487-20004.40 carboplatin, cisplatin, dicycloplatin, oxaliplatin, nedaplatin, satraplatin, and combinations thereof. In some embodiments, the chemotherapeutic agent comprises cisplatin or carboplatin, or a combination thereof.

[0063] In some embodiments of the methods provided herein for treating ovarian cancer, the oligopeptides or formulations described herein are administered as a co-treatment with any suitable chemotherapeutic agents, including for example frontline chemotherapy for ovarian cancer. The subject need not be resistant to the frontline chemotherapy or other treatment for ovarian cancer.

[0064] In some variations, when the oligopeptides or formulations described are administered as a co-treatment with any suitable chemotherapeutic agents, the therapeutic dose of the chemotherapeutic agents is reduced, in which the “the therapeutic dose of the chemotherapeutic agents” refers to the dose of the chemotherapeutic agents absent the coadministration of the oligopeptides or formulations described herein. In certain variations, the therapeutic dose of the chemotherapeutic agents is reduced between about 50% and about 90% (as compared to the dose of the chemotherapeutic agents absent the co-administration of the oligopeptides or formulations described herein). Such a result was unexpectedly observed in the experiments described herein, and the reduction of the dose of the chemotherapeutic agents in the overall treatment reduces toxicity for a patient.Methods of Use

[0065] In some aspects, provided is a method of delivering a composition comprising an oligopeptide with minimal oral, gastric, or intestinal digestion of the peptide to a subject. The composition may include any of the oligopeptides described herein, formulated as described herein for oral delivery. In some embodiments (e.g., in vivo embodiments), the pharmaceutical composition is administered by mouth. For instance, the formulation may be administered enterically. In some embodiments, the formulation is administered by a buccal, a sublabial, or a sublingual route. In some embodiments, the chemotherapeutic agent is administered orally. In some embodiments, the chemotherapeutic agent is administered intravenously.

[0066] The pharmaceutical compositions herein may be used to treat various indications and disorders. In some embodiments, the method comprises administering an effective amount of 14MF-366005067Docket No.: 30487-20004.40 any of the pharmaceutical compositions described herein to a subject in need thereof. In some variations, the subject is a mammal. In some variations, mammals include, but are not limited to, humans, non-human primates (e.g., monkeys), farm animals, sport animals, rodents (e.g., mice and rats) and pets (e.g., dogs and cats). In one variation, the subject is a human.

[0067] An “effective amount” of an agent disclosed herein (e.g., oligopeptide or formulation thereof) is an amount sufficient to carry out a specifically stated purpose. An “effective amount” may be determined empirically in relation to the stated purpose. An “effective amount” or an “amount sufficient” of an agent is that amount adequate to affect a desired biological effect, such as a beneficial result, including a beneficial clinical result. The term “therapeutically effective amount” refers to an amount of an agent (e.g., oligopeptide or formulation thereof) effective to “treat” a disease or disorder in a subject (e.g., a mammal such as a human). An “effective amount” or an “amount sufficient” of an agent may be administered in one or more doses.Increasing FTH1 mRNA Expression

[0068] In some embodiments, the pharmaceutical compositions of the present disclosure find use in methods and medicaments for increasing expression of FTH1 mRNA expression by mammalian cells. As used herein, the terms “ferritin heavy chain 1” and “FTH1” refer to the nucleic acid sequence encoding the “ferritin heavy chain” protein, which is also known as the “ferritin H subunit.” The amino acid sequence of the human ferritin heavy chain is set forth as GenBank Accession No. NP_002023, and the mRNA sequence is set forth as GenBank Accession No. NM_002032, with the coding sequence extending from nucleotides 210-761.

[0069] The term “increasing”, and grammatical equivalents as used herein in reference to expression or levels of FTH1 mRNA, refers to causing FTH1 mRNA to become greater in amount. Preferably, an increase in FTH1 mRNA encompasses a statistically significant increase, preferably an increase from about 2 to about 200 fold, from about 2 to 20 fold, from about 2 to 5 fold, preferably an increase of at least 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 3.0, 3.1, 3.2, 3.3, 3.4 or 3.5 fold.

[0070] In some embodiments, the mammalian cells are epithelial cells, such as human epithelial cells. In some preferred embodiments, the pharmaceutical compositions of the present disclosure find use in methods and medicaments for increasing serum ferritin concentration in a15MF-366005067Docket No.: 30487-20004.40 human subject in need thereof. In some preferred embodiments, the pharmaceutical compositions of the present disclosure find use in methods and medicaments for treating or preventing a disease or condition in a human subject in need, wherein the disease or condition is associated with an inadequate serum ferritin concentration.

[0071] In some aspects, the present disclosure provides methods and medicaments for increasing expression of ferritin heavy chain 1 (FTH1) mRNA in a mammalian subject in need thereof, comprising administering to the subject an effective amount of any of the pharmaceutical compositions described herein. In some embodiments, the mammalian subject is a human subject.

[0072] Ferritin is a widely expressed and highly conserved protein and consists of 2 types of oligopeptide chains: ferritin heavy chain and ferritin light chain. Ferritin heavy chain catalyzes the Fe2+oxidation reaction, whereas ferritin light chain plays an important role in the storage of Fe3+. Both chains are essential for maintaining iron homeostasis and preventing iron overload (Tian et al., Neurotherapeutics, 17:1796-1812, 2020). The FTH1 gene encodes the heavy subunit of ferritin. An increase in FTH1 expression, and thus ferritin, leads to an increase in iron absorption and bioavailability. This increase in iron absorption and bioavailability is beneficial to ameliorate diseases and disorders resulting from inadequate amounts of iron (e.g., iron deficient anemia).

[0073] In some embodiments, the methods for increasing expression of ferritin heavy chain 1 (FTH1) mRNA by mammalian cells, comprise contacting the mammalian cells with an effective amount of the formulation. In some embodiments, the method for increasing expression of FTH1 mRNA comprises contacting the mammalian cells with an effective amount of the formulation, wherein the increase is relative to baseline (e.g., pre-contact). In some embodiments, the method for increasing expression of FTH1 mRNA comprises contacting the mammalian cells with an effective amount of the formulation, wherein the increase is relative to mammalian cells not contacted with the formulation. In some embodiments, the method for increasing expression of FTH1 mRNA comprises contacting the mammalian cells with an effective amount of the formulation, wherein the increase is relative to mammalian cells contacted with a control formulation lacking the oligopeptide. In some embodiments, the method for increasing16MF-366005067Docket No.: 30487-20004.40 expression of FTH1 mRNA comprises contacting the mammalian cells with an effective amount of the formulation, wherein the increase is relative to mammalian cells containing a negative control oligopeptide.

[0074] In some embodiments, the contacting is in vivo. As such, in some embodiments, the methods and medicament for increasing ferritin heavy chain 1 (FTH1) expression in a mammalian subject in need thereof, comprise administering to the subject an effective amount of the formulation to increase FTH1 expression, wherein the increase is relative to baseline (e.g., pre-administration). In some embodiments, the methods and medicaments further comprise increasing serum ferritin concentration in a mammalian subject in need thereof. Thus, in some embodiments, the methods and medicaments for increasing serum ferritin concentration in a mammalian subject in need thereof, comprise administering to the subject an effective amount of the formulation to increase serum ferritin concentration, wherein the increase is relative to baseline (e.g., pre-administration).Cancer

[0075] In some embodiments, the oligopeptides and pharmaceutical compositions described herein may be suitable for use in treating cancers. In some variations of the foregoing, the oligopeptides or pharmaceutical compositions described herein is administered with another therapeutic agent, e.g., with a hormone agonist / antagonist, chemotherapy, a chemotherapeutic agent, or radiotherapy. In certain variations, the oligopeptides or compositions are coadministered to help address or overcome drug resistance for such cancers.

[0076] For example, in some embodiments, the oligopeptide is capable of increasing expression of ferritin heavy chain 1 (FTH1) mRNA by carcinoma cells when contacted with the oligopeptide in the presence of the nonsteroidal antiandrogen. In some embodiments, the oligopeptide is capable of increasing expression of FTH1 mRNA, wherein the increase of FTH1 mRNA is relative to carcinoma cells contacted with the nonsteroidal antiandrogen in the absence of the oligopeptide. In some embodiments, the oligopeptide is capable of increasing expression of FTH1 mRNA, wherein the increase of FTH1 mRNA is relative to carcinoma cells cultured under the same condition except for the absence of the oligopeptide. In some embodiments, the oligopeptide is capable of increasing expression of FTH1 mRNA, wherein the increase of FTH117MF-366005067Docket No.: 30487-20004.40 mRNA is relative to carcinoma cells cultured under the same condition except for the absence of the oligopeptide. In some embodiments, the oligopeptide is capable of increasing expression of FTH1 mRNA, wherein the increase of FTH1 mRNA is relative to carcinoma cells cultured under the same condition except for the presence of a negative control oligopeptide.

