Combination therapy including A2A / A2B inhibitor, PD-1 / PD-L1 inhibitor, and anti-CD73 antibody

Abstract

Combination therapies are disclosed that include administration of a CD73 inhibitor, an adenosine A2A or A2B receptor inhibitor, and a PD-1 / PD-L1 inhibitor. The disclosed combination therapies are useful for treating diseases associated with adenosine receptor and / or CD73 and / or PD-1 / PD-L1 activity, including, for example, cancer, inflammatory diseases, cardiovascular diseases, and neurodegenerative diseases. Anti-CD73 antibodies, PD-1 / PD-L1 inhibitors, and A2A / A2B inhibitors are also disclosed.

Description

[Technical Field]

[0001] Disclosed herein are combination therapies that include inhibitors of A2A / A2B, inhibitors of PD-1 / PD-L1, anti-CD73 antibodies, and methods of using them to treat disorders such as cancer. [Background technology]

[0002] Cluster of differentiation 73 (CD73) is a glycosylphosphatidylinositol (GPI)-linked membrane protein that catalyzes the conversion of extracellular adenosine monophosphate (AMP) to adenosine. It functions as a homodimer, can be shed, and is activated as a soluble protein in the circulation. In addition to its enzymatic function, CD73 is also a cell adhesion molecule and regulates leukocyte trafficking. CD73 levels are known to increase upon tissue injury or hypoxia, and many solid tumors have elevated CD73 levels. Increased CD73 activity within tumors contributes to an adenosine-rich tumor microenvironment, which has numerous tumor-promoting and immunosuppressive effects.

[0003] Adenosine is an extracellular signaling molecule that can regulate immune responses via many immune cell types. Adenosine was first recognized as a physiological regulator of coronary vascular tone by Drury and Szent-Gyorgyu (Sachdeva, S. and Gupta, M. Saudi Pharmaceutical Journal, 2013, 21, 245-253), but this role was not recognized until 1970, when Sattin and Rall demonstrated that adenosine regulates cellular function through the occupation of specific receptors on the cell surface (Sattin, A., and Rall, TW, 1970, Mol. Pharmacol. 6, 13-23; Hasko´, G., at al., 2007, Pharmacol. Ther. 113, 264-275).

[0004] Adenosine plays an important role in various other physiological functions. It is involved in the synthesis of nucleic acids, and when linked to three phosphate groups, it forms ATP, an essential component of the cellular energy system. Adenosine can be generated by enzymatic degradation of extracellular ATP or can be released from injured neurons and glial cells by crossing damaged cell membranes (Tautenhahn, M. et al. Neuropharmacology, 2012, 62, 1756-1766). Adenosine exerts various pharmacological effects in both the peripheral and central nervous systems through its action on specific receptors located on the cell membrane (Matsumoto, T. et al. Pharmacol. Res., 2012, 65, 81-90). Alternative pathways for extracellular adenosine production have been described. These pathways include the generation of adenosine from nicotinamide dinucleotide (NAD) instead of ATP through the coordinated action of CD38, CD203a, and CD73. CD73-independent production of adenosine can also occur by other phosphates such as alkaline phosphatase or prostate-specific phosphatase.

[0005] There are four known subtypes of adenosine receptors in humans, including A1, A2A, A2B, and A3 receptors. A1 and A2A are high-affinity receptors, while A2B and A3 are low-affinity receptors. Adenosine and its agonists can act through one or more of these receptors to regulate the activity of adenylate cyclase, an enzyme involved in increasing cyclic AMP (cAMP). Different receptors have different stimulatory and inhibitory effects on this enzyme. Increased intracellular concentrations of cAMP can suppress the activity of immune and inflammatory cells (Livingston, M. et al., Inflamm. Res., 2004, 53, 171-178).

[0006] A2A adenosine receptors can transmit signals in the periphery and the CNS (central nervous system), and agonists are being explored as anti-inflammatory drugs, while antagonists are being explored for neurodegenerative diseases (Carlsson, J. et al., J. Med. Chem., 2010, 53, 3748-3755). In most cell types, the A2A subtype inhibits intracellular calcium levels, while the A2B subtype enhances them. A2A receptors generally appear to inhibit inflammatory responses from immune cells (Borrmann, T. et al., J. Med. Chem., 2009, 52(13), 3994-4006).

[0007] A2B receptors are highly expressed in the gastrointestinal tract, bladder, lungs, and on mast cells (Antonioli, L. et al., Nature Reviews Cancer, 2013, 13, 842-857). A2B receptors are structurally closely related to A2A receptors and can activate adenylate cyclase, but are functionally distinct. It has been hypothesized that this subtype may utilize signaling pathways other than adenylate cyclase (Livingston, M. et al., Inflamm. Res., 2004, 53, 171-178). Among all adenosine receptors, A2B adenosine receptors are considered low-affinity receptors that remain silent under physiological conditions and are activated as a result of increased extracellular adenosine levels (Ryzhov, S. et al., Neoplasia, 2008, 10, 987-995). Activation of the A2B adenosine receptor can stimulate adenylate cyclase and phospholipase C through activation of Gs and Gq proteins, respectively. Coupling to mitogen-activated protein kinases has also been described (Borrmann, T. et al., J. Med. Chem., 2009, 52(13), 3994-4006).

[0008] In the immune system, the involvement of adenosine signaling may be an important regulatory mechanism that protects tissues from excessive immune responses. Adenosine can negatively regulate immune responses through many immune cell types, including T cells, natural killer cells, macrophages, dendritic cells, mast cells, and myeloid-derived suppressor cells (Allard, B. et al. Current Opinion in Pharmacology, 2016, 29, 7-16).

[0009] In tumors, this pathway is hijacked by the tumor microenvironment, disrupting the immune system's antitumor capabilities and promoting cancer progression. In the tumor microenvironment, adenosine is primarily generated from extracellular ATP by two ectonucleotidases, CD39 and CD73. Multiple cell types can produce adenosine by expressing CD39 and CD73. This is the case for tumor cells, T effector cells, T regulatory cells, tumor-associated macrophages, myeloid-derived suppressor cells (MDSCs), endothelial cells, cancer-associated fibroblasts (CAFs), and mesenchymal stromal / stem cells (MSCs). Furthermore, hypoxia and inflammation, conditions common in the tumor microenvironment, induce CD39 and CD73 expression, leading to increased adenosine production. As a result, adenosine levels in solid tumors are elevated compared to normal physiological conditions.

[0010] A2A is primarily expressed on lymphocyte-derived cells, such as T effector cells, T regulatory cells, and natural killer (NK) cells. Blockade of the A2A receptor prevents downstream immunosuppressive signals that temporarily inactivate T cells. A2B receptors are primarily expressed on monocyte-derived cells, such as dendritic cells, tumor-associated macrophages, myeloid-derived suppressor cells (MDSCs), and mesenchymal stromal / stem cells (MSCs). Blockade of the A2B receptor in preclinical models can suppress tumor growth, inhibit metastasis, and increase tumor antigen presentation.

[0011] Regarding the safety profile of ADORA2A / ADORA2B (A2A / A2B) blockade, all A2A and A2B receptor knockout (KO) mice are viable and fertile without growth abnormalities (Allard, B. et al. Current Opinion in Pharmacology, 2016, 29, 7-16). A2AKO mice showed increased levels of proinflammatory cytokines only upon lipopolysaccharide (LPS) challenge, but showed no evidence of inflammation at baseline (Antonioli, L. et al. Nature Reviews Cancer, 2013, 13, 842-857). A2B KO mice showed normal platelet, red blood cell, and white blood cell counts, but increased baseline inflammation, including TNF-α and IL-6 (Antonioli, L. et al. Nature Reviews Cancer, 2013, 13, 842-857). After LPS treatment, further increases in TNF-α and IL-6 production were detected. A2B KO mice also showed increased levels of vascular adhesion molecules that mediate inflammation and leukocyte adhesion / rolling, enhanced mast cell activation, increased susceptibility to IgE-mediated anaphylaxis, and increased vascular leakage and neutrophil influx under hypoxia (Antonioli, L. et al., Nature Reviews Cancer, 2013, 13, 842-857).

[0012] Some cancer patients have a poor long-term prognosis and / or are resistant to one or more types of treatment commonly used in the art. Thus, there remains a need for effective cancer therapies with increased efficacy and improved safety profiles in this difficult-to-treat patient population. Summary of the Invention

[0013] The present application provides, inter alia, a method of treating cancer in a subject, comprising administering to the subject: (i) A2A / A2B inhibitors; (ii) PD-1 / PD-L1 inhibitors and (iii) administering an inhibitor of human CD73.

[0014] The present application further provides a method of treating cancer in a subject, comprising administering to the subject:

[0015] (i) a PD-1 / PD-L1 inhibitor; and (ii) an inhibitor of human CD73. [Brief explanation of the drawings]

[0016] [Figure 1] 1 shows tumor growth inhibition (TGI) in a humanized mouse host bearing a human breast adenocarcinoma tumor, MDA-MB-231, using the treatment described in Example 1. [Figure 2] 1 shows a survival analysis of humanized mouse hosts bearing the human breast adenocarcinoma tumor MDA-MB-231 using the treatment described in Example 1. DETAILED DESCRIPTION OF THE INVENTION

[0017] The present application provides a method of treating cancer in a subject, comprising administering to the subject: (i) A2A / A2B inhibitors; (ii) a PD-1 / PD-L1 inhibitor; and (iii) an inhibitor of human CD73.

