EP3941467A1 - Combination therapy using a chemokine receptor 2 (ccr2) antagonist and a pd-1 and/or pd-l1 inhibitor - Google Patents
Combination therapy using a chemokine receptor 2 (ccr2) antagonist and a pd-1 and/or pd-l1 inhibitorInfo
- Publication number
- EP3941467A1 EP3941467A1 EP20772952.6A EP20772952A EP3941467A1 EP 3941467 A1 EP3941467 A1 EP 3941467A1 EP 20772952 A EP20772952 A EP 20772952A EP 3941467 A1 EP3941467 A1 EP 3941467A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- substituted
- unsubstituted
- group
- alkyl
- inhibitor
- 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
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Classifications
-
- 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
-
- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
-
- 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
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
-
- 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
- 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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Definitions
- Cancerous tumors exploit numerous mechanisms to evade the body’s natural cytotoxic immune response such that the tumors are tolerated by the immune system. These mechanisms include dysfunctional T-cell signaling, suppressive regulatory cells, and immune checkpoints that normally act to downregulate the intensity of adaptive immune responses and protect healthy tissues from collateral damage. For instance, tumors develop immune resistance, particularly to T cells that are specific to tumor antigens, by recruiting CCR2 + myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages to the tumors and their surrounding microenvironment.
- MDSCs myeloid-derived suppressor cells
- CCR2 + MDSCs have immunosuppressive functions. MDSCs play a key role in a tumor’s ability to suppress immune responses. Another key component to this suppression is the activation of immune checkpoints which, in turn, restricts T cell activation and infiltration into tumors. Immune checkpoints refer to inhibitory pathways of the immune system that are essential to maintaining self-tolerance and controlling immune responses in peripheral tissues to minimize collateral tissue damage.
- PD-1 is one of numerous immune checkpoint receptors that are expressed by activated T cells and mediate immunosuppression.
- Ligands of PD-1 include Programmed Death Ligand-1 (PD-L1) and Programmed Death Ligand-2 (PD-L2) which are expressed on antigen- presenting cells as well as on many human cancer cells.
- PD-L1 and PD-L2 can downregulate T cell activation and cytokine secretion upon binding to PD-1.
- PD-l/PD-Ll interaction inhibitors can mediate potent antitumor activity and are effective for treating some cancers. Despite these findings, there remains a need for an effective treatment for cancers such as solid tumor cancers.
- CCR2 Chemokine Receptor 2
- the CCR2 chemokine receptor antagonist has the formula I
- the CCR2 chemokine antagonist has the formula selected from the group consisting of
- the CCR2 antagonist has the formula
- the CCR2 antagonist has the formula
- the CCR2 antagonist has the formula
- the PD-1 and/or PD-L1 inhibitor is a PD-1 inhibitor.
- the PD-1 inhibitor is selected from the group consisting of pembrolizumab, nivolumab, IBI-308, mDX-400, BGB-108, MEDI-0680, SHR-1210, PF- 06801591, PDR-001, GB-226, STI-1110, biosimilars thereof, biobetters thereof, and bioequivalents thereof.
- the PD-1 and/or PD-L1 inhibitor is a PD-L1 inhibitor.
- the PD-L1 inhibitor is selected from the group consisting of durvalumab, atezolizumab, avelumab, BMS-936559, ALN-PDL, TSR-042, KD-033, CA- 170, STI-1014, KY-1003, biosimilars thereof, biobetters thereof, and bioequivalents thereof.
- the PD-1 and/or PD-L1 inhibitor is a compound of formula (II)
- the cancer is a central nervous system cancer. In some embodiments, the cancer is glioblastoma.
- a pharmaceutical combination for treating glioblastoma in a patient includes a PD-1 and/or PD-L1 inhibitor; and a compound or a pharmaceutically acceptable salt thereof of formula I:
- FIGS.1A-1E shows distinct cell populations of CCR2 and CX3CR1 expressing myeloid cells in glioma bearing mice.
- D Flow cytometric analysis of tumor isolates from Ccr2 RFP/WT ;Cx3cr1 GFP/WT mice.
- CD45 low events (upper) a primarily CX3CR1 + cell population
- CD45 hi events represent a heterogeneous cell population consisting of CCR2 + , CX3CR1 + , and CCR2-/CX3CR1- cells.
- Ly6C hi events represent a cell population that is primarily CCR2 + /CX3CR1 +
- FIGS.2A-2C show effect of Ccr2 deficiency on glioma bearing mice.
- FIGS.3A-3C show impact of Ccr2 deficiency on peripheral and tumor MDSC populations.
- FIGS.4A-4B show effect of combinatorial Compound 3/anti-PD-1 treatment on survival of KR158 and 005 GSC glioma bearing mice.
- FIG.5A-5D show impact of combinatorial Compound 3/anti-PD-1 treatment on peripheral and tumor myeloid cell populations.
- C) Flow cytometric analysis of tumor isolates from KR158 tumor bearing Ccr2 RFP/WT /Cx3cr1 GFP/WT mice depicting CCR2 + vs.
- CCR2 + /CX3CR1 + (p .032) events.
- Lower panels report a reduction (p .004) in Ly6C hi events within tumors.
- Lower panels report a reduction (p .020) in Ly6C hi events within tumors.
- FIGS.6A-6E show impact of combinatorial Compound 3/anti-PD-1 treatment on CD4 + and CD8 + T-cells.
- DETAILED DESCRIPTION OF THE INVENTION Abbreviation and Definitions [0027]
- the terms“a,”“an,” or“the” as used herein not only include aspects with one member, but also include aspects with more than one member. For instance, the singular forms“a,”“an,” and“the” include plural referents unless the context clearly dictates otherwise.
- reference to“a cell” includes a plurality of such cells and reference to“the agent” includes reference to one or more agents known to those skilled in the art, and so forth.
- the terms“about” and“approximately” shall generally mean an acceptable degree of error for the quantity measured given the nature or precision of the measurements.
- Typical, exemplary degrees of error are within 20 percent (%), preferably within 10%, and more preferably within 5% of a given value or range of values.
- the terms“about” and“approximately” may mean values that are within an order of magnitude, preferably within 5-fold and more preferably within 2- fold of a given value. Numerical quantities given herein are approximate unless stated otherwise, meaning that the term“about” or“approximately” can be inferred when not expressly stated.
- alkyl by itself or as part of another substituent, means, unless otherwise stated, a straight or branched chain hydrocarbon radical, having the number of carbon atoms designated (i.e. C 1 - 8 means one to eight carbons).
- alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n- octyl, and the like.
- alkenyl refers to an unsaturated alkyl group having one or more double bonds.
- alkynyl refers to an unsaturated alkyl group having one or more triple bonds.
- unsaturated alkyl groups include vinyl, 2- propenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and the higher homologs and isomers.
- cycloalkyl refers to hydrocarbon rings having the indicated number of ring atoms (e.g., C 3-6 cycloalkyl) and being fully saturated or having no more than one double bond between ring vertices.
- Cycloalkyl is also meant to refer to bicyclic and polycyclic hydrocarbon rings such as, for example, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, etc.
- heterocycloalkyl refers to a cycloalkyl group that contain from one to five heteroatoms selected from N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quaternized.
- the heterocycloalkyl may be a monocyclic, a bicyclic or a polycyclic ring system.
- heterocycloalkyl groups include pyrrolidine, imidazolidine, pyrazolidine, butyrolactam, valerolactam, imidazolidinone, hydantoin, dioxolane, phthalimide, piperidine, 1,4-dioxane, morpholine, thiomorpholine,
- a heterocycloalkyl group can be attached to the remainder of the molecule through a ring carbon or a heteroatom.
- a cycloalkyl or a heterocycloalkyl group is attached through an alkyl or alkylene linker to the remainder of the molecule.
- cyclobutylmethyl is a cyclobutyl ring that is attached to a methylene linker to the remainder of the molecule.
- alkylene by itself or as part of another substituent means a divalent radical derived from an alkane, as exemplified by -CH 2 CH 2 CH 2 CH 2 -.
- an alkyl (or alkylene) group will have from 1 to 24 carbon atoms, with those groups having 10 or fewer carbon atoms being preferred in the present invention.
- a “lower alkyl” or “lower alkylene” is a shorter chain alkyl or alkylene group, generally having four or fewer carbon atoms.
- alkenylene and alkynylene refer to the unsaturated forms of “alkylene” having double or triple bonds, respectively.
- a wavy line, " ", that intersects a single, double or triple bond in any chemical structure depicted herein, represents the point attachment of the single, double, or triple bond to the remainder of the molecule.
- heteroalkyl by itself or in combination with another term, means, unless otherwise stated, a stable straight or branched chain, or cyclic hydrocarbon radical, or combinations thereof, consisting of the stated number of carbon atoms and from one to three heteroatoms selected from the group consisting of O, N, Si and S, and wherein the nitrogen and sulfur atoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized.
- the heteroatom(s) O, N and S may be placed at any interior position of the heteroalkyl group.
- the heteroatom Si may be placed at any position of the heteroalkyl group, including the position at which the alkyl group is attached to the remainder of the molecule.
- heteroatoms Up to two heteroatoms may be consecutive, such as, for example, -CH 2 -NH-OCH 3 and -CH 2 -O-Si(CH 3 ) 3 .
- the terms“heteroalkenyl” and“heteroalkynyl” by itself or in combination with another term means, unless otherwise stated, an alkenyl group or alkynyl group, respectively, that contains the stated number of carbons and having from one to three heteroatoms selected from the group consisting of O, N, Si and S, and wherein the nitrogen and sulfur atoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized.
- the heteroatom(s) O, N and S may be placed at any interior position of the heteroalkyl group.
- heteroatoms can also occupy either or both of the chain termini (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, and the like).
- alkoxy alkylamino and “alkylthio” (or thioalkoxy) are used in their conventional sense, and refer to those alkyl groups attached to the remainder of the molecule via an oxygen atom, an amino group, or a sulfur atom, respectively. Additionally, for dialkylamino groups, the alkyl portions can be the same or different and can also be combined to form a 3-7 membered ring with the nitrogen atom to which each is attached. Accordingly, a group represented as -NR a R b is meant to include piperidinyl, pyrrolidinyl, morpholinyl, azetidinyl and the like.
- halo or halogen
- substituents mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom.
- terms such as “haloalkyl,” are meant to include monohaloalkyl and polyhaloalkyl.
- C 1 -4 haloalkyl is mean to include trifluoromethyl, 2,2,2-trifluoroethyl, 4- chlorobutyl, 3-bromopropyl, and the like.
- aryl means, unless otherwise stated, a polyunsaturated, typically aromatic, hydrocarbon group which can be a single ring or multiple rings (up to three rings) which are fused together or linked covalently.
- heteroaryl refers to aryl groups (or rings) that contain from one to five heteroatoms selected from N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quaternized.
- a heteroaryl group can be attached to the remainder of the molecule through a heteroatom.
