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EP4587459A1 - Combinaison de thérapie génique utilisant l'il-12 et d'inhibiteurs de point de contrôle immunitaire pour le traitement du cancer - Google Patents

Combinaison de thérapie génique utilisant l'il-12 et d'inhibiteurs de point de contrôle immunitaire pour le traitement du cancer

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Publication number
EP4587459A1
EP4587459A1 EP23866429.6A EP23866429A EP4587459A1 EP 4587459 A1 EP4587459 A1 EP 4587459A1 EP 23866429 A EP23866429 A EP 23866429A EP 4587459 A1 EP4587459 A1 EP 4587459A1
Authority
EP
European Patent Office
Prior art keywords
aspects
administered
dose
immune checkpoint
combination therapy
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
EP23866429.6A
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German (de)
English (en)
Inventor
Khursheed Anwer
Nicholas Borys
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Imunon Inc
Original Assignee
Imunon Inc
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Filing date
Publication date
Application filed by Imunon Inc filed Critical Imunon Inc
Publication of EP4587459A1 publication Critical patent/EP4587459A1/fr
Pending legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/177—Receptors; Cell surface antigens; Cell surface determinants
    • A61K38/1774—Immunoglobulin superfamily (e.g. CD2, CD4, CD8, ICAM molecules, B7 molecules, Fc-receptors, MHC-molecules)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/20—Interleukins [IL]
    • A61K38/208—IL-12
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
    • A61K39/39558—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against tumor tissues, cells, antigens
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
    • A61K48/0008—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy characterised by an aspect of the 'non-active' part of the composition delivered, e.g. wherein such 'non-active' part is not delivered simultaneously with the 'active' part of the composition
    • A61K48/0025—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy characterised by an aspect of the 'non-active' part of the composition delivered, e.g. wherein such 'non-active' part is not delivered simultaneously with the 'active' part of the composition wherein the non-active part clearly interacts with the delivered nucleic acid
    • A61K48/0041—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy characterised by an aspect of the 'non-active' part of the composition delivered, e.g. wherein such 'non-active' part is not delivered simultaneously with the 'active' part of the composition wherein the non-active part clearly interacts with the delivered nucleic acid the non-active part being polymeric
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
    • A61K48/005—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy characterised by an aspect of the 'active' part of the composition delivered, i.e. the nucleic acid delivered
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/52—Cytokines; Lymphokines; Interferons
    • C07K14/54—Interleukins [IL]
    • C07K14/5434—IL-12
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
    • C07K14/70578—NGF-receptor/TNF-receptor superfamily, e.g. CD27, CD30, CD40, CD95
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • C07K16/2818—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against CD28 or CD152
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/63—Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
    • C12N15/79—Vectors or expression systems specially adapted for eukaryotic hosts
    • C12N15/85—Vectors or expression systems specially adapted for eukaryotic hosts for animal cells
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • A61K2039/507—Comprising a combination of two or more separate antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/545—Medicinal preparations containing antigens or antibodies characterised by the dose, timing or administration schedule
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2830/00—Vector systems having a special element relevant for transcription
    • C12N2830/50—Vector systems having a special element relevant for transcription regulating RNA stability, not being an intron, e.g. poly A signal

Definitions

  • IL-12 is one of the most active cytokines for stimulating an immune response against cancer.
  • the GEN-1 is an IL-12 DNA plasmid vector formulated using a lipopolymeric delivery system. GEN-1 can be delivered locally (e.g., intraperitoneally), offering the potential for cytokines to be expressed specifically in the tumor micro-environment with the goal of achieving increased efficacy while minimizing potential systemic toxicity.
  • the lipopolymer comprises a polyethyleneimine (PEI) covalently linked independently to cholesterol and polyethylene glycol (PEG) groups (e.g., the lipopolymer of FIG. 2).
  • PEI polyethyleneimine
  • PEG polyethylene glycol
  • the anticancer agent is paclitaxel.
  • the immune checkpoint inhibitor is a LAG-3 antagonist, wherein the LAG-3 antagonist is relatlimab.
  • the combination therapy further comprises (c) a second immune checkpoint inhibitor.
  • the second immune checkpoint inhibitor is an inhibitor of an immune checkpoint protein selected from the group consisting of CTLA-4, PD-1 (and its ligands PD-L1 and PD-L2), and/or LAG-3.
  • the second immune checkpoint inhibitor is a CTLA-4 antagonist is ipilimumab.
  • the nucleic acid vector formulated with the lipopolymer is administered intratum orally or intraperitoneally.
  • an anticancer agent is administered (e.g., first), followed by the administration of the nucleic acid vector formulated with the lipopolymer (e.g., second), and followed by administration of the immune checkpoint inhibitor (e.g., third).
  • an anticancer agent is administered (e.g., first), followed by the administration of the nucleic acid vector formulated with the lipopolymer (e.g., second), followed by the immune checkpoint inhibitor (e.g. third), and followed by a surgery to remove all or part of a tissue or tumor (e.g., interval cytoreductive surgery) (e.g., fourth).
  • the administration of the anticancer agent comprises administering docetaxel at a dose of 25 - 250 mg/m 2 , optionally, followed by administering carboplatin at a dose of about AUC 4-6 IV.
  • the interleukin- 12 (IL-12) formulated with a lipopolymer is administered at a dose of about 35 mg/m 2 to about 80 mg/m 2 .
  • the cancer is selected from a group consisting of ovarian cancer, fallopian tube cancer, primary peritoneal cancer, cervical cancer, breast cancer, prostate cancer, colorectal cancer, bladder cancer, brain cancer (e.g., glioblastoma), lung cancer, and any combination thereof, and metastasis of any of the cancers.
  • nivolumab and the lipopolymer are administered every 1-4 weeks (e.g., every 2 weeks) for the duration of treatment.
  • the second inhibitor is ipilimumab, and wherein ipilimumab is administered at about 1 mg/kg.
  • ipilimumab is administered every 2-8 weeks (e.g., every 6 weeks) for the duration of treatment.
  • the nucleic acid vector is a plasmid.
  • the lipopolymer is a nanoparticle.
  • FIG. 2 shows the PEG-PEI-Cholesterol structure.
  • an effective amount means the amount of a nucleic acid or a bioactive agent that is sufficient to provide the desired local or systemic effect and performance at a reasonable risk/benefit ratio as would attend any medical treatment.
  • peptide means peptides of any length and includes proteins.
  • polypeptide and oligopeptide are used herein without any particular intended size limitation, unless a particular size is otherwise stated.
  • administering means delivering the composition to the individual being treated such that the composition is capable of being circulated systemically where the composition binds to a target cell and is taken up by endocytosis.
  • the composition is preferably administered systemically to the individual, typically by subcutaneous, intramuscular, transdermal, intravenous, or intraperitoneal routes.
