Molecular constructs for treating tumors

• US 10,668,165 B2
• Filed: 01/18/2016
• Issued: 06/02/2020
• Est. Priority Date: 01/16/2015
• Status: Active Grant

• Current Assignee: Immunwork Inc.
• Original Assignee: Immunwork Inc.
• Inventors: Chang, Tse-Wen, Lin, Chien-Jen, Chu, Hsing-Mao
• Primary Examiner(s): Halvorson, Mark
• Assistant Examiner(s): Akhoon, Kauser M
• Application Number:
  US14/997,874
• Publication Number:
  US 20160206754A1
• Time in Patent Office: 1,597 Days
• Field of Search: None
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 31/397 having four-membered rings, e.g. azetidine
• CPC Class Codes: A61K 31/4545 containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
• CPC Class Codes: A61K 31/4709 Non-condensed quinolines and containing further heterocyclic rings
• CPC Class Codes: A61K 31/4745 condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines yohimbine derivatives, vinblastine A61K31/475; ergoline derivatives A61K31/48
• CPC Class Codes: A61K 31/537 spiro-condensed or forming part of bridged ring systems
• CPC Class Codes: A61K 31/739 Lipopolysaccharides
• CPC Class Codes: A61K 47/58 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. poly[meth]acrylate, polyacrylamide, polystyrene, polyvinylpyrrolidone, polyvinylalcohol or polystyrene sulfonic acid resin
• CPC Class Codes: A61K 47/60 the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
• CPC Class Codes: A61K 47/61 the organic macromolecular compound being a polysaccharide or a derivative thereof
• CPC Class Codes: A61K 47/64 Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent peptidic linkers A61K47/65
• CPC Class Codes: A61K 47/6801 Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
• CPC Class Codes: A61K 47/68033 the drug being a maytansine
• CPC Class Codes: A61K 47/6843 the antibody targeting a material from animals or humans
• CPC Class Codes: A61K 47/6845 the antibody targeting a cytokine, e.g. growth factors, VEGF, TNF, a lymphokine or an interferon
• CPC Class Codes: A61K 47/6849 the antibody targeting a receptor, a cell surface antigen or a cell surface determinant
• CPC Class Codes: A61K 47/6851 the antibody targeting a determinant of a tumour cell
• CPC Class Codes: A61K 47/6883 Polymer-drug antibody conjugates, e.g. mitomycin-dextran-Ab; DNA-polylysine-antibody complex or conjugate used for therapy
• CPC Class Codes: A61K 51/065 conjugates with carriers being macromolecules
• CPC Class Codes: A61K 51/088 conjugates with carriers being peptides, polyamino acids or proteins antibodies A61K51/10
• CPC Class Codes: A61P 1/04 : for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 17/06 : Antipsoriatics
• CPC Class Codes: A61P 19/02 : for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 19/10 : for osteoporosis
• CPC Class Codes: A61P 27/02 : Ophthalmic agents
• CPC Class Codes: A61P 29/00 : Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 35/00 : Antineoplastic agents
• CPC Class Codes: A61P 35/02 : specific for leukemia
• CPC Class Codes: A61P 37/00 : Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/02 : Immunomodulators
• CPC Class Codes: A61P 37/06 : Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: C07K 14/485 : Epidermal growth factor [EGF], i.e. urogastrone
• CPC Class Codes: C07K 14/655 : Somatostatins
• CPC Class Codes: C07K 14/705 : Receptors; Cell surface antigens; Cell surface determinants tumour specific antigens C07K14/4748
• CPC Class Codes: C07K 14/70578 : NGF-receptor/TNF-receptor superfamily, e.g. CD27, CD30, CD40, CD95 NGF-receptor C07K14/71, TNF-receptor C07K14/7151
• CPC Class Codes: C07K 14/7151 : for tumor necrosis factor [TNF], for lymphotoxin [LT]
• CPC Class Codes: C07K 16/18 : against material from animals or humans
• CPC Class Codes: C07K 16/22 : against growth factors ; against growth regulators
• CPC Class Codes: C07K 16/241 : Tumor Necrosis Factors
• CPC Class Codes: C07K 16/244 : Interleukins [IL]
• CPC Class Codes: C07K 16/2803 : against the immunoglobulin superfamily
• CPC Class Codes: C07K 16/2809 : against the T-cell receptor (TcR)-CD3 complex
• CPC Class Codes: C07K 16/2818 : against CD28 or CD152
• CPC Class Codes: C07K 16/2863 : against receptors for growth factors, growth regulators
• CPC Class Codes: C07K 16/2875 : against the NGF/TNF superfamily, e.g. CD70, CD95L, CD153, CD154 against NGF C07K16/22, against TNF C07K16/241
• CPC Class Codes: C07K 16/2887 : against CD20
• CPC Class Codes: C07K 16/32 : against translation products of oncogenes
• CPC Class Codes: C07K 16/468 : Immunoglobulins having two or more different antigen binding sites, e.g. multifunctional antibodies
• CPC Class Codes: C07K 2317/21 : from primates, e.g. man
• CPC Class Codes: C07K 2317/24 : containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
• CPC Class Codes: C07K 2317/31 : multispecific
• CPC Class Codes: C07K 2317/524 : CH2 domain
• CPC Class Codes: C07K 2317/526 : CH3 domain
• CPC Class Codes: C07K 2317/55 : Fab or Fab'
• CPC Class Codes: C07K 2317/622 : Single chain antibody (scFv)
• CPC Class Codes: C07K 2317/64 : comprising a combination of variable region and constant region components
• CPC Class Codes: C07K 2317/71 : Decreased effector function due to an Fc-modification
• CPC Class Codes: C07K 2317/73 : Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
• CPC Class Codes: C07K 2317/732 : Antibody-dependent cellular cytotoxicity [ADCC]
• CPC Class Codes: C07K 2317/76 : Antagonist effect on antigen, e.g. neutralization or inhibition of binding
• CPC Class Codes: C07K 2317/94 : Stability, e.g. half-life, pH, temperature or enzyme-resistance
• CPC Class Codes: C07K 2319/30 : Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto
• CPC Class Codes: C07K 2319/32 : fusions with soluble part of a cell surface receptor, "decoy receptors"
• CPC Class Codes: C07K 2319/33 : fusions for targeting to specific cell types, e.g. tissue specific targeting, targeting of a bacterial subspecies

