Classifications

• • 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
  • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
  • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
  • A61K51/04—Organic compounds
  • A61K51/08—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins
  • A61K51/10—Antibodies or immunoglobulins; Fragments thereof, the carrier being an antibody, an immunoglobulin or a fragment thereof, e.g. a camelised human single domain antibody or the Fc fragment of an antibody
  • A61K51/1027—Antibodies or immunoglobulins; Fragments thereof, the carrier being an antibody, an immunoglobulin or a fragment thereof, e.g. a camelised human single domain antibody or the Fc fragment of an antibody against receptors, cell-surface antigens or cell-surface determinants
  • A61K51/1036—Antibodies or immunoglobulins; Fragments thereof, the carrier being an antibody, an immunoglobulin or a fragment thereof, e.g. a camelised human single domain antibody or the Fc fragment of an antibody against receptors, cell-surface antigens or cell-surface determinants against hormone receptors
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/50—Pyridazines; Hydrogenated pyridazines
  • A61K31/502—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with carbocyclic ring systems, e.g. cinnoline, phthalazine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
  • A61K31/5375—1,4-Oxazines, e.g. morpholine
  • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
• • 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
  • A61K39/3955—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against proteinaceous materials, e.g. enzymes, hormones, lymphokines
• • 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
  • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
  • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
  • A61K51/04—Organic compounds
  • A61K51/0474—Organic compounds complexes or complex-forming compounds, i.e. wherein a radioactive metal (e.g. 111In3+) is complexed or chelated by, e.g. a N2S2, N3S, NS3, N4 chelating group
  • A61K51/0482—Organic compounds complexes or complex-forming compounds, i.e. wherein a radioactive metal (e.g. 111In3+) is complexed or chelated by, e.g. a N2S2, N3S, NS3, N4 chelating group chelates from cyclic ligands, e.g. DOTA
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
  • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
  • A61K51/04—Organic compounds
  • A61K51/08—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins
  • A61K51/10—Antibodies or immunoglobulins; Fragments thereof, the carrier being an antibody, an immunoglobulin or a fragment thereof, e.g. a camelised human single domain antibody or the Fc fragment of an antibody
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
  • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
  • A61K51/04—Organic compounds
  • A61K51/08—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins
  • A61K51/10—Antibodies or immunoglobulins; Fragments thereof, the carrier being an antibody, an immunoglobulin or a fragment thereof, e.g. a camelised human single domain antibody or the Fc fragment of an antibody
  • A61K51/1027—Antibodies or immunoglobulins; Fragments thereof, the carrier being an antibody, an immunoglobulin or a fragment thereof, e.g. a camelised human single domain antibody or the Fc fragment of an antibody against receptors, cell-surface antigens or cell-surface determinants
  • A61K51/103—Antibodies or immunoglobulins; Fragments thereof, the carrier being an antibody, an immunoglobulin or a fragment thereof, e.g. a camelised human single domain antibody or the Fc fragment of an antibody against receptors, cell-surface antigens or cell-surface determinants against receptors for growth factors or receptors for growth regulators
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
  • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
  • A61K51/04—Organic compounds
  • A61K51/08—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins
  • A61K51/10—Antibodies or immunoglobulins; Fragments thereof, the carrier being an antibody, an immunoglobulin or a fragment thereof, e.g. a camelised human single domain antibody or the Fc fragment of an antibody
  • A61K51/1045—Antibodies or immunoglobulins; Fragments thereof, the carrier being an antibody, an immunoglobulin or a fragment thereof, e.g. a camelised human single domain antibody or the Fc fragment of an antibody against animal or human tumor cells or tumor cell determinants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
  • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
  • A61K51/04—Organic compounds
  • A61K51/08—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins
  • A61K51/10—Antibodies or immunoglobulins; Fragments thereof, the carrier being an antibody, an immunoglobulin or a fragment thereof, e.g. a camelised human single domain antibody or the Fc fragment of an antibody
  • A61K51/1075—Antibodies or immunoglobulins; Fragments thereof, the carrier being an antibody, an immunoglobulin or a fragment thereof, e.g. a camelised human single domain antibody or the Fc fragment of an antibody the antibody being against an enzyme
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
  • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
  • A61K51/04—Organic compounds
  • A61K51/08—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins
  • A61K51/10—Antibodies or immunoglobulins; Fragments thereof, the carrier being an antibody, an immunoglobulin or a fragment thereof, e.g. a camelised human single domain antibody or the Fc fragment of an antibody
  • A61K51/1093—Antibodies or immunoglobulins; Fragments thereof, the carrier being an antibody, an immunoglobulin or a fragment thereof, e.g. a camelised human single domain antibody or the Fc fragment of an antibody conjugates with carriers being antibodies
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
  • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
  • A61K51/04—Organic compounds
  • A61K51/08—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins
  • A61K51/10—Antibodies or immunoglobulins; Fragments thereof, the carrier being an antibody, an immunoglobulin or a fragment thereof, e.g. a camelised human single domain antibody or the Fc fragment of an antibody
  • A61K51/1093—Antibodies or immunoglobulins; Fragments thereof, the carrier being an antibody, an immunoglobulin or a fragment thereof, e.g. a camelised human single domain antibody or the Fc fragment of an antibody conjugates with carriers being antibodies
  • A61K51/1096—Antibodies or immunoglobulins; Fragments thereof, the carrier being an antibody, an immunoglobulin or a fragment thereof, e.g. a camelised human single domain antibody or the Fc fragment of an antibody conjugates with carriers being antibodies radioimmunotoxins, i.e. conjugates being structurally as defined in A61K51/1093, and including a radioactive nucleus for use in radiotherapeutic applications
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
  • A61P35/04—Antineoplastic agents specific for metastasis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
  • A61P37/02—Immunomodulators
  • A61P37/04—Immunostimulants
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
  • C07D237/26—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings condensed with carbocyclic rings or ring systems
  • C07D237/30—Phthalazines
  • C07D237/32—Phthalazines with oxygen atoms directly attached to carbon atoms of the nitrogen-containing ring
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
  • C07D471/04—Ortho-condensed systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
  • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
  • C07K16/28—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
  • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
  • C07K16/28—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
  • C07K16/2851—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the lectin superfamily, e.g. CD23, CD72
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
  • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
  • C07K16/28—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
  • C07K16/2863—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against receptors for growth factors, growth regulators
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
  • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
  • C07K16/32—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against translation products of oncogenes
• • 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
  • A61K2039/545—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