[0018] The present application further provides a method of treating cancer in a subject, comprising administering to the subject:

[0019] (i) a PD-1 / PD-L1 inhibitor; and (ii) an inhibitor of human CD73.

[0020] A2A / A2B adenosine receptor inhibitors The adenosine pathway is an important immunosuppressive pathway that protects tissues from excessive immune responses (Antonioli, L. et al. Nature Review Cancer. 2013, 13, 842-857; Inflamm. Res. 2004, 53: 171-178; Allard, et al. Current Opinion in Pharmacology 2016, 29:7). The immunosuppressive activity of adenosine is mediated through two G protein-coupled receptors (GPCRs), known as A2A and A2B. Both receptors are found to be expressed on many immune cell types, including T cells, natural killer cells, macrophages, dendritic cells, mast cells, and myeloid-derived suppressor cells (Saudi Pharmaceutical Journal. 2013, 21:245; Frontiers in Immunology. 2019, 10:925; J Clin Invest. 2017, 127(3):929; Neoplasia. 2008, 10:987; Neoplasia. 2013, 15:1400). High levels of adenosine production observed in the tumor microenvironment have been reported to suppress the immune system's antitumor capabilities, leading to cancer progression.

[0021] An exemplary amino acid sequence of the human A2A adenosine receptor protein (GenBank Accession No. NP_001265428) is as follows:

[0022] MPIMGSSVYITVELAIAVLAILGNVLVCWAVWLNSNLQNVTNYFVVSLAAADIAVGVLAIPFAITISTGFCAACHGCLFIACFVLVLTQSSIFSLLAIAIDRYIAIRIPLRYNGLVTGTRAKGIIAICWVLSFAIGLTPMLGWNNCGQPKEGKNHSQGCGEGQVACLFEDVVPMNYMVYFNFFACVLVPLLLMLGVYLRIFLAARRQLKQMESQPLPGERARSTLQKEVHAAKSLAIIVGLFALCWLPLHIINCFTFFCPDCSHAPLWLMYLAIVLSHTNSVVNPFIYAYRIREFRQTFRKIIRSHVLRQQEPFKAAGTSARVLAAHGSDGEQVSLRLNGHPPGVWANGSAPHPERRPNGYALGLVSGGSAQESQGNTGLPDVELLSHELKGVCPEPPGLDDPLAQDGAGVS (SEQ ID NO: 94).

[0023] An exemplary amino acid sequence of a human A2B adenosine receptor protein (GenBank Accession No. NP_000667) is as follows:

[0024] MLLETQDALYVALELVIAALSVAGNVLVCAAVGTANTLQTPTNYFLVSLAAADVAVGLFAIPFAITISLGFCTDFYGCLFLACFVLVLTQSSIFSLLAVAVDRYLAICVPLRYKSLVTGTRARGVIAVLWVLAFGIGLTPFLGWNSKDSATNNCTEPWDGTTNESCCLVKCLFENVVPMSYMVYFNFFGCVLPPLLIMLVIYIKIFLVACRQLQRTELMDHSRTTLQREIHAAKSLAMIVGIFALCWLPVHAVNCVTLFQPAQGKNKPKWAMNMAILLSHANSVVNPIVYAYRNRDFRYTFHKIISRYLLCQADVKSGNGQAGVQPALGVGL (SEQ ID NO: 95).

[0025] In some embodiments, the inhibitor of A2A / A2B is a compound selected from Table 1, or a pharmaceutically acceptable salt thereof. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5]

[0026] In some embodiments, the inhibitor of A2A / A2B is a compound of formula (I) [ka] or a pharmaceutically acceptable salt thereof, wherein: Cy 1 is phenyl substituted by 1 or 2 substituents independently selected from halo and CN; Cy 2 is a 4- to 7-membered heterocycloalkyl, wherein Cy 2 The 5- to 6-membered heteroaryl or 4- to 7-membered heterocycloalkyl is, respectively, C 1-3 , alkyl, C 1-3 Alkoxy, NH2, NH(C 1-3 alkyl) and N(C 1-3 each optionally substituted with 1, 2, or 3 groups independently selected from alkyl); R 2 is phenyl-C 1-3 Alkyl-, C 3-7 Cycloalkyl-C 1-3 Alkyl-, (5- to 7-membered heteroaryl)-C 1-3 Alkyl-, (4- to 7-membered heterocycloalkyl)-C 1-3 Alkyl- and ORa2 wherein R2 is selected from the group consisting of phenyl-C 1-3 Alkyl-, C 3-7 Cycloalkyl-C 1-3 Alkyl-, (5- to 7-membered heteroaryl)-C 1-3 Alkyl- and (4- to 7-membered heterocycloalkyl)-C 1-3 The alkyl group may be selected from 1, 2, or 3 independently selected R C optionally substituted with substituents; R a2 is one or two independently selected R C (5-7 membered heteroaryl)-C optionally substituted with a substituent 1-3 alkyl-; Each R C Ha, Halo, C 1-6 Alkyl, C6 aryl, 5- to 7-membered heteroaryl, (4- to 7-membered heterocycloalkyl)-C 1-3 Alkyl-, OR a4 , and NR c4 R d4 are independently selected from; Each R a4 , R c4 , and R d4 is H and C 1-6 alkyl.

[0027] In some embodiments of the compounds of Formula (I), Cy 2 is pyrimidinyl.

[0028] In some embodiments of the compounds of Formula (I), R 2 is selected from pyridin-2-ylmethyl, (2,6-difluorophenyl)(hydroxy)methyl, (5-(pyridin-2-yl)-1H-tetrazol-1-yl)methyl, (3-methylpyridin-2-yl)methoxy, and (5-(1H-pyrazol-1-yl)-1H-tetrazol-1-yl)methyl.

[0029] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is 3-(5-amino-2-(pyridin-2-ylmethyl)-8-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile, or a pharmaceutically acceptable salt thereof (Compound 1, see Table 1).

[0030] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is 3-(5-amino-2-((2,6-difluorophenyl)(hydroxy)methyl)-8-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile, or a pharmaceutically acceptable salt thereof (Compound 2, see Table 1).

[0031] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is 3-(5-amino-2-((5-(pyridin-2-yl)-2H-tetrazol-2-yl)methyl)-8-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile, or a pharmaceutically acceptable salt thereof (Compound 3A, see Table 1).

[0032] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is 3-(5-amino-2-((5-(pyridin-2-yl)-1H-tetrazol-1-yl)methyl)-8-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile, or a pharmaceutically acceptable salt thereof (Compound 3B, see Table 1).

[0033] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is 3-(5-amino-2-((3-methylpyridin-2-yl)methoxy)-8-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile, or a pharmaceutically acceptable salt thereof (Compound 4, see Table 1).

[0034] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is 3-(2-((5-(1H-pyrazol-1-yl)-2H-tetrazol-2-yl)methyl)-5-amino-8-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile, or a pharmaceutically acceptable salt thereof (Compound 21A, see Table 1).

[0035] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is 3-(2-((5-(1H-pyrazol-1-yl)-1H-tetrazol-1-yl)methyl)-5-amino-8-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile, or a pharmaceutically acceptable salt thereof (Compound 21B, see Table 1).

[0036] The synthesis and characterization of compounds of formula (I) can be found in WO2019 / 168847 and US 62 / 891,685, both of which are incorporated herein by reference in their entireties.

[0037] In some embodiments, the inhibitor of A2A / A2B is a compound of formula (II) [ka] or a pharmaceutically acceptable salt thereof, wherein: R 2 is selected from H and CN; Cy 1 is phenyl substituted by 1 or 2 substituents independently selected from halo and CN; L is C 1-3 alkylene, wherein said alkylene optionally contains one, two, or three independently selected R 8D substituted with a substituent; Cy 4is selected from phenyl, cyclohexyl, pyridyl, pyrrolidinonyl, and imidazolyl, wherein phenyl, cyclohexyl, pyridyl, pyrrolidinonyl, and imidazolyl are each independently selected from R 8D and R 8 optionally substituted with 1, 2, or 3 substituents independently selected from Each R 8 independently, halo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, phenyl, C 3-7 Cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-C 1-3 Alkyl, C 3-7 Cycloalkyl C 1-3 Alkyl, (5-6 membered heteroaryl)-C 1-3 Alkyl, and (4- to 7-membered heterocycloalkyl)-C 1-3 alkyl, wherein R 8 C 1-6 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, phenyl, C 3-7 Cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-C 1-3 Alkyl, C 3-7 Cycloalkyl C 1-3 Alkyl, (5-6 membered heteroaryl)-C 1-3 Alkyl, and (4- to 7-membered heterocycloalkyl)-C 1-3 Each alkyl is selected from 1, 2, or 3 independently selected R 8A optionally substituted with substituents; Each R 8A But independently, Halo, C 1-6 Alkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, CN, OR a81 , and NR c81 R d81 wherein R 8A C 1-6Alkyl, 5- to 6-membered heteroaryl, and 4- to 7-membered heterocycloalkyl each have one, two, or three independently selected R 8B optionally substituted with substituents; Each R a81 , R c81 , and R d81 are independent, H, C 1-6 alkyl, and 4- to 7-membered heterocycloalkyl, wherein R a81 , R c81 , and R d81 C 1-6 The alkyl and 4- to 7-membered heterocycloalkyl each have one, two, or three independently selected R 8B optionally substituted with substituents; Each R 8B But halo and C 1-3 independently selected from alkyl; and Each R 8D OH, CN, halo, C 1-6 Alkyl, and C 1-6 haloalkyl.