[0077] In some embodiments, the oligopeptide is capable of decreasing expression of transferrin receptor 1 (TFRC) mRNA by carcinoma cells when contacted with the oligopeptide in the presence of the nonsteroidal antiandrogen. In some embodiments, the oligopeptide is capable of decreasing expression of TFRC mRNA, wherein the decrease of TFRC mRNA is relative to carcinoma cells contacted with the nonsteroidal antiandrogen in the absence of the oligopeptide. In some embodiments, the oligopeptide is capable of decreasing expression of TFRC mRNA, wherein the decrease of TFRC mRNA is relative to carcinoma cells cultured under the same condition except for the absence of the oligopeptide. In some embodiments, the oligopeptide is capable of decreasing expression of TFRC mRNA, wherein the decrease of TFRC mRNA is relative to carcinoma cells cultured under the same condition except for the absence of the oligopeptide. In some embodiments, the oligopeptide is capable of decreasing expression of TFRC mRNA, wherein the decrease of TFRC mRNA is relative to carcinoma cells cultured under the same condition except for the presence of a negative control oligopeptide.

[0078] In some aspects, the present disclosure provides methods and medicaments for inhibiting proliferation of a carcinoma cell, comprising contacting the carcinoma cell with an effective amount of a nonsteroidal antiandrogen and an effective amount of an oligopeptide (or formulation comprising the oligopeptide). In some embodiments, the contacting is in vivo.

[0079] In some aspects, the present disclosure provides methods and medicaments for treating prostate cancer in a mammalian subject in need thereof, comprising administering to the subject an effective amount of a nonsteroidal antiandrogen and an effective amount of an oligopeptide (or formulation comprising the oligopeptide). In some embodiments, cells of the prostate cancer secrete prostate-specific antigen. In some embodiments, the prostate cancer is a metastatic carcinoma. In some embodiments, wherein the prostate cancer cell is androgen receptor-positive. In some embodiments, wherein the prostate cancer cell is androgen receptornegative.18MF-366005067Docket No.: 30487-20004.40

[0080] In some variations of the foregoing, an antiandrogen is a compound that inhibits the activity of an androgen. Antiandrogens are classified as steroidal anti-androgens or non-steroidal anti-androgens (NSAAs). In some embodiments, the NSAA is an androgen receptor antagonist that blocks the effects of testosterone and dihydrotestosterone. NSAAs are commonly used in combination with castration as a combined androgen blockade for treatment of prostate cancer (Crawford et al., J Urol, 200(5):956-966, 2018). In some embodiments, the NSAA is selected from the group consisting of bicalutamide, apalutamide, enzalutamide, flutamide, nilutamide, topilutamide, darolutamide, proxalutamide, and combinations thereof. In some embodiments, the nonsteroidal antiandrogen is bicalutamide. In other embodiments, the nonsteroidal antiandrogen is enzalutamide.

[0081] In other aspects, the present disclosure provides methods and medicaments for inhibiting proliferation of an ovarian cancer cell, comprising contacting the ovarian cancer cell with an effective amount of chemotherapy, a chemotherapeutic agent, or radiotherapy, and an effective amount of an oligopeptide (or formulation comprising the oligopeptide). In some embodiments, the contacting is in vivo.

[0082] In other aspects, the present disclosure provides methods and medicaments for treating ovarian cancer in a mammalian subject in need thereof, comprising administering to the subject an effective amount of chemotherapy, a chemotherapeutic agent, or radiotherapy, and an effective amount of an oligopeptide (or formulation comprising the oligopeptide).Treating or Preventing Iron Deficiency

[0083] In some aspects, provided herein is a method of treating or preventing a disease or condition in a mammalian subject in need thereof, comprising administering to the subject an effective amount of any one of the pharmaceutical compositions as described herein to treat or prevent the condition. In some embodiments, the disease or condition is associated with iron deficiency.

[0084] Iron is essential to human and animal physiology. Insufficient iron in humans and animals can cause a number of diseases and disorders, including iron deficient anemia and stunted growth. Iron deficiency can be classified into two levels, iron deficiency without anemia and iron deficiency with anemia (IDNA and IDA, respectively), according to the hemoglobin 19MF-366005067Docket No.: 30487-20004.40 measurement value. Iron deficiency without anemia (IDNA, also nonanemic iron deficiency) is usually insidious and a challenge for diagnosis and management (Zhu et al., Front Neur, 11:298, 2020). In some embodiments, the disease or condition to be treated or prevented is associated with iron deficiency without anemia. In other embodiments, the disease or condition to be treated or prevented is associated with iron deficiency with anemia.Treating or Preventing Anemia

[0085] In some aspects, provided herein is a method of treating or preventing a disease or condition in a mammalian subject in need thereof, comprising administering to the subject an effective amount of any one of the pharmaceutical compositions as described herein to treat or prevent the disease or condition, wherein the disease or condition is associated with anemia.

[0086] In another embodiment, the disorder is iron deficient anemia. Anemia is a disorder characterized by a deficiency of red blood cells. Iron deficient anemia is anemia that is caused by an inadequate amount of iron. This iron deficiency may result from inadequate amounts of iron ingested, inadequate absorption of iron, blood loss, or a combination of these.

[0087] Anemia by iron deficiency can be distinguished from many other anemias. For example, iron deficient anemia is different from anemia resulting from chronic infectious, inflammatory, or malignant disorders, such as arthritis or cancer.Treating Ovarian Cancer

[0088] In other aspects, the oligopeptides and formulations described herein find use in methods and medicaments for inhibiting proliferation of an ovarian cancer cell, in combination with a chemotherapeutic agent. In some embodiments, the oligopeptides and formulations herein find use in methods and medicaments for treating ovarian cancer in a human subject in need thereof, in combination with a chemotherapeutic agent.

[0089] In some aspects, the present disclosure provides methods and medicaments for inhibiting proliferation of an ovarian cancer cell, comprising contacting the ovarian cancer cell with an effective amount of a chemotherapeutic agent and an effective amount of an oligopeptide (or formulation comprising the oligopeptide). In some embodiments, the contacting is in vivo.20MF-366005067Docket No.: 30487-20004.40

[0090] In some aspects, the present disclosure provides methods and medicaments for treating ovarian cancer in a mammalian subject in need thereof, comprising administering to the subject an effective amount of a chemotherapeutic agent, and an effective amount of an oligopeptide (or formulation comprising the oligopeptide).

[0091] As used herein, the terms “treating” and “treatment” refer to an approach for obtaining beneficial or desired results, including clinical results. Beneficial or desired clinical results include, but are not limited to, alleviation or amelioration of one or more symptoms, diminishment of extent of disease, stabilized (i.e., not worsening) state of disease, preventing spread of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or total), whether detectable or undetectable.“Treatment” can also mean prolonging survival as compared to expected survival if not receiving treatment. As such, the terms “treating” and “treatment” as used herein, do not require complete alleviation of signs or symptoms, do not require a cure, and specifically include protocols that have a modest effect on the individual.

[0092] In some variations, administration “in combination with” or “in addition to” one or more further therapeutic agents includes simultaneous (concurrent) and consecutive administration in any order. In one variation, the oligopeptide (or formulation comprising the oligopeptide) is administered on a daily basis, and the therapeutic agent is administered in accordance with known dosing regimens (which may include daily, weekly, twice daily etc.). In another variation, dosing of the oligopeptide (or formulation comprising the oligopeptide) may be continuous, intermittent, cyclical, or synchronized with chemotherapy cycles. In certain embodiments, the oligopeptide (or formulation comprising the oligopeptide) is administered daily during chemotherapy cycles. In certain embodiments, the oligopeptide (or formulation comprising the oligopeptide) is administered during maintenance therapy with a therapeutic agent, including any of the therapeutic agents as described herein.

[0093] In certain aspects, the oligopeptide (or formulation comprising the oligopeptide) described herein is administered in combination with one or more frontline anticancer therapies for the treatment of ovarian cancer. The combination therapy may be used as an initial or first-line co-treatment and is not limited to cases in which resistance to treatment has developed. Accordingly, the oligopeptide (or formulation comprising the oligopeptide) described herein may 21MF-366005067Docket No.: 30487-20004.40 be administered concomitantly with frontline therapy to enhance therapeutic efficacy, delay disease progression, and reduce or delay the emergence of resistance. In one variation, the oligopeptide (or formulation comprising the oligopeptide) is administered prior to initiation of chemotherapy to prime tumor cells. In another variation, the oligopeptide (or formulation comprising the oligopeptide) is administered concurrently during chemotherapy cycles. In yet another variation, the oligopeptide (or formulation comprising the oligopeptide) is continued during maintenance therapy. In yet other variations, the oligopeptide (or formulation comprising the oligopeptide) is administered both during cytotoxic chemotherapy and subsequent therapy with other chemotherapeutic agents, including for example, platinum-based agent (e.g., cisplatin or carboplatin).