Definitions

• the targeting moiety is an antibody or an antigen-binding fragment thereof.
• the targeting moiety is capable of binding to a tumor-associated antigen, and said therapeutic effect comprises an increase in T cells specific for the tumor-associated antigen.
• said increase in T cells occurs in the tumor.
• said increase in the T cells in the tumor is relative to T cells in the spleen.
• said administering results in at least 15% of the total T cell population in a sample from the mammal being specific for the tumor-associated antigen.
• said administering results in at least 25% of the total T cell population in a sample from the mammal being specific for the tumor-associated antigen.
• each R N1 is, independently, H, OH, NO2, N(R N2 )2, S0 2 0R N2 , S0 2 R N2 , SOR N2 , an /V-protecting group, alkyl, alkenyl, alkynyl, alkoxy, aryl, alkaryl, cycloalkyl, alkcycloalkyl, carboxyalkyl (e.g., optionally substituted with an O-protecting group, such as optionally substituted arylalkoxycarbonyl groups or any described herein), sulfoalkyl, acyl (e.g., acetyl, trifluoroacetyl, or others described herein), alkoxycarbonylalkyl (e.g., optionally substituted with an O- protecting group, such as optionally substituted arylalkoxycarbonyl groups or any described herein),
• Amino groups can be unsubstituted amino (i.e. , -NH2) or substituted amino (i.e., -N(R N1 )2) groups.
• amino is -NH2 or -NHR N1 , wherein R N1 is, independently, OH, NO2, NH2, NR N2 2, S0 2 0R N2 , S0 2 R N2 , SOR N2 , alkyl, carboxyalkyl, sulfoalkyl, acyl (e.g., acetyl, trifluoroacetyl, or others described herein), alkoxycarbonylalkyl (e.g., t-butoxycarbonylalkyl) or aryl, and each R N2 can be H, C1-20 alkyl (e.g., C1-6 alkyl), or C6-io aryl.
• amino acid refers to a molecule having a side chain, an amino group, and an acid group (e.g., a carboxy group of -C0 2 H or a sulfo group of -SOsH), wherein the amino acid is attached to the parent molecular group by the side chain, amino group, or acid group (e.g., the side chain).
• the amino acid is attached to the parent molecular group by a carbonyl group, where the side chain or amino group is attached to the carbonyl group.
• Exemplary side chains include an optionally substituted alkyl, aryl, heterocyclyl, alkaryl, alkheterocyclyl, aminoalkyl, carbamoylalkyl, and carboxyalkyl.
• Exemplary amino acids include alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, hydroxynorvaline, isoleucine, leucine, lysine, methionine, norvaline, ornithine, phenylalanine, proline, pyrrolysine, selenocysteine, serine, taurine, threonine, tryptophan, tyrosine, and valine.
• R A is selected from the group consisting of (a) C1-20 alkyl (e.g., Ci-e alkyl), (b) C2-20 alkenyl (e.g., C2-6 alkenyl), (c) Ce-io aryl, (d) hydrogen, (e) Ci-e alk-Ce-io aryl, (f) amino-Ci
• arylalkyl represents an aryl group, as defined herein, attached to the parent molecular group through an alkylene group, as defined herein.
• exemplary unsubstituted arylalkyl groups are from 7 to 30 carbons (e.g., from 7 to 16 or from 7 to 20 carbons, such as C1-6 alk-Ce-io aryl, Ci- 10 alk-Ce-io aryl, or C1-20 alk-Ce-io aryl).
• the alkylene and the aryl each can be further substituted with 1 , 2, 3, or 4 substituent groups as defined herein for the respective groups.
• Other groups preceded by the prefix“alk-” are defined in the same manner, where“alk” refers to a Ci-e alkylene, unless otherwise noted, and the attached chemical structure is as defined herein.
• cyano represents an -CN group.
• cycloalkyl represents a monovalent saturated or unsaturated nonaromatic cyclic hydrocarbon group from three to eight carbons, unless otherwise specified, and is exemplified by cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicycle heptyl, and the like.
• the cycloalkyl group includes one carbon-carbon double bond or one carbon-carbon triple bond
• the cycloalkyl group can be referred to as a“cycloalkenyl” or“cycloalkynyl” group respectively.
• diastereomer as used herein means stereoisomers that are not mirror images of one another and are non-superimposable on one another.
• heteroaryl represents that subset of heterocyclyls, as defined herein, which are aromatic: i.e. , they contain 4n+2 pi electrons within the mono- or multicyclic ring system.
• Exemplary unsubstituted heteroaryl groups are of 1 to 12 (e.g., 1 to 1 1 , 1 to 10, 1 to 9, 2 to 12, 2 to 1 1 , 2 to 10, or 2 to 9) carbons.
• the heteroaryl is substituted with 1 , 2, 3, or 4 substituents groups as defined for a heterocyclyl group.
• heteroarylalkyl refers to a heteroaryl group, as defined herein, attached to the parent molecular group through an alkylene group, as defined herein.
• exemplary unsubstituted heteroarylalkyl groups are from 2 to 32 carbons (e.g., from 2 to 22, from 2 to 18, from 2 to 17, from 2 to 16, from 3 to 15, from 2 to 14, from 2 to 13, or from 2 to 12 carbons, such as Ci-e alk-Ci-12 heteroaryl, CMO alk-Ci-12 heteroaryl, or C1-20 alk-Ci-12 heteroaryl).
• the alkylene and the heteroaryl each can be further substituted with 1 , 2, 3, or 4 substituent groups as defined herein for the respective group.
• Heteroarylalkyl groups are a subset of heterocyclylalkyl groups.
• Heterocyclics include pyrrolyl, pyrrolinyl, pyrrolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, piperidinyl, homopiperidinyl, pyrazinyl, piperazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidiniyl, morpholinyl, thiomorpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, indolyl, indazolyl, quinolyl, isoquinolyl, quinoxalinyl, dihydroquinoxalinyl, quinazolinyl, cinnolinyl,
• E' is selected from the group consisting of -N- and -CH-;
• G' is selected from the group consisting of -CH- and -N-.
• each of these groups can be further substituted as described herein.
• hydroxyl represents an -OH group.