[0038] In some embodiments, the compound of Formula (II), or a pharmaceutically acceptable salt thereof, is 3-(5-amino-2-(hydroxy(phenyl)methyl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile, or a pharmaceutically acceptable salt thereof (Compound 5, see Table 1).

[0039] In some embodiments, the compound of Formula (II), or a pharmaceutically acceptable salt thereof, is 3-(5-amino-2-((2,6-difluorophenyl)(hydroxy)methyl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)-2-fluorobenzonitrile, or a pharmaceutically acceptable salt thereof (Compound 6, see Table 1).

[0040] In some embodiments, the compound of Formula (II), or a pharmaceutically acceptable salt thereof, is 5-amino-7-(3-cyano-2-fluorophenyl)-2-((2,6-difluorophenyl)(hydroxy)methyl)-[1,2,4]triazolo[1,5-c]pyrimidine-8-carbonitrile, or a pharmaceutically acceptable salt thereof (Compound 7, see Table 1).

[0041] In some embodiments, the compound of Formula (II), or a pharmaceutically acceptable salt thereof, is 3-(5-amino-2-((2-fluoro-6-(((1-methyl-2-oxopyrrolidin-3-yl)amino)methyl)phenyl)(hydroxy)methyl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)-2-fluorobenzonitrile, or a pharmaceutically acceptable salt thereof (Compound 8, see Table 1).

[0042] The synthesis and characterization of compounds of formula (II) can be found in WO2019 / 222677, which is incorporated herein by reference in its entirety.

[0043] In some embodiments, the inhibitor of A2A / A2B is a compound of formula (III) [ka] or a pharmaceutically acceptable salt thereof, wherein: Cy 1 is phenyl substituted by 1 or 2 substituents independently selected from halo and CN; R 2 is selected from 5- to 6-membered heteroaryl and 4- to 7-membered heterocycloalkyl, wherein R 2 The 5- to 6-membered heteroaryl and 4- to 7-membered heterocycloalkyl each optionally contain 1, 2, or 3 independently selected R 2A substituted with a substituent; Each R 2A independently, D, halo, C 1-6 Alkyl, and C 1-6 haloalkyl; R 4 is phenyl-C 1-3 Alkyl-, C 3-7 Cycloalkyl-C 1-3 Alkyl-, (5-6 membered heteroaryl)-C 1-3 Alkyl-, (4- to 7-membered heterocycloalkyl)-C 1-3 alkyl, wherein R 4 Phenyl-C 1-3 Alkyl, C 3-7 Cycloalkyl-C 1-3 Alkyl-, (5-6 membered heteroaryl)-C 1-3 Alkyl- and (4- to 7-membered heterocycloalkyl)-C 1-3 The alkyl group may be selected from 1, 2, or 3 independently selected R 4A optionally substituted with substituents; Each R 4A But, Halo, C 1-6 Alkyl, C 1-6 Haloalkyl, CN, OR a41 , and NR c41 R d41 are independently selected from: Each R a41 , R c41 , and R d41 However, H and C 1-6 alkyl.

[0044] In some embodiments, the compound of Formula (III), or a pharmaceutically acceptable salt thereof, is 3-(8-amino-5-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-2-(pyridin-2-ylmethyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile, or a pharmaceutically acceptable salt thereof (Compound 9, see Table 1).

[0045] In some embodiments, the compound of Formula (III), or a pharmaceutically acceptable salt thereof, is 3-(8-amino-2-((2,6-difluorophenyl)(hydroxy)methyl)-5-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile, or a pharmaceutically acceptable salt thereof (Compound 10, see Table 1).

[0046] In some embodiments, the compound of Formula (III), or a pharmaceutically acceptable salt thereof, is 3-(8-amino-2-(amino(2,6-difluorophenyl)methyl)-5-(4-methyloxazol-5-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile, or a pharmaceutically acceptable salt thereof (Compound 11, see Table 1).

[0047] In some embodiments, the compound of Formula (III), or a pharmaceutically acceptable salt thereof, is 3-(8-amino-2-((2,6-difluorophenyl)(hydroxy)methyl)-5-(2,6-dimethylpyridin-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile, or a pharmaceutically acceptable salt thereof (Compound 12, see Table 1).

[0048] The synthesis and characterization of compounds of formula (III) can be found in PCT / US2019 / 040496, which is incorporated herein by reference in its entirety.

[0049] In some embodiments, the inhibitor of A2A / A2B is a compound of formula (IV) [ka] or a pharmaceutically acceptable salt thereof, wherein: Cy 1 is phenyl substituted by 1 or 2 substituents independently selected from halo and CN; Cy 2is selected from 5- to 6-membered heteroaryl and 4- to 7-membered heterocycloalkyl, wherein said Cy 2 Each of the 5- to 6-membered heteroaryl and 4- to 7-membered heterocycloalkyl groups is selected from 1, 2, or 3 independently selected R 6 optionally substituted by substituents; Each R 6 But, Halo, C 1-6 Alkyl, and C 1-6 haloalkyl; R 2 is phenyl-C 1-3 Alkyl- or (5-6 membered heteroaryl)-C 1-3 alkyl-, wherein R2 is phenyl-C 1-3 Alkyl- and (5- to 6-membered heteroaryl)-C 1-3 Each alkyl- is selected from 1, 2, or 3 independently selected R 2A optionally substituted by substituents; Each R 2A independently, Halo, C 1-6 Alkyl, and C 1-6 haloalkyl.

[0050] In some embodiments, the compound of Formula (IV), or a pharmaceutically acceptable salt thereof, is 3-(4-amino-2-(pyridin-2-ylmethyl)-7-(pyrimidin-4-yl)-2H-[1,2,3]triazolo[4,5-c]pyridin-6-yl)benzonitrile, or a pharmaceutically acceptable salt thereof (Compound 13, see Table 1).

[0051] In some embodiments, the compound of Formula (IV), or a pharmaceutically acceptable salt thereof, is 3-(4-amino-2-((3-fluoropyridin-2-yl)methyl)-7-(pyrimidin-4-yl)-2H-[1,2,3]triazolo[4,5-c]pyridin-6-yl)benzonitrile, or a pharmaceutically acceptable salt thereof (Compound 14, see Table 1).

[0052] In some embodiments, the compound of Formula (IV), or a pharmaceutically acceptable salt thereof, is 3-(4-amino-2-((3-fluoropyridin-2-yl)methyl)-7-(pyridin-4-yl)-2H-[1,2,3]triazolo[4,5-c]pyridin-6-yl)benzonitrile, or a pharmaceutically acceptable salt thereof (Compound 15, see Table 1).

[0053] In some embodiments, the compound of Formula (IV), or a pharmaceutically acceptable salt thereof, is 3-(4-amino-7-(1-methyl-1H-pyrazol-5-yl)-2-(pyridin-2-ylmethyl)-2H-[1,2,3]triazolo[4,5-c]pyridin-6-yl)-2-fluorobenzonitrile, or a pharmaceutically acceptable salt thereof (Compound 16, see Table 1).

[0054] The synthesis and characterization of compounds of formula (IV) can be found in US 62 / 798,180, which is incorporated herein by reference in its entirety.

[0055] In some embodiments, the inhibitor of A2A / A2B is a compound of formula (V) [ka] or a pharmaceutically acceptable salt thereof, wherein: R 2 H, D, Halo, C 1-6 Alkyl, and C 1-6 haloalkyl; R 3 is H and C 1-6 alkyl, R 4 is H and C 1-6 alkyl, R 5 H, halo, CN, C 1-6 alkyl, Each R 6 is phenyl, C 3-7 cycloalkyl, 5- to 7-membered heteroaryl, and 4- to 7-membered heterocycloalkyl;6 Phenyl, C 3-7 Cycloalkyl, 5- to 7-membered heteroaryl, and 4- to 7-membered heterocycloalkyl are each selected from one, two, or three independently selected R A optionally substituted with substituents; Each R A is (5-10 membered heteroaryl)-C 1-3 Alkyl- and (4- to 10-membered heterocycloalkyl)-C 1-3 alkyl-, wherein R A (5-10 membered heteroaryl)-C 1-3 Alkyl- and (4- to 10-membered heterocycloalkyl)-C 1-3 Each alkyl- is selected from one or two independently selected R B optionally substituted with substituents; Each R B Ha, Halo, C 1-6 Alkyl and C(O)R b26 are independently selected from; Each R b26 However, H and C 1-3 alkyl, b26 C 1-3 alkyl is one or two independently selected R C optionally substituted with substituents; Each R C But, Halo, C 1-6 Alkyl, CN, OR a36 , and NR c36 R d36 are independently selected from Each R a36 , R c36 , and R d36 is H and C 1-6 alkyl.

[0056] In some embodiments, the compound of Formula (V), or a pharmaceutically acceptable salt thereof, is 7-(1-((5-chloropyridin-3-yl)methyl)-1H-pyrazol-4-yl)-3-methyl-9-pentyl-6,9-dihydro-5H-pyrrolo[3,2-d][1,2,4]triazolo[4,3-a]pyrimidin-5-one, or a pharmaceutically acceptable salt thereof (Compound 17, see Table 1).