- Non-limiting examples of aryl groups include phenyl, naphthyl and biphenyl, while non-limiting examples of heteroaryl groups include pyridyl, pyridazinyl, pyrazinyl, pyrimindinyl, triazinyl, quinolinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalaziniyl, benzotriazinyl, purinyl, benzimidazolyl, benzopyrazolyl, benzotriazolyl, benzisoxazolyl, isobenzofuryl, isoindolyl, indolizinyl, benzotriazinyl, thienopyridinyl, thienopyrimidinyl, pyrazolopyrimidinyl, imidazopyridines, benzothiaxolyl, benzofuranyl, benzothienyl, indolyl, quinoly
- aryl when used in combination with other terms (e.g., aryloxy, arylthioxy, arylalkyl) includes both aryl and heteroaryl rings as defined above.
- arylalkyl is meant to include those radicals in which an aryl group is attached to an alkyl group that is attached to the remainder of the molecule (e.g., benzyl, phenethyl, pyridylmethyl and the like).
- alkyl in some embodiments, will include both substituted and unsubstituted forms of the indicated radical. Preferred substituents for each type of radical are provided below.
- aryl and heteroaryl will refer to substituted or unsubstituted versions as provided below, while the term “alkyl” and related aliphatic radicals is meant to refer to an unsubstituted version, unless indicated to be substituted.
- Substituents for the alkyl radicals can be a variety of groups selected from: -halogen, -OR’,
- R’, R” and R”’ each independently refer to hydrogen, unsubstituted C 1-8 alkyl, unsubstituted heteroalkyl, unsubstituted aryl, aryl substituted with 1-3 halogens, unsubstituted C 1-8 alkyl, C 1-8 alkoxy or C 1-8 thioalkoxy groups, or unsubstituted aryl-C 1 -4 alkyl groups.
- R’ and R” are attached to the same nitrogen atom, they can be combined with the nitrogen atom to form a 3-,
- -NR’R is meant to include 1-pyrrolidinyl and 4-morpholinyl.
- R’, R” and R”’ are independently selected from hydrogen, C 1-8 alkyl, C 3-6 cycloalkyl, C 2-8 alkenyl, C 2-8 alkynyl, unsubstituted aryl and heteroaryl, (unsubstituted aryl)- C 1 - 4 alkyl, and unsubstituted aryloxy-C 1 - 4 alkyl.
- R substituents include each of the above aryl substituents attached to a ring atom by an alkylene tether of from 1-4 carbon atoms.
- Two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -T-C(O)-(CH 2 ) q -U-, wherein T and U are independently -NH-, -O-, -CH 2 - or a single bond, and q is an integer of from 0 to 2.
- two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -A-(CH 2 )r-B-, wherein A and B are independently -CH 2 -, -O-, -NH-, -S-, -S(O)-, -S(O) 2 -, -S(O) 2 NR’- or a single bond, and r is an integer of from 1 to 3.
- One of the single bonds of the new ring so formed may optionally be replaced with a double bond.
- two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -(CH 2 )s- X-(CH 2 ) t -, where s and t are independently integers of from 0 to 3, and X is -O-, -NR’-, -S-, - S(O)-,
- the substituent R’ in -NR’- and -S(O) 2 NR’- is selected from hydrogen or unsubstituted C 1-6 alkyl.
- heteroatom is meant to include oxygen (O), nitrogen (N), sulfur (S) and silicon (Si).
- a bond that is drawn from a substituent (typically an R group) to the center of an aromatic ring will be understood to refer to a bond providing a connection at any of the available atoms of the aromatic ring.
- the depiction will also include connection at a ring which is fused to the aromatic ring.
- a bond drawn to the center of the benzene portion of an indole will indicate a bond to any available vertex of the six- or five-membered ring portions of the indole.
- salts are meant to include salts of the active compounds which are prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein.
- base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of salts derived from
- pharmaceutically-acceptable inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, zinc and the like.
- Salts derived from pharmaceutically-acceptable organic bases include salts of primary, secondary and tertiary amines, including substituted amines, cyclic amines, naturally- occurring amines and the like, such as arginine, betaine, caffeine, choline, N,N’- dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperadine, polyamine resins, procaine, purines, theobromine, tri
- acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent.
- pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric,
- salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like (see, for example, Berge, S.M., et al., “Pharmaceutical Salts”, Journal of Pharmaceutical Science, 1977, 66, 1-19).
- Certain specific compounds of the present invention contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.
- the neutral forms of the compounds may be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner.
- the parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to the parent form of the compound for the purposes of the present invention.
- the present invention provides compounds which are in a prodrug form.
- Prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under physiological conditions to provide the compounds of the present invention.
- prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to the compounds of the present invention when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent.
- Certain compounds of the present invention can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present invention. Certain compounds of the present invention may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the present invention and are intended to be within the scope of the present invention.
- Certain compounds of the present invention possess asymmetric carbon atoms (optical centers) or double bonds; the racemates, diastereomers, geometric isomers, regioisomers and individual isomers (e.g., separate enantiomers) are all intended to be encompassed within the scope of the present invention.
- R or S or with dashed or wedge bond designations
- those compounds will be understood by one of skill in the art to be substantially free of other isomers (e.g., at least 80%, 90%, 95%, 98%, 99%, and up to 100% free of the other isomer).
- the compounds of the present invention may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds.
- Unnatural proportions of an isotope may be defined as ranging from the amount found in nature to an amount consisting of 100% of the atom in question.
- the compounds may incorporate radioactive isotopes, such as for example tritium ( 3 H), iodine-125 ( 125 I) or carbon-14 ( 14 C), or non-radioactive isotopes, such as deuterium ( 2 H) or carbon-13 ( 13 C).
- radioactive isotopes such as for example tritium ( 3 H), iodine-125 ( 125 I) or carbon-14 ( 14 C), or non-radioactive isotopes, such as deuterium ( 2 H) or carbon-13 ( 13 C).
- isotopic variations can provide additional utilities to those described elsewhere within this application.
- isotopic variants of the compounds of the invention may find additional utility, including but not limited to, as diagnostic and/or imaging reagents, or as cytotoxic/radiotoxic therapeutic agents. Additionally, isotopic variants of the compounds of the invention can have altered pharmacokinetic and pharmacodynamic characteristics which can contribute to enhanced safety, tolerability or efficacy during treatment. All isotopic variations of the compounds of the present invention, whether radioactive or not, are intended to be encompassed within the scope of the present invention.
- the term“cancer” refers to a disease characterized by the uncontrolled growth of aberrant cells. Cancer cells can spread locally or through the bloodstream and lymphatic system to other parts of the body. Examples of various cancers are described herein and include but are not limited to, breast cancer, prostate cancer, ovarian cancer, cervical cancer, skin cancer, pancreatic cancer, colorectal cancer, renal cancer, liver cancer, brain cancer, lymphoma, leukemia, lung cancer, glioblastoma and the like.
- the terms“tumor” and “cancer” are used interchangeably herein, e.g., both terms encompass solid and liquid, e.g., diffuse or circulating, tumors. As used herein, the term“cancer” or“tumor” includes premalignant, as well as malignant cancers and tumors.
- PD-1 refers to the programmed death-1 protein, a T- cell co-inhibitor, also known as CD279.
- the amino acid sequence of the human full-length PD-1 protein is set forth, for example, in GenBank Accession Number NP_005009.2.
- PD-1 is a 288 amino acid protein with an extracellular N-terminal domain which is IgV-like, a transmembrane domain and an intracellular domain containing an immunoreceptor tyrosine- based inhibitory (ITIM) motif and an immunoreceptor tyrosine-based switch (ITSM) motif (Chattopadhyay et al., Immunol Rev, 2009, 229(1):356-386).
- ITIM immunoreceptor tyrosine-based inhibitory
- ITSM immunoreceptor tyrosine-based switch
- the term“PD-1” includes recombinant PD-1 or a fragment thereof, or variants thereof.
- the PD-1 receptor has two ligand
- PD-L1 or“programmed death ligand 1” refers to a ligand of the PD-1 receptor also known as CD274 and B7H 1.
- the amino acid sequence of the human full- length PD-L1 protein is set forth, for example, in GenBank Accession Number NP_054862.1 PD-L1 is a 290 amino acid protein with an extracellular IgV-like domain, a transmembrane domain and a highly conserved intracellular domain of approximately 30 amino acids.
- PD- L1 is constitutively expressed on many cells such as antigen presenting cells (e.g., dendritic cells, macrophages, and B-cells) and on hematopoietic and non-hematopoietic cells (e.g., vascular endothelial cells, pancreatic islets, and sites of immune privilege). PD-L1 is also expressed on a wide variety of tumors, virally-infected cells and autoimmune tissue.
- antigen presenting cells e.g., dendritic cells, macrophages, and B-cells
- hematopoietic and non-hematopoietic cells e.g., vascular endothelial cells, pancreatic islets, and sites of immune privilege.
- PD-L1 is also expressed on a wide variety of tumors, virally-infected cells and autoimmune tissue.
- the programmed death 1 (PD-1/PD-L1) pathway acts as a checkpoint to limit T- cell–mediated immune responses.
- Both PD-1 ligands, PD-L1 and PD-L2 can engage the PD-1 receptor and induce PD-1 signaling and reversible inhibition of T-cell activation and proliferation.
- PD-1 ligands on the surface or cancer cells or neighboring cells these ligands bind to PD-1 receptor positive immune effector cells and utilize the PD-1 pathway to evade an immune response.
- inhibitors refers to any agent, molecule, compound, chemical, protein, polypeptide, macromolecule, etc. that blocks or inhibits in a statistically, clinically, or biologically significant manner, the inhibitory pathways of the immune system.
- inhibitors may include small molecule inhibitors or may include antibodies, or antigen binding fragments thereof, that bind to and block or inhibit immune checkpoint receptors or antibodies that bind to and block or inhibit immune checkpoint receptor ligands.
- Illustrative immune checkpoint molecules that may be targeted for blocking or inhibition include, but are not limited to, CTLA-4, 4-1BB (CD137), 4-1BBL (CD137L), PDLl, PDL2, PD-l, B7-H 3 , B7-H4, BTLA, HVEM, TIM3, GAL9, LAG3, TIM3, B7H 3 , B7H4, VISTA, KIR, 2B4 (belongs to the CD2 family of molecules and is expressed on all NK, gd, and memory CD8+ (ab) T cells), CD160 (also referred to as BY55) and CGEN-15049.
- CTLA-4 CTLA-4
- 4-1BB CD137
- 4-1BBL CD137L
- PDLl PDL2, PD-l, B7-H 3 , B7-H4, BTLA, HVEM, TIM3, GAL9, LAG3, TIM3, B7H 3 , B7H4, VISTA, KIR, 2B4 (
- Illustrative immune checkpoint inhibitors include durvalumab (anti-PD-L1 antibody; MEDI4736), pembrolizumab (anti-PD-1 monoclonal antibody), nivolumab (anti-PD-l antibody), pidilizumab (CT-011; humanized anti-PD-l monoclonal antibody), AMP224 (recombinant B7-DC-Fc fusion protein), BMS-936559 (anti-PD-Ll antibody), atezolizumab (MPLDL3280A; human Fc-optimized anti-PD-Ll monoclonal antibody), avuelumab (MSB0010718C; human anti-PD-Ll antibody), ipilimumab (anti- CTLA-4 checkpoint inhibitor), tremelimumab (CTLA-4 blocking antibody), and anti-OX40.