[0094] The terms “individual” and “subject” refer to mammals. “Mammals” include, but are not limited to, humans, non-human primates (e.g., monkeys), farm animals, sport animals, rodents (e.g., mice and rats) and pets (e.g., dogs and cats). In some variations, the subject is a human. In one variation, the subject is a female human. In another variation, the subject is an adult human. In yet another variation, the subject is an adult female human.ENUMERATED EMBODIMENTS

[0095] The following enumerated embodiments are representative of some aspects of the invention.Al. A pharmaceutical composition formulated for oral administration, comprising:(i) an oligopeptide, or a salt thereof; and(ii) a polymer comprising repeating units of formula (U):[ T0ORs s -(U), or a salt thereof,wherein R is H, alkyl, or benzyl,wherein the polymer at least partially encapsulates the oligopeptide; andoptionally one or more pharmaceutically acceptable excipients or carriers.22MF-366005067Docket No.: 30487-20004.40 A2. The composition of embodiment Al, wherein the polymer has an average molecular weight between about 800 Da and about 5000 Da.A3. The composition of embodiment Al or A2, wherein the oligopeptide and the polymer are present in a ratio of between about 1% and about 80% wt / wt.A4. The composition of any one of embodiments Al to A3, wherein the oligopeptide has an overall negative charge at pH 7 as determined by pKa values of side chain groups, or the oligopeptide has an isoelectric point of less than about 7.5.A5. The composition of embodiment A4, wherein the oligopeptide has an overall negative charge of -2, -3, or -4 at pH 7 as determined by pKa values of side chain groups.A6. The composition of any one of embodiments Al to A5, wherein the oligopeptide consists of at least 4 amino acid residues; between 4 and 50 amino acid residues; or between 4 and 35 amino acid residues.A7. The composition of any one of embodiments Al to A6, wherein the oligopeptide has an amino acid sequence of Xm(R / D)EES(G / D)(E / K)Xn(Consensus No. 1), wherein m and n are integers independently selected from the range of from 0-10, and each X, if present, is independently selected from any amino acid.A8. The composition of embodiment A7, wherein the oligopeptide comprises an amino acid sequence of LREESGEP (SEQ ID NO:9).A9. The composition of any one of embodiments Al to A8, wherein the oligopeptide is a therapeutic agent.A 10. The composition of any one of embodiments Al to A9, wherein the oligopeptide is capable of increasing expression of ferritin heavy chain 1 (FTH1) mRNA by mammalian cells contacted with the oligopeptide.All. The composition of any one of embodiments Al to A 10, wherein the composition is a tablet, a capsule, powder, gel or syrup.23MF-366005067Docket No.: 30487-20004.40 A 12. A medicament comprising the composition of any one of embodiments Al to Al 1.A13. A method of preparing a composition comprising an oligopeptide that is at least partially encapsulated, the method comprising:a) providing an oligopeptide mixture comprising an oligopeptide and an anionic initiator;b) providing a monomeric mixture comprising a monomer of formula (M),(T 'OR\ QS" (M), or a salt thereof; andc) combining the oligopeptide mixture and the monomeric mixture to polymerize the monomer of formula (M), or the salt thereof, thereby producing the composition comprising the oligopeptide at least partially encapsulated by the polymer formed from the monomer of formula (M), wherein R is H, alkyl, or benzyl.A14. The method of embodiment A13, wherein the anionic initiator comprises a phosphate.A 15. The method of embodiment A13 or A14, wherein the anionic initiator comprises ammonium hexafluorophosphate.A 16. The method of any one of embodiments A13 to A15, wherein the oligopeptide mixture and the monomeric mixture are gradually combined over a combining time to form a reaction mixture.A17. The method of any one of embodiments A13 to A16, wherein the polymer has an average molecular weight between about 800 Da and about 5000 Da.A18. The method of any one of embodiments A13 to A17, wherein the oligopeptide and the polymer are present in a ratio of between about 1% and about 80% wt / wt.A 19. The method of any one of embodiments A13 to A18, wherein the oligopeptide consists of at least 4 amino acid residues; between 4 and 50 amino acid residues; or between 4 and 35 amino acid residues.24MF-366005067Docket No.: 30487-20004.40 A20. The method of any one of embodiments A13 to A19, wherein the oligopeptide has an amino acid sequence of Xm(R / D)EES(G / D)(E / K)Xn(Consensus No. 1), wherein m and n are integers independently selected from the range of from 0-10, and each X, if present, is independently selected from any amino acid.A21. The method of embodiment A20, wherein the oligopeptide comprises an amino acid sequence of LREESGEP (SEQ ID NO:9).A22. The method of any one of embodiments A13 to A21, wherein the oligopeptide is a therapeutic agent.A23. The method of any one of embodiments A13 to A22, wherein the oligopeptide has an overall negative charge at pH 7 as determined by pKa values of side chain groups, and wherein the oligopeptide mixture does not comprise an acid whose pKa is less than about 1.5.A24. The method of any one of embodiments A13 to A22, wherein the oligopeptide has an overall negative charge at pH 7 as determined by pKa values of side chain groups, and wherein the oligopeptide mixture does not comprise trifluoro acetic acid.A25. The method of any one of embodiments A13 to A22, wherein the oligopeptide has an overall neutral or positive charge at pH 7 as determined by pKa values of side chain groups, and wherein the oligopeptide mixture further comprises an acid whose pKa is less than about 1.5.A26. The method of embodiment A25, wherein the acid is trifluoro acetic acid.A27. A method of delivering an oligopeptide with minimal oral, gastric, or intestinal digestion of the oligopeptide to a subject, the method comprising:orally administering to the subject the pharmaceutical composition of any one of embodiments Al to All.A28. A method of treating a disease or condition in a subject in need thereof, comprising: orally administering to the subject the pharmaceutical composition of any one of embodiments Al to A 12,25MF-366005067Docket No.: 30487-20004.40 optionally, wherein the pharmaceutical composition is orally administered at a daily dose between about 100 mg and about 1000 mg.A29. A method of treating a disease or condition in a subject in need thereof, comprising: intravenously or subcutaneously administering to the subject the pharmaceutical composition of any one of embodiments Al to A 12,optionally, wherein the pharmaceutical composition is intravenously or subcutaneously administered at a daily dose between about 10 mg and about 100 mg.A30. The method of embodiment A28 or A29, wherein the disease or condition is cancer, and the method comprises administering to the subject the pharmaceutical composition in combination with administering a therapeutic agent suitable for treating cancer.A31. The method of embodiment A30, wherein the therapeutic agent suitable for treating cancer is a hormone agonist / antagonist, chemotherapy, chemotherapeutic agent, or radiotherapy, optionally a nonsteroidal antiandrogen or a platinum-based chemotherapeutic agent.A32. The method of any one of embodiments A28 to A31, wherein the cancer is prostate cancer.A33. The method of embodiment A32, wherein the therapeutic agent is a nonsteroidal antiandrogen.Bl. A method for inhibiting proliferation of an ovarian cancer cell, comprising contacting the ovarian cancer cell with an effective amount of a chemotherapeutic agent, and an effective amount of a formulation comprising an oligopeptide consisting of the amino acid sequence of Xm(R / D)EES(G / D)(E / K)Xn (Consensus No. 1), in which m and n are integers independently selected from the range of from 0-10, and each X, if present, is independently selected from any amino acid.B2. A method for inhibiting proliferation of an ovarian cancer cell, comprising contacting the ovarian cancer cell with an effective amount of a chemotherapeutic agent, and an effective amount of a formulation comprising an oligopeptide consisting of the amino acid sequence of26MF-366005067Docket No.: 30487-20004.40 Xp(R / D)EESGEPXq (SEQ ID NO: 10), in which p is an integer selected from the range of from 0-10, q is an integer selected from the range of from 0-9, and each X, if present, is independently selected from any amino acid.B3. The method of embodiment Bl or B2, comprising the amino acid sequence of Xr(R / D)EESGEP (SEQ ID NO: 11), in which Xr is leucine or absent.B4. The method of embodiment B3, wherein the oligopeptide comprises the amino acid sequence of LREESGEP (SEQ ID NO:9).B5. The method of embodiment B3, wherein the oligopeptide comprises the amino acid sequence of LDEESGEP (SEQ ID NOG).B6. The method of embodiment Bl or B2, wherein the oligopeptide comprises the amino acid sequence of LREESGEP (SEQ ID NO:9), LDEESGEP (SEQ ID NOG), REESGEP (SEQ ID NOG), REESGE (SEQ ID NO:1), KEEDEESGE (SEQ ID NOG), KPREESGE (SEQ ID NO:4), REESDKPMY (SEQ ID NOG), PREESDKP (SEQ ID NOG), or REESGEL (SEQ ID NOG).B7. The method of any one of embodiments Bl to B6, wherein contacting the cancer cell with both the chemotherapeutic agent, and the formulation reduces proliferation of the cancer cell to a greater extent than does contacting the cancer cell with the chemotherapeutic agent alone.B8. The method of any one of embodiments Bl to B7, wherein the contacting is in vivo.B9. A method for treating ovarian cancer in a mammalian subject in need thereof, comprising: administering to the subject i) an effective amount of a chemotherapeutic agent, and ii) an effective amount of a formulation comprising an oligopeptide consisting of the amino acid sequence of Xm(R / D)EES(G / D)(E / K)Xn (Consensus No. 1), in which m and n are integers independently selected from the range of from 0-10, and each X, if present, is independently selected from any amino acid.27MF-366005067Docket No.: 30487-20004.40 BIO. The method of embodiment B9, wherein administering the chemotherapeutic agent, and the formulation reduces proliferation of cells of the ovarian cancer to a greater extent than does administering the chemotherapeutic agent alone.B 11. The method of embodiment B9 or B 10, wherein the mammalian subject is a human subject.B12. The method of any one of embodiments B9 to Bll, wherein the oligopeptide comprises the amino acid sequence of LREESGEP (SEQ ID NO:9).B13. The method of any one of embodiments B9 to Bll, wherein the oligopeptide comprises the amino acid sequence of LDEESGEP (SEQ ID NOG).B14. The method of any one of embodiments B9 to Bll, wherein the oligopeptide comprises the amino acid sequence of LREESGEP (SEQ ID NO:9), LDEESGEP (SEQ ID NOG), REESGEP (SEQ ID NOG), REESGE (SEQ ID NO:1), KEEDEESGE (SEQ ID NOG), KPREESGE (SEQ ID NO:4), REESDKPMY (SEQ ID NOG), PREESDKP (SEQ ID NOG), or REESGEL (SEQ ID NO: 8).B15. The method of any one of the preceding embodiments, wherein the oligopeptide is synthetically produced.B16. The method of any one of the preceding embodiments, wherein the formulation further comprises at least one pharmaceutically acceptable excipient.B17. The method of any one of the preceding embodiments, wherein the chemotherapeutic agent is a platinum-based agent, optionally wherein the platinum-based agent comprises cisplatin or carboplatin, or a combination thereof.B 18. The method of embodiment B 17, wherein the chemotherapeutic agent is cisplatin.B 19. The method of embodiment B 17, wherein the chemotherapeutic agent is carboplatin.B20. The method of any one of embodiments B9 to B 19, wherein prior to administration of the formulation comprising the oligopeptide, the subject had been undergoing chemotherapy.28MF-366005067Docket No.: 30487-20004.40 B21. The method of embodiment B20, wherein prior to administration of the formulation comprising the oligopeptide, the subject was developing resistance to the chemotherapy.B22. An isolated oligopeptide comprising an amino acid sequence of LREESGEP (SEQ ID NO: 9), wherein the oligopeptide is 8 to 20 amino acids in length, optionally from 8 to 15 amino acids in length, or further optionally from 8 to 9 or 10 amino acids in length.B23. Use of an oligopeptide and a chemotherapeutic agent in the manufacture of a medicament for combination therapy for treating ovarian cancer in a subject in need thereof, wherein the oligopeptide consists of the amino acid sequence of Xm(R / D)EES(G / D)(E / K)Xn (Consensus No.1), in which m and n are integers independently selected from the range of from 0-10, and each X, if present, is independently selected from any amino acid.B24. Use of an oligopeptide in the manufacture of a medicament for use in combinatorial therapy for treating ovarian cancer in a subject in need thereof, wherein said medicament is to be administered to the subject in combination with a chemotherapeutic agent, wherein the oligopeptide consists of the amino acid sequence of Xm(R / D)EES(G / D)(E / K)Xn (Consensus No.1), in which m and n are integers independently selected from the range of from 0-10, and each X, if present, is independently selected from any amino acid.B25. Use of an oligopeptide in the manufacture of a first medicament and use of a chemotherapeutic agent in the manufacture of a second medicament, wherein the first medicament and the second medicament are to be used in combination therapy to treat ovarian cancer is a subject in need thereof, wherein the oligopeptide consists of the amino acid sequence of Xm(R / D)EES(G / D)(E / K)Xn (Consensus No. 1), in which m and n are integers independently selected from the range of from 0-10, and each X, if present, is independently selected from any amino acid.B26. The use of any one of embodiments B23-B25, wherein:i) the oligopeptide comprises the amino acid sequence of LREESGEP (SEQ ID NO:9), LDEESGEP (SEQ ID NOG), REESGEP (SEQ ID NOG), REESGE (SEQ ID NO:1), KEEDEESGE (SEQ ID NOG), KPREESGE (SEQ ID NO:4), REESDKPMY (SEQ ID NO:6), PREESDKP (SEQ ID NOG), or REESGEL (SEQ ID NOG); or29MF-366005067Docket No.: 30487-20004.40 ii) the oligopeptide consists of the amino acid sequence of Xp(R / D)EESGEPXq (SEQ ID NO: 10), in which p is an integer selected from the range of from 0-10, q is an integer selected from the range of from 0-9, and each X, if present, is independently selected from any amino acid; oriii) the oligopeptide consists of the amino acid sequence of Xr(R / D)EESGEP (SEQ ID NO: 11), in which Xr is leucine or absent.EXAMPLES