[0057] In some embodiments, the compound of Formula (V), or a pharmaceutically acceptable salt thereof, is 3-methyl-7-(1-((5-methylpyridin-3-yl)methyl)-1H-pyrazol-4-yl)-9-pentyl-6,9-dihydro-5H-pyrrolo[3,2-d][1,2,4]triazolo[4,3-a]pyrimidin-5-one, or a pharmaceutically acceptable salt thereof (Compound 18, see Table 1).

[0058] In some embodiments, the compound of Formula (V), or a pharmaceutically acceptable salt thereof, is 3-methyl-9-pentyl-7-(1-(thieno[3,2-b]pyridin-6-ylmethyl)-1H-pyrazol-4-yl)-6,9-dihydro-5H-pyrrolo[3,2-d][1,2,4]triazolo[4,3-a]pyrimidin-5-one, or a pharmaceutically acceptable salt thereof (Compound 19, see Table 1).

[0059] In some embodiments, the compound of Formula (V), or a pharmaceutically acceptable salt thereof, is 7-(1-((2-(2-(dimethylamino)acetyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)methyl)-1H-pyrazol-4-yl)-3-methyl-9-pentyl-6,9-dihydro-5H-pyrrolo[3,2-d][1,2,4]triazolo[4,3-a]pyrimidin-5-one, or a pharmaceutically acceptable salt thereof (Compound 20, see Table 1).

[0060] The synthesis and characterization of compounds of formula (V) can be found in US-2019-0337957, which is incorporated herein by reference in its entirety.

[0061] Other inhibitors of the A2A and / or A2B adenosine receptors useful in the methods described herein are known in the art.

[0062] In some cases, the inhibitor of the A2A and / or A2B adenosine receptor is CPI-444 (also referred to herein as "Compound B"; 7-(5-methylfuran-2-yl)-3-[[6-[[(3S)-oxolan-3-yl]oxymethyl]pyridin-2-yl]methyl]triazolo[4,5-d]pyrimidin-5-amine).

[0063] In some cases, the inhibitor of the A2A and / or A2B adenosine receptor is AB928 (3-[2-amino-6-[1-[[6-(2-hydroxypropan-2-yl]methyl]triazol-4-yl]pyrimidin-4-yl]-2-methylbenzonitrile).

[0064] In some cases, the inhibitor of the A2A and / or A2B adenosine receptors is AZD4635 (6-(2-chloro-6-methylpyridin-4-yl)-5-(4-fluorophenyl)-1,2,4-triazin-3-amine).

[0065] In some cases, the inhibitor of the A2A and / or A2B adenosine receptor is NIR-178 (5-bromo-2,6-di(1H-pyrazol-1-yl)pyrimidin-4-amine).

[0066] In some cases, the inhibitor of A2A and / or A2B adenosine receptors is EOS100850.

[0067] In some cases, the inhibitor of the A2A and / or A2B adenosine receptor is a compound, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof described in U.S. Patent Application Publication No. 2019 / 0292188, the entire contents of which are incorporated herein by reference.

[0068] As used herein, "about" when referring to a measurable value such as an amount, dosage, temporal duration, etc. is meant to encompass a ±10% variation. In certain embodiments, "about" can include a ±5%, ±1%, or ±0.1% variation from the specified value, and any variation therebetween, where such variation is appropriate for practicing the disclosed methods.

[0069] In some embodiments, the compound disclosed herein is the (S)-enantiomer of one of the aforementioned compounds, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is the (R)-enantiomer of one of the aforementioned compounds, or a pharmaceutically acceptable salt thereof.

[0070] It is further understood that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination.

[0071] The term "n-membered," where n is an integer, typically refers to the number of ring-forming atoms at the moiety where n is the number of ring-forming atoms. For example, piperidinyl is an example of a 6-membered heterocycloalkyl ring, pyrazolyl is an example of a 5-membered heteroaryl ring, pyridyl is an example of a 6-membered heteroaryl ring, and 1,2,3,4-tetrahydro-naphthalene is an example of a 10-membered cycloalkyl group.

[0072] As used herein, the phrase "optionally substituted" means unsubstituted or substituted. The substituents are independently selected, and substitution may occur at any chemically accessible position. As used herein, the term "substituted" means that a hydrogen atom is removed and replaced with a substituent. A single divalent substituent, for example, oxo, can replace two hydrogen atoms. It should be understood that substitution at a given atom is limited by atomic valence.

[0073] As used herein, the phrase "each 'variable' is independently selected from" means substantially the same as "at each occurrence, 'variable' is selected from."

[0074] Through definition, "C n~m " denotes a range inclusive of the endpoints, where n and m are integers and indicate the number of carbons. Examples include C 1-3 , C 1-4 , C 1-6 Examples include:

[0075] As used herein, "C" when used alone or in combination with other terms n-m The term "alkyl" refers to a saturated hydrocarbon group having n to m carbons, which may be straight-chained or branched. Examples of alkyl moieties include, but are not limited to, chemical groups such as methyl (Me), ethyl (Et), n-propyl (n-Pr), isopropyl (iPr), n-butyl, tert-butyl, isobutyl, sec-butyl, and higher homologs such as 2-methyl-1-butyl, n-pentyl, 3-pentyl, n-hexyl, 1,2,2-trimethylpropyl, and the like. In some embodiments, an alkyl group contains 1 to 6 carbon atoms, 1 to 4 carbon atoms, 1 to 3 carbon atoms, or 1 to 2 carbon atoms.

[0076] As used herein, "C" when used alone or in combination with other terms n~m The term "alkoxy" refers to a group of formula -O-alkyl, where the alkyl group has n to m carbons. Exemplary alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), butoxy (e.g., n-butoxy and tert-butoxy), and the like.

[0077] As used herein, the term "aryl," used alone or in combination with other terms, refers to an aromatic hydrocarbon group, which may be monocyclic or polycyclic (e.g., having 2, 3, or 4 fused rings). n~m The term "aryl" refers to an aryl group having n to m ring carbon atoms. Examples of aryl groups include phenyl, naphthyl, anthracenyl, phenanthrenyl, indanyl, indenyl, and the like. In some embodiments, an aryl group has 5 to 10 carbon atoms. In some embodiments, an aryl group is phenyl or naphthyl. In some embodiments, an aryl is phenyl (i.e., C6 aryl).

[0078] As used herein, "halo" or "halogen" refers to F, Cl, Br, or I. In some embodiments, halo is F, Cl, or Br. In some embodiments, halo is F or Cl. In some embodiments, halo is F. In some embodiments, halo is Cl.

[0079] As used herein, "C" when used alone or in combination with other terms n~m The term "haloalkyl" refers to an alkyl group having from 1 to 2s+1 halogen atoms (which may be the same or different), where "s" is the number of carbon atoms in the alkyl group, and the alkyl group has n to m carbon atoms. In some embodiments, the haloalkyl group is exclusively fluorinated. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. Exemplary haloalkyl groups include CF3, C2F5, CHF2, CH2F, CCl3, CHCl2, C2Cl5, and the like.

[0080] As used herein, "cycloalkyl" refers to a non-aromatic cyclic hydrocarbon, including cyclized alkyl and alkenyl groups. Cycloalkyl groups can include monocyclic or polycyclic (e.g., having two fused rings), spirocyclic, and bridged rings (e.g., bridged bicycloalkyl groups). Ring-forming carbon atoms of a cycloalkyl group can be optionally substituted with oxo or sulfido (e.g., C(O) or C(S)). Also included within the definition of cycloalkyl are moieties having one or more aromatic rings fused to (i.e., having a common bond with) the cycloalkyl ring, e.g., benzo or thienyl derivatives such as cyclopentane, cyclohexane, etc. Cycloalkyl groups containing fused aromatic rings can be bonded through any ring-forming atom, including the ring-forming atoms of the fused aromatic ring. Cycloalkyl groups can have 3, 4, 5, 6, 7, 8, 9, or 10 ring-forming carbon atoms (i.e., C 3-10 In some embodiments, the cycloalkyl may have C 3-10 In some embodiments, the cycloalkyl is a monocyclic or bicyclic cycloalkyl of the formula: 3~7 In some embodiments, the cycloalkyl is C 4-7 In some embodiments, the cycloalkyl is a monocyclic cycloalkyl of C 4-10 and spirocyclic or bridged cycloalkyl (e.g., bridged bicycloalkyl). Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl, norcarnyl, cubane, adamantane, bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptanyl, bicyclo[3.1.1]heptanyl, bicyclo[2.2.2]octanyl, spiro[3.3]heptanyl, and the like. In some embodiments, the cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0081] As used herein, "heteroaryl" refers to a monocyclic or polycyclic (e.g., having two fused rings) aromatic heterocycle having at least one heteroatom ring member selected from N, O, S, and B. In some embodiments, the heteroaryl ring has 1, 2, 3, or 4 heteroatom ring members independently selected from N, O, S, and B. In some embodiments, any ring-forming N in the heteroaryl moiety can be an N-oxide. In some embodiments, the heteroaryl is a 5-10 membered monocyclic or bicyclic heteroaryl having 1, 2, 3, or 4 heteroatom ring members independently selected from N, O, S, and B. In some embodiments, the heteroaryl is a 5-10 membered monocyclic or bicyclic heteroaryl having 1, 2, 3, or 4 heteroatom ring members independently selected from N, O, and S. In some embodiments, heteroaryl is a 5-6 membered monocyclic heteroaryl having 1 or 2 heteroatom ring members independently selected from N, O, S, and B. In some embodiments, heteroaryl is a 5-6 membered monocyclic heteroaryl having 1 or 2 heteroatom ring members independently selected from N, O, and S. In some embodiments, heteroaryl groups contain 3 to 10, 4 to 10, 5 to 10, 5 to 7, 3 to 7, or 5 to 6 ring-forming atoms. In some embodiments, heteroaryl groups contain 1 to 4 ring-forming heteroatoms, 1 to 3 ring-forming heteroatoms, 1 to 2 ring-forming heteroatoms, or 1 ring-forming heteroatom. When a heteroaryl group contains more than one heteroatom ring member, the heteroatoms can be the same or different.Examples of heteroaryl groups include thienyl (or thiophenyl), furyl (or furanyl), pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl, 1,2,3-triazolyl, tetrazolyl, 1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-triazolyl, 1,2,4-thiadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-triazolyl, 1,3,4-thiadiazolyl, 1,3,4-oxadiazolyl, and 1,2-dihydro-1,2-azaborine, pyridinyl, pyrimidinyl, pyrazinyl, pyridazolyl, and the like. These include, but are not limited to, thiazolyl, quinolinyl, isoquinolinyl, indolyl, benzothiophenyl, benzofuranyl, benzisoxazolyl, imidazo[1,2-b]thiazolyl, purinyl, triazinyl, thieno[3,2-b]pyridinyl, imidazo[1,2-a]pyridinyl, 1,5-naphthyridinyl, 1H-pyrazolo[4,3-b]pyridinyl, triazolo[4,3-a]pyridinyl, 1H-pyrrolo[3,2-b]pyridinyl, 1H-pyrrolo[2,3-b]pyridinyl, pyrazolo[1,5-a]pyridinyl, indazolyl, and the like.

