# US 2014/0193398 A1 · Polymalic acid-based nanobiopolymer compositions > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 2014/0193398 A1 - Document ID: US20140193398A1 - Status: Published application - Kind: A1 - Application number: 13/930,533 - Filed: 2013-06-28 - Published: 2014-07-10 - Earliest claimed: 2010-12-30 - Assignees: Cedars-Sinai Medical Center - Applicants: Cedars-Sinai Medical Center - Inventors: Satoshi Inoue; Hui Ding; Eggehard Holler; Keith L. Black; Julia Y. Ljubimova - Web page: https://patentgrep.com/patent/US20140193398A1 ## CPC - A61K 31/713: Double-stranded nucleic acids or oligonucleotides - C07K 16/2881: {against CD71} - C07K 16/32: against translation products of oncogenes - A61K 2039/505: {comprising antibodies} - A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D) - C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00) ## Abstract Nanobiopolymeric conjugates based on biodegradable, non-toxic and non-immunogenic poly (β-L-malic acid) PMLA covalently linked to molecular modules that include morpholino antisense oligonucleotides (AONa), an siRNA or an antibody specific for an oncogenic protein in a cancer cell, and an antibody specific for a transferrin receptor protein, are provided. Methods for treating a cancer in subject with nanobiopolymeric conjugates are described. ## Claims ### Claim 1 A drug delivery composition for treating a cancer in a subject comprising: a plurality of biologically active molecular modules comprising at least one module that targets a tumorigenic cell or a cancer cell, at least one module that inhibits synthesis or activity of a human epidermal growth factor receptor (HER) protein in the tumorigenic cell or the cancer cell, and at least one module for cytoplasmic delivery; and a polymalic acid-based molecular scaffold, wherein the molecular modules are covalently linked to the scaffold. ### Claim 2 (depends on 1) The drug delivery composition according to claim 1, wherein the HER protein is at least one protein selected from the group comprising: HER1, HER2, HER3 and HER4. ### Claim 3 (depends on 1) The drug delivery composition according to claim 1, wherein the at least one module that inhibits synthesis or activity of the protein is selected from the group consisting of: an antisense oligonucleotide (AON), an siRNA oligonucleotide, an antibody, a polypeptide, an oligopeptide and a low molecular weight drug. ### Claim 4 (depends on 3) The drug delivery composition according to claim 3, wherein the AON is a Morpholino AON having a sequence complementary to a sequence contained in an mRNA transcript of HER2/neu protein. ### Claim 5 (depends on 4) The drug delivery composition according to claim 4, wherein the sequence of the Morpholino AON is selected from the group consisting of: 5′-AGGGAGCCGCAGCTTCATGTCTGTG-3′ (SEQ ID NO: 1), and 5′-CATGGTGCTCACTGCGGCTCCGGC-3′ (SEQ ID NO:2). ### Claim 6 (depends on 1) The drug delivery composition according to claim 1, wherein the at least one module that targets the tumorigenic cell or the cancer cell comprises an antibody that binds specifically to a vasculature protein in the tumorigenic cell or the cancer cell. ### Claim 7 (depends on 6) The drug delivery composition according to claim 6, wherein the vasculature protein comprises a transferrin receptor protein. ### Claim 8 (depends on 6) The drug delivery composition according to claim 6, wherein the antibody is anti-human. ### Claim 9 (depends on 6) The drug delivery composition according to claim 6, wherein the antibody is selected from at least one of: rat anti-mouse, rat anti-human, rabbit anti-human and goat anti-human. ### Claim 10 (depends on 1) The drug delivery composition according to claim 1, wherein the at least one module that inhibits activity of the HER protein comprises an antibody that binds specifically to a HER2/neu protein. ### Claim 11 (depends on 10) The drug delivery composition according to claim 10, wherein the antibody comprises Herceptin®. ### Claim 12 (depends on 3) The drug delivery composition according to claim 3, wherein the AON is a Morpholino AON having a sequence complementary to a sequence contained in an mRNA transcript of HER1. ### Claim 13 (depends on 12) The drug delivery composition according to claim 12, wherein the sequence of the Morpholino AON comprises 5′-TCGCTCCGGCTCTCCCGATCAATAC-3′ (SEQ ID NO:3). ### Claim 14 (depends on 3) The drug delivery composition