[0096] The presently disclosed subject matter will be better understood by reference to the following Examples, which are provided as exemplary of the invention, and not by way of limitation.Example 1: Preparation of Exemplary Oligopeptide for Oral Delivery

[0097] In this example, FT-002a was formulated into an oral delivery formulation labeled as FT-002a-O. FT-002a is an 8-amino acid peptide HC1 salt: LREESGEP (SEQ ID NO:9). FT-002a-0 is a preparation comprising cationically polymerized alpha lipoic acid and FT-002a in various proportions together with an anionic initiator (ammonium hexafluorophosphate; “AP”).

[0098] In a reaction vessel equipped with a magnetic stirrer was added 0.1 mole (91.5 g) FT-002a + 163 mg AP + 120 mL methylene chloride and the suspension was vortexed. A saturated solution of 150 g of alpha lipoic acid in dichloro methane was prepared and added into the above suspension over 10 minutes while vortexing continued. The mixture was stirred for an additional 20 minutes. The reaction mass was pumped dry under vacuum to give a yellow / orange powder / gel labeled as FT-002a-O. It should be understood that when the amount of oligopeptide was < -40%, a gel was observed to be formed (rather than a powder). The formulation (FT-002a-O) contained 61.8% FT-002a as measured by HPLC, after total depolymerization of the alpha lipoic acid polymer was carried out in aqueous medium at alkaline pH 7.4 over 4 hours or pH 8.5 in 20 minutes, at 30°C as shown in Table 1 below.30MF-366005067Docket No.: 30487-20004.40 Table 1. Characteristics of FT-002a and FT-002a-0Retention Oral Gastric Intestinal Time Baseline* digestion* % digestion % digestion % Test Article Structure (minutes) area % area % Hyd area % Hyd area % Hyd FT-002a LREESGEP 8.83 99.8 99.5 0.3% 59.3 40.4% 32.7 67.1% FT-002a-0 LREESGEP 8.92 99.7 99.6 0.1% 91.5 8.1% 79.1 20.6%Example 2: Preparation of Exemplary Oligopeptide for Oral Delivery

[0099] In a reaction vessel equipped with a magnetic stirrer was added 0.1 mole (91.4 g) LRKESGKP (SEQ ID NO: 18) + 100 mg TFA + 120 mL methylene chloride and the suspension was vortexed. A saturated solution of 150 g of alpha lipoic acid + 163 mg AP in dichloromethane was prepared and added into the above suspension over 10 minutes while vortexing continued. The mixture was stirred for an additional 20 minutes. The reaction mass was pumped dry under vacuum to give a yellow / orange gel labeled as LRKESGKP-O. The formulation (LRKESGKP-O) contained 6.1% LRKESGKP as measured by HPLC, after total depolymerization of the alpha lipoic acid polymer was carried out in aqueous medium at alkaline pH 7.4 over 4 hours or pH 8.5 in 20 minutes, at 30°C.Example 3: Stability of Peptides and Their Formulations Under Oral, Gastric, and Intestinal Digestion

[0100] Stability of various peptides and their oral delivery formulations under oral, gastric, and intestinal digestion were tested.