[0082] As used herein, "heterocycloalkyl" refers to a monocyclic or polycyclic heterocycle having at least one non-aromatic ring (saturated or partially unsaturated), wherein one or more of the ring-forming carbon atoms of the heterocycloalkyl are replaced by a heteroatom selected from N, O, S, and B; and wherein the ring-forming carbon atoms and heteroatoms of the heterocycloalkyl group are optionally substituted by one or more oxo or sulfide (e.g., C(O), S(O), C(S), or S(O)). When a ring-forming carbon atom or heteroatom of a heterocycloalkyl group is optionally substituted by one or more oxo or sulfide, the O or S in said group is additional to the number of ring-forming atoms specified herein (e.g., 1-methyl-6-oxo-1,6-dihydropyridazin-3-yl is a 6-membered heterocycloalkyl group wherein a ring-forming carbon atom is substituted by an oxo group, and the 6-membered heterocycloalkyl group is further substituted by a methyl group). Heterocycloalkyl groups include monocyclic and polycyclic (e.g., having two fused rings) systems. Heterocycloalkyls include monocyclic and polycyclic 3- to 10-membered, 4- to 10-membered, 5- to 10-membered, 4- to 7-membered, 5- to 7-membered, or 5- to 6-membered heterocycloalkyl groups. Heterocycloalkyl groups can also include spirocycles and bridged rings (e.g., 5- to 10-membered bridged biheterocycloalkyl rings having one or more ring-forming carbon atoms replaced by heteroatoms independently selected from N, O, S, and B). Heterocycloalkyl groups can be bonded through a ring-forming carbon atom or ring-forming heteroatom. In some embodiments, heterocycloalkyl groups contain zero to three double bonds. In some embodiments, heterocycloalkyl groups contain zero to two double bonds.

[0083] Also included within the definition of heterocycloalkyl are moieties having one or more aromatic rings fused to (i.e., having a bond in common with) a non-aromatic heterocyclic ring, e.g., a benzo or thienyl derivative, such as piperidine, morpholine, azepine, etc. Heterocycloalkyl groups containing fused aromatic rings can be bonded through any ring-forming atom, including a ring-forming atom of the fused aromatic ring.

[0084] In some embodiments, a heterocycloalkyl group contains 3 to 10 ring-forming atoms, 4 to 10 ring-forming atoms, 3 to 7 ring-forming atoms, or 5 to 6 ring-forming atoms. In some embodiments, a heterocycloalkyl group has 1 to 4 heteroatoms, 1 to 3 heteroatoms, 1 to 2 heteroatoms, or 1 heteroatom. In some embodiments, a heterocycloalkyl is a monocyclic 4-6 membered heterocycloalkyl having 1 or 2 heteroatoms independently selected from N, O, S, and B and having one or more oxidized ring members. In some embodiments, a heterocycloalkyl is a monocyclic or bicyclic 5-10 membered heterocycloalkyl having 1, 2, 3, or 4 heteroatoms independently selected from N, O, S, and B and having one or more oxidized ring members. In some embodiments, a heterocycloalkyl is a monocyclic or bicyclic 5-10 membered heterocycloalkyl having 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S and having one or more oxidized ring members. In some embodiments, the heterocycloalkyl is a monocyclic 5-6 membered heterocycloalkyl having 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S, and having one or more oxidized ring members.

[0085] Exemplary heterocycloalkyl groups include pyrrolidin-2-one (or 2-oxopyrrolidinyl), 1,3-isoxazolidin-2-one, pyranyl, tetrahydropyran, oxetanyl, azetidinyl, morpholino, thiomorpholino, piperazinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, pyrrolidinyl, isoxazolidinyl, isothiazolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, imidazolidinyl, and azepanyl. , 1,2,3,4-tetrahydroisoquinoline, benzazapene, azabicyclo[3.1.0]hexanyl, diazabicyclo[3.1.0]hexanyl, oxobicyclo[2.1.1]hexanyl, azabicyclo[2.2.1]heptanyl, diazabicyclo[2.2.1]heptanyl, azabicyclo[3.1.1]heptanyl, diazabicyclo[3.1.1]heptanyl, azabicyclo[3.2.1]octanyl, diazabicyclo[3.2.1]octanyl, oxobicyclo [2.2.2]octanyl, azabicyclo[2.2.2]octanyl, azaadamantanyl, diazaadamantanyl, oxo-adamantanyl, azaspiro[3.3]heptanyl, diazaspiro[3.3]heptanyl, oxo-azaspiro[3.3]heptanyl, azaspiro[3.4]octanyl, diazaspiro[3.4]octanyl, oxo-azaspiro[3.4]octanyl, azaspiro[2.5]octanyl, diazaspiro[2.5]octanyl, azaspiro[4.4 ]nonanyl, diazaspiro[4.4]nonanyl, oxo-azaspiro[4.4]nonanyl, azaspiro[4.5]decanyl, diazaspiro[4.5]decanyl, diazaspiro[4.4]nonanyl, oxo-diazaspiro[4.4]nonanyl, oxo-dihydropyridazinyl, oxo-2,6-diazaspiro[3.4]octanyl, oxohexahydropyrrolo[1,2a]pyrazinyl, 3-oxopiperazinyl, oxo-pyrrolidinyl, oxo-pyrazinyl, and the like. For example, heterocycloalkyl groups include the following groups (with or without N-methyl substitution): [ka]

[0086] As used herein, "C o~p Cycloalkyl-C n~m "Alkyl-" refers to a group of the formula cycloalkyl-alkylene- where the cycloalkyl has from o to p carbon atoms and the alkylene linking group has from n to m carbon atoms.

[0087] As used herein, "C o~p Aryl-C n~m "Alkyl-" refers to a group of formula aryl-alkylene- where the aryl has from o to p carbon atoms and the alkylene linking group has from n to m carbon atoms.

[0088] As used herein, "heteroaryl-C n~m "Alkyl-" refers to a group of formula heteroaryl-alkylene-, where the alkylene linking group has n to m carbon atoms.

[0089] As used herein, "heterocycloalkyl-C n-m "Alkyl-" refers to a group of formula heterocycloalkyl-alkylene-, where the alkylene linking group has n to m carbon atoms.

[0090] In certain places, definitions or embodiments refer to specific rings (e.g., azetidine rings, pyridine rings, etc.). Unless otherwise specified, these rings can be attached to any ring member as long as the valence of the atom is not exceeded. For example, an azetidine ring can be attached at any position on the ring, whereas a pyridin-3-yl ring is attached at the 3-position.

[0091] As used herein, the term "oxo" refers to an oxygen atom (i.e., =0) as a divalent substituent which, when attached to carbon, forms a carbonyl group (e.g., C=O or C(O)), or to a nitrogen or sulfur heteroatom to form a nitroso, sulfinyl, or sulfonyl group.

[0092] As used herein, the term "independently selected from" means that each occurrence of a variable or substituent is independently selected at every occurrence from the applicable list.

[0093] The compounds described herein can be asymmetric (e.g., having one or more stereocenters). All stereoisomers, such as enantiomers and diastereomers, are intended unless otherwise specified. Compounds of the present disclosure containing an asymmetrically substituted atom can be isolated in optically active or racemic forms. Methods for preparing optically active forms from optically inactive starting materials are known in the art, such as by resolution of racemic mixtures or stereoselective synthesis. Many geometric isomers of olefins, C=N double bonds, and the like can also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. Cis and trans geometric isomers of the compounds of the present disclosure are described and can be isolated as a mixture of isomers or as separated isomeric forms. In some embodiments, the compounds have the (R)-configuration. In some embodiments, the compounds have the (S)-configuration. The formulas provided herein (e.g., Formulas (I), (II), etc.) include stereoisomers of the compounds.