  • injectables for such use can be prepared in conventional forms, either as a liquid solution or suspension, or in a solid form that is suitable for preparation as a solution or suspension in a liquid prior to injection, or as an emulsion.
  • Suitable excipients that can be used for administration include, for example, water, saline, dextrose, glycerol, ethanol, and the like; and if desired, minor amounts of auxiliary substances such as wetting or emulsifying agents, buffers, and the like.
  • "efficacy” and similar terms means disappearance of tumor or shrinkage of tumor in size or reduction in tumor density or increase in lymphocyte count or increase in neutrophil count or improvement in survival, or all of the above.
  • promoter/regulatory sequence refers to a nucleic acid sequence required to express a gene product operably linked to a promoter/regulatory sequence.
  • constitutive refers to a nucleotide sequence that, when operably linked to a polynucleotide encoding or specifying a gene product, results in the production of a gene product in the cell under most or all physiological conditions of the cell.
  • a gene product can be either a nucleic acid, e.g., a messenger RNA produced by transcription of a gene, or a polypeptide which is translated from a transcript.
  • Gene products described herein further include nucleic acids with post transcriptional modifications, e.g., polyadenylation, or polypeptides with post translational modifications, e.g., methylation, glycosylation, the addition of lipids, association with other protein subunits, proteolytic cleavage, and the like.
  • operably linked refers to a functional linkage between a regulatory sequence and a heterologous nucleic acid sequence, which results in the expression of the latter.
  • first nucleic acid sequence and the second nucleic acid sequence are arranged in a functional relationship, the first nucleic acid sequence and the second nucleic acid sequence are operably linked.
  • the promoter affects the transcription or expression of a coding sequence, the promoter is operably linked to the coding sequence.
  • the operably linked DNA sequences may be adjacent to each other, and for example, in the case where two protein coding regions need to be linked, the DNA sequences are in the same reading frame.
  • transfer vector refers to a composition containing an isolated nucleic acid and a substance that can be used to deliver the isolated nucleic acid to the inside of a cell.
  • Many vectors are known in the art, including but not limited to linear polynucleotides, polynucleotides associated with ionic or amphiphilic compounds, plasmids, and viruses.
  • transfer vector should also be interpreted to further include nonplasmid and non-viral compounds that facilitate the transfer of nucleic acids into cells, such as polylysine compounds, liposomes, and the like.
  • the term "host cell” can be any type of cell, e.g., a primary cell, a cell in culture, or a cell from a cell line.
  • the term “host cell” refers to a cell transfected with a nucleic acid molecule and the progeny or potential progeny of such a cell. Progeny of such a cell may not be identical to the parent cell transfected with the nucleic acid molecule, e.g., due to mutations or environmental influences that may occur in succeeding generations or integration of the nucleic acid molecule into the host cell genome.
  • the % identity values can be generated using the WU-BL AST-2 computer program (Altschul et al., 1996, Methods in Enzymology 266:460-480, which is incorporated herewith by reference).
  • the following parameters are used, when carrying out the WU-BLAST-2 computer program: Most of the WU-BLAST-2 search parameters are set to the default values.
  • the HSP S and HSP S2 parameters which are dynamic values used by BLAST-2, are established by the program itself depending upon the composition of the sequence of interest and composition of the database against which the sequence is being searched.
  • a % sequence identity value can be determined by dividing (a) the number of matching identical amino acid residues between a particular amino acid sequence as set forth herein which is subjected to comparison (e.g. a particular polypeptide sequence characterized by a sequence identifier in the sequence listings) and the candidate amino acid sequence of interest to be compared, for example the number of matching identical amino acid residues as determined by WU-BLAST-2, by (b) the total number of amino acid residues of the polypeptide sequence as set forth herein which is subjected to comparison (e.g. a particular polypeptide sequence characterized by a SEQ. ID. NO. in the sequence listings).
  • identity percent refers to two or more sequences that are the same.
  • identity percent refers to two or more sequences that are the same.
  • sequence comparison algorithms e.g., 60% identity, optionally 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity over a specified region, or if not specified, over the entire sequence), then the two sequences are "substantially the same".
  • the identity exists over a region of at least about 50 nucleotides (or 10 amino acids) in length, or more preferably over a region of 100 to 500 or 1000 or more nucleotides in length (Or 20, 50, 200 or more amino acids).
  • a sequence serves as a reference sequence against which the test sequence is compared.
  • a sequence comparison algorithm is used, a test sequence and a reference sequence are input into a computer, and the sub-sequence coordinates and the sequence algorithm program parameters are specified, if necessary. Default program parameters can be used, or alternative parameters can be specified.
  • the sequence comparison algorithm calculates the percent sequence identity of the test sequence relative to the reference sequence based on the program parameters. Methods of sequence alignment for comparison are well known in the art as disclosed above.
  • the terms “therapeutically effective amount”, “therapeutically effective”, “effective amount” or “in an effective amount” are used interchangeably herein and refer to the amount of a compound, preparation, substance or composition that is effective to achieve a specific biological result as described herein, such as but not limited to treating or reducing the growth of a cancer or tumor.
  • therapeutically effective amount refers to the amount of a compound, preparation, substance or composition that is effective to achieve a specific biological result as described herein, such as but not limited to treating or reducing the growth of a cancer or tumor.
  • anti-tumor effective amount anti-tumor effective amount
  • “tumor-suppressing effective amount” or “therapeutically effective amount” the precise number of immune effector cells and therapeutic agents of the present disclosure to be administered can be determined by a physician in consideration of the individual's age, weight, tumor size, degree of infection or metastasis, and the condition of a patient (subject).
  • pharmaceutically acceptable refers to those compounds, materials, compositions, formulations, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • excipients are not meant to be exhaustive but merely illustrative as a person of ordinary skill in the art would recognize that additional types and combinations of excipients could be used to achieve the desired goals for delivery of a drug.
  • the excipient can be an inert substance, an inactive substance, and/or a not medicinally active substance.
  • the excipient can serve various purposes.
  • immune response refers to a biological response within an organism against a foreign agent or abnormal cell (e.g., a tumor cell), wherein the response protects the organism against such agents/cells and diseases caused by them.
  • autologous refers to any material derived from an individual that will later be reintroduced into that same individual.
  • variable region refers to the domain of an antibody heavy or light chain that is involved in binding the antibody to antigen.
  • the variable domains of the heavy chain and light chain (VH and VL, respectively) of a native antibody generally have similar structures, with each domain comprising four conserved framework regions (FRs) and three hypervariable regions (HVRs), including the complementarity determining regions (CDRs) (see, e.g., Kindt et al. Kuby Immunology, 6th ed., W.H. Freeman and Co., page 91 (2007)).