- durvalumab anti-PD-L1 antibody
- MEDI4736 pembrolizumab
- nivolumab anti
- CCR2 antagonist and“ CCR2 chemokine receptor antagonist” are used interchangeably and refer to a small molecule that antagonizes the interaction of the chemokine receptor CCR2 and any one of its ligands. Such a compound could inhibit processes normally triggered by the receptor ligand interaction.
- “complete response” or“CR” refers to disappearance of all target lesions
- “partial response” or“PR” refers to at least a 30% decrease in the sum of the longest diameters (SLD) of target lesions, taking as reference the baseline SLD
- “stable disease” or“SD” refers to neither sufficient shrinkage of target lesions to qualify for PR, nor sufficient increase to qualify for PD, taking as reference the smallest SLD since the treatment started.
- progressive disease or“PD” refers to at least a 20% increase in the SLD of target lesions, taking as reference the smallest SLD recorded since the treatment started or the presence of one or more new lesions.
- progression free survival refers to the length of time during and after treatment during which the disease being treated (e.g., cancer) does not get worse. Progression-free survival may include the amount of time patients have experienced a complete response or a partial response, as well as the amount of time patients have experienced stable disease.
- ORR all response rate
- “overall survival” refers to the percentage of individuals in a group who are likely to be alive after a particular duration of time.
- mammal is defined herein to include humans, other primates, cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice and the like.
- the compounds, agents and compositions described herein are useful for treating a wide variety of cancers including solid tumor cancers.
- terapéuticaally effective amount means the amount of the subject compound that will elicit the biological or medical response of a cell, tissue, system, or animal, such as a human, that is being sought by the researcher, veterinarian, medical doctor or other treatment provider.
- the present disclosure is drawn to the surprising and unexpected finding that combination therapy using a CCR2 antagonist and a PD-1 and/or PD-L1 inhibitor significantly improves cancer treatment as compared to PD-1 and/or PD-L1 inhibition on its own.
- Combination Therapy using a CCR2 Antagonist and a PD-1 and/or PD-L1 Inhibitor significantly improves cancer treatment as compared to PD-1 and/or PD-L1 inhibition on its own.
- kits that take advantage of the synergistic effect of CCR2 antagonists and PD-1 and/or PD-L1 inhibitors in treating cancer.
- a combination treatment that includes both a CCR2 antagonist and PD-1 and/or PD-L1 inhibitor is more effective at treating cancer compared to either compound/antibody alone.
- kits for treating cancer in a mammal comprises administering to the subject in need thereof a therapeutically effective amount of a CCR2 chemokine receptor antagonist and a therapeutically effective amount of a PD-1 and/or PD-L1 inhibitor.
- the method comprises administering to the subject in need thereof a therapeutically effective amount of a CCR2 chemokine receptor antagonist and a therapeutically effective amount of a PD-1 inhibitor.
- the method comprises administering to the subject in need thereof a therapeutically effective amount of a CCR2 chemokine receptor antagonist and a therapeutically effective amount of a PD-L1 inhibitor.
- the CCR2 chemokine receptor antagonist is a compound of formula I of a subformulae thereof, below. In some embodiments, the CCR2 chemokine receptor antagonist is selected from the group consisting of
- the PD-1 inhibitor is selected from the group consisting of pembrolizumab, nivolumab, IBI-308, mDX-400, BGB-108, MEDI-0680, SHR-1210, PF- 06801591, PDR-001, GB-226, STI-1110, biosimilars thereof, biobetters thereof, and bioequivalents thereof.
- the PD-1 inhibitor is selected from the group consisting of pembrolizumab, nivolumab, IBI-308, mDX-400, BGB-108, MEDI-0680, SHR-1210, PF- 06801591, PDR-001, GB-226, and STI-1110.
- the PD-1 inhibitor is RPM1-14.
- the PD-L1 inhibitor is selected from the group consisting of durvalumab, atezolizumab, avelumab, BMS-936559, ALN-PDL, TSR-042, KD-033, CA- 170, STI-1014, KY-1003, biosimilars thereof, biobetters thereof, and bioequivalents thereof.
- the PD-L1 inhibitor is selected from the group consisting of durvalumab, atezolizumab, avelumab, BMS-936559, ALN-PDL, TSR-042, KD-033, CA- 170, CA-327, STI-1014, KY-1003, biosimilars thereof, biobetters thereof, and bioequivalents thereof.
- the PD-L1 inhibitor is selected from the group consisting of durvalumab, atezolizumab, avelumab, BMS-936559, ALN-PDL, TSR-042, KD-033, CA- 327, STI-1014, KY-1003, biosimilars thereof, biobetters thereof, and bioequivalents thereof.
- the PD-L1 inhibitor is selected from the group consisting of durvalumab, atezolizumab, avelumab, BMS-936559, ALN-PDL, TSR-042, KD-033, CA- 170, STI-1014, and KY-1003.
- the PD-1 and/or PD-L1 inhibitor is selected from the compounds disclosed in US2015291549, WO16039749, WO15034820, and US2014294898 (BRISTOL MYERS SQUIBB CO) which are thereby incorporated by reference.
- the PD-1 and/or PD-L1 inhibitor is selected from the compounds disclosed in WO14151634, WO15160641, WO16039749, WO16077518, WO16100608, WO16149351, WO 2 016057624, WO 2 016100285, US2016194307,
- the small molecule PD-1 and/or PD-L1 inhibitor is selected from the compounds or pharmaceutical compositions disclosed in WO 2018/005374 filed by ChemoCentryx on June 26, 2017. The contents of which is incorporated herein for all purposes.
- the CCR2 chemokine receptor antagonist and the PD-1 inhibitor or the PD-L1 inhibitor are formulated for concomitant administration.
- the CCR2 chemokine receptor antagonist and the PD-1 inhibitor or the PD-L1 inhibitor are formulated for sequential administration.
- the central nervous system tumor can be a malignant or potentially malignant neoplasm or tissue mass of any size, and includes primary tumors and secondary neoplasms.
- a solid tumor can be an abnormal growth or mass of tissue that does not contain cysts or liquid areas.
- administering the compounds, agents and compositions of the present invention can decrease or reduce tumor burden, tumor load, tumor size, and/or the number of tumors in a subject.
- the compounds, agents and compositions can prevent or minimize tumor metastasis.
- the compounds, agents and compositions can promote or increase necrosis of the tumor.
- administering the compounds, agents and compositions of the present invention can lead to partial response or complete response (progression-free survival), delay progressive disease, and/or improve overall survival.
- the compounds, agents and compositions can increase the durability of overall response to treatment, promote tumor regression, cancer regression, or disease stabilization, and/or provide a clinical benefit.
- the compounds, agents and compositions can decrease the severity of at least one disease symptom, increase the frequency and duration of disease symptom-free periods, or prevent impairment or disability due to the cancer.
- cancer development or cancer recurrence can be decreased.
- Central nervous system cancers include, but are not limited to, neuroblastoma, glioma. astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, meningioma, melanoma, neuroblastoma, and ganglioglioma.
- the central nervous system cancer is glioblastoma.
- the glioma may be characterized as an IDH-mutant type cancer.
- astrocytic tumors include, but are not limited to, pilocytic astrocytoma, subependymal giant cell astrocytoma, pleomorphic xanthoastrocytoma, glioblastoma, and anaplastic pleomorphic xanthoastrocytoma.
- ependymal tumors include, but are not limited to, subependymoma, myxopapillary ependymoma, ependymoma (RELA fusion-positive), and anaplastic ependymoma.
- neuronal and mixed neuronal-glial tumors include, but are not limited to, dysembryoplastic neuroepithelial tumor, gangliocytoma,
- ganglioglioma anaplastic ganglioglioma, dysplastic cerebellar gangliocytoma (Lhermitte- Duclos disease), desmoplastic infantile astrocytoma, papillary glioneuronal tumor, rosette- forming glioneuronal tumor, diffuse leptomeningeal glioneuronal tumor, central
- neurocytoma extraventricular neurocytoma, cerebellar liponeurocytoma, and paraganglioma.
- the central nervous system cancer may be characterized as being CCR2 + .
- the administering of the compound of formula I or a pharmaceutically acceptable salt thereof may promote a decrease in CD45 hi /CD11b + /Ly6C hi cells in a tumor microenvironment and promotes an increase in CD45 hi /CD11b + /Ly6C hi cells in bone marrow.
- the administering to the patient of the immune checkpoint inhibitor and the compound of formula I or a pharmaceutically acceptable salt thereof may promote an infiltration of a population of T-cells into a tumor microenvironment in the subject.
- the population of T-cells may comprise a subpopulation of T-cells characterized as being CD45 + /CD3 + /CD4 + .
- the population of T-cells may comprise a subpopulation of T- cells characterized as being CD45 + /CD3 + /CD8 + .
- the CCR2 antagonist is a small molecule inhibitor of CCR2 having the formula (I):
- Ar is selected from the group consisting of substituted or unsubstituted C 6-10 aryl and
- R 1 is selected from the group consisting of hydrogen, substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 alkynyl, and substituted or unsubstituted 3- to 10-membered heterocyclyl;
- Y 1 is selected from the group consisting of—CR 2a —,—N—, and—N + (O)-—;
- Y 2 is selected from the group consisting of—CR 2b —,—N—, and—N + (O)-—;
- Y 3 is selected from the group consisting of—CR 2c —,—N—, and—N + (O)-—;
- R 2a , R 2b , and R 2c are each independently selected from the group consisting of hydrogen, halogen,—CN,—C(O)R 3 ,—CO 2 R 3 ,—C(O)NR 3 R 4 ,—OR 3 ,—OC(O)R 3 ,
- R 3 , R 4 , and R 5 are each independently selected from the group consisting of hydrogen,
- substituted or unsubstituted C 1-8 alkyl substituted or unsubstituted C 2-8 alkenyl, substituted or unsubstituted C 2-8 alkynyl, substituted or unsubstituted C 6-10 aryl, substituted or unsubstituted 5- to 10-membered heteroaryl, and substituted or unsubstituted 3- to 10-membered heterocyclyl;
- R 3 and R 4 , R 4 and R 5 or R 3 and R 5 may, together with the atoms to which they are attached, form a substituted or unsubstituted 5-, 6-, or 7-membered ring;
- Y 4 is selected from the group consisting of—N— and—N + (O)-—;
- L is selected from the group consisting of a bond,—O—,—S—,—S(O)—,—S(O) 2 —, —CR 6 R 7 —,—NR 8 —,—C(O)—,—C(O)NR 8 —, and—NR 8 C(O)—;
- R 6 and R 7 are each independently selected from the group consisting of hydrogen, halogen, substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted 3- to 10-membered heterocyclyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 alkynyl,—CN,—OR 9 ,—NR 10 R 11 ,—S(O)R 9 , and—S(O) 2 R 9 ;
- R 6 and R 7 may, together with the carbon atom to which they are attached, form substituted or unsubstituted C 3-8 cycloalkyl or substituted or unsubstituted 3- to 10-membered heterocyclic ring;
- R 9 is independently selected from the group consisting of hydrogen, substituted or
- R 10 and R 11 are each independently selected from the group consisting of substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted 3- to 10-membered heterocyclyl, substituted or unsubstituted C 6-10 aryl, substituted or unsubstituted 5- to 10-membered heteroaryl, substituted or unsubstituted C 2-8 alkenyl, and substituted or unsubstituted C 2-8 alkynyl;
- R 10 and R 11 of—NR 10 R 11 may, together with the nitrogen, form substituted or unsubstituted 3- to 10-membered heterocyclyl;
- R 8 is selected from the group consisting of hydrogen, C(O)R 12 , S(O) 2 R 12 , CO 2 R 12 , substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted 3- to 10-membered heterocyclyl, substituted or unsubstituted C 2-6 alkenyl, and substituted or unsubstituted C 2-6 alkynyl;
- R 12 is selected from the group consisting of substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 alkynyl, substituted or unsubstituted 3- to 10-membered heterocyclyl, substituted or unsubstituted C 6-10 aryl, and substituted or unsubstituted 5- to 10-membered heteroaryl;
- Z 1 is selected from the group consisting of substituted or unsubstituted C 6-10 aryl, substituted or unsubstituted 5- to 10-membered heteroaryl, substituted or unsubstituted 3- to 10- membered heterocyclyl, and—NR 13 R 14 ;
- R 13 and R 14 are each independently selected from the group consisting of hydrogen
- substituted or unsubstituted C 1-8 alkyl substituted or unsubstituted C 2-8 alkenyl, substituted or unsubstituted C 2-8 alkynyl, substituted or unsubstituted 3- to 10-membered heterocyclyl, substituted or unsubstituted C 6-10 aryl, substituted or unsubstituted 5- to 10- membered heteroaryl, substituted or unsubstituted (C 1-4 alkyl)-(C 6-10 aryl), and substituted or unsubstituted
- R 13 and R 14 may, together with the nitrogen, form a substituted or unsubstituted 4-, 5-, 6-, or 7-membered heterocyclyl.