• the hydroxyl group can be substituted with 1 , 2, 3, or 4 substituent groups (e.g., O-protecting groups) as defined herein for an alkyl.
• isomer means any tautomer, stereoisomer, enantiomer, or diastereomer of any compound. It is recognized that the compounds can have one or more chiral centers and/or double bonds and, therefore, exist as stereoisomers, such as double-bond isomers (i.e. , geometric E/Z isomers) or diastereomers (e.g., enantiomers (i.e., (+) or (-)) or cis/trans isomers).
• stereoisomers such as double-bond isomers (i.e. , geometric E/Z isomers) or diastereomers (e.g., enantiomers (i.e., (+) or (-)) or cis/trans isomers).
• stereomers depicted herein encompass all of the corresponding stereoisomers, that is, both the stereomerically pure form (e.g., geometrically pure, enantiomerically pure, or diastereomerically pure) and enantiomeric and stereoisomeric mixtures, e.g., racemates.
• Enantiomeric and stereoisomeric mixtures of compounds can typically be resolved into their component enantiomers or stereoisomers by well-known methods, such as chiral-phase gas chromatography, chiral-phase high performance liquid chromatography, crystallizing the compound as a chiral salt complex, or crystallizing the compound in a chiral solvent.
• Enantiomers and stereoisomers can also be obtained from stereomerically or enantiomerically pure intermediates, reagents, and catalysts by well-known asymmetric synthetic methods.
• V-protected amino refers to an amino group, as defined herein, to which is attached one or two /V-protecting groups, as defined herein.
• polyethylene glycol represents an alkoxy chain comprised of one or more monomer units, each monomer unit consisting of -OChbChh-.
• Polyethyelene glycol (PEG) is also sometimes referred to as polyethylene oxide (PEO) or polyoxyethylene (POE), and these terms may be considered interchangeable for the purpose of this disclosure.
• Polyethylene glycol may also be considered to include an amino-polyethylene glycol of -NR N1 (CH 2 )s 2 (CH 2 CH 2 0) si (CH 2 )s3NR N1 -, wherein s1 is an integer from 1 to 10 (e.g., from 1 to 6 or from 1 to 4), each of s2 and s3, independently, is an integer from O to 10 (e.g., from 0 to 4, from 0 to 6, from 1 to 4, from 1 to 6, or from 1 to 10), and each R N1 is, independently, hydrogen or optionally substituted Ci-e alkyl.
• s1 is an integer from 1 to 10 (e.g., from 1 to 6 or from 1 to 4)
• each of s2 and s3, independently is an integer from O to 10 (e.g., from 0 to 4, from 0 to 6, from 1 to 4, from 1 to 6, or from 1 to 10)
• each R N1 is, independently, hydrogen or optionally substituted Ci-e alkyl.
• checkpoint inhibitor also known as“immune checkpoint inhibitor” or“ICI,” refers to an agent which blocks the action of an immune checkpoint protein, e.g., blocks such immune checkpoint proteins from binding to their partner proteins.
• chelate refers to an organic compound or portion thereof that can be bonded to a central metal or radiometal atom at two or more points.
• Tautomeric forms result from the swapping of a single bond with an adjacent double bond and the concomitant migration of a proton.
• Tautomeric forms include prototropic tautomers which are isomeric protonation states having the same empirical formula and total charge.
• substituents of compounds of the present disclosure are disclosed in groups or in ranges. It is specifically intended that the present disclosure include each and every individual subcombination of the members of such groups and ranges.
• the term“Ci-e alkyl” is specifically intended to individually disclose methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl.
• a phrase of the form“optionally substituted X” e.g. , optionally substituted alkyl
• X optionally substituted alkyl
• cross-linking group refers to any reactive group that is able to join two or more molecules by a covalent bond.
• the cross-linking group is an amino- reactive or thiol-reactive cross-linking group.
• the amino-reactive or thiol-reactive cross-linking group comprises an activated ester such as a hydroxysuccinimide ester, 2, 3,5,6- tetrafluorophenol ester, 4-nitrophenol ester or an imidate, anhydride, thiol, disulfide, maleimide, azide, alkyne, strained alkyne, strained alkene, halogen, sulfonate, haloacetyl, amine, hydrazide, diazirine, phosphine, tetrazine, isothiocyanate.
• an activated ester such as a hydroxysuccinimide ester, 2, 3,5,6- tetrafluorophenol ester, 4-nitrophenol ester or an imidate
• anhydride, thiol, disulfide maleimide
• azide alkyne
• strained alkyne strained alkene
• halogen, sulfonate
• the cross-linking group may be glycine- glycine-glycine and/or leucine-proline-(any amino acid)-threonine-glycine, which are the recognition sequences for coupling targeting agents with the linker using a sortase-mediated coupling reaction.
• the person having ordinary skill in the art will understand that the use of cross-linking groups are not limited to the specific constructs disclosed herein, but rather may include other known cross-linking groups.
• the terms“decrease,”“decreased,”“increase,”“increased,” or“reduction,” “reduced,” have meanings relative to a reference level.
• the reference level is a level as determined by the use of said method with a control in an experimental animal model or clinical trial.
• the reference level is a level in the same subject before or at the beginning of treatment.
• the reference level is the average level in a population not being treated by said method of treatment.
• lower effective dose when used as a term in conjunction with an agent (e.g., a therapeutic agent) refers to a dosage of the agent which is effective therapeutically in the combination therapies of the invention and which is lower than the dose which has been determined to be effective therapeutically when the agent is used as a monotherapy in reference experiments or by virtue of other therapeutic guidance.