  • FRs conserved framework regions
  • HVRs hypervariable regions
  • CDRs complementarity determining regions
  • a "paratope” or an “antigen binding site”, as used interchangeably herein, refers to a part of an antibody which recognizes and binds to an antigen.
  • An antigen binding site is formed by several individual amino acid residues from the antibody's heavy and light chain variable domains arranged that are arranged in spatial proximity in the tertiary structure of the Fv region.
  • the antigen binding site is defined as a set of the six CDRs comprised in a cognate VH/VL pair.
  • CDRs complementarity determining regions
  • antibodies comprise six CDRs: three in the VH domain (CDR-H1, CDR-H2, CDR-H3), and three in the VL domain (CDR-L1, CDR-L2, CDR- L3).
  • CDR residues and other residues in the variable domain are numbered herein according to the Kabat numbering system (Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md., 1991).
  • An "acceptor human framework” for the purposes herein is a framework comprising the amino acid sequence of a light chain variable domain (VL) framework or a heavy chain variable domain (VH) framework derived from a human immunoglobulin framework or a human consensus framework, as defined below.
  • VL light chain variable domain
  • VH heavy chain variable domain
  • Framework refers to variable domain amino acid residues other than CDR residues.
  • the framework of a variable domain generally consists of four framework domains: FR1, FR2, FR3, and FR4. Accordingly, the CDR and FR amino acid sequences generally appear in the following sequence in the (a) VH domain: FR1-CDR-H1- FR2-CDR-H2-FR3-CDR-H3-FR4; and (b) in the VL domain: FR1-CDR-L1-FR2-CDR-L2- FR3-CDR-L3-FR4.
  • affinity refers to the strength of the sum total of noncovalent interactions between a single binding site of a molecule (e.g., an antibody) and its binding partner (e.g., an antigen).
  • binding affinity refers to intrinsic binding affinity which reflects a 1 : 1 interaction between members of a binding pair (e.g., antibody and antigen).
  • the affinity of a molecule X for its partner Y can generally be represented by the dissociation constant (KD). Affinity can be measured by common methods known in the art, including those described herein. Specific illustrative and exemplary embodiments for measuring binding affinity are described herein.
  • epitope denotes the site on an antigen, either proteinaceous or non-proteinaceous, to which an antibody binds.
  • Epitopes can be formed both from contiguous amino acid stretches (linear epitope) or comprise non-contiguous amino acids (conformational epitope), e.g. coming in spatial proximity due to the folding of the antigen, i.e. by the tertiary folding of a proteinaceous antigen.
  • Linear epitopes are typically still bound by an antibody after exposure of the proteinaceous antigen to denaturing agents, whereas conformational epitopes are typically destroyed upon treatment with denaturing agents.
  • An epitope comprises at least 3, at least 4, at least 5, at least 6, at least 7, or 8-10 amino acids in a unique spatial conformation.
  • Screening for antibodies binding to a particular epitope can be done using methods routine in the art such as, e.g., without limitation, alanine scanning, peptide blots (see Meth. Mol. Biol. 248 (2004) 443-463), peptide cleavage analysis, epitope excision, epitope extraction, chemical modification of antigens (see Prot. Sci. 9 (2000) 487-496), and cross-blocking (see “Antibodies”, Harlow and Lane (Cold Spring Harbor Press, Cold Spring Harb., NY).
  • Antigen Structure-based Antibody Profiling also known as Modification- Assisted Profiling (MAP)
  • MAP Modification- Assisted Profiling
  • the antibodies in each bin bind to the same epitope which may be a unique epitope either distinctly different from or partially overlapping with epitope represented by another bin.
  • competitive binding can be used to easily determine whether an antibody binds to the same epitope, or competes for binding with, a reference antibody.
  • composition refers to a preparation which is in such form as to permit the biological activity of the active ingredient to be effective, and which contains no additional components which are unacceptably toxic to a subject to which the composition would be administered.
  • the composition can be sterile.
  • Interleukin- 12 is a pro-inflammatory cytokine that plays an important role in innate and adaptive immunity. Gately, MK et al., Annu Rev Immunol. 16: 495-521 (1998). IL-12 functions primarily as a 70 kDa heterodimeric protein consisting of two disulfide- linked p35 and p40 subunits. IL-12 p40 homodimers do exist, but other than functioning as an antagonist that binds the IL- 12 receptor, they do not appear to mediate a biologic response. Id.
  • IL- 12-induced anti-cancer activity is largely mediated by the secondary secretion of IFNy
  • the concomitant induction of IFNy along with other cytokines (e.g., TNF-a) or chemokines (IP- 10 or MIG) by IL-12 caused severe toxicity. Id.
  • IL-12 IL-12 receptor
  • IL-12R The IL-12 receptor (IL-12R) consists of two chains, IL-12RP1 and IL-12RP213 and signals predominately through STAT4.
  • the IL-12R is expressed mainly by activated NK and T cells; it is barely detectable in resting T cells but is expressed at a low level in NK, probably explaining their rapid response to IL-12. Nevertheless, TCR activation and co-stimuli like B7, IFN-a, IFN-y and IL- 12 itself upregulate IL-12R expression (particularly IL-12RP2).
  • IL-12 Antitumor activity of systemic or local administration of IL-12 has been established in preclinical studies against various tumor cell lines. Dose and model dependent response as well as a memory antitumor effect were observed. Other studies suggest that IL- 12 is more efficacious against early stage or microscopic tumors than advanced disease. The T cell response is responsible for its antitumor activity and NK/NKT cell activation seems to prevent metastasis.
  • IL-12 inhibits tumor derived regulatory T cells (Treg) either through suppression of T cell IL-2 production, induction of apoptosis or by IFN-y mediated cell arrest, thus enhancing the Teff/Treg ratio both in vitro and in vivo.
  • IL-12 was also reported to mediate reprogramming of intratumoral myeloid derived suppressor cells (MDSC) to enhance CTL activity in a B16 melanoma model, reversing their suppressive role in vivo.
  • MDSC intratumoral myeloid derived suppressor cells
  • IL-12 is a key mediator of the Thl response
  • IL-12 has improved immune responses but this did not translate into clinically significant anti-tumor effects.
  • Ovarian cancer represents the fifth most common form of cancer affecting women and is the most lethal of gynecological malignancies, ranking fourth in cancer deaths among women.
  • First-line chemotherapy regimens for the treatment of ovarian cancer are typically platinum-based combination therapies that are administered intravenously (IV) for 4 to 6 treatments every 21 to 28 days. Although nearly 90% of women respond initially to platinumbased therapies, 55-75% of women will develop recurrent ovarian cancer within 2 years.
  • the second and third line therapies are generally ineffective and toxic including immune checkpoint inhibitors with a 11-15% response rate in platinum resistant, recurrent patients. There is an immediate need for safer and more effective therapies for the treatment of ovarian cancer.