[0094] Resolution of racemic mixtures of compounds can be carried out by any of a number of methods well known in the art. An exemplary method includes fractional recrystallization using a chiral resolving acid, which is an optically active, salt-forming organic acid. Suitable resolving agents for fractional recrystallization include, for example, optically active acids such as D- and L-forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, and lactic acid, or various optically active camphorsulfonic acids, such as β-camphorsulfonic acid. Other resolving agents suitable for fractional crystallization include stereomerically pure α-methylbenzylamine (e.g., S- and R-forms, or diastereomerically pure forms), 2-phenylglycinol, norephedrine, ephedrine, N-methylephedrine, cyclohexylethylamine, 1,2-diaminocyclohexane, and the like.

[0095] Resolution of racemic mixtures can also be carried out by elution on a column packed with an optically active resolving agent (e.g., dinitrobenzoylphenylglycine). Suitable elution solvent compositions can be determined by one skilled in the art.

[0096] The compounds described herein also include tautomeric forms. Tautomeric forms are obtained by the interchange of adjacent double and single bonds with the concomitant migration of a proton. Tautomeric forms include prototropic tautomers, which are isomeric protonation states with the same empirical formula and total charge. Examples of prototropic tautomers include ketone-enol pairs, amide-imidic acid pairs, lactam-lactim pairs, enamine-imine pairs, and cyclic forms in which protons can occupy more than one position on a heterocyclic ring system, such as 1H-imidazole and 3H-imidazole, 1H-1,2,4-triazole, 2H-1,2,4-triazole and 4H-1,2,4-triazole, 1H-isoindole and 2H-isoindole, 2-hydroxypyridine and 2-pyridone, and 1H-pyrazole and 2H-pyrazole. Tautomeric forms may be in equilibrium or may be sterically locked into one form by appropriate substitution.

[0097] All compounds and pharmaceutically acceptable salts thereof may be found together with other substances such as water and solvents (eg, hydrates and solvates) or may be isolated.

[0098] In some embodiments, preparation of compounds may involve the addition of acids or bases, for example to affect catalysis of a desired reaction or the formation of salt forms, such as acid addition salts.

[0099] In some embodiments, the compounds described herein or salts thereof are substantially isolated. "Substantially isolated" means that the compounds are at least partially or substantially separated from the environment in which they were formed or detected. Partial separation can include, for example, compositions enriched for the compounds described herein. Substantial separation can include compositions containing at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 97%, or at least about 99% by weight of the compounds described herein or salts thereof. Methods for isolating compounds and their salts are routine in the art.

[0100] The term "compound," as used herein, is meant to include all stereoisomers, geometric isomers, tautomers, and isotopes of the structures depicted. Compounds herein identified by name or structure as one particular tautomeric form are intended to include other tautomeric forms unless otherwise specified.

[0101] The phrase "pharmaceutically acceptable" is used herein to refer to compounds, materials, compositions, and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0102] The present application also includes pharmaceutically acceptable salts of the compounds described herein. As used herein, "pharmaceutically acceptable salts" refers to derivatives of the disclosed compounds in which the parent compound has been modified by converting an existing acid or base moiety into its salt form. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic residues such as amines, alkali or organic salts of acidic residues such as carboxylic acids, and the like. The pharmaceutically acceptable salts of the present disclosure include conventional non-toxic salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. The pharmaceutically acceptable salts of the present disclosure can be synthesized from the parent compound containing a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent, or a mixture of the two; generally, non-aqueous media such as ether, ethyl acetate, alcohol (e.g., methanol, ethanol, isopropanol, or butanol), or acetonitrile (ACN) are preferred. Lists of suitable salts can be found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418 and Journal of Pharmaceutical Science, 66, 2 (1977), which are incorporated herein by reference in their entireties.

[0103] The compounds described herein, including their salts, can be prepared using known organic synthesis techniques, or can be synthesized according to any of a number of possible synthetic routes.

[0104] The reactions for preparing the compounds described herein can be carried out in a suitable solvent that can be easily selected by those skilled in the art of organic synthesis. A suitable solvent can be substantially non-reactive with the starting material (reactant), intermediate, or product at the temperature at which the reaction is carried out (for example, a temperature that can range from the freezing temperature of the solvent to the boiling temperature of the solvent). A given reaction can be carried out in one solvent or a mixture of more than one solvent. Depending on the specific reaction step, a suitable solvent for a particular reaction step can be selected by those skilled in the art.

[0105] Preparation of the compounds described herein can involve the protection and deprotection of various chemical groups. The need for protection and deprotection, and the selection of appropriate protecting groups, can be readily determined by one skilled in the art. The chemistry of protecting groups can be found, for example, in TW Greene and PG M Buts, Protective Groups in Organic Synthesis, 3 rd Ed., Wiley & Sons, Inc., New York (1999), which is incorporated herein by reference in its entirety.

[0106] The reaction can be monitored according to any suitable method known in the art. For example, product formation can be monitored by nuclear magnetic resonance spectroscopy (e.g., 1 H or 13The compounds can be monitored by spectroscopic means such as infrared spectroscopy, spectrophotometry (e.g., ultraviolet-visible), mass spectrometry, or by chromatographic methods such as high performance liquid chromatography (HPLC), liquid chromatography-mass spectroscopy (LCMS), or thin-layer chromatography (TLC). Compounds can be purified by those skilled in the art by a variety of methods, including high performance liquid chromatography (HPLC) ("Preparative LC-MS Purification: Improved Compound Specific Method Optimization," Karl F. Blom, et al. J. Combi. Chem. 2004, 6(6), 874-883, which is incorporated herein by reference in its entirety) and normal-phase silica chromatography.

[0107] The compounds described herein can modulate the activity of one or more G-protein-coupled receptors (GPCRs), including, for example, A2A / A2B. The term "modulate" is meant to refer to the ability to increase or decrease the activity of one or more members of the A2A / A2B family. Accordingly, the compounds described herein can be used in methods of modulating A2A / A2B by contacting A2A / A2B with any one or more of the compounds or compositions described herein. In some embodiments, the compounds of the present invention can act as inhibitors of one or both of A2A and A2B. In further embodiments, the compounds described herein can be used to modulate A2A / A2B activity in an individual in need of receptor modulation by administering a modulating amount of a compound described herein, or a pharmaceutically acceptable salt thereof. In some embodiments, the modulation is inhibition.

[0108] Given that cancer cell growth and survival are influenced by multiple signaling pathways, the present invention is useful for treating disease states characterized by drug-resistant mutants. Furthermore, different GPCR inhibitors that exhibit different preferences for the GPCRs they regulate can be used in combination. This approach is highly efficient for treating disease states by targeting multiple signaling pathways, reducing the likelihood of drug resistance developing in cells and reducing the toxicity of disease treatment.

[0109] The GPCRs that the present compounds bind to and / or modulate (eg, inhibit) include any member of the A2A / A2B family.

[0110] In some embodiments, two or more compounds described herein are used to inhibit the activity of one GPCR (eg, A2A).

[0111] In some embodiments, two or more compounds described herein are used to inhibit two or more GPCRs, such as at least two GPCRs (eg, A2A and A2B).

[0112] In some embodiments, one or more compounds are used in combination with another GPCR antagonist to inhibit the activity of one GPCR (eg, A2A or A2B).

[0113] The A2A / A2B inhibitors described herein can be selective. "Selective" means that the compound binds to or inhibits the GPCR with greater affinity or potency, respectively, compared to at least one other GPCR. In some embodiments, the compounds described herein are selective inhibitors of A2A or A2B. In some embodiments, the compounds described herein are selective inhibitors of A2A (e.g., over A2B). In some embodiments, the compounds described herein are selective inhibitors of A2B (e.g., over A2A). In some embodiments, the selectivity can be at least about 2-fold, 5-fold, 10-fold, at least about 20-fold, at least about 50-fold, at least about 100-fold, at least about 200-fold, at least about 500-fold, or at least about 1000-fold. Selectivity can be measured by methods routine in the art. In some embodiments, selectivity can be tested by biochemical affinity for each GPCR. In some embodiments, the selectivity of the compounds described herein can be determined by cellular assays related to specific A2A / A2B GPCR activity.

[0114] PD-1 / PD-L1 inhibitors The immune system plays a crucial role in the control and eradication of diseases such as cancer. However, cancer cells often develop strategies to evade or suppress the immune system to promote their growth. One such mechanism is altering the expression of costimulatory and co-inhibitory molecules expressed on immune cells (Postow et al., J. Clinical Oncology 2015, 1-9). Blocking the signaling of inhibitory immune checkpoints, such as PD-1, has proven to be a promising and effective treatment.

[0115] Programmed death-1 ("PD-1," also known as "CD279") is an approximately 31 kD type I membrane protein member of the extended CD28 / CTLA-4 family of T cell regulators that broadly negatively regulates immune responses (Ishida, Y. et al. (1992) EMBO J. 11:3887-3895; U.S. Patent Publication Nos. 2007 / 0202100; 2008 / 0311117; and 2009 / 00110667; U.S. Patent Nos. 6,808,710; 7,101,550; 7,488,802; 7,635,757; and 7,722,868; PCT Publication No. WO01 / 14557).