- the CCR2 antagonists are represented by the formula (Ia)
- formula (Ia) is a subembodiment of formula (I), wherein
- Y 5 , Y 6 and Y 7 are each independently selected from the group consisting of hydrogen, halogen,—CN,—C(O)R 15 ,—CO 2 R 15 ,—C(O)NR 15 R 16 ,—OR 15 ,—OC(O)R 15 ,— OC(O)NR 15 R 16 ,
- R 15 , R 16 and R 17 are each independently selected from the group consisting of hydrogen, substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted C 2-8 alkenyl, substituted or unsubstituted C 2-8 alkynyl, substituted or unsubstituted 3- to 10-membered heterocyclyl, substituted or unsubstituted C 6-10 aryl, and substituted or unsubstituted 5- to 10-membered heteroaryl; R 15 , R 16 and R 17 are each independently selected from the group consisting of hydrogen, substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted C 2-8 al
- R 15 and R 16 , R 16 and R 17 or R 15 and R 17 may, together with the atoms to which they are
- the CCR2 antagonists are represented by the formula (Ib)
- formula (Ib) is a subembodiment of formula (I), wherein
- R 1 , L and Z 1 are as defined above;
- X 2 , X 3 , X 4 , X 5 , and X 6 are each independently selected from the group consisting of
- R 18 and R 19 , R 19 and R 20 or R 18 and R 20 may, together with the atoms to which they are
- Y 8 , Y 9 and Y 10 are each independently selected from the group consisting of hydrogen,
- R 21 , R 22 and R 23 are each independently selected from the group consisting of hydrogen, substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted C 2-8 alkenyl, substituted or unsubstituted C 2-8 alkynyl, substituted or unsubstituted C 6-10 aryl, substituted or unsubstituted 5- to 10-membered heteroaryl, and substituted or unsubstituted 3- to 10-membered heterocyclyl;
- R 21 and R 22 , R 22 and R 23 or R 21 and R 23 may, together with the atoms to which they are
- the CCR2 antagonists are represented by the formula (Ic)
- formula (Ic) is a subembodiment of formula (I), wherein
- X 4 , X 3 , and Y 9 are as defined above;
- Y 11 is—CH—,—N—, and—N + (O)-—. [0092] In some embodiments, Y 11 of formula Ic is—CH—. In some embodiments, Y 11 of formula Ic is—N—.
- Y 9 of formula Ib or Ic is selected from the group consisting of hydrogen, halogen, and substituted or unsubstituted C 1-8 alkyl.
- Y 9 of Formula Ib or Ic is Cl. In some embodiments Y 9 of formula Ib or Ic is CH 3 .
- X 4 and X 3 of formula Ib or Ic are independently selected from the group consisting of hydrogen, halogen, C 1-8 alkyl, C 1-8 haloalkyl.
- X 4 of formula Ib or Ic is a halo. In some embodiments, X 4 of formula Ib or Ic is C 1-8 alkyl.
- X 4 of formula Ib or Ic is a Cl. In some embodiments, X 4 of formula Ib or Ic is CH 3 .
- X 3 of formula Ib or Ic is C 1-8 haloalkyl. In some embodiments, X 3 of formula Ib or Ic is CF3. [0099] In some embodiments, the CCR2 antagonist has the formula selected from the group consisting of
- the CCR2 antagonist has the formula
- the CCR2 antagonist has the formula
- the CCR2 antagonist has the formula
- PD-1 Inhibitors and PD-L1 Inhibitors [0103]
- the methods, compositions, and kits provided herein include immune checkpoint inhibitors such as PD-1/PD-L1 pathway inhibitors (agents).
- the PD-1 and/or PD-L1 inhibitors of the present invention include small molecules and antibodies.
- a PD-L1 inhibitor can be durvalumab or atezolizumab or avelumab or BMS-936559 (MDX-1105) or ALN-PDL or TSR-042 or KD-033 or CA-170 or CA-327 or STI-1014 or MEDI-0680 or KY-1003.
- a PD-L1 inhibitor can be durvalumab or atezolizumab or avelumab or BMS-936559 (MDX-1105) or ALN-PDL or TSR-042 or KD-033 or CA-170 or STI-1014 or MEDI-0680 or KY-1003.
- Durvalumab (MEDI4736) is a human monoclonal antibody directed against PD-L1.
- Atrexolizumab MPDL3280A
- Avelumab (MSB0010718C) is a fully humanized, engineered IgG1 monoclonal antibody against PD-L1.
- BMS-936559 (MDX- 1105) is a fully human IgG4 monoclonal antibody against PD-L1.
- ALN-PDL is an inhibitory RNA (RNAi) targeting PD-L1.
- TSR-042 refers to an engineered chimeric antibody that is directed against the PD-1/PD-L1 pathway.
- KD-033 refers to a bifunctional anti-PD-L1/IL-15 fusion protein wherein the anti-PD-L1 antibody is linked at its tail to the cytokine IL-15 by the sushi domain of the IL-15 receptor.
- CA-170 refers to a small molecule antagonist of PD- L1 and VISTA.
- STI-1014 refers to an anti-PD-L1 antibody.
- KY-1003 is a monoclonal antibody against PD-L1.
- CA-327 refers to a small molecule antagonist of PD-L1 and TIM3.
- the PD-1 and/or PD-L1 inhibitor is selected from the group consisting of durvalumab, atezolizumab, pembrolizumab, nivolumab, AP-106, AP-105, MSB-2311, CBT-501, avelumab, AK-105, IO-102, IO-103, PDR-001, CX-072, SHR-1316, JTX-4014, GNS-1480, recombinant humanized anti-PD1 mAb (Shanghai Junshi
- THERAVECTYS BGB-A317, recombinant humanized anti-PD-1 mAb (Bio-Thera Solutions), Probody targeting PD-1 (CytomX), XmAb-20717, FS-118, PSI-001, SN-PDL01, SN-PD07, PD-1 modified TILs (Sangamo Therapeutics), PRS-332, FPT-155, jienuo mAb (Genor Biopharma), TSR-042, REGN-1979, REGN-2810, resminostat, FAZ-053, PD- 1/CTLA-4 bispecific antibody (MacroGenics), MGA-012, MGD-013, M-7824, PD-1 based bispecific antibody (Beijing Hanmi Pharmaceutical), AK-112, AK-106, AK-104, AK-103, BI-754091, ENUM-244C8, MCLA-145, MCLA-134, anti-PD1 oncolytic monoclonal antibody (Transgen
- a PD-1 inhibitor can be pembrolizumab or nivolumab or IBI- 308 or mDX-400 or BGB-108 or MEDI-0680 or SHR-1210 or PF-06801591 or PDR-001 or GB-226 or STI-1110.
- Nivolumab also known as OPDIVO TM , MDX-1106, BMS-936558, and ONO-4538
- OPDIVO TM is a human IgG4 monoclonal antibody against PD-1.
- Pembrolizumab (also known as KEYTRUDA ® , lambrolizumab, and MK-34) is a humanized IgG4 kappa isotype monoclonal antibody against PD-1.
- IBI-308 refers to a monoclonal antibody directed to PD- 1.
- mDX-400 refers to a mouse antibody against PD-1.
- BGB-108 is a humanized monoclonal antibody against PD-1.
- MEDI-0680 (AMP-514) is a humanized IgG4 monoclonal antibody against PD-1.
- SHR-1210 refers to a monoclonal antibody against PD-1.
- PF-06801591 is a monoclonal antibody against PD-1.
- PDR-001 refers to a monoclonal antibody against PD-1.
- GB-226 refers to a monoclonal antibody against PD-1.
- STI-1110 refers to a monoclonal antibody
- the PD-1 inhibitor is RPM1-14.
- the PD-1 inhibitor is an antibody selected from Nivolumab, Pembrolizumab, and Pidilizumab.
- anti-PD-1 antibodies, and antibody fragments described herein encompass proteins having amino acid sequences that vary from those of the described antibodies, but that retain the ability to bind PD-1.
- the anti-PD-1 antibodies include bispecific antibodies and antibody-like therapeutic proteins including DARTs ® , DUOBODIES ® , BITES ® , XmAbs ® , TandAbs ® , Fab derivatives, and the like that bind to PD-1.
- the anti-PD-L1 antibodies and antibody fragments described herein encompass proteins having amino acid sequences that vary from those of the described antibodies, but that retain the ability to bind PD-L1.
- Such variant antibodies and fragments thereof can comprise one or more additions, deletions, or substitutions of amino acids when compared to the parent sequence, but exhibit biological activity that is essentially equivalent or essentially bioequivalent to that of the described antibodies.
- the anti-PD-L1 antibodies include bispecific antibodies and antibody-like therapeutic proteins including DARTs ® , DUOBODIES ® , BITES ® , XmAbs ® , TandAbs ® , Fab derivatives, and the like that bind to PD-L1.
- Non-limiting examples of additional PD-1/PD-L1 pathway inhibitors are described in, e.g., Chen and Han, Jour Clin Invest, 2015, 125(9):3384-3391, U.S. Patent Nos.
- a biological product e.g., an antibody or a fragment thereof, is considered a biosimilar if, for example, the biological product is highly similar to an already FDA- approved biological product, known as the reference product.
- a biosimilar has no clinically meaningful differences in terms of safety and effectiveness from the reference product.
- a biosimilar can also have the same mechanism of action, route of administration, dosage form, and strength as its reference product.
- Two biological products e.g., antibodies or fragments thereof, are considered bioequivalent if, for example, they are pharmaceutical equivalents or pharmaceutical alternatives whose rate and extent of absorption do not show a significant difference when administered at the same molar dose under similar experimental conditions, either single dose or multiple doses.