  • Cancers can evade detection and destruction by the immune system despite the fact that many tumors elicit a strong immune response evident in lymphocyte infiltrates of the primary lesion.
  • Tumor immune evasion can be categorized into induction of immune tolerance and resistance to killing by activated immune effector cells.
  • the 'immunoediting' hypothesis suggests that tumors manipulate their microenvironment by creating complex local and regional immunosuppressive networks comprising various tumor-derived cytokines and other soluble factors. Therefore, by the time tumors have become clinically detectable, the tumor has already evolved mechanisms to evade the immune response mounted by the host against it. Such resistance mechanisms must be overcome to create effective and durable antitumor immunity.
  • TME tumor microenvironment
  • a GOG trial evaluated GEN-1 in 16 patients with persistent or recurrent platinum- resistant EOC.
  • higher doses of GEN-1 were assessed in combination with intravenous pegylated liposomal doxorubicin (PLD) 40 mg/m 2 (dose level 1 and 2) or 50 mg/m 2 (dose level 3) every 28 days and intraperitoneal GEN-1 at 24 mg/m 2 (dose level 1) or 36 mg/m 2 (dose level 2 and 3) on days 1, 8, 15, and 22 of a 28-day cycle. Cycles were repeated every 28 days until disease progression.
  • nucleic acid vector (e.g., a plasmid) comprises a promoter operably linked to a nucleic acid encoding a p35 subunit of IL- 12 and a promoter operably linked to a nucleic acid encoding a p40 subunit of IL12.
  • the human IL-12 p35 comprises an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% identity to SEQ ID NO: 85.
  • the human IL-12 p40 comprises an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% identity to SEQ ID NO: 86.
  • a cationic gene delivery polymer suitable for the present disclosure is a PEI derivative comprising a PEI backbone, a lipid, and a hydrophilic polymer spacer wherein the lipid is directly bound to the polyethylenimine backbone or covalently bound to the polyethylene glycol spacer, which in turn is bound, via a bio compatible bond, to the PEI.
  • the cationic gene delivery polymer of the present disclosure may further comprise a targeting moiety including antibodies or antibody fragments, cell receptors, growth factor receptors, cytokine receptors, folate, transferrin, epidermal growth factor (EGF), insulin, asialoorosomucoid, mannose-6-phosphate (monocytes), mannose (macrophage, some B cells), Lewis x and sialyl Lewis x (endothelial cells), N-acetyllactosamine (T cells), galactose (colon carcinoma cells), and thrombomodulin (mouse lung endothelial cells), fusogenic agents such as polymixin B and hemaglutinin HA2, lysosomotrophic agents, nucleus localization signals (NLS) such as T-antigen, and the like.
  • a targeting moiety including antibodies or antibody fragments, cell receptors, growth factor receptors, cytokine receptors, folate, transferrin, epidermal growth factor (EGF
  • a cationic gene delivery polymer suitable for the present invention is a polyethylenimine derivative comprising a polyethylenimine (PEI) backbone, a lipid, and a polyethylene glycol spacer wherein the lipid is directly bound to the polyethylenimine backbone or covalently bound to the polyethylene glycol spacer, which in turn is bound, via a biocompatible bond, to the PEI.
  • PEI polyethylenimine
  • the gene delivery polymer comprises a mixture of the lipopolyamine and an alkylated derivative of the lipopolyamine.
  • the alkylated derivative of the lipopolyamine is a polyoxyalkylene, polyvinylpyrrolidone, polyacrylamide, polydimethylacrylamide, polyvinyl alcohol, dextran, poly (L-glutamic acid), styrene maleic anhydride, poly-N-(2-hydroxypropyl) methacrylamide, or polydivinylether maleic anhydride.
  • the alkylated derivative of the lipopolyamine has the following formula:
  • n an integer from 10 to 100 repeating units containing 2-5 carbon atoms each.
  • the alkylated derivative of the lipopolyamine has the following formula:
  • n 11 (Staramine-mPEG515).
  • alkylated derivative of the lipopolyamine has the following formula:
  • the ratio of amine nitrogen in the lipopolyamine to phosphate in the nucleic acid vector is from about 0.1 : 1 to about 50: 1 (e.g., about 0.1:1 to about 40:1; about 0.1:1 to about 30:1; about 0.1:1 to about 20:1; about 0.1:1 to about 10:1, or about 0.1:1 to about 5:1). In some aspects, the ratio of amine nitrogen in the lipopolyamine to phosphate in the nucleic acid vector is from about 1 : 10 to about 10:1.
  • the gene delivery polymer comprises a mixture of the lipopolyamine and an alkylated derivative of the lipopolyamine.
  • the alkylated derivative of the lipopolyamine is a polyoxyalkylene, polyvinylpyrrolidone, polyacrylamide, polydimethylacrylamide, polyvinyl alcohol, dextran, poly (L-glutamic acid), styrene maleic anhydride, poly-N-(2-hydroxypropyl) methacrylamide, or polydivinylether maleic anhydride.
  • the ratio of the lipopolyamine to the alkylated derivative of the lipopolyamine in the mixture is 1:1 to 10:1.
  • the gene delivery polymer is present in a solution with the nucleic acid vector from about 0.1% - about 5% or about 0.5% - about 5%.
  • the gene delivery polymer comprises BD15-12.
  • the ratio of nucleotide to BD15-12 polymer is 5: 1.
  • the gene delivery polymer comprises Omnifect.
  • the ratio of nucleotide to Omnifect polymer (N:P) is 10: 1.
  • the nanoparticle that comprises a DNA plasmid that encodes interleukin- 12 (IL- 12) and a synthetic polymer facilitating plasmid delivery is delivered intraperitoneally.
  • the nanoparticle is administered at a dose of about 35 mg/m 2 to about 80 mg/m 2 . In some aspects, the nanoparticle is administered at a dose of about 40 mg/m 2 to about 80 mg/m 2 . In some aspects, the nanoparticle is administered at a dose of about 45 mg/m 2 to about 80 mg/m 2 . In some aspects, the nanoparticle is administered at a dose of about 50 mg/m 2 to about 80 mg/m 2 . In some aspects, the nanoparticle is administered at a dose of about 55 mg/m 2 to about 80 mg/m 2 . In some aspects, the nanoparticle is administered at a dose of about 60 mg/m 2 to about 80 mg/m 2 .
  • the nanoparticle is administered at a dose of about 65 mg/m 2 to about 80 mg/m 2 . In some aspects, the nanoparticle is administered at a dose of about 70 mg/m 2 to about 80 mg/m 2 . In some aspects, the nanoparticle is administered at a dose of about 75 mg/m 2 to about 80 mg/m 2 . In some aspects, the nanoparticle is administered at a dose of about 35 mg/m 2 to about 75 mg/m 2 . In some aspects, the nanoparticle is administered at a dose of about 35 mg/m 2 to about 70 mg/m 2 . In some aspects, the nanoparticle is administered at a dose of about 35 mg/m 2 to about 65 mg/m 2 .