[0101] Stability under oral digestion was tested by mixing each peptide or its formulation with simulated salivary fluid containing porcine salivary amylase under agitation at pH 7.0 and 37° C for 2 minutes. Immediately after aliquoting 1.0 mL of the oral-phase mixture for HPLC, stability under gastric digestion was tested by adding a simulated gastric fluid containing porcine pepsin at a starting pH 3.0 followed by agitation at 37° C for 2 hours. After aliquoting 1.0 mL of the gastric-phase mixture for HPLC, stability under intestinal digestion was tested by adding a simulated intestinal fluid containing porcine pancreatin and bile salts at a starting pH 7.031MF-366005067Docket No.: 30487-20004.40 followed by agitation at 37° C for 2 hours. 1.0 mL of the intestinal-phase mixture was aliquoted for HPLC.

[0102] The HPLC results are summarized in Table 2 below. The formulations with names ending in “-O” were prepared using the same process described in Example 1, except that the indicated oligopeptide was used. The formulations in with names ending in “-OTFA” were prepared using the same process described in Example 2, except that the indicated peptide was used. In Table 2, * HPLC with XBridge Peptide BEH C18 Column (pore size=300 A, particle size=3.5 pm, inner diameter=4.6 mm, length=150 mm); mobile phase A: water with 0.1% TFA; mobile phase B: acetonitrile with 0.1% TFA. Standard gradient from 5 to 70% acetonitrile over 30 minutes. UV detector at 218 nm wavelength; ** Isoelectric point; # %'w w of active peptide in the total formulation; and ## % Hyd is the estimated % of the peptide hydrolyzed up to the end of each digestion step.

[0103] The sequences of the test articles of Table 2 are as follows: LREESGEP (SEQ ID NO:9); REESGE (SEQ ID NO:1); HAEGTFTSDVSSYLEGQAAKEFIAWLVKGRG (SEQ ID NO: 14); DEQE (SEQ ID NO: 15); PFADEEQELI (SEQ ID NO: 16): NWFIDEQAYRIC (SEQ ID NO: 17); KEEDEESGE (SEQ ID NOG): LRKESGKP (SEQ ID NO: 18); RKQR (SEQ ID NO: 19): HXEGTFTSDVSSYLEGQAAKEFIAWLVRGRG with side chain (K20 acylation) and non-natural amino acid at X2 (SEQ ID NO:20).32MF-366005067Docket No.: 30487-20004.40 Table 2. HPLC Results of Oligopeptide FormulationsAfterAfter Oral After Gastric # active Test * Retention Baseline* % % Intestinal %digestion digestion Charge pl ** peptide Article Time (min) (area %) Hyd Hyd digestion Hyd(area %) (area %) (%w / w)(area %)1 FT-002 8.83 99.8 99.5 0.3% 59.3 40.4% 32.7 67.1% -2 3.96FT-002a-0 99.7 99.6 0.1% 91.5 8.1% 79.1 20.6% 61.8 2 FT-001 7.66 99.3 99.1 0.2% 40.4 59.2% 23.9 75.9% -2 3.96FT-OOl-O 99.2 98.9 0.3% 84.2 14.9% 72.4 26.8% 64.5 3 GLP1 24.11 96.1 90.6 5.7% 11.8 87.0% 6.0 93.4% -1 5.39GLP1-0 97.4 95.1 2.4% 57.8 39.2% 38.8 59.2% 8.2 4 4-aa 4.32 99.5 99.2 0.3% 53.6 46.0% 27.5 72.3% -3 2.884-aa-0 99.3 99.2 0.1% 88.1 11.2% 76.2 23.2% 54.1 5 10-aa 10.78 98.0 97.3 0.7% 61.9 36.4% 45.3 53.4% -4 2.8310-aa-O 97.9 96.4 1.5% 76.4 20.7% 70.1 27.3% 49.9 6 12-aa 13.94 98.6 98.5 0.1% 55.2 44.0% 22.4 77.3% -1 3.9712-aa-0 98.9 98.9 0.0% 66.3 33.0% 59.6 39.7% 53.0 7 FT-006 11.83 99.2 99.1 0.1% 48.5 51.1% 28.9 70.8% -5 3.45FT-006-0 98.7 97.6 1.1% 63.7 34.7% 57.7 40.9% 40.7 8 8-aa 9.59 97.3 97.4 -0.1% 58.4 40.0% 30.1 69.1% 2 10.68-aa-OTFA 98.1 95.2 3.0% 72.0 24.4% 54.3 43.0% 6.1 9 4-aa 4.77 96.4 95.3 1.1% 56.9 40.3% 26.0 72.7% 3 12.54-aa-OTFA 96.8 94.8 2.1% 68.1 28.2% 42.4 55.3% 7.4 10 semaglutide 28.45 98.9 96.6 2.3% 18.6 80.7% 5.6 94.2% 0 7.13sema-OTFA 99.2 95.0 4.2% 39.8 58.1% 43.8 53.9% 8.233MF-366005067Docket No.: 30487-20004.40 Example 4: Determination of Effects of Oligopeptides in Combination with Chemotherapeutic Agents on Ovarian Tumor Cells

[0104] This example describes the effects of oligopeptides and two exemplary chemotherapeutic agents — cisplatin and carboplatin, on (1) sensitizing ovarian tumor cells to chemotherapy, and (2) cell proliferation when used in combination with chemotherapy.

[0105] In this example, primary resected tissue was treated ex vivo with one of the oligopeptides (at 1 mg / mL) during 24h alone, then in combination with cisplatin or carboplatin for an additional 24h. Molecular analysis was carried out 48h after the last treatment. The biomarkers for proliferation (Ki-67), apoptosis (CC3) and epithelial cells (Pan-CK) were assessed by immunofluorescence.Materials and Methods

[0106] Tumor collection and transportation: The ovarian tumor was collected. After collection, the tissue was dissected in small pieces (-5x5x5 cm) and immersed for preservation. The tissue was kept at 4°C for all transportation time and is processed within a maximum of 24h after collection.

[0107] Fresh tissue quality control (QC): 1-3 pieces of the fresh tissue were flash frozen. 5 pm slides were cut and stained with hematoxylin and eosin (H&E) for assessment.

[0108] Devices preparation: Devices were washed with 100% ethanol then incubated for 10 minutes with 70% ethanol for sterilization. Then devices were pre-treated with a 10 mg / mL solution of Pluronic F-108 in PBS. The pluronic solution was left at least 2 hours in the incubator (37°C, 5% CO2). A final wash was realized by replacing the pluronic with HBSS complemented with antibiotics. Devices were stored at 4°C until use.

[0109] MDTs generation and culture: After visual evaluation and validation of tissue quality, the sample was cut into microdissected tumor tissues (MDTs) of -350 pm. One device per condition was filled with 32 MDTs. Devices were kept in an incubator (37°C, 5% CO2) during the 7-day culture period. The culture medium used was the Ovarian TumorMACS Medium complemented with Primocin at 100 pg / mL. After an initial 24h incubation, the culture medium34MF-366005067Docket No.: 30487-20004.40 was changed to remove stress factors. An additional 48h rest period in the culture medium was done before initiating the testing regimen. In this case, the oligopeptide (test material) was diluted in sterile water, which was used as a vehicle. A stock solution of each peptide was prepared at 100 mg / mL. The stock solution was then freshly diluted in culture medium to obtain a final working concentration of 1 mg / mL. MDTs were incubated with each peptide alone for 24h followed by a 24h incubation period with the test material (oligopeptide) and a chemotherapeutic agent. Finally, all treatments are washed out from the devices and replaced by culture medium. MDTs were cultured in untreated culture medium for 48h. Detailed working concentrations are described in Table 3.Table 3. Concentrations for test material (oligopeptides) and chemotherapy agentsTest Material / WorkingDoseChemotherapeutic Agent ConcentrationFT-002a na 1 mg / mL FT-005 na 1 mg / mL SPH-E na 1 mg / mL Cisplatin Low Dose 2.5 pM Cisplatin High Dose 20 pM Carboplatin Low Dose 150 pM Carboplatin High Dose 300 pM

[0110] SPH-E (soluble protein hydrolysate-E) is a hydrolysate produced from egg-shell membranes. Egg shell membranes were separated from egg shells using mechanical means such as stirring and sonication. 50 grams of dry egg shell membranes were suspended in flOO ml of water and the suspension heated to 55C under stirring. 0.5 g of Corolase 8000 (a fungal alkaline protease enzyme preparation) was added to suspension and stirred for 20 minutes. 0.5g of Corolase 7089 (a liquid-formulated, bacterial endopeptidase enzyme preparation) was further added and stirred for further 20 minutes. 0.25g of more Corolase 8000 was added and stirred for further 10 minutes. The suspension was heated to 90C for 5 minutes, cooled and filtered. The filtrate was lyophilized to yield SPH-E as a yellow powder.35MF-366005067Docket No.: 30487-20004.40

[0111] Paraffin embedding and cutting: For each device, culture medium was replaced with 10% buffered formalin for 40 minutes, and followed by progressive 50%, 70%, 80% (with phloxine-B), 90%, 95%, 100% ethanol changes. Each reagent was incubated for a total of 30 minutes. After complete tissue dehydration, xylene substitute was added and incubated for 15 minutes. Devices were then opened and MDTs were transferred into paraffin for an hour-long incubation in order to obtain complete infiltration of each tissue. After the block formation / cooling phase, a final incubation of several hours in a 60°C oven allowed MDTs gravitational migration to ensure their alignment on the block face. Each sample was cut at 4 pm with a microtome and slides are dried overnight. Slides were stocked at room temperature.