• A“pharmaceutically acceptable excipient,” as used herein, refers any ingredient other than the compounds described herein (for example, a vehicle capable of suspending or dissolving the active compound) and having the properties of being nontoxic and non-inflammatory in a patient.
• Excipients may include, for example: antiadherents, antioxidants, binders, coatings, compression aids,
• disintegrants dyes (colors), emollients, emulsifiers, fillers (diluents), film formers or coatings, flavors, fragrances, glidants (flow enhancers), lubricants, preservatives, printing inks, radioprotectants, sorbents, suspending or dispersing agents, sweeteners, or waters of hydration.
• excipients include, but are not limited to: ascorbic acid, histidine, phosphate buffer, butylated hydroxytoluene (BHT), calcium carbonate, calcium phosphate (dibasic), calcium stearate, croscarmellose, crosslinked polyvinyl pyrrolidone, citric acid, crospovidone, cysteine, ethylcellulose, gelatin, hydroxypropyl cellulose, hydroxypropyl methylcellulose, lactose, magnesium stearate, maltitol, mannitol, methionine,
• BHT butylated hydroxytoluene
• salts of the compounds described here that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and animals without undue toxicity, irritation, or allergic response.
• Pharmaceutically acceptable salts are well known in the art. For example, pharmaceutically acceptable salts are described in: Berge et al., J. Pharmaceutical Sciences 66:1-19, 1977 and in Pharmaceutical Salts: Properties, Selection, and Use, (Eds. P.H. Stahl and C.G. Wermuth), Wiley-VCH, 2008.
• the salts can be prepared in situ during the final isolation and purification of the compounds described herein or separately by reacting the free base group with a suitable organic acid.
• Compounds may have ionizable groups so as to be capable of preparation as pharmaceutically acceptable salts.
• These salts may be acid addition salts involving inorganic or organic acids or the salts may, in the case of acidic forms of compounds, be prepared from inorganic or organic bases.
• the compounds are prepared or used as pharmaceutically acceptable salts prepared as addition products of pharmaceutically acceptable acids or bases.
• Suitable pharmaceutically acceptable acids and bases are well-known in the art, such as hydrochloric, sulphuric, hydrobromic, acetic, lactic, citric, or tartaric acids for forming acid addition salts, and potassium hydroxide, sodium hydroxide, ammonium hydroxide, caffeine, various amines for forming basic salts. Methods for preparation of the appropriate salts are well- established in the art.
• alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium, as well as nontoxic ammonium, quaternary ammonium, and amine cations, including, but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, and ethylamine.
• radioconjugate refers to any conjugate that includes a radioisotope or radionuclide, such as any of the radioisotopes or radionuclides described herein.
• radioimmunotherapy may include administration of a radioimmunoconjugate to a subject in need thereof, wherein administration of the radioimmunoconjugate produces a therapeutic effect in the subject.
• radioimmunotherapy may include administration of a radioimmunoconjugate to a cell, wherein administration of the radioimmunoconjugate kills the cell.
• radioimmunotherapy involves the selective killing of a cell, in some embodiments the cell is a cancer cell in a subject having cancer.
• radioactive decay refers to an atom capable of undergoing radioactive decay
• subject is meant a human or non-human animal (e.g., a mammal).
• substantially identical is meant a polypeptide sequence that has the same polypeptide sequence, respectively, as a reference sequence, or has a specified percentage of amino acid residues, respectively, that are the same at the corresponding location within a reference sequence when the two sequences are optimally aligned.
• an amino acid sequence that is “substantially identical” to a reference sequence has at least 50%, 60%, 70%, 75%, 80%, 85%, 90%,
• sequence identity may be measured using sequence analysis software, e.g., on the default setting (e.g., Sequence Analysis Software Package of the Genetics Computer Group, University of Wisconsin Biotechnology Center, 1710 University Avenue, Madison, Wl 53705). Such software may match similar sequences by assigning degrees of homology to various substitutions, deletions, and other modifications.
• therapeutic moiety refers to any molecule or any part of a molecule that confers a therapeutic benefit.
• the therapeutic moiety is a protein or polypeptide, e.g., an antibody, an antigen-binding fragment thereof.
• the therapeutic moiety is a small molecule.
• beneficial or desired results can include, but are not limited to, alleviation or amelioration of one or more symptoms or conditions; diminishment of extent of disease, disorder, or condition; stabilized (i.e., not worsening) state of disease, disorder, or condition; preventing spread of disease, disorder, or condition; delay or slowing the progress of the disease, disorder, or condition; amelioration or palliation of the disease, disorder, or condition; and remission (whether partial or total), whether detectable or undetectable.
• tumor-specific antigen refers to an antigen that is endogenously present only on tumor cells.
• Figure 1 illustrates relative tumor volume in the CT26 syngeneic mouse tumor model after treatment with various checkpoint inhibitors.
• Figure 2 illustrates [ 177 Lu]-FPI-1755 biodistribution in the CT-26 syngeneic mouse tumor model.
• Figure 4 illustrates synergy between [ 225 Ac]-FPI-1792 and a-CTLA-4/PD-1 treatment in the CT26 syngeneic mouse model.