  • the nanoparticle is administered at a dose of about 35 mg/m 2 to about 60 mg/m 2 . In some aspects, the nanoparticle is administered at a dose of about 35 mg/m 2 to about 55 mg/m 2 . In some aspects, the nanoparticle is administered at a dose of about 35 mg/m 2 to about 50 mg/m 2 . In some aspects, the nanoparticle is administered at a dose of about 35 mg/m 2 to about 45 mg/m 2 . In some aspects, the nanoparticle is administered at a dose of about 35 mg/m 2 to about 40 mg/m 2 .
  • the nanoparticle is administered at a dose of about 35 mg/m 2 , about 40 mg/m 2 , about 45 mg/m 2 , about 50 mg/m 2 , about 55 mg/m 2 , about 60 mg/m 2 , about 65 mg/m 2 , about 70 mg/m 2 , about 75 mg/m 2 , or about 80 mg/m 2 .
  • the nanoparticle is administered at a dose of about 60 mg/m 2 .
  • Immune checkpoint proteins interact with specific ligands which send a signal into T-cells that inhibits T-cell function. Cancer cells exploit this by driving high level expression of checkpoint proteins on their surface thereby suppressing the anti-cancer immune response.
  • An immune checkpoint inhibitor comprises any compound capable of inhibiting the function of an immune checkpoint protein. Inhibition includes reduction of function as well as full blockade.
  • the immune checkpoint protein is a human checkpoint protein.
  • ipilimumab is administered at a dose of about 0.5 mg/kg, about 1 mg/kg, about 1.5 mg/kg, about 2 mg/kg, about 2.5 mg/kg, about 3 mg/kg, about 3.5 mg/kg, about 4 mg/kg, about 4.5 mg/kg, or about 5 mg/kg.
  • ipilimumab is administered at a dose of about 1 mg/kg.
  • nivolumab is administered at a dose of about 240 mg.
  • the anti-PD-1 antibodies of the combination therapy disclosed herein include mAbs that bind specifically to human PD-1 with a KD of 1 x 10' 7 M or less, as determined by surface plasmon resonance using a Biacore biosensor system; (b) does not substantially bind to human CD28, CTLA-4 or ICOS; (c) increases T-cell proliferation in a Mixed Lymphocyte Reaction (MLR) assay; (d) increases interferon-y production in an MLR assay; (e) increases IL-2 secretion in an MLR assay; (f) binds to human PD-1 and cynomolgus monkey PD-1; (g) inhibits the binding of PD-L1 and/or PD-L2 to PD-1; (h) stimulates antigen-specific memory responses; (i) stimulates Ab responses; and (j) inhibits tumor cell growth in vivo.
  • the anti-PD-1 antibodies of the combination therapy disclosed herein include mAbs that bind specifically to human bind specifically
  • the anti-PD-1 antibody is pembrolizumab.
  • Pembrolizumab also known as "KEYTRUDA®", lambrolizumab, and MK-3475
  • S228P humanized monoclonal IgG4
  • Pembrolizumab is described, for example, in U.S. Patent Nos. 8,354,509 and 8,900,587.
  • Pembrolizumab has been approved by the FDA for the treatment of relapsed or refractory melanoma.
  • the anti-PD-1 antibody is REGN2810. In some aspects, the anti- PD-1 antibody is PDR001. Another known anti-PD-1 antibody is pidilizumab (CT-011). In some aspects, the anti-PD-1 antibody is MEDI0608 (formerly AMP-514), which is a monoclonal antibody. MEDI0608 is described, for example, in U.S. Patent No. 8,609,089. In some aspects, the anti-PD-1 antibody or antigen binding fragment thereof is BGB-A317, which is a humanized monoclonal antibody. BGB-A317 is described in U.S. Publ. No.
  • Anti-human-PD-1 antibodies (or VH and/or VL domains derived therefrom) suitable for uses disclosed herein can be generated using methods well known in the art. Alternatively, art recognized anti-PD-1 antibodies can be used.
  • Anti-PD-1 antibodies useful for the combination therapy of the disclosed invention also include antigen-binding portions of the above antibodies. It has been amply demonstrated that the antigen-binding function of an antibody can be performed by fragments of a full-length antibody. Examples of binding fragments encompassed within the term "antigen-binding portion" of an antibody include (i) a Fab fragment, a monovalent fragment consisting of the VL, VH, CL and CHI domains; (ii) a F(ab')2 fragment, a bivalent fragment comprising two Fab fragments linked by a disulfide bridge at the hinge region; (iii) a Fd fragment consisting of the VH and CHI domains; and (iv) a Fv fragment consisting of the VL and VH domains of a single arm of an antibody.
  • Anti-PD-1 antibodies suitable for use in the disclosed combination therapies are antibodies that bind to PD-1 with high specificity and affinity, block the binding of PD-L1 and or PD-L2, and inhibit the immunosuppressive effect of the PD-1 signaling pathway.
  • the anti-PD-1 antibody or antigen-binding portion thereof crosscompetes with nivolumab for binding to human PD-1.
  • the anti-PD-1 antibody or antigen-binding portion thereof is a chimeric, humanized or human monoclonal antibody or a portion thereof.
  • the antibody is a humanized antibody. In other embodiments, the antibody is a human antibody.
  • Antibodies of an IgGl, IgG2, IgG3 or IgG4 isotype can be used.
  • the anti-PD-1 antibody or antigen binding fragment thereof comprises a heavy chain constant region which is of a human IgGl or IgG4 isotype.
  • the sequence of the IgG4 heavy chain constant region of the anti-PD-1 antibody or antigen binding fragment thereof contains an S228P mutation which replaces a serine residue in the hinge region with the proline residue normally found at the corresponding position in IgGl isotype antibodies.
  • the PD-1 antagonist is selected from the group consisting of nivolumab, pembrolizumab, cemiplimab, and dostarlimab.
  • the anti-PD-Ll antibody is BMS-936559 (formerly 12A4 or MDX-1105) (see, e.g., U.S. Patent No. 7,943,743; WO 2013/173223).
  • the anti-PD-Ll antibody is MPDL3280A (also known as RG7446 and atezolizumab) (see, e.g., Herbst et al. 2013 J Clin Oncol 31 (suppl): 3000; U.S. Patent No. 8,217,149), MEDI4736 (Khleif, 2013, In: Proceedings from the European Cancer Congress 2013; September 27- October 1, 2013; Amsterdam, The Netherlands.
  • antibodies that cross-compete for binding to human PD-L1 with, or bind to the same epitope region of human PD-L1 as the above-references PD-L1 antibodies are mAbs.
  • these cross-competing antibodies can be chimeric antibodies, or can be humanized or human antibodies.