[0112] H&E and Immunofluorescence (IF): Both stainings were performed at the CRCHUM’s molecular pathology platform. The first slide was used for H&E. The coloration was realized on the automated system. For IF, slides were stained on the automated system. Briefly, epitopes were revealed by heat in an acid or basic solution. Primary antibodies and secondary antibodies were added sequentially and incubated each for Ih. Secondary antibodies were coupled with fluorophores for marker detection. Finally, nuclei were stained with DAPI. Slides were scanned by the platform personnel on the Aperio 200 at 20X. Images generated in SDF format were visualized. Antibody concentrations are described in Table 4.Table 4. Concentration for antibodies used in immunofluorescence stainingAntibody F unction / Epitope Dilution Ki-67 Proliferation 1:500 Cleaved Caspase-3 (CC3) Apoptosis 1:200Pan-Cytokeratin Epithelial cells 1:200aMs-Ax488 Mouse IgGl 1:200aRb-Ax750 Rabbit IgGl 1:200aGp-Ax647 Guinea Pig IgG 1:200DAPI Nuclei na

[0113] Image analysis: Images were analyzed with software. Briefly, for each image, tissue and each fluorescent channel was sequentially and automatically detected. After each run,36MF-366005067Docket No.: 30487-20004.40 images were quality controlled for automatic detection and manually corrected if necessary. Finally for each region-of-interest (ROI) described, the total pixel area was calculated.Results

[0114] Tissue collection: A sample was obtained from a tumor that was an ovarian high grade serous carcinoma.MDTs generation and culture

[0115] Test material dilution: All three oligopeptides (test material) were diluted fresh in sterile water before the first incubation. Vials of the stock solution were then kept at 4°C until second use the next day. FT-002a and SPH-E were resuspended to obtain a stock solution at 100 mg / mL. During resuspension, FT-005 was found to be very difficult to dissolve. Stock solution concentration was lowered to 10 mg / mL to help the dissolution. However, even with a larger volume of water and being slightly warmed (40°C for a few minutes), the FT-005 solution still showed small observable crystals. The FT-005 solution was used as obtained, and was very carefully mixed before use in order to ensure overall distribution of the few remaining crystals.

[0116] MDT culture: After MDT generation, MDTs were left to rest in culture medium for 24h. After a first medium change to remove stress factors, a second rest period of 48h was carried out. Supernatants were then collected before the addition of the test material (oligopeptides) in order to have baseline data. Incubation time was as follows: 24h with oligopeptides or vehicle alone, then 24h with chemotherapy and oligopeptide. Media was changed and a final rest period of 48h was done before fixation. Supernatants were also collected at the end of the culture period and are stored at MISO facilities for potential future studies.

[0117] Biomarker analysis by IF: To assess the cancer cells response to the oligopeptides in combination with cisplatin or carboplatin, the epithelial compartment containing ovarian cancer cells was evaluated with a Pan-CK biomarker in IF. The tissue epithelial fraction was maintained over 69% in MDTs treated with vehicles and low- (LD) or high-dose (HD) chemotherapy agents, which was consistent with the baseline tumor result (73%) suggesting little or no effect of these treatments (FIG. 1A). However, in combination with cisplatin, both FT-002a and FT-005 reduced the epithelial fraction and this decrease was dose-dependent (FT-002a37MF-366005067Docket No.: 30487-20004.40 LD / HD: 64% and 51%; FT-005 LD / HD: 58% and 54%). A decrease was also observed with FT-002a combined with HD carboplatin (55%). No important effects were observed with cisplatin and SPH-E or carboplatin and FT-005. Although the results could be explained in part by tumor heterogeneity, as shown by the inter-device variation with control conditions (Veh Cis / Carbo: 85% and 79%), the important shrinkage of the epithelial compartment treated with FT-002a and FT-005 combined with cisplatin compared to cisplatin alone suggests increased activity of the chemotherapeutic agent with the oligopeptides tested.

[0118] DAPI (cell nuclei), Ki-67 (cell proliferation) and CC3 (cell apoptosis) were used to evaluate cell number and viability in the epithelial fraction. In response to FT-002a combined with cisplatin, a dose-dependent reduction in epithelial cell density was observed (FT-002a LD / HD: 16% and 13%), but not with cisplatin alone (FIG. IB). With HD carboplatin, both FT-002a and FT-005 increased the treatment's ability to reduce epithelial cell numbers. Regarding cell death (FIG. 1C), SPH-E and HD cisplatin was the only combination showing an increased level of apoptosis (9%) compared to HD cisplatin alone (4%). With HD carboplatin, the addition of FT-002a also increased the cell death level. Since CC3 is an early biomarker of cell death, it is possible that the low expression levels observed with FT-002a and FT-005 combined with HD cisplatin and FT-005 combined with carboplatin could be explained by the rapid death of cancer cells in response to the combinations during the last 48h incubation period. For SPH-E, although it increased the number of cells in the early apoptotic stage, it was not effective in decreasing cancer cells proliferation (FIG. ID), which could explain the lack of impact on the epithelial fraction. In contrast, both FT-002a and FT-005 improved the decrease in epithelial cell proliferation caused by the chemotherapeutic agents.Example 5: Ex Vivo Efficacy of FT-002a in Human Ovarian Cancer Tissue ExplantsStudy Design

[0119] Patient-derived tumor explants were obtained from three independent cancer specimens and processed into micro-dissected tissues (MDTs) of approximately 350 pm using the MISO Chip tumor explant platform and Micro-Dissected Tissue Microarray (MDTMA) technique. MDTs were treated ex vivo with FT-002a (LREESGEP) at three concentrations (0.5 mg / mL [low dose, LD], 1 mg / mL [intermediate dose, INT], and 2 mg / mL [high dose, HD]). FT- 38MF-366005067Docket No.: 30487-20004.40 002a was first incubated for 24 hours as monotherapy to modulate IREB2 and downstream gene expression, followed by an additional 24-hour co-incubation with cisplatin. Molecular analysis was performed 48 hours after final treatment. Immunofluorescence was used to assess cell density (DAPI+), proliferation (Ki-67), apoptosis (cleaved caspase-3, CC3), and epithelial cell identity (Pan-Cytokeratin, PanCK) to distinguish tumor cells (PanCK+) from stroma (PanCK-). In brief, the proliferative index was determined by calculating the proportion of Ki-67 positive cells (based on count), while the apoptotic index was determined by calculating the proportion of CC3 positive area, normalized to the nuclei area (area based). Treatment conditions and numbers of MDTs following ex vivo vulture is shown in Table 5.Table 5. Ex Vivo MDT Culture ConditionsSample ID Condition MDT CountMI25S029 Vehicle 28MI25S029 Cisplatin [2 pM] 30MI25S029 Cisplatin [2 pM] +FT LD [0.5 mg / ml] 27MI25S029 Cisplatin [2 pM] +FT INT [1 mg / ml] 32MI25S029 Cisplatin [2 pM] +FT HD [2 mg / ml] 31MI26S001 Vehicle 31MI26S001 Cisplatin [20 pM] 32MI26S001 Cisplatin [20 pM] +FT LD [0.5 mg / ml] 31MI26S001 Cisplatin [20 pM] +FT INT [1 mg / ml] 32MI26S001 Cisplatin [20 pM] +FT HD [2 mg / ml] 31MI26S005 Vehicle 32MI26S005 Cisplatin [20 pM] 32MI26S005 Cisplatin [20 pM] +FT LD [0.5 mg / ml] 32MI26S005 Cisplatin [20 pM] +FT INT [1 mg / ml] 32MI26S005 Cisplatin [20 pM] +FT HD [2 mg / ml] 31

[0120] The three specimens encompassed distinct histological subtypes and clinical contexts: (i) a colonic metastasis from a BRC A 1 / 2-negative high-grade serous carcinoma of suspected gynecologic / peritoneal origin in a patient who had received neoadjuvant chemotherapy (MI25S029); (ii) a stage pT3b high-grade serous ovarian carcinoma, treatment-naive (MI26S001); and (iii) a stage pT3a ovarian clear cell carcinoma, treatment-naive (MI26S005). The 3 samples displayed distinct tissue compositions. For MI25S029, the tissue compartment ratios were largely preserved. In contrast, sample MI26S001 contained very few cancerous cells after39MF-366005067Docket No.: 30487-20004.40 microdissection, despite an initial estimate of 80% epithelial content. Therefore, the MDT exhibited a phenotype closer to tumor- associated stroma, which is representative of the desmoplastic microenvironment in advanced ovarian cancer rather than cancerous tissue. The low epithelial count precluded an assessment of treatment efficacy on cancerous cells, and consequently analysis for this sample was restricted to the stromal (Pan-CK negative) compartment. Finally, sample MI26S005 exhibited a lower overall cell density, consistent with its clear cell phenotype. The composition was predominantly epithelial, providing an ideal model to evaluate the impact of treatment on cancerous cells. The cell density of MDTs treated with vehicle alone is shown in FIG. 2.Experiment 1: Unexpected Bio-efficacy at Sub-Therapeutic Cisplatin Dose

[0121] In this experiment, a dosing calculation resulted in the MDT from MI25S029 receiving cisplatin at a concentration of 2 pM, which is one-tenth (l / 10th) the intended therapeutic dose of 20 pM.