[0116] PD-1 is expressed on activated T cells, B cells, and monocytes (Agata, Y. et al. (1996) Int. Immunol. 8(5):765-772; Yamazaki, T. et al. (2002) J. Immunol. 169:5538-5545) and at low levels on natural killer (NK) T cells (Nishimura, H. et al. (2000) J. Exp. Med. 191:891-898; Martin-Orozco, N. et al. (2007) Semin. Cancer Biol. 17(4):288-298).

[0117] The extracellular region of PD-1 consists of a single immunoglobulin (Ig) V domain that shares 23% identity with the equivalent domain in CTLA-4 (Martin-Orozco, N. et al. (2007) Semin. Cancer Biol. 17(4):288-298). The extracellular Ig V domain is followed by a transmembrane region and an intracellular tail. The intracellular tail contains two phosphorylation sites located in an immunoreceptor tyrosine-based inhibitory motif and an immunoreceptor tyrosine-based switch motif, suggesting that PD-1 negatively regulates TCR signaling (Ishida, Y. et al. (1992) EMBO J. 11:3887-2895; Blank, C. et al. (2006) Immunol. Immunother. 56(5):739-745).

[0118] PD-1 mediates inhibition of the immune system by binding to B7-H1 and B7-DC (Flies, DB et al. (2007) J. Immunother. 30(3):251-260; U.S. Patent Nos. 6,803,192; 7,794,710; U.S. Patent Application Publication Nos. 2005 / 0059051; 2009 / 0055944; 2009 / 0274666; 2009 / 0313687; PCT Publication Nos. WO01 / 39722; WO02 / 086083).

[0119] The amino acid sequence of human PD-1 protein (Genbank accession number NP_005009) is MQIPQAPWPVVWAVLQLGWRPGWFLDSPDRPWNPPTFSPALLVVTEGDNATFTCSFSNTSESFVLNWYRMSPSNQTDKLAAFPEDRSQPGQDCRFRVTQLPNGRDFHMSVVRARRNDSGTYLCGAISLAPKAQIKESLRAELRVTERRAEVPTAHPSPSPRPAGQFQTLVVGVVGGLLGSLVLLVWVLAVICSRAARGTIGARRTGQPLKEDPSAVPVFSVDYGELDFQWREKTPEPPVPCVPEQTEYATIVFPSGMGTSSPARRGSADGPRSAQPLRPEDGHCSWPL (SEQ ID NO: 1).

[0120] PD-1 has two ligands, PD-L1 and PD-L2 (Parry et al., Mol Cell Biol 2005, 9543-9553; Latchman et al., Nat Immunol 2001, 2, 261-268), which differ in their expression patterns. PD-L1 protein is elevated on macrophages and dendritic cells in response to lipopolysaccharide and GM-CSF treatment, and on T cells and B cells upon T cell receptor and B cell receptor signaling. PD-L1 is also highly expressed on almost all tumor cells, and expression is further increased after IFN-γ treatment (Iwai et al., PNAS 2002, 99(19):12293-7; Blank et al., Cancer Res 2004, 64(3):1140-5). Indeed, tumor PD-L1 expression status has been shown to predict prognosis in multiple tumor types (Wang et al., Eur J Surg Oncol 2015; Huang et al., Oncol Rep 2015; Sabatier et al., Oncotarget 2015, 6(7):5449-5464). In contrast, PD-L2 expression is more restricted and is primarily expressed by dendritic cells (Nakae et al., J Immunol 2006, 177:566-73). Ligation of PD-1 and its ligands PD-L1 and PD-L2 on T cells transduces signals that inhibit the production of IL-2 and IFN-γ, as well as cell proliferation induced upon T cell receptor activation (Carter et al., Eur J Immunol 2002, 32(3):634-43; Freeman et al., J Exp Med 2000, 192(7):1027-34). This mechanism involves recruitment of SHP-2 or SHP-1 phosphatases to inhibit T cell receptor signaling, including Syk and Lck phosphorylation (Sharpe et al., Nat Immunol 2007, 8, 239-245). Activation of the PD-1 signaling axis also attenuates phosphorylation of the PKC-θ activation loop, which is involved in the activation of NF- kIt is required for activation of the B and AP1 pathways and for the production of cytokines such as IL-2, IFN-γ, and TNF (Sharpe et al, Nat Immunol 2007, 8, 239-245; Carter et al, Eur J Immunol 2002, 32(3):634-43; Freeman et al, J Exp Med 2000, 192(7):1027-34).

[0121] Several lines of evidence from preclinical animal studies indicate that PD-1 and its ligands negatively regulate immune responses. PD-1-deficient mice have been shown to develop lupus-like glomerulonephritis and dilated cardiomyopathy (Nishimura et al., Immunity 1999, 11:141-151; Nishimura et al., Science 2001, 291:319-322). Using an LCMV model of chronic infection, PD-1 / PD-L1 interactions have been shown to inhibit the activation, expansion, and acquisition of virus-specific CD8 T cell effector functions (Barber et al., Nature 2006, 439, 682-7). Collectively, these data support the development of therapeutic approaches that block PD-1-mediated inhibitory signaling cascades to enhance or "rescue" T cell responses. Therefore, new methods are needed to block PD-1 / PD-L1 protein / protein interactions and thereby treat cancers of interest.

[0122] In some embodiments, the PD-1 / PD-L1 inhibitor is nivolumab (OPDIVO®, BMS-936558, MDX1106, or MK-34775), pembrolizumab (KEYTRUDA®, MK-3475, SCH-900475, lambrolizumab), CAS Registry Number 1374853-91-4), atezolizumab (Tecentriq®, CAS Registry Number 1374853-91-4), or rituximab (Tecentriq®, CAS Registry Number 1374853-91-4). Reg No. 1380723-44-3), durvalumab, avelumab (Bavencio®), cemiplimab, AMP-224, AMP-514 / MEDI-0680, atezolizumab, avelumab, BGB-A317, BMS936559, durvalumab, JTX-4014, SHR-1210, pidilizumab (CT-011), REGN2810, BGB-1 08, BGB-A317, SHR-1210 (HR-301210, SHR1210, or SHR-1210), BMS-936559, MPDL3280A, MEDI4736, MSB0010718C, MDX1105-01, and U.S. Patent Nos. 7,488,802, 7,943,743, 8,008,449, 8,168,757, and 8,217,149. or publication numbers WO03042402, WO2008 / 156712, WO2010 / 089411, WO2010 / 036959, WO2011 / 066342, WO2011 / 159877, WO2011 / 082400, WO2011 / 161699, WO2017 / 070089, WO2017 / 087777, WO2017 / 106634, and WO2017 / 11273 and WO2019 / 217821, and any combination thereof. The disclosures of each of the patents, applications, and published patent applications set forth herein are incorporated by reference in their entirety.

[0123] In some embodiments, the inhibitor of PD-1 / PD-L1 is selected from compounds such as those disclosed in WO2018 / 119266.

[0124] (S)-1-((7-chloro-2-(2'-chloro-3'-(5-(((2-hydroxyethyl)amino)methyl)picolinamido)-2-methyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)piperidine-2-carboxylic acid, or a pharmaceutically acceptable salt thereof; (S)-1-((7-chloro-2-(3'-(7-chloro-5-(((S)-3-hydroxypyrrolidin-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylic acid, or a pharmaceutically acceptable salt thereof; (R)-1-((7-cyano-2-(3'-(3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylic acid, or a pharmaceutically acceptable salt thereof; (S)-1-((2-(2'-chloro-3'-(1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-2-methylbiphenyl-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylic acid, or a pharmaceutically acceptable salt thereof; (R)-1-((7-cyano-2-(2,2'-dimethyl-3'-(4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)biphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylic acid, or a pharmaceutically acceptable salt thereof; (R)-1-((7-cyano-2-(3'-(5-(2-(dimethylamino)acetyl)-5,6-dihydro-4H-pyrrolo[3,4-d]thiazol-2-yl)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylic acid, or a pharmaceutically acceptable salt thereof; and 1-((7-cyano-2-(3'-(5-(2-(dimethylamino)acetyl)-5,6-dihydro-4H-pyrrolo[3,4-d]thiazol-2-yl)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)piperidine-4-carboxylic acid, or a pharmaceutically acceptable salt thereof.

[0125] In some embodiments, the PD-1 / PD-L1 inhibitor is (R)-1-((7-cyano-2-(3'-(3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylic acid, or a pharmaceutically acceptable salt thereof. (R)-1-((7-cyano-2-(3'-(3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylic acid is disclosed in WO2018 / 119266, which is incorporated herein by reference in its entirety.

[0126] In some embodiments, the inhibitor of PD-1 / PD-L1 is selected from: (R)-1-((7-cyano-2-(3'-(3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylic acid hydrobromide; (R)-1-((7-cyano-2-(3'-(3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylic acid oxalate; (R)-1-((7-cyano-2-(3'-(3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylic acid hydrochloride; (R)-1-((7-cyano-2-(3'-(3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylic acid L-tartrate; (R)-1-((7-cyano-2-(3'-(3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylic acid malonate; and (R)-1-((7-cyano-2-(3'-(3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylic acid phosphate.

[0127] In some embodiments, the inhibitor of PD-1 / PD-L1 is selected from compounds such as those disclosed in WO2018 / 119224.