  • Such chimeric, humanized or human mAbs can be prepared and isolated by methods well known in the art.
  • the anti-PD-Ll antibody is selected from the group consisting of BMS-936559 (also known as 12A4, MDX-1105; see, e.g., U.S. Patent No.
  • Atezolizumab (Roche; also known as TECENTRIQ®; MPDL3280A, RG7446; see US 8,217,149; see, also, Herbst et al. (2013) J Clin Oncol 31 (suppl): 3000), durvalumab (AstraZeneca; also known as IMFINZITM, MEDL4736; see WO 2011/066389), avelumab (Pfizer; also known as BAVENCIO®, MSB-0010718C; see WO 2013/079174), STI-1014 (Sorrento; see WO2013/181634), CX-072 (Cytomx; see W02016/149201), KN035 (3D Med/Alphamab; see Zhang et al., Cell Discov.
  • the PD-L1 antibody is atezolizumab (TECENTRIQ®).
  • Atezolizumab is a fully humanized IgGl monoclonal anti-PD-Ll antibody.
  • the PD-L1 antibody is durvalumab (IMFINZITM). Durvalumab is a human IgGl kappa monoclonal anti-PD-Ll antibody. [0274] In some aspects, the PD-L1 antibody is avelumab (BAVENCIO®). Avelumab is a human IgGl lambda monoclonal anti-PD-Ll antibody.
  • the anti-PD-Ll monoclonal antibody is selected from the group consisting of 28-8, 28-1, 28-12, 29-8, 5H1, and any combination thereof.
  • the anti-PD-Ll antibodies of the disclosed methods comprise isolated antibodies that bind specifically to human PD-L1 and cross-compete for binding to human PD-L1 with any anti-PD-Ll antibody disclosed herein, e.g., atezolizumab, durvalumab, and/or avelumab.
  • the anti-PD-Ll antibody binds the same epitope as any of the anti-PD-Ll antibodies described herein, e.g., atezolizumab, durvalumab, and/or avelumab.
  • Anti-PD-Ll antibodies for use in the methods disclosed herein can include antigen-binding portions of the above antibodies. It has been amply demonstrated that the antigen-binding function of an antibody can be performed by fragments of a full-length antibody.
  • Monoclonal antibodies that specifically bind to CTLA-4 include, without limitation, Ipilimumab (Yervoy®; BMS) and Tremelimumab (AstraZeneca/Medlmmune), as well as antibodies disclosed in U.S. Patent Application Publication Nos. 2005/0201994, 2002/0039581, and 2002/0086014, the contents of each of which are incorporated herein by reference, and antibodies disclosed in U.S. Pat. Nos.
  • IMP731 H5L7BW
  • MK-4280 28G-10
  • REGN3767 described in Journal for ImmunoTherapy of Cancer, (2016) Vol. 4, Supp. Supplement 1 Abstract Number: Pl 95, BAP050 described in WO2017/019894
  • IMP-701 LAG-525
  • IMP321 eftilagimod alpha
  • Sym022 TSR-033, MGD013, BI754111, FS118, AVA-017 and GSK2831781.
  • the anti-cancer agent comprises carboplatin.
  • the anti-cancer agent comprises docetaxel.
  • the anticancer agent is administered prior to the interval cytoreductive surgery every three weeks for about 12 weeks to about 18 weeks.
  • a surgery to remove all or part of a tissue or tumor is administered (e.g., first), followed by the administration of the nucleic acid vector formulated with the lipopolymer is administered (e.g., second), and followed by administration of an immune checkpoint inhibitor (e.g., third, fourth, etc. depending on how many immune checkpoint inhibitors are administered).
  • an anticancer agent is administered, followed by the administration of a DNA plasmid, followed by the immune checkpoint inhibitor, followed by an interval cytoreductive surgery.
  • the anticancer agent is administered prior to the interval cytoreductive surgery every three weeks for about 12 weeks to about 18 weeks.
  • the administration of the anticancer agent comprises administering paclitaxel at a dose of about 25 mg/m 2 , about 50 mg/m 2 , about 75 mg/m 2 , about 100 mg/m 2 , about 125 mg/m 2 , about 150 mg/m 2 , about 175 mg/m 2 , about 200 mg/m 2 , about 225 mg/m 2 , or about 250 mg/m 2 , optionally, followed by administering carboplatin at a dose of about AUC 4-6 IV.
  • nucleic acid vector (e.g., a plasmid) comprises an intron, a 3' UTR (e.g., hGH 3' UTR), an antibiotic resistance gene, or any combination thereof (e.g., the elements of FIG. 1).
  • a 3' UTR e.g., hGH 3' UTR
  • an antibiotic resistance gene e.g., the elements of FIG. 1.
  • the immune checkpoint inhibitor is an antibody.
  • the immune checkpoint inhibitor is a LAG-3 antagonist, wherein the LAG-3 antagonist is relatlimab.
  • the combination further comprises an anticancer agent.
  • the chemotherapeutic agent is selected from the group consisting of doxorubicin, paclitaxel, carboplatin, docetaxel, nab-paclitaxel, olaparib, and any combination thereof.
  • the anticancer agent is doxorubicin.
  • the anticancer agent is carboplatin.
  • the anticancer agent is docetaxel. [0349] In some aspects, the anticancer agent is nab-paclitaxel.
  • the anticancer agent is olaparib.
  • the nucleic acid vector formulated with the lipopolymer is administered intratum orally or intraperitoneally.
  • the nucleic acid vector formulated with the lipopolymer is administered intravenously.
  • the immune checkpoint inhibitor is administered intratumorally intraperitoneally, intravesicularly, or any combination thereof.
  • the immune checkpoint inhibitor is administered intravenously.
  • the administration of the anticancer agent comprises administering paclitaxel at a dose of about 25 - 250 mg/m 2 , about 50 - 250 mg/m 2 , about 75 - 250 mg/m 2 , about 100 - 250 mg/m 2 , about 125 - 250 mg/m 2 , about 150 - 250 mg/m 2 , about 175 - 250 mg/m 2 , about 200 - 250 mg/m 2 , about 225 - 250 mg/m 2 , about 25 - 225 mg/m 2 , about 25 - 200 mg/m 2 , about 25 - 175 mg/m 2 , about 25 - 150 mg/m 2 , about 25 - 125 mg/m 2 , about 25 - 250 mg/m 2 , about 25 - 100 mg/m 2 , about 25 - 75 mg/m 2 , or about 25 - 50 mg/m 2 , optionally, followed by administering carboplatin at a dose of about AUC 4-6
  • the administration of the anticancer agent comprises administering paclitaxel at a dose of about 25 mg/m 2 , about 50 mg/m 2 , about 75 mg/m 2 , about 100 mg/m 2 , about 125 mg/m 2 , about 150 mg/m 2 , about 175 mg/m 2 , about 200 mg/m 2 , about 225 mg/m 2 , or about 250 mg/m 2 , optionally, followed by administering carboplatin at a dose of about AUC 4-6 IV.