[0122] The clinically established concentration of cisplatin required to elicit meaningful antitumor activity in ovarian cancer tissue is 20 pM, which corresponds to pharmacologically relevant plasma concentrations achieved during standard intravenous chemotherapy. At one- tenth this concentration (2 pM), cisplatin alone would not be expected to produce any cytotoxicity in most ovarian cancer tissues, as this falls well below the established IC50 values for cisplatin in ovarian cancer cell lines. The observation that combination with FT-002a produced substantial cell killing at this sub-therapeutic cisplatin dose (FIG. 3) demonstrates a potent sensitization effect that is not predictable from the known pharmacology of either agent alone.

[0123] More significantly, observations in the stromal (TME) compartment of this specimen suggested a potential metabolic shift in non-cancerous cells in response to FT-002a treatment, consistent with the compound’s mechanism of action through modulation of iron metabolism via IREB2 suppression. The ability of FT-002a to convert a sub-therapeutic cisplatin exposure into a biologically active combination represents a novel and non-obvious therapeutic approach with significant clinical implications, particularly for dose reduction strategies that could minimize40MF-366005067Docket No.: 30487-20004.40 cisplatin-associated toxicides (nephrotoxicity, neurotoxicity, ototoxicity) while maintaining or enhancing anti-tumor efficacy.Experiment 2: Tumor Microenvironment Modulation in High-Grade Serous Ovarian Carcinoma

[0124] The MI26S001 MDT is from a stage pT3b high-grade serous ovarian carcinoma, which presented with very low tumor cellularity in the processed MDT (0.5% PanCK-i- cells). This phenotype consistent with tumor- associated stroma rather than malignant epithelium.Although direct anti-tumor efficacy could not be assessed in the epithelial compartment due to the sparse cancer cell population, the stromal compartment provided a robust and interpretable dataset.

[0125] Stromal cell density remained stable across all treatment conditions with no treatment-induced mortality, confirming tissue viability. Cisplatin-treated MDTs at 20 pM exhibited the expected pharmacological response: decreased proliferation and increased apoptosis (FIG.4), confirming tissue sensitivity to the chemotherapeutic agent. The addition of FT-002a to cisplatin produced a dose-dependent decrease in the stromal proliferative index, with the high dose reducing proliferation by more than 50% relative to vehicle control. Concurrently, CC3 apoptotic levels remained stable or slightly declined compared to cisplatin alone.

[0126] These results demonstrate that FT-002a modulates the tumor-associated stroma through proliferation suppression without driving excessive stromal cell death. This functional modulation, rather than nonspecific cytotoxicity, is consistent with the compound’s mechanism of action through IREB 2 -mediated iron metabolism disruption in the tumor microenvironment. In the context of ovarian cancer, where tumor- associated stroma actively supports chemoresistance and disease recurrence, this stromal modulation by FT-002a supports its utility as an adjunct to cisplatin-based therapy for improved disease control.41MF-366005067Docket No.: 30487-20004.40 Experiment 3: Conversion of Cytostatic to Cytotoxic Response in Ovarian Clear Cell Carcinoma

[0127] The MDT MI26S005 is from a stage pT3a ovarian clear cell carcinoma with predominantly epithelial composition, which provided an ideal model to evaluate the direct impact of FT-002a on cancerous cells. A dose-dependent reduction in total cell density was observed across treatment groups, with this decrease primarily concentrated within the epithelial (PanCK+) compartment, indicating a selective effect of FT-002a on malignant cells (FIG. 5A-5B).

[0128] Critically, cisplatin alone at 20 pM reduced cancer cell proliferation to approximately 40% of vehicle but did not induce cell death, a purely cytostatic response. The addition of FT-002a triggered a fundamental shift from this cytostatic response to a robust cytotoxic phenotype (FIG. 5A). While the proliferative index stabilized at approximately 30% (a further 10% decrease compared to cisplatin alone), there was a dramatic, dose-dependent increase in apoptotic marker expression, reaching up to 1500% of vehicle following FT-002a administration.

[0129] This metabolic-to-cytotoxic conversion is of particular significance for ovarian clear cell carcinoma, a histological subtype that is inherently resistant to platinum-based chemotherapy and for which effective treatment options are severely limited.

[0130] The ability of FT-002a to convert an inadequate cytostatic response to cisplatin into a potent cytotoxic response demonstrates synergistic anti-tumor activity and supports the compound’s role as a chemosensitizing agent capable of overcoming intrinsic platinum resistance.Conclusions

[0131] Taken together, these three independent ex vivo experiments in patient-derived ovarian cancer tissue demonstrate that the peptide FT-002a (LREESGEP) enhances cisplatin-mediated ovarian cancer control through multiple convergent mechanisms:

[0132] Chemosensitization at sub-therapeutic cisplatin doses: FT-002a unexpectedly showed significant bioefficacy at one-tenth the clinically relevant cisplatin concentration (2 p M 42MF-366005067Docket No.: 30487-20004.40 vs. 20 pM). This finding supports the inventive step of using FT-002a to reduce the effective dose of cisplatin required for anti-tumor activity, with direct clinical implications for minimizing dose-limiting chemotherapy toxicides.

[0133] (b) Conversion of cytostatic to cytotoxic response: In ovarian clear cell carcinoma — a platinum-resistant histological subtype — FT-002a converted an inadequate cytostatic response to cisplatin into a potent cytotoxic response, with apoptotic indices reaching 1500% of vehicle control in a dose-dependent manner. This synergistic activity establishes FT-002a as a chemosensitizing agent for cisplatin-resistant ovarian cancer.

[0134] (c) Tumor microenvironment (TME) modulation: In tumor-associated stroma, FT- 002a produced dose-dependent suppression of stromal cell proliferation exceeding 50% at the highest dose, without driving excessive stromal apoptosis. This functional modulation of the tumor- supportive microenvironment, consistent with the compound’s IREB2-mediated mechanism of action on iron metabolism, represents an additional axis of anti-cancer activity that complements the direct anti-tumor effects.

[0135] This example demonstrates the unexpected bioefficacy at sub-therapeutic cisplatin concentrations, the conversion of cytostatic to cytotoxic response in platinum-resistant disease, and the concurrent modulation of the tumor microenvironment.

[0136] As used herein and in the appended claims, the singular forms “a,” “or,” and “the” include plural references unless the context indicates otherwise. For example, “an excipient” includes one or more excipients.

[0137] It is understood that aspects and embodiments described herein as “comprising” include “consisting of’ and / or “consisting essentially of’ aspects and embodiments.

[0138] The term “about,” as used herein when referring to a measurable value such as an amount of a compound, dose, time, temperature, and the like, refers to variations of 20%, 10%, 5%, 1%, 0.5%, or even 0.1% of the specified amount. It is contemplated that, at each instance, such terms may be replaced with the notation “±10%”, or the like (or by indicating a variance of43MF-366005067Docket No.: 30487-20004.40 a specific amount calculated based on the relevant value). It is also contemplated that, at each instance, such terms may be deleted.

[0139] Reference to “between” two values or parameters herein includes (and describes) embodiments that include those two values or parameters per se. For example, description referring to “between x and y” includes description of “x” and “y” per se. Further, it should also be understood that “between x and y” can also be expressed as “about x to y” or “about x-y”.44MF-366005067

Claims

Docket No.: 30487-20004.40CLAIMSWhat is claimed is:

1. A pharmaceutical composition formulated for oral administration, comprising:(i) an oligopeptide, or a salt thereof; and(ii) a polymer comprising repeating units of formula (U):[ T ° ORs s -(U), or a salt thereof,wherein R is H, alkyl, or benzyl,wherein the polymer at least partially encapsulates the oligopeptide; andoptionally one or more pharmaceutically acceptable excipients or carriers.

2. The composition of claim 1, wherein the polymer has an average molecular weight between about 800 Da and about 5000 Da.