• Figure 5 illustrates the development of protective immunity in [ 225 Ac]-FPI-1792 (“[ 225 Ac]-FPI-TAT” in the graph labels) treated mice upon CT26 re-challenge.
• Figure 6 illustrates cytokine response and T-cell recruitment after [ 225 Ac]-FPI-1792 treatment.
• Figure 7 illustrates“humanized” IGF-1 R model development.
• the present disclosure relates to combination therapies for inducing or improving an immune response to cancer using radioimmunoconjugates and checkpoint inhibitors.
• use of methods disclosed herein results in treatment or amelioration of cancer.
• a lower effective dose of the radioimmunoconjugate and/or of the checkpoint inhibitor is used.
• Radiolabelled targeting moieties are designed to target a protein or receptor that is upregulated in a disease state and/or specific to diseased cells (e.g., tumor cells) to deliver a radioactive payload to damage and kill cells of interest.“Radioimmunotherapy” refers to this therapy when the targeting moiety comprises an antibody, typically a monoclonal antibody.
• Radioactive decay of the payload produces an alpha, beta, or gamma particle or Auger electron that can cause direct effects to DNA (such as single or double stranded DNA breaks) or indirect effects such as by-stander or crossfire effects.
• Radioimmunoconjugates typically contain a biological targeting moiety (e.g., an antibody or antigen binding fragment thereof that specifically binds to a molecule expressed on or by a tumor, e.g., IGF-1 R or TEM-1/endosialin), a chelating moiety or a metal complex of a chelating moiety (e.g., comprising a radioisotope), and a linker.
• Conjugates may be formed by appending a bifunctional chelate to the biological targeting molecule so that structural alterations are minimal while maintaining target affinity.
• a radioimmunoconjugate may be formed by radiolabelling such a conjugate.
• Radioimmunoconjugates suitable for use in accordance with the present disclosure generally have the structure of Formula l-a:
• B is a targeting moiety
• the radioimmunoconjugate comprises the following structure:
• Radioimmunotherapy may provide a viable mechanism for treating cancers overexpressing the IGF-1 receptor by utilizing the ability of IGF-1 R to undergo antibody triggered internalization and lysosomal degradation to deliver targeted radioisotopes inside cancer cells.
• Internalization and lysosomal degradation of an IGF-1 R targeted radioimmunoconjugate prolongs the residence time of the delivered radioisotope inside cancer cells, thereby maximizing the potential for a cell killing emission to occur.
• actinium-225 which yields 4 alpha particles per decay chain
• cell death can be accomplished by as little as 1 atom of radionuclide delivered per cell [Sgouros, et al. J Nucl Med.
• IGF-1 R antibodies have been developed and investigated for the treatment of various types of cancers, including figitumumab, cixutumumab, ganitumab, AVE1642 (also known as humanized EM164 and huEM164), BIIB002, robatumumab, and teprotumumab. After binding to IGF-1 R, these antibodies are internalized into the cell and degraded by lysosomal enzymes. The combination of overexpression on tumor cells and internalization offers the possibility of delivering detection agents directly to the tumor site while limiting the exposure of normal tissues to toxic agents.
• the CDRs of the heavy chain variable region of AVE1642 have the sequences:
• the heavy chain variable region of AVE1642 has the sequence:
• Endosialin also known as TEM-1 or CD-248, is an antigen expressed by tumor-associated endothelial cells, stromal cells, and pericytes.
• endosialin antibodies examples include hMP-E-8.3 (disclosed in WO 2017/134234, the entire contents of which are incorporated by reference herein) and ontuxizumab (MORAb-004).
• the endosialin antibody or antigen-binding fragment thereof recognizes an epitope having an amino acid sequence of SRDHQIPVIAAN (SEQ ID NO: 9).
• the heavy chain variable region of the endosialin antibody or antibodybinding fragment thereof comprises the complementarity determining regions (CDRs) having the following sequences:
• CDR-H1 GYGVN (SEQ ID NO: 10) or GFSLTGYGVN (SEQ ID NO: 1 1)
• the light chain variable region of the endosialin antibody or antibodybinding fragment thereof comprises the complementarity determining regions (CDRs) having the following sequences:
• CDR-L2 KASNLHT (SEQ ID NO: 15)
• the light chain variable region of the endosialin antibody or antigenbinding fragment thereof comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 21 , 22, 23, or 24:
• Nanobodies are antibody fragments consisting of a single monomeric variable antibody domain. Nanobodies may also be referred to as single-domain antibodies. Like antibodies, nanobodies bind selectively to a specific antigen. Nanobodies may be heavy-chain variable domains or light chain domains. Nanobodies may occur naturally or be the product of biological engineering. Nanobodies may be biologically engineered by site-directed mutagenesis or mutagenic screening (e.g., phage display, yeast display, bacterial display, mRNA display, ribosome display).
• site-directed mutagenesis or mutagenic screening e.g., phage display, yeast display, bacterial display, mRNA display, ribosome display.
• Affibodies are polypeptides or proteins engineered to bind to a specific antigen. As such, affibodies may be considered to mimic certain functions of antibodies.
• Affibodies may be engineered variants of the B-domain in the immunoglobulin-binding region of staphylococcal protein A.
• Affibodies may be engineered variants of the Z-domain, a B-domain that has lower affinity for the Fab region.
• Affibodies may be biologically engineered by site-directed mutagenesis or mutagenic screening (e.g., phage display, yeast display, bacterial display, mRNA display, ribosome display).