- Some antibodies will be considered equivalents or pharmaceutical alternatives if they are equivalent in the extent of their absorption but not in their rate of absorption and yet may be considered bioequivalent because such differences in the rate of absorption are intentional and are reflected in the labeling, are not essential to the attainment of effective body drug concentrations on, e.g., chronic use, and are considered medically insignificant for the particular drug product studied.
- two biological products e.g., two antibodies or fragments thereof
- two biological products are bioequivalent if there are no clinically meaningful differences in their safety, purity, or potency.
- two biological products are bioequivalent if a patient can be switched one or more times between the reference product and the biological product without an expected increase in the risk of adverse effects, including a clinically significant change in immunogenicity, or diminished effectiveness, as compared to continued therapy without such switching.
- two biological products e.g., two antibodies or fragments thereof
- two biological products are bioequivalent if they both act by a common mechanism of action for the condition of use, to the extent that such mechanisms are known.
- Bioequivalence may be demonstrated by in vivo and/or in vitro methods.
- Bioequivalence measures include, e.g., (a) an in vivo test in humans or other mammals, in which the concentration of the antibody or its metabolites is measured in blood, plasma, serum, or other biological fluid as a function of time; (b) an in vitro test that has been correlated with and is reasonably predictive of human in vivo bioavailability data; (c) an in vivo test in humans or other mammals in which the appropriate acute pharmacological effect of the antibody (or its target) is measured as a function of time; and (d) in a well-controlled clinical trial that establishes safety, efficacy, or bioavailability or bioequivalence of an antibody.
- Biobetter variants of the antibodies described herein may be based on an existing reference antibody specific for an target antigen, e.g., PD-1 or PD-L1, which has undergone changes such that, for example, it has a higher binding affinity to its target antigen and/or binds to a different epitope than the reference antibody, or has more desirable therapeutic efficacy, expression and/or biophysical characteristics.
- an target antigen e.g., PD-1 or PD-L1
- Biobetter variants of the antibodies described herein may be based on an existing reference antibody specific for an target antigen, e.g., PD-1 or PD-L1, which has undergone changes such that, for example, it has a higher binding affinity to its target antigen and/or binds to a different epitope than the reference antibody, or has more desirable therapeutic efficacy, expression and/or biophysical characteristics.
- the PD-1 and/or PD-L1 inhibitor is a small molecule PD-1 and/or PD-L1 inhibitor, or a pharmaceutically acceptable salt thereof, of the formula:
- the PD-1 and/or PD-L1 inhibitor is a small molecule PD- 1/PD-L1 inhibitor having the formula (II)
- R 1 is selected from the group consisting of halogen, C5-8 cycloalkyl, C 6-10 aryl and thienyl, wherein the C 6-10 aryl and thienyl are optionally substituted with 1 to 5 R x substituents;
- each R x is independently selected from the group consisting of halogen, -CN, -R c , -CO 2 R a , -CONR a R b , -C(O)R a , -OC(O)NR a R b , -NR b C(O)R a , -NR b C(O) 2 R c , -NR a -C(O)NR a R b , -NR a R b , -OR a , -O-X 1 -OR a , -O- X 1 -CO 2 R a , -O-X 1 -CONR a R b , -X 1 -OR a , -X 1 -NR a R b , -X 1 -CO 2 R a , -X 1 -CONR a R b , -X 1 -OR a , -X 1 -
- each R 2a , R 2b and R 2c is independently selected from the group consisting of H, halogen, -CN, -R d , -CO 2 R e , -CONR e R f , -C(O)R e , -OC(O)NR e R f , -NR f C(O)R e , -NR f C(O) 2 R d , -NR e -C(O)NR e R f , -NR e R f , -OR e , -O-X 2 -OR e , -O-X 2 -NR e R f , -O- X 2 -CO 2 R e ,
- each R d is independently selected from hydrogen, C 1-8 alkyl, and C 1-8 haloalkyl, or when attached to the same nitrogen atom can be combined with the nitrogen atom to form a five or six-membered ring having from 0 to 2 additional heteroatoms as ring members selected from N, O and S, and optionally substituted with oxo; each R d is independently selected from hydrogen, C 1-8 alkyl, and C 1-8 haloalkyl, or when attached to the same nitrogen atom can be combined with the nitrogen atom to form a five or six-membered ring having from 0 to 2 additional heteroatoms as ring members selected from N, O and S, and optionally substituted with oxo; each R d is
- R 3 is selected from the group consisting of -NR g R h and C 4-12 heterocyclyl, wherein the C 4-12 heterocyclyl is optionally substituted with 1 to 6 R y ;
- each R y is independently selected from the group consisting of
- each R j and R k is independently selected from hydrogen, C 1-8 alkyl optionally substituted with 1 to 2 substituents selected from OH, SO 2 NH 2 , CONH 2 , CONOH, PO 3 H 2 , COO-C 1-8 alkyl or CO 2 H, and C 1-8 haloalkyl optionally substituted with 1 to 2 substituents selected from OH, SO 2 NH 2 , CONH 2 , CONOH, PO 3 H 2 , COO-C 1-8 alkyl or CO 2 H, or when attached to the same nitrogen atom R j and R k can be combined with the nitrogen atom to form a five or six-membered ring having from 0 to 2 additional heteroatoms as ring members selected from N, O or S, and optionally substituted with oxo; each R i is independently selected from the group consisting of–OH, C 1-8 alkyl,
- R g is selected from the group consisting of H, C 1-8 haloalkyl and C 1-8 alkyl;
- R h is selected from -C 1-8 alkyl, C 1-8 haloalkyl, C 1-8 alkyl-COOH, C 1-8 alkyl-OH, C 1-8 alkyl- CONH 2 , C 1-8 alkyl-SO 2 NH 2 , C 1-8 alkyl-PO 3 H 2 , C 1-8 alkyl-CONOH, C 1-8 alkyl- NR h1 R h2 ,
- R h combined with the N to which it is attached is a mono-, di- or tri-peptide comprising 1-3 natural amino acids and 0-2 non-natural amino acids, wherein
- the non-natural aminoacids have an alpha carbon substituent selected from the group consisting of C 2-4 hydroxyalkyl, C 1-3 alkyl-guanidinyl, and C 1 -4 alkyl- heteroaryl,
- alpha carbon of each natural or non-natural amino acids are optionally further substituted with a methyl group
- the terminal moiety of the mono-, di-, or tri-peptide is selected from the group consisting of C(O)OH, C(O)O-C 1-6 alkyl, and PO 3 H 2 , wherein
- R h1 and R h2 are each independently selected from the group consisting of H, C 1-6 alkyl, and C 1-4 hydroxyalkyl;
- the C 1-8 alkyl portions of R h are optionally further substituted with from 1 to 3 substituents independently selected from OH, COOH, SO 2 NH 2 , CONH 2 , CONOH, COO-C 1-8 alkyl, PO 3 H 2 and C5-6 heteroaryl optionally substituted with 1 to 2 C 1-3 alkyl substituents,
- R h the C10 carbocyclyl, C5-10 heteroaryl and the C 6-10 aryl portions of R h are optionally substituted with 1 to 3 substituents independently selected from OH, B(OH) 2 , COOH, SO 2 NH 2 , CONH 2 , CONOH, PO 3 H 2 , COO-C 1-8 alkyl, C 1 -4 alkyl, C 1 -4 alkyl-OH,
- each R w substituent is independently selected from C 1 -4 alkyl, C 1 -4 alkyl-OH, C 1 -4 alkyl- COOH, C 1-4 alkyl-SO 2 NH 2 , C 1-4 alkyl CONH 2 , C 1-4 alkyl- CONOH, C 1-4 alkyl-PO 3 H, OH,
- COO-C 1-8 alkyl COOH, SO 2 NH 2 , CONH 2 , CONOH, PO 3 H 2 and oxo;
- R 4 is selected from the group consisting of O-C 1-8 alkyl, O-C 1-8 haloalkyl, O-C 1-8 alkyl-R z , C 6-10 aryl, C 5-10 heteroaryl , -O-C 1-4 alkyl-C 6-10 aryl and -O-C 1-4 alkyl-C 5-10 heteroaryl, wherein the C 6-10 aryl and the C5-10 heteroaryl are optionally substituted with 1 to 5 R z ; each R z is independently selected from the group consisting of halogen, -CN, -R m , -CO 2 R n , -CONR n R p , -C(O)R n , -OC(O)NR n R p , -NR n C(O)R p , -NR n C(O) 2 R m , -NR n - C(O)NR n R p ,
- each X 3 is a C 1 -4 alkylene; each R n and R p is independently selected from hydrogen, C 1-8 alkyl, and C 1-8 haloalkyl, or when attached to the same nitrogen atom can be combined with the nitrogen atom to form a five or six-membered ring having from 0 to 2 additional heteroatoms as ring members selected from N, O or S, and optionally substituted with oxo; each R m is independently selected from the group consisting of C 1-8 alkyl, C 2-8 alkenyl, and C 1-8 haloalkyl; and optionally when two R z substituents are on adjacent atoms, they are combined to form a fused five or six-membered carbocyclic or heterocyclic ring optionally substituted with oxo;
- R 6a is selected from the group consisting of H, C 1-4 alkyl and C 1-4 haloalkyl;
- each R 6b is independently selected from the group consisting of F, C 1-4 alkyl, O-R u , C 1-4 haloalkyl, NR u R v , wherein each R u and R v is independently selected from hydrogen, C 1-8 alkyl, and C 1-8 haloalkyl, or when attached to the same nitrogen atom can be combined with the nitrogen atom to form a five or six-membered ring having from 0 to 2 additional heteroatoms as ring members selected from N, O or S, and optionally substituted with oxo; and
- the small molecule PD-1/PD-L1 inhibitor is selected from the compounds or pharmaceutical compositions disclosed in WO 2018/005374 filed by ChemoCentryx on June 26, 2017. The contents of which is incorporated herein for all purposes.
- the PD-1 and/or PD-L1 inhibitors of the present disclosure can be formulated to retard the degradation of the compound or antibody or to minimize the immunogenicity of the antibody. A variety of techniques are known in the art to achieve these purposes.
- compositions provided herein such as those including compounds for modulating CCR2 activity and agents for blocking the PD-1/PD-L1 pathway can contain a pharmaceutical carrier or diluent.
- composition as used herein is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
- pharmaceutically acceptable it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
- Biological products such as antibodies of the present invention may be constituted in a pharmaceutical composition containing one or antibodies or a fragment thereof and a pharmaceutically acceptable carrier.
- a“pharmaceutically acceptable carrier” includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like that are physiologically compatible.
- the carrier is suitable for intravenous, intramuscular, subcutaneous, parenteral, spinal or epidermal administration (e.g., by injection or infusion).
- a pharmaceutical composition of the invention may include one or more pharmaceutically acceptable salts, anti-oxidant, aqueous and nonaqueous carriers, and/or adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents.
- compositions for the administration of the compounds and agents of this invention may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy and drug delivery. All methods include the step of bringing the active ingredient into association with the carrier which constitutes one or more accessory ingredients.
- the pharmaceutical compositions are prepared by uniformly and intimately bringing the active ingredient into association with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired formulation.