according to claim 3, wherein the AON is a Morpholino AON having a sequence complementary to a sequence contained in an mRNA transcript of at least one subunit of laminin-411. ### Claim 15 (depends on 14) The drug delivery composition according to claim 14, wherein the at least one subunit is selected from α4 subunit and β1 subunit. ### Claim 16 (depends on 3) The drug delivery composition according to claim 3 wherein the siRNA oligonucleotide comprises a sequence complementary to a gene encoding a HER1 protein. ### Claim 17 (depends on 16) The drug delivery composition according to claim 16, wherein the sequence is selected from the group consisting of: a sense sequence and an antisense sequence. ### Claim 18 (depends on 16) The drug delivery composition according to claim 16, wherein the sequence is selected from the group consisting of: 5′-CCUAUAAUGCUACGAAUAUtt-3′ (SEQ ID NO:6) and 5′-AUAUUCGUAGCAUUUAUGGag-3′ (SEQ ID NO:7). ### Claim 19 (depends on 3) The drug delivery composition according to claim 3, wherein the siRNA oligonucleotide comprises a sequence complementary to a gene encoding a HER2 protein. ### Claim 20 (depends on 19) The drug delivery composition according to claim 19, wherein the sequence is selected from the group consisting of a sense sequence and an antisense sequence. ### Claim 21 (depends on 20) The drug delivery composition according to claim 20, wherein the sequence is selected from the group consisting of: 5′-GUUGGAUGAUUGACUCUGAtt-3′ (SEQ ID NO: 8) and 5′-UCAGAGUCAAUCAUCCAACat-3′ (SEQ ID NO: 9). ### Claim 22 (depends on 1) The drug delivery composition according to claim 1, wherein the at least one module for cytoplasmic delivery comprises an endosome escape unit. ### Claim 23 (depends on 22) The drug delivery composition according to claim 22, wherein the endosome escape unit comprises a leucine ethylester. ### Claim 24 (depends on 1) The drug delivery composition according to claim 1, wherein the plurality of modules further comprises a polyethylene glycol. ### Claim 25 (depends on 1) The drug delivery composition according to claim 1, wherein the scaffold comprises a polymalic acid (PMLA). ### Claim 26 (depends on 1) The drug delivery composition according to claim 1 present in a unit dose effective for treatment of the cancer in the subject. ### Claim 27 (depends on 26) The drug delivery composition according to claim 26, wherein the unit dose is at least one selected from the group consisting of: 1 μg/kg, 50 μg/kg, 100 μg/kg, 500 μg/kg, 1 mg/kg, 5 mg/kg, 10 mg/kg, 50 mg/kg, and 100 mg/kg. ### Claim 28 (depends on 1) The drug delivery composition according to claim 1, wherein the cancer is at least one selected from the group consisting of: gastric, endometrial, salivary gland, lung, non-small cell lung, pancreatic, peritoneal, prostate, colorectal, breast, cervical, uterine, ovarian, brain, head and neck, testicular and teratoma cancers. ### Claim 29 (depends on 28) The drug delivery composition according to claim 28, wherein the cancer is selected from the group consisting of a primary cancer and a metastatic cancer. ### Claim 30 (depends on 28) The drug delivery composition according to claim 28, wherein the cancer comprises cells overexpressing a HER2/neu receptor protein. ### Claim 31 (depends on 28) The drug delivery composition according to claim 28, wherein the breast cancer is a triple-negative breast cancer. ### Claim 32 A kit for treating a patient having a cancer comprising a drug delivery composition comprising a nanobiopolymeric conjugate of a scaffold comprising a polymalic acid (PMLA) and molecular modules comprising an antisense molecule that substantially inhibits synthesis or activity of a human epidermal growth factor receptor (HER) protein, a molecular module to facilitate delivery of the antisense molecule to cytoplasm, at least one targeting antibody specific for the HER protein, at least one antibody specific for a tumor vasculature protein, and a molecular module that prolongs circulation of the composition, wherein the PMLA is covalently linked to the molecular modules, in a container. ### Claim 33 (depends on 32) The kit according to claim 32 further comprising a pharmaceutically acceptable buffer. ### Claim 34 A method for treating a cancer in a subject, comprising: contacting the subject with a drug delivery composition comprising a polymalic acid (PMLA) covalently linked to a plurality of molecular