• Affibody molecules showing specific binding to a variety of different proteins e.g. insulin, fibrinogen, transferrin, tumor necrosis factor-a, IL-8, gp120, CD28, human serum albumin, IgA, IgE, IgM, HER2 and EGFR
• proteins e.g. insulin, fibrinogen, transferrin, tumor necrosis factor-a, IL-8, gp120, CD28, human serum albumin, IgA, IgE, IgM, HER2 and EGFR
• the Fibronectin type III domain is an evolutionarily conserved protein domain found in a wide- variety of extracellular proteins.
• the Fibronectin type III domain has been used as a molecular scaffold to produce molecules capable of selectively binding a specific antigen.
• Variants of the Fibronectin type III domains (FN3) that have been engineered for selective-binding may also be referred to as monobodies.
• FN3 domains may be biologically engineered by site-directed mutagenesis or mutagenic screening (e.g., CIS-display, phage display, yeast display, bacterial display, mRNA display, ribosome display).
• Polypeptides used in accordance with the disclosure may have a modified amino acid sequence.
• Modified polypeptides may be substantially identical to the corresponding reference polypeptide (e.g., the amino acid sequence of the modified polypeptide may have at least 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to the amino acid sequence of the reference polypeptide).
• the modification does not destroy significantly a desired biological activity (e.g., binding to IGF-1 R or to endosialin).
• the modification may reduce (e.g., by at least 5%, 10%, 20%, 25%, 35%, 50%, 60%, 70%, 75%, 80%, 90%, or 95%), may have no effect, or may increase (e.g., by at least 5%, 10%, 25%, 50%, 100%, 200%, 500%, or 1000%) the biological activity of the original polypeptide.
• the modified polypeptide may have or may optimize a characteristic of a polypeptide, such as in vivo stability, bioavailability, toxicity, immunological activity, immunological identity, and conjugation properties.
• Modifications include those by natural processes, such as post-translational processing, or by chemical modification techniques known in the art. Modifications may occur anywhere in a polypeptide including the polypeptide backbone, the amino acid side chains and the amino- or carboxy-terminus. The same type of modification may be present in the same or varying degrees at several sites in a given polypeptide, and a polypeptide may contain more than one type of modification. Polypeptides may be branched as a result of ubiquitination, and they may be cyclic, with or without branching. Cyclic, branched, and branched cyclic polypeptides may result from post-translational natural processes or may be made synthetically.
• a modified polypeptide can also include an amino acid insertion, deletion, or substitution, either conservative or non-conservative (e.g., D-amino acids, desamino acids) in the polypeptide sequence (e.g., where such changes do not substantially alter the biological activity of the polypeptide).
• conservative or non-conservative e.g., D-amino acids, desamino acids
• the addition of one or more cysteine residues to the amino or carboxy-terminus of a polypeptide can facilitate conjugation of these polypeptides by, e.g., disulfide bonding.
• a polypeptide can be modified to include a single cysteine residue at the amino-terminus or a single cysteine residue at the carboxy-terminus.
• Amino acid substitutions can be conservative (i.e., wherein a residue is replaced by another of the same general type or group) or non-conservative (i.e., wherein a residue is replaced by an amino acid of another type).
• a naturally occurring amino acid can be substituted for a non-naturally occurring amino acid (i.e. , non-naturally occurring conservative amino acid substitution or a non-naturally occurring non-conservative amino acid substitution).
• Phenylglycine may substitute for Trp, Tyr, or Phe; citrulline and methionine sulfoxide are neutral nonpolar, cysteic acid is acidic, and ornithine is basic.
• Proline may be substituted with hydroxyproline and retain the conformation conferring properties.
• chelating moieties include, but are not limited to, DOTA (1 ,4,7,10- tetraazacyclododecane-1 ,4,7,10-tetraacetic acid), DOTMA (1 R,4R,7R,10R)-a, a’, a”, a’”-tetramethyl-
• DTPA diethylenetriaminepentaacetic acid
• DTPA-BMA diethylenetriaminepentaacetic acid-bismethylamide
• HOPO octadentate hydroxypyridinones
• radioimmunoconjugates comprising such detectable chelating moieties can therefore be used as diagnostic or theranostic agents.
• the metal complex comprises a radionuclide.
• suitable radioisotopes and radionuclides include, but are not limited to, 3 H, 14 C, 15 N, 18 F, 35 S, 47 Sc, 55 Co, 60 Cu,
• the radionuclide is an alpha emitter, e.g. , Astatine-21 1 ( 211 At), Bismuth- 212 ( 212 Bi), Bismuth-213 ( 213 Bi), Actinium-225 ( 225 Ac), Radium-223 ( 223 Ra), Lead-212 ( 212 Pb), Thorium- 227 ( 227 Th), or Terbium-149 ( 149 Tb).
• Astatine-21 1 211 At
• Bismuth- 212 212 Bi
• Bismuth-213 213 Bi
• Actinium-225 225 Ac
• Radium-223 223 Ra
• Thorium- 227 227 Th
• Terbium-149 149 Tb
• the linker is as shown within the structure of Formula l-b, as that part of Formula l-b absent A and B:
• the amino- reactive or thiol-reactive cross-linking group comprises an activated ester such as a hydroxysuccinimide ester, 2,3,5,6-tetrafluorophenol ester, 4-nitrophenol ester or an imidate, anhydride, thiol, disulfide, maleimide, azide, alkyne, strained alkyne, strained alkene, halogen, sulfonate, haloacetyl, amine, hydrazide, diazirine, phosphine, tetrazine, isothiocyanate, or oxaziridine.
• an activated ester such as a hydroxysuccinimide ester, 2,3,5,6-tetrafluorophenol ester, 4-nitrophenol ester or an imidate
• anhydride, thiol, disulfide maleimide
• azide alkyne
• strained alkyne strained alkene