- the active object compound is included in an amount sufficient to produce the desired effect upon the process or condition of diseases.
- compositions containing the active ingredient may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions and self-emulsifications as described in U.S. Pat. No.6,451,339, hard or soft capsules, syrups, elixirs, solutions, buccal patch, oral gel, chewing gum, chewable tablets, effervescent powder and effervescent tablets.
- compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents, antioxidants and preserving agents in order to provide pharmaceutically elegant and palatable preparations.
- Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets.
- excipients may be for example, inert diluents, such as cellulose, silicon dioxide, aluminum oxide, calcium carbonate, sodium carbonate, glucose, mannitol, sorbitol, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example, PVP, cellulose, PEG, starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc.
- the tablets may be uncoated or they may be coated, enterically or otherwise, by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
- a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. They may also be coated by the techniques described in the U.S. Pat. Nos.4,256,108; 4,166,452; and 4,265,874 to form osmotic therapeutic tablets for control release.
- Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
- emulsions can be prepared with a non-water miscible ingredient such as oils and stabilized with surfactants such as mono-diglycerides, PEG esters and the like.
- Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions.
- excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxy- propylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxy- ethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbito
- the aqueous suspensions may also contain one or more preservatives, for example ethyl, or n- propyl, p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.
- preservatives for example ethyl, or n- propyl, p-hydroxybenzoate
- coloring agents for example ethyl, or n- propyl, p-hydroxybenzoate
- coloring agents for example ethyl, or n- propyl, p-hydroxybenzoate
- flavoring agents such as sucrose or saccharin.
- sweetening agents such as sucrose or saccharin.
- Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin.
- the oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
- Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives.
- a dispersing or wetting agent e.g., sodium EDTA
- suspending agent e.g., sodium EDTA
- preservatives e.g., sodium EDTA, sodium bicarbonate, sodium bicarbonate
- the pharmaceutical compositions of the invention may also be in the form of oil-in- water emulsions.
- the oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these.
- Suitable emulsifying agents may be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally- occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate.
- the emulsions may also contain sweetening and flavoring agents.
- Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents. Oral solutions can be prepared in
- the pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension.
- This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above.
- the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3-butane diol.
- the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
- sterile, fixed oils are conventionally employed as a solvent or suspending medium.
- any bland fixed oil may be employed including synthetic mono- or diglycerides.
- fatty acids such as oleic acid find use in the preparation of injectables.
- the compounds and agents of the present invention may also be administered in the form of suppositories for rectal administration of the drug.
- These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
- a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
- Such materials include cocoa butter and polyethylene glycols.
- the compounds can be administered via ocular delivery by means of solutions or ointments.
- transdermal delivery of the subject compounds can be accomplished by means of iontophoretic patches and the like.
- creams, ointments, jellies, solutions or suspensions, etc., containing the compounds of the present invention are employed.
- topical application is also meant to include the use of mouth washes and gargles.
- the compounds of this invention may also be coupled a carrier that is a suitable polymers as targetable drug carriers.
- suitable polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxy-propyl-methacrylamide-phenol, polyhydroxyethyl-aspartamide- phenol, or polyethyleneoxide-polylysine substituted with palmitoyl residues.
- the compounds of the invention may be coupled to a carrier that is a class of biodegradable polymers useful in achieving controlled release of a drug, for example polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans,
- a carrier that is a class of biodegradable polymers useful in achieving controlled release of a drug, for example polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans,
- Polymers and semipermeable polymer matrices may be formed into shaped articles, such as valves, stents, tubing, prostheses and the like.
- the compound of the invention is coupled to a polymer or semipermeable polymer matrix that is formed as a stent or stent-graft device.
- the compounds and agents of the invention may be formulated for depositing into a medical device, which may include any of variety of conventional grafts, stents, including stent grafts, catheters, balloons, baskets or other device that can be deployed or permanently implanted within a body lumen.
- a medical device which may include any of variety of conventional grafts, stents, including stent grafts, catheters, balloons, baskets or other device that can be deployed or permanently implanted within a body lumen.
- a medical device which may include any of variety of conventional grafts, stents, including stent grafts, catheters, balloons, baskets or other device that can be deployed or permanently implanted within a body lumen.
- the compound and agent can be delivers to the tumor or the microenvironment surrounding the tumor.
- the term“deposited” means that the compound and agent are coated, adsorbed, placed, or otherwise incorporated into the device by methods known in the art.
- the compound and agent may be embedded and released from within (“matrix type”) or surrounded by and released through (“reservoir type”) polymer materials that coat or span the medical device.
- the compound and agent may be entrapped within the polymer materials or coupled to the polymer materials using one or more the techniques for generating such materials known in the art.
- the compound and agent may be linked to the surface of the medical device without the need for a coating by means of detachable bonds and release with time, can be removed by active mechanical or chemical processes, or are in a permanently immobilized form that presents the inhibitory agent at the implantation site.
- the compound and agent may be incorporated with polymer compositions during the formation of biocompatible coatings for medical devices, such as stents.
- the coatings produced from these components are typically homogeneous and are useful for coating a number of devices designed for implantation.
- the polymer may be either a biostable or a bioabsorbable polymer depending on the desired rate of release or the desired degree of polymer stability, but a bioabsorbable polymer is preferred for this embodiment since, unlike a biostable polymer, it will not be present long after implantation to cause any adverse, chronic local response.
- Bioabsorbable polymers that could be used include, but are not limited to, poly(L-lactic acid), polycaprolactone, polyglycolide (PGA), poly(lactide-co-glycolide) (PLLA/PGA), poly(hydroxybutyrate), poly(hydroxybutyrate-co-valerate), polydioxanone, polyorthoester, polyanhydride, poly(glycolic acid), poly(D-lactic acid), poly(L-lactic acid), poly(D,L-lactic acid), poly(D,L- lactide) (PLA), poly(L-lactide) (PLLA), poly(glycolic acid-co-trimethylene carbonate) (PGA/PTMC), polyethylene oxide (PEO), polydioxanone (PDS), polyphosphoester, polyphosphoester urethane, poly(amino acids), cyanoacrylates, poly(trimethylene carbonate), poly(iminocarbonate), copoly(ether-esters) (e.g.,
- biostable polymers with a relatively low chronic tissue response such as polyurethanes, silicones, and polyesters could be used and other polymers could also be used if they can be dissolved and cured or polymerized on the medical device such as polyolefins,
- polyisobutylene and ethylene-alphaolefin copolymers acrylic polymers and copolymers, vinyl halide polymers and copolymers, such as polyvinyl chloride; polyvinylpyrrolidone; polyvinyl ethers, such as polyvinyl methyl ether; polyvinylidene halides, such as
- polyvinylidene fluoride and polyvinylidene chloride polyacrylonitrile, polyvinyl ketones; polyvinyl aromatics, such as polystyrene, polyvinyl esters, such as polyvinyl acetate;
- copolymers of vinyl monomers with each other and olefins such as ethylene-methyl methacrylate copolymers, acrylonitrile-styrene copolymers, ABS resins, and ethylene-vinyl acetate copolymers; pyran copolymer; polyhydroxy-propyl-methacrylamide-phenol; polyhydroxyethyl-aspartamide-phenol; polyethyleneoxide-polylysine substituted with palmitoyl residues; polyamides, such as Nylon 66 and polycaprolactam; alkyd resins, polycarbonates; polyoxymethylenes; polyimides; polyethers; epoxy resins, polyurethanes; rayon; rayon-triacetate; cellulose, cellulose acetate, cellulose butyrate; cellulose acetate butyrate; cellophane; cellulose nitrate; cellulose propionate; cellulose ethers; and
- the compound and agent are formulated for release from the polymer coating into the environment in which the medical device is placed.
- the compound and agent are released in a controlled manner over an extended time frame (e.g., weeks or months) using at least one of several well-known techniques involving polymer carriers or layers to control elution. Some of these techniques were previously described in U.S. Patent App. Publ. No.20040243225.
- the present disclosure provides a combination therapy for the treatment of cancer.
- the combination therapy includes a therapeutically effective amount of a CCR2 antagonist and a therapeutically effective amount of a PD-1 and/or PD-L1 inhibitor.
- the combination of therapeutic agents can act synergistically to effect the treatment or prevention of cancer.
- the compounds, antibodies, and formulations of the present disclosure may be administered by oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous, ICV, intracisternal injection or infusion, subcutaneous injection, or implant), inhalation, nasal, vaginal, rectal, sublingual, or topical routes of administration.
- parenteral e.g., intramuscular, intraperitoneal, intravenous, ICV, intracisternal injection or infusion, subcutaneous injection, or implant
- inhalation nasal, vaginal, rectal, sublingual, or topical routes of administration.
- the compounds and antibodies may be formulated, alone or together, in suitable dosage unit formulations containing conventional nontoxic pharmaceutically acceptable carriers, adjuvants and vehicles appropriate for each rouse of administration.
- the present disclosure also contemplates administration of the compounds and antibodies of the present disclosure in a depot formulation.
- an appropriate dosage level of a CCR2 antagonist will generally be about 0.001 to 100 mg per kg patient body weight per day which can be administered in single or multiple doses.
- the dosage level will be about 0.01 to about 25 mg/kg per day; more preferably about 0.05 to about 10 mg/kg per day.
- a suitable dosage level may be about 0.01 to 25 mg/kg per day, about 0.05 to 10 mg/kg per day, or about 0.1 to 5 mg/kg per day.
- the dosage may be 0.005 to 0.05, 0.05 to 0.5 or 0.5 to 5.0 mg/kg per day.
- the compositions are preferably provided in the form of tablets containing 1.0 to 1000 milligrams of the active ingredient, particularly 1.0, 5.0, 10.0, 15.0, 20.0, 25.0, 50.0, 75.0, 100.0, 150.0, 200.0, 250.0, 300.0, 400.0, 500.0, 600.0, 750.0, 800.0, 900.0, and 1000.0 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated.
- the compounds may be administered on a regimen of 1 to 4 times per day, preferably once or twice per day.
- An appropriate dosage level of a PD-1 inhibitor and/or a PD-L1 inhibitor will generally be about 0.0001 to about 100 mg/kg, usually from about 0.001 to about 20 mg/kg, and more usually from about 0.01 to about 10 mg/kg, of the subject's body weight.
- the dosage is within the range of 0.1-10 mg/kg body weight.
- dosages can be 0.1, 0.3, 1, 3, 5 or 10 mg/kg body weight, and more preferably, 0.3, 1, 3, or 10 mg/kg body weight.
- the dosing schedule can typically be designed to achieve exposures that result in sustained receptor occupancy (RO) based on typical pharmacokinetic properties of an antibody.
- RO sustained receptor occupancy
- An exemplary treatment regime of anitibodies entails administration once per week, once every two weeks, once every three weeks, once every four weeks, once a month, once every 3 months or once every three to 6 months.
- a dosing schedule may comprise administering an antibody: (i) every two weeks in 6-week cycles; (ii) every four weeks for six dosages, then every three months; (iii) every three weeks; (iv) 3-10 mg/kg body weight once followed by 1 mg/kg body weight every 2-3 weeks.