  • the administration of the anticancer agent comprises administering docetaxel at a dose of 25 - 250 mg/m 2 , optionally, followed by administering carboplatin at a dose of about AUC 4-6 IV.
  • the administration of the anticancer agent comprises administering docetaxel at a dose of about 25 mg/m 2 , about 50 mg/m 2 , about 75 mg/m 2 , about 100 mg/m 2 , about 125 mg/m 2 , about 150 mg/m 2 , about 175 mg/m 2 , about 200 mg/m 2 , about 225 mg/m 2 , or about 250 mg/m 2 , optionally, followed by administering carboplatin at a dose of about AUC 4-6 IV.
  • the administration of the anticancer agent comprises administering nab-paclitaxel at a dose of 25 - 350 mg/m 2 , optionally followed by administering carboplatin at a dose of about AUC 4-6 IV.
  • the administration of the anticancer agent comprises administering nab-paclitaxel at a dose of about 25 - 250 mg/m 2 , about 50 - 250 mg/m 2 , about 75 - 250 mg/m 2 , about 100 - 250 mg/m 2 , about 125 - 250 mg/m 2 , about 150 - 250 mg/m 2 , about 175 - 250 mg/m 2 , about 200 - 250 mg/m 2 , about 225 - 250 mg/m 2 , about 25 - 225 mg/m 2 , about 25 - 200 mg/m 2 , about 25 - 175 mg/m 2 , about 25 - 150 mg/m 2 , about 25 - 125 mg/m 2 , about 25 - 250 mg/m 2 , about 25 - 100 mg/m 2 , about 25 - 75 mg/m 2 , or about 25 - 50 mg/m 2 , optionally, followed by administering carboplatin at a dose of about 25 - 250 mg/m
  • the administration of the anticancer agent comprises administering nab-paclitaxel at a dose of about 25 mg/m 2 , about 50 mg/m 2 , about 75 mg/m 2 , about 100 mg/m 2 , about 125 mg/m 2 , about 150 mg/m 2 , about 175 mg/m 2 , about 200 mg/m 2 , about 225 mg/m 2 , or about 250 mg/m 2 , optionally, followed by administering carboplatin at a dose of about AUC 4-6 IV.
  • the administration of the nanoparticle prior to the interval cytoreductive surgery begins 15 days after the first administration of the anticancer agent, every week for at least about 12 weeks to about 18 weeks.
  • the nanoparticle is administered at a dose of about 65 mg/m 2 to about 80 mg/m 2 . In some aspects, the nanoparticle is administered at a dose of about 70 mg/m 2 to about 80 mg/m 2 . In some aspects, the nanoparticle is administered at a dose of about 75 mg/m 2 to about 80 mg/m 2 . In some aspects, the nanoparticle is administered at a dose of about 35 mg/m 2 to about 75 mg/m 2 . In some aspects, the nanoparticle is administered at a dose of about 35 mg/m 2 to about 70 mg/m 2 . In some aspects, the nanoparticle is administered at a dose of about 35 mg/m 2 to about 65 mg/m 2 .
  • the nanoparticle is administered at a dose of about 35 mg/m 2 to about 60 mg/m 2 . In some aspects, the nanoparticle is administered at a dose of about 35 mg/m 2 to about 55 mg/m 2 . In some aspects, the nanoparticle is administered at a dose of about 35 mg/m 2 to about 50 mg/m 2 . In some aspects, the nanoparticle is administered at a dose of about 35 mg/m 2 to about 45 mg/m 2 . In some aspects, the nanoparticle is administered at a dose of about 35 mg/m 2 to about 40 mg/m 2 .
  • the nanoparticle is administered at a dose of about 35 mg/m 2 , about 40 mg/m 2 , about 45 mg/m 2 , about 50 mg/m 2 , about 55 mg/m 2 , about 60 mg/m 2 , about 65 mg/m 2 , about 70 mg/m 2 , about 75 mg/m 2 , or about 80 mg/m 2 .
  • the nanoparticle is administered at a dose of about 60 mg/m 2 .
  • the immune checkpoint inhibitor is ipilimumab.
  • ipilimumab is administered at a dose of about 0.5 to about 5 mg/kg. In some aspects, ipilimumab is administered at a dose of about 1 to about 5 mg/kg. In some aspects, ipilimumab is administered at a dose of about 1.5 to about 5 mg/kg. In some aspects, ipilimumab is administered at a dose of about 2 to about 5 mg/kg. In some aspects, ipilimumab is administered at a dose of about 2.5 to about 5 mg/kg. In some aspects, ipilimumab is administered at a dose of about 3 to about 5 mg/kg.
  • ipilimumab is administered at a dose of about 3.5 to about 5 mg/kg. In some aspects, ipilimumab is administered at a dose of about 4 to about 5 mg/kg. In some aspects, ipilimumab is administered at a dose of about 0.5 to about 4 mg/kg. In some aspects, ipilimumab is administered at a dose of about 0.5 to about 3 mg/kg. In some aspects, ipilimumab is administered at a dose of about 0.5 to about 2.5 mg/kg. In some aspects, ipilimumab is administered at a dose of about 0.5 to about 2 mg/kg. In some aspects, ipilimumab is administered at a dose of about 0.5 to about 1.5 mg/kg.
  • ipilimumab is administered every 2-8 weeks (e.g., every 6 weeks) during the treatment.
  • nivolumab is administered at a dose of about 120 mg to about 320 mg. In some aspects, nivolumab is administered at a dose of about 120 mg to about 300 mg. In some aspects, nivolumab is administered at a dose of about 120 mg to about 280 mg. In some aspects, nivolumab is administered at a dose of about 120 mg to about 260 mg. In some aspects, nivolumab is administered at a dose of about 120 mg to about 240 mg. In some aspects, nivolumab is administered at a dose of about 120 mg to about 220 mg. In some aspects, nivolumab is administered at a dose of about 120 mg to about 200 mg.
  • nivolumab is administered at a dose of about 120 mg to about 180 mg. In some aspects, nivolumab is administered at a dose of about 120 mg to about 160 mg. In some aspects, nivolumab is administered at a dose of about 120 mg to about 140 mg. In some aspects, nivolumab is administered at a dose of about 240 mg to about 360 mg. In some aspects, nivolumab is administered at a dose of about 260 mg to about 360 mg. In some aspects, nivolumab is administered at a dose of about 280 mg to about 360 mg. In some aspects, nivolumab is administered at a dose of about 300 mg to about 360 mg.