3. The composition of claim 1, wherein the oligopeptide and the polymer are present in a ratio of between about 1% and about 80% wt / wt.

4. The composition of claim 1, wherein the oligopeptide has an overall negative charge at pH 7 as determined by pKa values of side chain groups, or the oligopeptide has an isoelectric point of less than about 7.5.

5. The composition of claim 1, wherein the oligopeptide consists of at least 4 amino acid residues; between 4 and 50 amino acid residues; or between 4 and 35 amino acid residues.

6. The composition of claim 1, wherein the oligopeptide has an amino acid sequence of Xm(R / D)EES(G / D)(E / K)Xn (Consensus No. 1), wherein m and n are integers independently selected from the range of from 0-10, and each X, if present, is independently selected from any amino acid.45MF-366005067Docket No.: 30487-20004.40 7. The composition of claim 6, wherein the oligopeptide comprises an amino acid sequence of LREESGEP (SEQ ID NO:9).

8. The composition of claim 1, wherein the composition is a tablet, a capsule, powder, gel or syrup.

9. A method of preparing a pharmaceutical composition of claim 1, the method comprising:a) providing an oligopeptide mixture comprising an oligopeptide and an anionic initiator;b) providing a monomeric mixture comprising a monomer of formula (M),(M), or a salt thereof; andc) combining the oligopeptide mixture and the monomeric mixture to polymerize the monomer of formula (M), or the salt thereof, thereby producing the composition comprising the oligopeptide at least partially encapsulated by the polymer formed from the monomer of formula (M), wherein R is H, alkyl, or benzyl.

10. A method of delivering an oligopeptide with minimal oral, gastric, or intestinal digestion of the oligopeptide to a subject, the method comprising:administering to the subject the pharmaceutical composition of claim 1,optionally wherein the pharmaceutical composition is orally, intravenously or subcutaneously administered.

11. A method of treating cancer in a subject in need thereof, comprising:administering to the subject the pharmaceutical composition of claim 1,optionally wherein the pharmaceutical composition is orally, intravenously or subcutaneously administered.

12. The method of claim 11, further comprising administering a therapeutic agent suitable for treating cancer in combination with the pharmaceutical composition,optionally, wherein the therapeutic agent suitable for treating cancer is a hormone agonist / antagonist, chemotherapy, chemotherapeutic agent, or radiotherapy.46MF-366005067Docket No.: 30487-20004.40 13. The method of claim 11, wherein the cancer is prostate cancer,optionally, wherein the therapeutic agent is a nonsteroidal antiandrogen.

14. A method for inhibiting proliferation of an ovarian cancer cell, comprising contacting the ovarian cancer cell with an effective amount of a chemotherapeutic agent and an effective amount of a formulation comprising:(i) an oligopeptide consisting of the amino acid sequence of Xm(R / D)EES(G / D)(E / K)Xn (Consensus No. 1), in which m and n are integers independently selected from the range of from 0-10, and each X, if present, is independently selected from any amino acid,optionally, wherein the oligopeptide comprises the amino acid sequence of LREESGEP (SEQ ID NO:9), LDEESGEP (SEQ ID NOG), REESGEP (SEQ ID NOG), REESGE (SEQ ID NO:1), KEEDEESGE (SEQ ID NOG), KPREESGE (SEQ ID NO:4), REESDKPMY (SEQ ID NOG), PREESDKP (SEQ ID NOG), or REESGEL (SEQ ID NOG); or(ii) an oligopeptide consisting of the amino acid sequence of Xp(R / D)EESGEPXq (SEQ ID NO: 10), in which p is an integer selected from the range of from 0-10, q is an integer selected from the range of from 0-9, and each X, if present, is independently selected from any amino acid.

15. The method of claim 14, wherein contacting the cancer cell with both the chemotherapeutic agent and the formulation reduces proliferation of the cancer cell to a greater extent than does contacting the cancer cell with the chemotherapeutic agent alone, optionally, wherein the contacting is in vivo.

16. A method for treating ovarian cancer in a mammalian subject in need thereof, comprising: administering to the subject:i) an effective amount of a chemotherapeutic agent, andii) an effective amount of a formulation comprising an oligopeptide consisting of the amino acid sequence of Xm(R / D)EES(G / D)(E / K)Xn (Consensus No. 1), in which m and n are integers independently selected from the range of from 0-10, and each X, if present, is independently selected from any amino acid,optionally, wherein administering the chemotherapeutic agent and the formulation reduces proliferation of cells of the ovarian cancer to a greater extent than does administering the47MF-366005067Docket No.: 30487-20004.40 chemotherapeutic agent alone,optionally, wherein the mammalian subject is a human subject.

17. The method of any one of claims 14 to 16, wherein the oligopeptide comprises:i) the amino acid sequence of Xr(R / D)EESGEP (SEQ ID NO: 11), in which Xr is leucine or absent, orii) the amino acid sequence of LREESGEP (SEQ ID NO:9), oriii) the amino acid sequence of LDEESGEP (SEQ ID NOG), oriv) the amino acid sequence of LREESGEP (SEQ ID NO:9), LDEESGEP (SEQ ID NOG), REESGEP (SEQ ID NOG), REESGE (SEQ ID NO:1), KEEDEESGE (SEQ ID NOG), KPREESGE (SEQ ID NO:4), REESDKPMY (SEQ ID NOG), PREESDKP (SEQ ID NOG), or REESGEL (SEQ ID NO: 8),optionally, wherein the oligopeptide is synthetically produced.

18. The method of any one of claims 14 to 17, wherein the dose of the chemotherapeutic agent administered is lower than the therapeutic dose of the chemotherapeutic agent administered absent the co-administration of the formulation,optionally wherein the therapeutic dose of the chemotherapeutic agent is lowered by between 50% and 90% as compared to the therapeutic dose of the chemotherapeutic agent administered absent the co-administration of the formulation.

19. The method of any one of claims 14 to 18, wherein the chemotherapeutic agent is a platinum-based agent, optionally wherein the platinum-based agent comprises cisplatin or carboplatin, or a combination thereof.

20. The method of any one of claims 16 to 19, wherein prior to administration of the formulation comprising the oligopeptide:i) the subject had been undergoing chemotherapy; orii) the subject was developing resistance to the chemotherapy.

21. An isolated oligopeptide comprising an amino acid sequence of LREESGEP (SEQ ID NO: 9), wherein the oligopeptide is 8 to 20 amino acids in length, optionally from 8 to 15 amino acids in length, or further optionally from 8 to 9 or 10 amino acids in length.48MF-366005067Docket No.: 30487-20004.40 22. Use of an oligopeptide and a chemotherapeutic agent in the manufacture of a medicament for combination therapy for treating ovarian cancer in a subject in need thereof, wherein the oligopeptide consists of the amino acid sequence of Xm(R / D)EES(G / D)(E / K)Xn (Consensus No.1), in which m and n are integers independently selected from the range of from 0-10, and each X, if present, is independently selected from any amino acid.

23. Use of an oligopeptide in the manufacture of a medicament for use in combinatorial therapy for treating ovarian cancer in a subject in need thereof, wherein said medicament is to be administered to the subject in combination with a chemotherapeutic agent, wherein the oligopeptide consists of the amino acid sequence of Xm(R / D)EES(G / D)(E / K)Xn (Consensus No.1), in which m and n are integers independently selected from the range of from 0-10, and each X, if present, is independently selected from any amino acid.

24. Use of an oligopeptide in the manufacture of a first medicament and use of a chemotherapeutic agent in the manufacture of a second medicament, wherein the first medicament and the second medicament are to be used in combination therapy to treat ovarian cancer is a subject in need thereof, wherein the oligopeptide consists of the amino acid sequence of Xm(R / D)EES(G / D)(E / K)Xn (Consensus No. 1), in which m and n are integers independently selected from the range of from 0-10, and each X, if present, is independently selected from any amino acid.

25. The use of any one of claims 22-24, wherein:i) the oligopeptide comprises the amino acid sequence of LREESGEP (SEQ ID NO:9), LDEESGEP (SEQ ID NOG), REESGEP (SEQ ID NOG), REESGE (SEQ ID NO:1), KEEDEESGE (SEQ ID NOG), KPREESGE (SEQ ID NO:4), REESDKPMY (SEQ ID NOG), PREESDKP (SEQ ID NOG), or REESGEL (SEQ ID NOG); orii) the oligopeptide consists of the amino acid sequence of Xp(R / D)EESGEPXq (SEQ ID NO: 10), in which p is an integer selected from the range of from 0-10, q is an integer selected from the range of from 0-9, and each X, if present, is independently selected from any amino acid; oriii) the oligopeptide consists of the amino acid sequence of Xr(R / D)EESGEP (SEQ ID NO: 11), in which Xr is leucine or absent.49MF-366005067

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