- a preferred dosage regimen for an anti-PD-1 or anti-PD-L1 antibody comprises 0.3-10 mg/kg body weight, preferably 3-10 mg/kg body weight, more preferably 3 mg/kg body weight via intravenous administration, with the antibody being given every 14 days in up to 6-week or 12-week cycles until complete response or confirmed progressive disease.
- An exemplary treatment regime of small molecules entails administration daily, twice per week, three times per week, or once per week.
- the dosage and scheduling may change during a course of treatment.
- two or more antibodies with different binding specificities are administered simultaneously, in which case the dosage of each antibody administered falls within the ranges indicated.
- the antibody can be administered on multiple occasions. Intervals between single dosages can be, for example, weekly, every 2 weeks, every 3 weeks, monthly, every three months or yearly. Intervals can also be irregular as indicated by measuring blood levels of antibody to the target antigen in the patient.
- dosage is adjusted to achieve a plasma antibody concentration of about 1-1000 mg/ml and in some methods about 25-300 mg/ml.
- the therapeutic compound and agent in the combination therapy disclosed herein may be administered either alone or in a pharmaceutical composition which comprises the therapeutic compound and agent and one or more pharmaceutically acceptable carriers, excipients and diluents.
- the therapeutic compound and agent are each provided in an amount that would be sub-therapeutic if provided alone or without the other.
- “combinations” can involve combinations in treatments (i.e., two or more drugs can be administered as a mixture, or at least concurrently or at least introduced into a subject at different times but such that both are in a subject at the same time).
- compounds, agents and compositions of the present invention may be used in combination with other drugs that are used in the treatment, prevention, suppression or amelioration of cancer.
- Such other drugs may be administered, by a route and in an amount commonly used therefor, contemporaneously or sequentially with a compound, agent or composition of the present invention.
- a pharmaceutical composition containing such other drugs in addition to the compound, agent or composition of the present invention is preferred.
- pharmaceutical compositions can include those that also contain one or more other active ingredients or therapeutic agents, in addition to a compound, agent or composition of the present invention.
- Combination therapy includes co-administration of the CCR2 antagonist and the PD-1 and/or PD-L1 inhibitor, sequential administration of the CCR2 antagonist and the PD-1 and/or PD-L1 inhibitor, administration of a composition containing the CCR2 antagonist and the PD-1 and/or PD-L1 inhibitor, or simultaneous administration of separate compositions such that one composition contains the CCR2 antagonist and another composition contains the PD-1 and/or PD-L1 inhibitor.
- Co-administration includes administering the CCR2 antagonist of the present invention within 0.5, 1, 2, 4, 6, 8, 10, 12, 16, 20, or 24 hours of the PD-1 and/or PD-L1 inhibitor of the present invention. Co-administration also includes administering
- the CCR2 antagonist and PD- 1 and/or PD-L1inhibitor can each be administered once a day, or two, three, or more times per day so as to provide the preferred dosage level per day.
- kits containing a CCR2 chemokine receptor antagonist and a PD-1 and/or PD-L1 inhibitor disclosed herein that are useful for treating a cancer.
- a kit can contain a pharmaceutical composition containing a CCR2 chemokine receptor antagonist compound, e.g., a small molecule inhibitor of CCR2 and a pharmaceutical composition containing an PD-1 and/or PD-L1, e.g., an antibody inhibitor.
- the kit includes written materials e.g., instructions for use of the compound, antibody or pharmaceutical compositions thereof.
- the kit may include buffers, diluents, filters, needles, syringes, and package inserts with instructions for performing any methods disclosed herein.
- Suitable CCR2 chemokine receptor antagonist and PD-1 and/or PD-L1 inhibitors include the compounds described herein. Examples Example 1:
- KR158 glioma cells were maintained in Dulbecco’s modified Eagle’s medium (DMEM) supplemented with 10% heat-inactivated fetal bovine serum (FBS) and 1% penicillin–streptomycin.005 GSC glioma cells were cultured as neurospheres in serum free Advanced DMEM/F12 medium supplemented with 2 mM L-glutamine, 1% N2 supplement, 2 mg/mL heparin, 0.5% penicillin-streptomycin, 20 ng/mL recombinant human EGF, and 20 ng/mL recombinant human FGF-basic.
- DMEM Dulbecco’s modified Eagle’s medium
- FBS heat-inactivated fetal bovine serum
- penicillin–streptomycin.005 GSC glioma cells were cultured as neurospheres in serum free Advanced DMEM/F12 medium supplemented with 2 mM L-glutamine, 1% N2 supplement, 2 mg
- GL261 glioma cells were cultured in Roswell Park Memorial Institute (RPMI)-1640 supplemented with 10% FBS, 4 mM L-glutamine, and 1% penicillin–streptomycin. All cells were grown in a humidified incubator at 37°C with 5% CO 2 .
- DMEM, Advanced DMEM/F12, N2 supplement, EGF, bFGF, L-glutamine and antibiotics were obtained from Gibco-BRL (Invitrogen, Carlsbad, CA). Heparin was purchased from Sigma–Aldrich (St Louis, MO).
- FBS was from HyClone (Thermo Scientific, Waltham, MA).
- Wild type (WT) C57BL/6, Ccr2 deficient (Ccr2 RFP/RFP [B6.129(Cg)-Ccr2 tm2.1Ifc /J]), and Cx3cr1 deficient (Cx3cr1 GFP/GFP [B6.129P-Cx3cr1 tm1Litt /J]) mice were obtained from Jackson Laboratory (Bar Harbor, ME).
- Ccr2 RFP/WT /Cx3cr1 GFP/WT mice (double knock-in) were generated via in house breeding.
- Compound 3 was delivered for 21 days, beginning on day 7 after tumor cell injection, by oral gavage at a dose of 90 mg/kg, twice daily. Animals also received either anti-PD-1 (catalog# BE0146, clone RMP1-14, BioXcell) or non-immune IgG (catalog# BE0089, clone 2A, BioXcell) treatment injected intraperationally alone or in combination with Compound 3, every third day beginning 7 days after implantation for a total of 5 doses (loading dose of 500 ug/100uL, followed by 4 doses of 200ug/100uL). A control group of mice was treated in parallel to drug administration with vehicle and/or non-immune IgG. The number of mice used in each treated group is indicated within the figure legends.
- Bone Marrow imaging [0169] Mice were euthanized, after which femurs were removed and fixed in 4% PFA at 4°C for 3 days with constant agitation. Following fixation, femurs were decalcified using 14% ethylenediaminetetraacetic acid (EDTA)/9% ammonium hydroxide (w/v, pH 7.1) decalcifying solution at 4°C for 3 days with constant agitation, changing solution every 24 hours. Bones were then washed in phosphate buffered saline (PBS) for 2 hours then soaked in 30% sucrose at 4°C overnight with constant agitation. Bones were then embedded in optimal cutting temperature (OCT) medium, sectioned, and analyzed by fluorescent microscopy.
- EDTA ethylenediaminetetraacetic acid
- OCT optimal cutting temperature
- mice were euthanized using CO 2 asphyxiation at experimental endpoint. Following euthanasia, the spleen and femur were removed and placed in PBS. The animal was subsequently perfused with 0.9% saline via cardiac puncture and the brain removed. Bone marrow was extracted by flushing with PBS using a 25G needle. Splenocytes were liberated by fracturing the organ capsule between glass slides and rinsing with fluorescence-activated cell sorter washing buffer (PBS and 1% FBS, FACS), followed by needle puncture with an 18G needle.
- PBS and 1% FBS, FACS fluorescence-activated cell sorter washing buffer
- Splenocytes were then collected by centrifugation (4°C, 380G, 5 minutes), re- suspended in FACS and passed through a 50 mm cell strainer. Splenocytes and bone marrow samples were then centrifuged (4°C, 380G, 5 minutes), re-suspended in ACK lysis buffer (Gibco, Invitrogen, Carlsbad, CA), and incubated for 1.5 minutes at room temperature (Splenocytes) or 10 minutes (bone marrow) at 4°C. At end of incubation, lysis was halted using 9 mL FACS buffer.
- This cell suspension was then gently layered beneath a 37% Percoll layer (4 mL, 37% Percoll and 1% PBS in RPMI 1640 cell medium) using an 18G needle, centrifuged (30 minutes, room temperature, 500G), the interface removed and placed into a 1.5 mL microcentrifuge tube. All cells were then washed with ice cold PBS, counted by trypan blue exclusion, aliquoted to 1x10 6 cells/100 mL, and blocked using 0.5 mg anti-mouse CD16/32 (101320, Biolegend, San Diego CA) for 30 minutes at 4°C. Subsequently, cells were stained for markers of interest for 30 minutes at 4°C.
- CCR2 + cells do not represent the sole myeloid cell type present in gliomas, as CX3CR1 + CNS resident microglia are known to infiltrate as well.
- CCR2 RFP/WT double transgenic mice which carry RFP in place of the CCR2 gene
- CX3CR1 GFP/WT CX3CR1 GFP/WT
- CD45 hi (FIG.1D middle) events represent a more heterogeneous cell population consisting of CCR2 + , CX3CR1 + , and CCR2- /CX3CR1- cells.
- Murine monocytic MDSCs are typically classified as CD11b + /Ly6C hi /Ly6G- .
- CCR2 + and CX3CR1 + populations were scrutinized by expression of CD11b/Ly6C/Ly6G.
- Flow cytometric analysis of Ly6C/Ly6G noted three distinct Ly6C populations: negative, intermediate, and high (FIG.1E). Ly6G expression was minimal in the tumors.
- Ly6C hi events (FIG.1E upper) represented a cell population that is primarily CCR2 + /CX3CR1 +
- Ly6C- (FIG.1E lower) events consist of CCR2 + , CX3CR1 + , and CCR2-/CX3CR1- cells.
- Ly6C inter events were determined to be CCR2/CX3CR1 double positive. Similar analysis within bone marrow isolates revealed four distinct populations: negative, Ly6C inter /Ly6G-, Ly6C hi /Ly6G-, and Ly6C inter /Ly6G + .
- Ly6C hi /Ly6G- events were primarily CCR2 + /CX3CR1 + , while Ly6C-/Ly6G-, Ly6C inter /Ly6G-, Ly6C inter /Ly6G + events were predominantly CCR2-/CX3CR1-.
- Additional flow cytometry analysis of CCR2- and CX3CR1-expressing cells determined that CCR2 + /CX3CR1- cells are MHCII + /F4/80-/CD11c + /CD11b lo , CCR2 + /CX3CR1 + cells are
- CCR2-/CX3CR1 + cells are MHCII + /F4/80 + /CD11c- /CD11b medium .
- invading myeloid cells expressing the two chemokine receptors within the tumor microenvironment are predominantly CCR2 + or CCR2 + /CX3CR1 + double positive, while resident myeloid-like cells are predominantly CX3CR1 + .
- CCR2 deficiency unmasks an anti-PD-1 effect in immune checkpoint inhibitor resistant glioma.
- CCR2 deficiency also augmented PD-1 blockade in GL261 tumor bearing animals, with differential outcomes based on initial treatment time and total dosing of the antibody. Indeed, the variation in responses of GL261 gliomas to anti-PD-1 monotherapy is known.
- CCR2 deficiency has reciprocal effects on presence of MDSCs in tumor and bone marrow
- CCR2 antagonist Compound 3 enhances an anti-PD-1 effect to improve survival.