modules comprising at least one module that targets a tumorigenic cell or a cancer cell, at least one module that inhibits synthesis or activity of a human epidermal growth factor receptor (HER) protein in the cell, and at least one module for cytoplasmic delivery, wherein the drug delivery composition is effective for at least one of inhibiting tumor growth, tumor regression and eliminating cancer in a subject. ### Claim 35 (depends on 34) The method according to claim 34, wherein the HER protein is selected from a group consisting of: HER1, HER2, HER3, and HER4. ### Claim 36 (depends on 34) The method according to claim 34, wherein the module that inhibits synthesis or activity of the HER protein is at least one selected from the group consisting of: an antisense oligonucleotide (AON), an siRNA oligonucleotide, an antibody, a polypeptide, an oligopeptide and a low molecular weight drug. ### Claim 37 (depends on 36) The method according to claim 36, wherein the AON has a sequence complementary to an mRNA transcript of at least one protein selected from the group consisting of: HER2, HER1, and a subunit of laminin-411. ### Claim 38 (depends on 37) The method according to claim 37, wherein the sequence complementary to the mRNA transcript is selected from the group consisting of: (SEQ ID NO: 1), 5′AGGGAGCCGCAGCTTCATGTCTGTG-3′ (SEQ ID NO: 2), and 5′-CATGGTGCTCACTGCGGCTCCGGC-3′ (SEQ ID NO: 3). 5′-TCGCTCCGGCTCTCCCGATCAATAC-3′ ### Claim 39 (depends on 37) The method according to claim 37, wherein the subunit of laminin-411 is selected from the group consisting of: an α4 subunit and a β1 subunit. ### Claim 40 (depends on 36) The method according to claim 36, wherein the siRNA oligonucleotide comprises a sequence complementary to a gene encoding at least one of HER1 and HER2. ### Claim 41 (depends on 40) The method according to the claim 40 wherein the sequence is selected from the group consisting of: (SEQ ID NO: 6), 5′-CCUAUAAUGCUACGAAUAUtt-3′ (SEQ ID NO: 7), 5′-AUAUUCGUAGCAUUUAUGGag-3′ (SEQ ID NO: 8), and 5′-GUUGGAUGAUUGACUCUGAtt-3′ (SEQ ID NO: 9). 5′-UCAGAGUCAAUCAUCCAACat-3′ ### Claim 42 (depends on 36) The method according to claim 36, wherein the antibody binds specifically to HER2/neu protein. ### Claim 43 (depends on 42) The method according to claim 42, wherein the antibody comprises Trastuzumab Herceptin®. ### Claim 44 (depends on 34) The method according to claim 34, wherein the at least one module that targets the tumorigenic cell or the cancer cell comprises an antibody that binds specifically to a transferrin receptor protein. ### Claim 45 (depends on 44) The method according to claim 44, wherein the antibody is anti-human. ### Claim 46 (depends on 44) The method according to claim 44, wherein the antibody is selected from at least one of the group consisting of: rat anti-mouse, rat anti-human, rabbit anti-human and goat anti-human. ### Claim 47 (depends on 34) The method according to claim 34, wherein the at least one module for cytoplasmic delivery comprises an endosome escape unit. ### Claim 48 (depends on 47) The method according to claim 47, wherein the endosome escape unit comprises a leucine ethylester. ### Claim 49 (depends on 34) The method according to claim 34, wherein the plurality of modules further comprises a polyethylene glycol. ### Claim 50 (depends on 34) The method according to claim 34, wherein inhibition of tumor growth comprises more than about 60%, 70%, 80% or 90% inhibition of tumor growth in the subject. ### Claim 51 (depends on 34) The method according to claim 34, wherein the drug delivery composition is further effective for inhibiting expression of cancer stem cell markers in the subject. ### Claim 52 (depends on 51) The method according to claim 51, wherein the cancer stem cell markers include at least one marker selected from the group consisting of: c-myc protein, CD44 protein, Notch1 protein, and nestin protein. ### Claim 53 (depends on 34) The method according to claim 34, wherein the subject is a mammal. ### Claim 54 (depends on 53) The method according to claim 53, wherein the mammal is selected from the group consisting of: a rodent, an experimental human-breast tumor-bearing nude mouse and a human. ### Claim 55 (depends on 34) The method according to claim 34, wherein contacting the subject with the composition further includes providing the composition in a unit dose effective for treatment of cancer in the subject.