• the checkpoint inhibitor is a PD-L1 antibody.
• PD- L1 antibodies include atezolizumab, avelumab, and durvalumab.
• compositions comprising include agents (e.g., compounds as disclosed herein) dissolved or suspended in an acceptable carrier, preferably an aqueous carrier, e.g., water, buffered water, saline, or PBS, among others, e.g., for parenteral administration.
• an acceptable carrier preferably an aqueous carrier, e.g., water, buffered water, saline, or PBS, among others, e.g., for parenteral administration.
• Compositions may contain pharmaceutically acceptable auxiliary substances to approximate
• the therapeutic effect comprises an immune response
• an immune response comprises an increase in T cells, e.g. CD8+ (e.g., IFNy-producing CD8+ cells) and/or CD4+ cells.
• the T cells comprise T cells specific for a tumor-associated antigen or tumor-specific antigen expressed on the cancer being treated or ameliorated.
• the increase in T cells is observed in the tumor relative to the spleen.
• the step of administering results in at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, or at least 70% of the total T cell population in a sample in the mammal being specific for the tumor-associated antigen or tumor-specific antigen.
• the sample is a tumor sample
• the therapeutic effect comprises a decrease in tumor volume, a stable tumor volume, or a reduced rate of increase in tumor volume. In some embodiments, the therapeutic effect comprises a decreased incidence of recurrence or metastasis.
• antiproliferative or“antiproliferative agent,” as used interchangeably herein, is meant any anticancer agent, including those antiproliferative agents listed in Table 2, any of which can be used in combination with a radioimmunoconjugate to treat a condition or disorder.
• Antiproliferative agents also include organo-platinum derivatives, naphtoquinone and benzoquinone derivatives, chrysophanic acid and anthroquinone derivatives thereof.
• immuno-modulator or“immunomodulatory agent,” as used interchangeably herein, is meant any immuno-modulator, including those listed in Table 2, any of which can be used in combination with a radioimmunoconjugate.
• MAB391 a murine monoclonal antibody against IGF-1 R, was conjugated with FPI-1397 (a bifunctional chelate) and radiolabeled with Lu-177 using methods well known in the art to form [ 177 Lu]-FPI- 1755.
• FPI-1397 a bifunctional chelate
• Lu-177 a bifunctional chelate
• the ability of [ 177 Lu]-FPI-1755 to target antigen expressing mouse IGF-1 R overexpressing tumors in vivo was demonstrated using the CT-26 syngeneic model. Tumor uptake was steady at 15-17% injected dose/g (ID/g) from 24-96 hours post injection. See Figure 2.
• MAB391 a murine monoclonal antibody against IGF-1 R, was conjugated with FPI-1397 (a bifunctional chelate) and radiolabeled with [ 225 Ac] using standard techniques to form [ 225 Ac]-FPI-1792.
• FPI-1397 a bifunctional chelate
• [ 225 Ac]-FPI-1792 was co-administered with ether CTLA-4 or PD-1 or both, a synergistic effect was seen— co-administration resulted in significantly smaller tumor volume when compared to treatment with [ 225 Ac]- FPI-1792, or when compared to treatment with the CTLA-4 inhibitor or the PD-1 inhibitor alone. See Figure 4.
• Cytokine response and T-cell recruitment after [ 225 Ac]-FPI-1792 treatment is measured. Mice were inoculated with 1 x 10 6 CT26 cells. Mice were then treated with either [ 225 Ac]-FPI-1792, the unconjugated MAB391 antibody or vehicle. Samples from the tumor, spleen and blood plasma are analyzed for the presence of cytokines at 24, 48, or 72 hours. Additional samples are taken from the tumor and spleen at 72 hours, 5 days and 8 days for immunohistochemistry to assess the presence of different T-cell types. Finally, at 8 days, tumor-infiltrating lymphocytes are extracted, isolated and quantified using flow cytometry. See Figure 6.
• CT26 cells were stably transfected with human IGF-1 R plasmid.
• Western blot analysis was conducted for the presence of hlGF-1 R for the selection of hlGF-1 R expressing clones. See Figure 7.
• the best clones are chosen based on both in vitro and in vivo characteristics.
• the resulting cell lines will be used as an immunocompetent mouse model for testing [ 225 Ac]-FPI-1434 and other
• Example 7 Combination therapies result in increased tumor-associated antigen-specific CD8+ T cells in both the spleen and tumor itself.
• Ac-TAB-199 is a radioimmunoconjugate comprising human monoclonal IGF-1 R antibody labeled with 225 -Actinium.
• Combinations with Ac-TAB-199 and checkpoint inhibitors (a-PD-1 , a-CTLA-4, or both a- PD-1 and a-CTLA-4) were tested in the CT26 syngeneic mouse model. Mice were re-challenged with CT26 cells at day 28 after initial tumor inoculation. CD8+ and CD4+ T cell populations were assessed in both the spleen and the tumor after re-challenge. In mice treated with Ac-TAB-199 and checkpoint inhibitors, both the spleen and the tumor exhibited the presence of CD8+ T-cells. Importantly, an increase in the CD8+ T-cell frequency in the tumor, relative to controls, was observed. These results suggest that these combination treatments lead to improved levels of therapeutically effective CD8+ T cells.
• Antigen-specific T-cells were detected and enumerated using an MHC class I tetramer assay.
• MHC I molecules presenting an epitope specific to CT26 cells are labelled with biotin.
• streptavidin these MHC I molecules tetramerize.
• CD8+ T cells specific for the CD26 epitope are thereby labelled when their T-cell receptors bind to MHC I/CT26 epitope complexes within tetramers.
• CD8+ T cells Based on tetramer analysis, approximately 35%, 62%, and 75% of the CD8+ T cells were antigen-specific in mice treated with Ac-TAB-199/a-CTLA-4, Ac-TAB-199/a-PD-1 , and Ac-TAB-199/a-CTLA-4/a-PD-1 , respectively.