Abstract

The present disclosure provides various molecular constructs having a targeting element and an effector element. Methods for treating various diseases using such molecular constructs are also disclosed.

Claims

1. A molecular construct comprising,

a pair of CH2-CH3 segments of an IgG Fc;

a peptide extension having a sequence of (G_2-4S)_2-8C and linked to the C-terminus of one of the pair of CH2-CH3 segments;

a coupling arm linked to the C-terminus of the peptide extension via thiol-maleimide reaction occurred therebetween;

a first pair of effector elements, wherein each effector element is a drug bundle; and

a first pair of targeting elements, wherein the targeting element is a growth factor or a peptide hormone, wherein,

the effector elements are respectively linked to the C-termini of the pair of CH2-CH3 segments, and the targeting elements are respectively linked to the N-termini of the pair of CH2-CH3 segments; and

the drug bundle comprises,

a center core that is a compound having a plurality of amine groups or a polypeptide comprising a plurality of lysine (K) residues, wherein each K residue and its next K residue are separated by a filler sequence comprising glycine (G) and serine (S) residues, and the number of K residues ranges from 2 to 15;

a plurality of linking arms, each having one terminus linked to the center core by reacting with one of the amine groups of the compound or one of the K residues, and carrying a maleimide group at the free terminus thereof; and

a plurality of molecules of, a cytotoxic drug, a toll-like receptor (TLR) agonist, or a chelator complexed with a radioactive nuclide, wherein each of the molecules is linked to the center core via connecting through the linking arm by reacting with the maleimide group, and the drug bundle is linked to the coupling arm via inverse electron demand Diels-Alder (iEDDA) reaction, strain-promoted azide-alkyne click chemistry (SPAAC) reaction, or Copper(I)-catalyzed alkyne-azide cycloaddition (CuAAC) reaction occurred therebetween;

wherein the amino acid residue at the N- or C-terminus of the center core has an azide group or an alkyne group;

or the amino acid residue at the N- or C-terminus of the center core is a cysteine residue, and the cysteine residue of the center core is linked with the coupling arm having an alkyne group, azide group, tetrazine group, or strained alkyne group at the free terminus of the coupling arm.

2. The molecular construct of claim 1, wherein the pair of CH2-CH3 segments is derived from human γ

4 or γ

1 immunoglobulin.

3. The molecular construct of claim 1, further comprising a second pair of targeting elements, wherein the second pair of targeting elements is linked, in a tandem or diabody configuration, to the N-termini of the first pair of targeting elements.

4. The molecular construct of claim 1, wherein the cytotoxic drug is auristatin, maytansine, doxorubicin, calicheamicin, or camptothecin.

5. The molecular construct of claim 1, wherein the TLR agonist is LPS, monophosphoryl lipid A, motolimod, imiquimod, resiquimod, gardiquimod, CpG DON, lipoteichoic acid, β

-glucan, or zymosan.

6. The molecular construct of claim 1, wherein the chelator is DOTA, NOTA, NODA, or DTPA.

7. The molecular construct of claim 1, wherein the radioactive nuclide is ⁹⁰Y, ¹¹¹In, or ¹⁷⁷Lu.

8. The molecular construct of claim 1, wherein the growth factor is epidermal growth factor (EGF), mutant EGF, epiregulin, heparin-binding epidermal growth factor (HB-EGF), VEGF-A, basic fibroblast growth factor (bFGF), or hepatocyte growth factor (HGF).

9. The molecular construct of claim 1, wherein the hapten is dinitrophenol (DNP), trinitrophenol (TNP), dansyl, penicillin, p-aminobenzoic acid, or a polypeptide having the amino acid sequence of SEQ ID No:

20.

10. The molecular construct of claim 1, wherein the peptide hormone is cholecystokinin (CCK), somastatin, or thyroid-stimulating hormone (TSH).

11. The molecular construct of claim 1, wherein,

the effector element is the drug bundle comprising the plurality of molecules of the cytotoxic drug;

and

the targeting element is EGF.