- Compound 3 impedes invasion of MDSC into tumors and prevents egress from bone marrow.
- CD45 hi /CD11b + /Ly6C hi cells within the tumor microenvironment (FIG.5A).
- Compound 3/anti-PD-1 combination therapy reduces exhaustion in intratumoral T-cells.
- CCR2 Disruption of CCR2 not only leads to reduced MDSCs within tumors, but an associated accumulation of these cells in the bone marrow.
- a role for CCR2 in mobilization of leukocytes from the bone marrow likely involves interactions with another chemokine receptor, CXCR4.
- CXCR4 another chemokine receptor
- the egress of CCR2 + cells from the bone marrow and influx into the tumors may be mediated by any known ligand for CCR2.
- MCP-3 CCL7 has been shown to be integral in migration of CCR2 + monocytes out of the bone marrow (47).
- MDSCs have potential for wide-ranging impacts on T-cell activation and
- a method of treating a central nervous system cancer in a subject comprising:
- Ar is selected from the group consisting of substituted or unsubstituted C 6-10 aryl and
- R 1 is selected from the group consisting of hydrogen, substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 alkynyl, and substituted or unsubstituted 3- to 10-membered heterocyclyl;
- Y 1 is selected from the group consisting of—CR 2a —,—N—, and—N + (O)-—;
- Y 2 is selected from the group consisting of—CR 2b —,—N—, and—N + (O)-—;
- Y 3 is selected from the group consisting of—CR 2c —,—N—, and—N + (O)-—;
- R 2a , R 2b , and R 2c are each independently selected from the group consisting of hydrogen, halogen,—CN,—C(O)R 3 ,—CO 2 R 3 ,—C(O)NR 3 R 4 ,—OR 3 ,—OC(O)R 3 ,
- R 3 , R 4 , and R 5 are each independently selected from the group consisting of hydrogen,
- substituted or unsubstituted C 1-8 alkyl substituted or unsubstituted C 2-8 alkenyl, substituted or unsubstituted C 2-8 alkynyl, substituted or unsubstituted C 6-10 aryl, substituted or unsubstituted 5- to 10-membered heteroaryl, and substituted or unsubstituted 3- to 10-membered heterocyclyl;
- R 3 and R 4 , R 4 and R 5 or R 3 and R 5 may, together with the atoms to which they are attached, form a substituted or unsubstituted 5-, 6-, or 7-membered ring;
- Y 4 is selected from the group consisting of—N— and—N + (O)-—;
- L is selected from the group consisting of a bond,—O—,—S—,—S(O)—,—S(O) 2 —, —CR 6 R 7 —,—NR 8 —,—C(O)—,—C(O)NR 8 —, and—NR 8 C(O)—;
- R 6 and R 7 are each independently selected from the group consisting of hydrogen, halogen, substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted 3- to 10-membered heterocyclyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 alkynyl,—CN,—OR 9 ,—NR 10 R 11 ,—S(O)R 9 , and—S(O) 2 R 9 ;
- R 6 and R 7 may, together with the carbon atom to which they are attached, form substituted or unsubstituted C 3-8 cycloalkyl or substituted or unsubstituted 3- to 10-membered heterocyclic ring;
- R 9 is selected from the group consisting of hydrogen, substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted C 2-8 alkenyl, substituted or unsubstituted C 2-8 alkynyl, substituted or unsubstituted C 6-10 aryl, substituted or unsubstituted 5- to 10-membered heteroaryl, and substituted or unsubstituted 3- to 10-membered heterocyclyl;
- R 10 and R 11 are each independently selected from the group consisting of substituted or
- R 10 and R 11 of—NR 10 R 11 may, together with the nitrogen, form substituted or unsubstituted 3- to 10-membered heterocyclyl;
- R 8 is selected from the group consisting of hydrogen, C(O)R 12 , S(O) 2 R 12 , CO 2 R 12 , substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted 3- to 10-membered heterocyclyl, substituted or unsubstituted C 2-6 alkenyl, and substituted or unsubstituted C 2-6 alkynyl;
- R 12 is selected from the group consisting of substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 alkynyl, substituted or unsubstituted 3- to 10-membered heterocyclyl, substituted or unsubstituted C 6-10 aryl, and substituted or unsubsti
- Z 1 is selected from the group consisting of substituted or unsubstituted C 6-10 aryl, substituted or unsubstituted 5- to 10-membered heteroaryl, substituted or unsubstituted 3- to 10- membered heterocyclyl, and—NR 13 R 14 ;
- R 13 and R 14 are each independently selected from the group consisting of hydrogen
- substituted or unsubstituted C 1-8 alkyl substituted or unsubstituted C 2-8 alkenyl, substituted or unsubstituted C 2-8 alkynyl, substituted or unsubstituted 3- to 10-membered heterocyclyl, substituted or unsubstituted C 6-10 aryl, substituted or unsubstituted 5- to 10- membered heteroaryl, substituted or unsubstituted (C 1 -4 alkyl)-(C 6-10 aryl), and substituted or unsubstituted (C 1 -4 alkyl)-(5- to 10-membered heteroaryl);
- R 13 and R 14 may, together with the nitrogen, form a substituted or unsubstituted 4-, 5-, 6-, or 7-membered heterocyclyl.
- the method of statement 10 wherein the population of T-cells comprises a subpopulation of T-cells characterized as being CD45 + /CD3 + /CD4 + . 12. The method of any one of statements 10-11, wherein the population of T-cells comprises a subpopulation of T-cells characterized as being CD45 + /CD3 + /CD8 + . 13. The method of any one of statements 1-12, wherein the compound of Formula I or a pharmaceutically acceptable salt thereof is provided as a pharmaceutical composition for oral administration. 14. The method of any one of statements 1-13, wherein the effective amount of the compound of Formula I or a pharmaceutically acceptable salt thereof is from 50 mg to 300 mg. 15. A method of treating glioblastoma in a subject, comprising: administering to the subject in need thereof an effective amount of an immune checkpoint inhibitor and a compound selected from the group consisting of:
- the immune checkpoint inhibitor is selected from the group consisting of pembrolizumab, nivolumab, IBI-308, mDX-400, BGB-108, MEDI-0680, SHR-1210, PF-06801591, PDR-001, GB-226, STI-1110, biosimilars thereof, biobetters thereof, and bioequivalents thereof.
- the immune checkpoint inhibitor is an anti-PD-1 antibody is selected from the group consisting of Nivolumab,
- Pembrolizumab, and Pidilizumab 18.
- the immune checkpoint inhibitor is a PD-L1 inhibitor is selected from the group consisting of durvalumab, atezolizumab, avelumab, BMS-936559, ALN-PDL, TSR-042, KD-033, CA-170, CA-327, STI-1014, KY- 1003, biosimilars thereof, biobetters thereof, and bioequivalents thereof.
- the compound of Formula I, or a pharmaceutically acceptable salt thereof, and the immune checkpoint inhibitor are administered concomitantly.
- Ar is selected from the group consisting of substituted or unsubstituted C 6-10 aryl and substituted or unsubstituted 5- to 10-membered heteroaryl.
- R 1 is selected from the group consisting of hydrogen, substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 alkynyl, and substituted or unsubstituted 3- to 10-membered heterocyclyl;
- Y 1 is selected from the group consisting of—CR 2a —,—N—, and—N + (O)-—;
- Y 2 is selected from the group consisting of—CR 2b —,—N—, and—N + (O)-—;
- Y 3 is selected from the group consisting of—CR 2c —,—N—, and—N + (O)-—;
- R 2a , R 2b , and R 2c are each independently selected from the group consisting of hydrogen,
- R 3 , R 4 , and R 5 are each independently selected from the group consisting of hydrogen,
- substituted or unsubstituted C 1-8 alkyl substituted or unsubstituted C 2-8 alkenyl, substituted or unsubstituted C 2-8 alkynyl, substituted or unsubstituted C 6-10 aryl, substituted or unsubstituted 5- to 10-membered heteroaryl, and substituted or unsubstituted 3- to 10-membered heterocyclyl;
- R 3 and R 4 , R 4 and R 5 or R 3 and R 5 may, together with the atoms to which they are attached, form a substituted or unsubstituted 5-, 6-, or 7-membered ring;
- Y 4 is selected from the group consisting of—N— and—N + (O)-—;
- L is selected from the group consisting of a bond,—O—,—S—,—S(O)—,—S(O) 2 —,
- R 6 and R 7 are each independently selected from the group consisting of hydrogen, halogen, substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted 3- to 10-membered heterocyclyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 alkynyl,—CN,—OR 9 ,—NR 10 R 11 ,—S(O)R 9 , and—S(O) 2 R 9 ;
- R 6 and R 7 may, together with the carbon atom to which they are attached, form substituted or unsubstituted C3-8 cycloalkyl or substituted or unsubstituted 3- to 10-membered heterocyclic ring;
- R 9 is selected from the group consisting of hydrogen, substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted C 2-8 alkenyl, substituted or unsubstituted C 2-8 alkynyl, substituted or unsubstituted C 6-10 aryl, substituted or unsubstituted 5- to 10-membered heteroaryl, and substituted or unsubstituted 3- to 10-membered heterocyclyl;
- R 10 and R 11 are each independently selected from the group consisting of substituted or
- R 10 and R 11 of—NR 10 R 11 may, together with the nitrogen, form substituted or unsubstituted 3- to 10-membered heterocyclyl;
- R 8 is selected from the group consisting of hydrogen, C(O)R 12 , S(O) 2 R 12 , CO 2 R 12 , substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted 3- to 10-membered heterocyclyl, substituted or unsubstituted C 2-6 alkenyl, and substituted or unsubstituted C 2-6 alkynyl;
- R 12 is selected from the group consisting of substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 alkynyl, substituted or unsubstituted 3- to 10-membered heterocyclyl, substituted or unsubstituted C 6-10 aryl, and substituted or unsubstituted 5- to 10-membered heteroaryl;
- Z 1 is selected from the group consisting of substituted or unsubstituted C 6-10 aryl, substituted or unsubstituted 5- to 10-membered heteroaryl, substituted or unsubstituted 3- to 10-membered heterocyclyl, and—NR 13 R 14 ;
- R 13 and R 14 are each independently selected from the group consisting of hydrogen, substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted C 2-8 alkenyl, substituted or unsubstituted C 2-8 alkynyl, substituted or unsubstituted 3- to 10-membered heterocyclyl, substituted or unsubstituted C 6-10 aryl, substituted or unsubstituted 5- to 10-membered heteroaryl, substituted or unsubstituted (C 1 -4 alkyl)-(C 6-10 aryl), and substituted or unsubstituted (C 1 -4 alkyl)-(5- to 10-membered heteroaryl);
- R 13 and R 14 may, together with the nitrogen, form a substituted or unsubstituted 4-, 5-, 6-, or 7-membered heterocyclyl.
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US16/358,329 US20190269664A1 (en) | 2018-01-08 | 2019-03-19 | Methods of treating solid tumors with ccr2 antagonists |
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PCT/US2020/023722 WO2020191240A1 (en) | 2019-03-19 | 2020-03-19 | Combination therapy using a chemokine receptor 2 (ccr2) antagonist and a pd-1 and/or pd-l1 inhibitor |
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