Landscapes

• Health & Medical Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
• Chemical & Material Sciences (AREA)
• Medicinal Chemistry (AREA)
• General Health & Medical Sciences (AREA)
• Immunology (AREA)
• Veterinary Medicine (AREA)
• Public Health (AREA)
• Animal Behavior & Ethology (AREA)
• Pharmacology & Pharmacy (AREA)
• Proteomics, Peptides & Aminoacids (AREA)
• Organic Chemistry (AREA)
• Epidemiology (AREA)
• Physics & Mathematics (AREA)
• Optics & Photonics (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Chemical Kinetics & Catalysis (AREA)
• General Chemical & Material Sciences (AREA)
• Genetics & Genomics (AREA)
• Molecular Biology (AREA)
• Biochemistry (AREA)
• Biophysics (AREA)
• Oncology (AREA)
• Engineering & Computer Science (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Endocrinology (AREA)
• Mycology (AREA)
• Microbiology (AREA)
• Biomedical Technology (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
• Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
• Medicinal Preparation (AREA)
• Peptides Or Proteins (AREA)

Priority Applications (18)

Applications Claiming Priority (2)

Related Child Applications (3)

Publications (1)

Family

ID=70973593

Family Applications (2)

Family Applications After (1)

Country Status (18)

Cited By (2)

Families Citing this family (10)

Citations (3)

Family Cites Families (29)

• 2019
  • 2019-12-03 US US16/619,433 patent/US20220088231A1/en active Pending
  • 2019-12-03 SG SG11202105112RA patent/SG11202105112RA/en unknown
  • 2019-12-03 PE PE2021000815A patent/PE20211286A1/es unknown
  • 2019-12-03 MA MA054399A patent/MA54399A/fr unknown
  • 2019-12-03 EA EA202191557A patent/EA202191557A1/ru unknown
  • 2019-12-03 JP JP2021531486A patent/JP2022511471A/ja active Pending
  • 2019-12-03 CN CN202311139310.7A patent/CN117482261A/zh active Pending
  • 2019-12-03 WO PCT/IB2019/001342 patent/WO2020115556A1/en not_active Ceased
  • 2019-12-03 MX MX2021006408A patent/MX2021006408A/es unknown
  • 2019-12-03 MX MX2021006407A patent/MX2021006407A/es unknown
  • 2019-12-03 SG SG11202105192WA patent/SG11202105192WA/en unknown
  • 2019-12-03 CA CA3119915A patent/CA3119915A1/en active Pending
  • 2019-12-03 WO PCT/IB2019/001292 patent/WO2020115548A1/en not_active Ceased
  • 2019-12-03 EP EP19893184.2A patent/EP3890790A4/en active Pending
  • 2019-12-03 KR KR1020217020517A patent/KR20210099073A/ko not_active Ceased
  • 2019-12-03 JP JP2021531492A patent/JP2022513700A/ja active Pending
  • 2019-12-03 KR KR1020217020519A patent/KR20210099074A/ko not_active Ceased
  • 2019-12-03 MA MA054401A patent/MA54401A/fr unknown
  • 2019-12-03 US US16/619,432 patent/US11446401B2/en active Active
  • 2019-12-03 EP EP19892173.6A patent/EP3890789A4/en active Pending
  • 2019-12-03 CN CN202510572446.XA patent/CN120393061A/zh active Pending
  • 2019-12-03 PE PE2021000808A patent/PE20211961A1/es unknown
  • 2019-12-03 CN CN201980079758.XA patent/CN113474014A/zh active Pending
  • 2019-12-03 BR BR112021010799-1A patent/BR112021010799A2/pt not_active Application Discontinuation
  • 2019-12-03 BR BR112021010670-7A patent/BR112021010670A2/pt unknown
  • 2019-12-03 CN CN201980079705.8A patent/CN113164632A/zh active Pending
  • 2019-12-03 EA EA202191556A patent/EA202191556A1/ru unknown
  • 2019-12-03 CA CA3119917A patent/CA3119917A1/en active Pending
  • 2019-12-03 AU AU2019394888A patent/AU2019394888A1/en active Pending
  • 2019-12-03 AU AU2019393257A patent/AU2019393257A1/en active Pending
• 2021
  • 2021-05-20 ZA ZA2021/03429A patent/ZA202103429B/en unknown
  • 2021-05-28 PH PH12021551282A patent/PH12021551282A1/en unknown
  • 2021-05-28 PH PH12021551237A patent/PH12021551237A1/en unknown
  • 2021-06-01 CL CL2021001432A patent/CL2021001432A1/es unknown
  • 2021-06-01 IL IL283598A patent/IL283598A/en unknown
  • 2021-06-01 CL CL2021001433A patent/CL2021001433A1/es unknown
  • 2021-06-01 IL IL283613A patent/IL283613A/en unknown
  • 2021-06-02 US US17/337,358 patent/US20210290788A1/en active Pending
  • 2021-06-02 US US17/337,357 patent/US20210290789A1/en active Pending
• 2022
  • 2022-08-15 US US17/819,911 patent/US20230270895A1/en not_active Abandoned
• 2024
  • 2024-11-05 JP JP2024193520A patent/JP2025013486A/ja active Pending

Patent Citations (3)

Also Published As

Similar Documents

Legal Events