  • nivolumab is administered at a dose of about 120 mg, about 140 mg, about 160 mg, about 180 mg, about 200 mg, about 220 mg, about 240 mg, about 260 mg, about 280 mg, about 300 mg, about 320 mg, about 340 mg, or about 360 mg.
  • nivolumab is administered at a dose of about 240 mg.
  • nivolumab is administered every 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, or 8 weeks.
  • the second immune checkpoint inhibitor is a PD-1 antagonist, wherein the PD-1 antagonist is nivolumab.
  • the second immune checkpoint inhibitor is a PD-L1 antagonist selected from the group consisting of atezolizumab, durvalumab, and avelumab.
  • the second immune checkpoint inhibitor is a CTLA-4 antagonist is ipilimumab.
  • the second immune checkpoint inhibitor is a LAG-3 antagonist, wherein the LAG-3 antagonist is relatlimab.
  • the first immune checkpoint inhibitor is nivolumab
  • the second immune checkpoint inhibitor is ipilimumab
  • the nivolumab is administered at about 240 mg every 2 weeks, and the ipilimumab is administered at about 1 mg/kg every 6 weeks.
  • the immune checkpoint inhibitor is administered prior to the interval cytoreductive surgery, at least about 22 days after the first administration of the anticancer agent, every week for at least about 12 weeks to up about 18 weeks.
  • the immune checkpoint inhibitor is administered at least about 28 days after the interval cytoreductive surgery, and at least about 22 days after the first administration of the anticancer agent, every week for at least about 9 weeks.
  • the interval cytoreductive surgery is administered at least about 7 days following the administration of the DNA plasmid.
  • interval cytoreductive surgery is administered at least about 7 days following the administration of the DNA plasmid.
  • the interval cytoreductive surgery is administered at least about 28 days before the administration of the immune checkpoint inhibitor.
  • the interval cytoreductive surgery is administered at least about 28 days following the administration of the immune checkpoint inhibitor.
  • Ovarian cancer is the most lethal gynecologic cancer in the US.
  • the five- year overall survival rate is 20-30% in advanced stage OC, with more than 50% of patients that respond to current therapies experiencing recurrence of their disease.
  • platinum-resistant OC is characterized by only minimal responses to chemotherapy ( ⁇ 10- 15%) and a poor prognosis, with overall survival estimated to be ⁇ 12 months.
  • ICI immune checkpoint inhibitors
  • the impact of immune checkpoint inhibitors (ICI) has been significant, providing durable response rates in several cancers.
  • the response rates in ovarian cancer are low, ranging from 11-15% in platinum-resistant, recurrent settings.
  • dual immunotherapy with nivolumab and ipilimumab was associated with a higher objective response rate (31% vs. 12%) but with limited durability (3.9 vs. 2 months).
  • a combination strategy including IL- 12 gene therapy (GEN-1) and CTLA4-PD-1 blockade will be tested.
  • the mechanisms of action of known sites for activity for IL-12 and CTLA4-PD-1 blockade are non-redundant. Therefore, combination therapy of rhIL-12 and immune checkpoint inhibitors (ipilimumab and nivolumab) will be tested for anti-tumor activity. Further, the study will assess enhanced efficacy of current PD1/PD-L1 -based immunotherapy by targeting pathways that mediate resistance to ICI.
  • Phase I The safety, tolerability, and recommended phase 2 dose of the regimen will be evaluated by a Data and Safety Monitoring Board (DSMB). Details regarding their responsibilities will be elucidated in a DSMB charter which will be drafted for approval by the DSMB prior to initiation of the study.
  • DSMB Data and Safety Monitoring Board
  • Phase II The overall objective response rate will be determined by using RECIST 1.1
  • Each cycle of study treatment will be defined as being 6 weeks. On day 1 of each cycle all subjects will receive a fixed dose of the dual ICI (nivolumab and ipilimumab) followed by the prescribed dose of Gen-1. Dosing by cycle is presented in the table below:
  • Subjects will be monitored for safety (with physical exams and assessment of AEs) at every treatment visit from the time of signing informed consent until at least 30 days following their last dose of study drug. Any suspected drug related adverse events may be reported at any time during follow up until resolution to a grade 2 (CTCAE v5.0).
  • the primary end point is objective tumor response (complete or partial) by RECIST, version 1.1,16 prior to progression will be used as a method to evaluate efficacy.
  • Measurable disease Measurable lesions are defined as those that can be accurately measured in at least one dimension (longest diameter to be recorded) as 20 mm by chest x- ray, as 10 mm with CT scan, 10 mm with calipers by clinical exam. All tumor measurements must be recorded in millimeters (or decimal fractions of centimeters).
  • Non-measurable disease All other lesions (or sites of disease), including small lesions (longest diameter ⁇ 10 mm or pathological lymph nodes with 10 to ⁇ 15 mm short axis), are considered non-measurable disease. Leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, and abdominal masses (identified by physical exam and not CT or MRI), are considered as non- measurable. [0480] Bone lesions: Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue components, that can be evaluated by CT or MRI can be considered as measurable lesions if the soft tissue component meets the definition of measurability described above. Blastic bone lesions are non-measurable.

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Abstract

La présente invention concerne une polythérapie comprenant un inhibiteur de point de contrôle immunitaire, un plasmide formulé dans des nanoparticules contenant un acide nucléique codant pour IL-12, et, facultativement, au moins un médicament chimiothérapeutique auxiliaire, ainsi que des méthodes de traitement utilisant de telles polythérapies et/ou compositions.
EP23866429.6A 2022-09-13 2023-09-13 Combinaison de thérapie génique utilisant l'il-12 et d'inhibiteurs de point de contrôle immunitaire pour le traitement du cancer Pending EP4587459A1 (fr)

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US202263375529P 2022-09-13 2022-09-13
PCT/US2023/074062 WO2024059629A1 (fr) 2022-09-13 2023-09-13 Combinaison de thérapie génique utilisant l'il-12 et d'inhibiteurs de point de contrôle immunitaire pour le traitement du cancer

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EP4587459A1 true EP4587459A1 (fr) 2025-07-23

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EP (1) EP4587459A1 (fr)
JP (1) JP2025531136A (fr)
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CA (1) CA3267638A1 (fr)
MX (1) MX2025002926A (fr)
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KR102608966B1 (ko) * 2016-08-26 2023-12-04 베이롤 칼리지 오브 메드신 세포 치료요법을 위한 항상성 활성 사이토킨 수용체
AU2018270111B2 (en) * 2017-05-18 2022-07-14 Modernatx, Inc. Polynucleotides encoding tethered interleukin-12 (IL12) polypeptides and uses thereof

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MX2025002926A (es) 2025-06-02
KR20250094749A (ko) 2025-06-25
CA3267638A1 (fr) 2024-03-21
JP2025531136A (ja) 2025-09-19
CN120418280A (zh) 2025-08-01

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