[0128] (S)-1-((2-(2'-chloro-3'-(1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-2-methylbiphenyl-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylic acid, or a pharmaceutically acceptable salt thereof; (R)-1-((2-(2'-chloro-3'-(6-isopropyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridin-2-yl)-2-methylbiphenyl-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylic acid, or a pharmaceutically acceptable salt thereof; (S)—N-(2-chloro-3′-(5-(2-hydroxypropyl)-1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamide)-2′-methylbiphenyl-3-yl)-5-isopropyl-1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamide, or a pharmaceutically acceptable salt thereof; cis-4-((2-((2,2'-dichloro-3'-(1-methyl-5-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-[1,1'-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)methyl)cyclohexane-1-carboxylic acid, or a pharmaceutically acceptable salt thereof; trans-4-(2-(2-((2,2'-dichloro-3'-(5-(2-hydroxyethyl)-1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-[1,1'-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)ethyl)cyclohexane-1-carboxylic acid, or a pharmaceutically acceptable salt thereof; trans-4-(2-(2-((2-chloro-2'-methyl-3'-(1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-[1,1'-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)ethyl)cyclohexane-1-carboxylic acid, or a pharmaceutically acceptable salt thereof; and cis-4-((2-(2-chloro-3'-(5-(2-(ethyl(methyl)amino)acetyl)-5,6-dihydro-4H-pyrrolo[3,4-d]thiazol-2-yl)-2'-methylbiphenyl-3-ylcarbamoyl)-1-methyl-6,7-dihydro-1H-imidazo[4,5-c]pyridin-5(4H)-yl)methyl)cyclohexane-1-carboxylic acid, or a pharmaceutically acceptable salt thereof.

[0129] In some embodiments, the inhibitor of PD-1 / PD-L1 is selected from compounds such as those disclosed in WO2019 / 191707.

[0130] (R)-1-((7-cyano-2-(3'-(7-((3-hydroxypyrrolidin-1-yl)methyl)-2-methylpyrido[3,2-d]pyrimidin-4-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)piperidine-4-carboxylic acid, or a pharmaceutically acceptable salt thereof; (R)-1-((7-cyano-2-(3'-(7-(((S)-1-hydroxypropan-2-ylamino)methyl)-2-methylpyrido[3,2-d]pyrimidin-4-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylic acid, or a pharmaceutically acceptable salt thereof; (R)-1-((7-cyano-2-(3'-(2-(difluoromethyl)-7-((3-hydroxypyrrolidin-1-yl)methyl)pyrido[3,2-d]pyrimidin-4-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)piperidine-4-carboxylic acid, or a pharmaceutically acceptable salt thereof; (R)-1-((7-cyano-2-(3'-(2-(difluoromethyl)-7-((3-hydroxypyrrolidin-1-yl)methyl)pyrido[3,2-d]pyrimidin-4-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)piperidine-4-carboxylic acid, or a pharmaceutically acceptable salt thereof; (R)-1-((7-cyano-2-(3'-(2-cyclopropyl-7-(((R)-3-hydroxypyrrolidin-1-yl)methyl)pyrido[3,2-d]pyrimidin-4-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylic acid, or a pharmaceutically acceptable salt thereof; and (R)-1-((7-cyano-2-(3'-(3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-6-methyl-1,7-naphthyridin-8-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylic acid, or a pharmaceutically acceptable salt thereof.

[0131] In some embodiments, the inhibitor of PD-1 / PD-L1 is selected from compounds such as those disclosed in WO2019 / 217821.

[0132] 4-(2-(2-((2,2'-dichloro-3'-(1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-[1,1'-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)ethyl)bicyclo[2.2.1]heptane-1-carboxylic acid, or a pharmaceutically acceptable salt thereof; 4-(2-(2-((3'-(5-((1H-pyrazol-3-yl)methyl)-1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-2,2'-dichloro-[1,1'-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)ethyl)bicyclo[2.2.1]heptane-1-carboxylic acid, or a pharmaceutically acceptable salt thereof; (R)-4-(2-(2-((2,2'-dichloro-3'-(5-(2-hydroxypropyl)-1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-[1,1'-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)ethyl)bicyclo[2.2.1]heptane-1-carboxylic acid, or a pharmaceutically acceptable salt thereof; 4,4'-(((((2,2'-dichloro-[1,1'-biphenyl]-3,3'-diyl)bis(azanediyl))bis(carbonyl))bis(1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-2,5-diyl))bis(ethane-2,1-diyl))bis(bicyclo[2.2.1]heptane-1-carboxylic acid), or a pharmaceutically acceptable salt thereof; 4-(2-(2-((2-chloro-2'-methyl-3'-(1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-[1,1'-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)ethyl)bicyclo[2.2.1]heptane-1-carboxylic acid, or a pharmaceutically acceptable salt thereof; 4-(2-(2-((2,2'-dimethyl-3'-(1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-[1,1'-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)ethyl)bicyclo[2.2.1]heptane-1-carboxylic acid, or a pharmaceutically acceptable salt thereof; and 4-(2-(2-((3'-(5-(trans-4-carboxy-4-methylcyclohexyl)-1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-2,2'-dichloro-[1,1'-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)ethyl)bicyclo[2.2.1]heptane-1-carboxylic acid, or a pharmaceutically acceptable salt thereof.

[0133] In some embodiments, the inhibitor of PD-1 / PD-L1 is a humanized antibody.

[0134] In some embodiments, the PD-1 / PD-L1 inhibitor is pembrolizumab.

[0135] In some embodiments, the PD-1 / PD-L1 inhibitor is nivolumab.

[0136] In some embodiments, the PD-1 / PD-L1 inhibitor is atezolizumab.

[0137] In some embodiments, the inhibitor of PD-1 / PD-L1 is an antibody or antigen-binding fragment thereof that binds to human PD-1. In some embodiments, the antibody or antigen-binding fragment thereof that binds to human PD-1 is a humanized antibody.

[0138] In some embodiments, the PD-1 / PD-L1 inhibitor is retifanlimab (ie, MGA-012).

[0139] Retifanlimab is a humanized IgG4 monoclonal antibody that binds to human PD-1. See U.S. Patent No. 10,577,422, hPD-1 mAb 7(1.2), which is incorporated herein by reference in its entirety. The amino acid sequences of the mature retifanlimab heavy and light chains are set forth below. Complementarity-determining regions (CDRs) 1, 2, and 3 of the variable heavy (VH) and variable light (VL) domains are shown in order from the N-terminus to the C-terminus of the mature VL and VH sequences and are both underlined and bold. An antibody consisting of the mature heavy chain (SEQ ID NO: 2) and mature light chain (SEQ ID NO: 3) listed below is referred to as retifanlimab.

[0140] Mature retifanlimab heavy chain (HC) [ka] Mature retifanlimab light chain (LC) [ka] The variable heavy (VH) domain of retifanlimab has the following amino acid sequence:

[0141] [ka] The variable light (VL) domain of retifanlimab has the following amino acid sequence:

[0142] [ka] The amino acid sequences of the VH CDRs of retifanlimab are listed below.

[0143] VH CDR1: SYWMN (SEQ ID NO: 6), VH CDR2: VIHPSDSETWLDQKFKD (SEQ ID NO: 7), VH CDR3: EHYGTSPFAY (SEQ ID NO: 8) The amino acid sequences of the VL CDRs of retifanlimab are listed below.

[0144] VL CDR1: RASESVDNYGMSFMNW (SEQ ID NO: 9), VL CDR2: AASNQGS (SEQ ID NO: 10), and VL CDR3: QQSKEVPYT (SEQ ID NO: 11).

[0145] In some embodiments, the inhibitor of PD-1 / PD-L1 is an antibody or antigen-binding fragment thereof that binds to human PD-1, wherein the antibody or antigen-binding fragment thereof comprises a variable heavy (VH) complementarity-determining region (CDR) domain comprising VH CDR1, VH CDR2, and VH CDR3, wherein: the VH CDR1 comprises the amino acid sequence SYWMN (SEQ ID NO: 6); the VH CDR2 comprises the amino acid sequence VIHPSDSETWLDQKFKD (SEQ ID NO: 7); the VH CDR3 comprises the amino acid sequence EHYGTSPFAY (SEQ ID NO: 8); wherein the antibody comprises a variable light (VL) domain comprising a VL CDR1, a VL CDR2, and a VL CDR3, wherein: the VL CDR1 comprises the amino acid sequence RASESVDNYGMSFMNW (SEQ ID NO: 9); the VL CDR2 comprises the amino acid sequence AASNQGS (SEQ ID NO: 10); The VL CDR3 comprises the amino acid sequence QQSKEVPYT (SEQ ID NO: 11).

[0146] Anti-CD73 antibody CD73 (also known as "5'-nucleotidase" and "ecto-5'-nucleotidase") is a dimeric enzyme (EC:3.1.3.5) that functions as a homodimer bound by a GPI linkage to the outer surface of the plasma membrane. CD73 can be shed and is activated as a soluble protein in the circulation. CD73 catalyzes the conversion of extracellular AMP to adenosine. CD73 enzymatic activity requires substrate binding in the open CD73 conformation. After substrate binding, CD73 undergoes a major conformational change from an open to a closed conformation, converting AMP to adenosine (see, e.g., Knapp et al., 2012, Structure, 20(12):2161-73). CD73 also functions as a cell adhesion molecule and plays a role in regulating leukocyte trafficking.

[0147] CD73 enzymatic activity plays a role in cancer progression and metastasis (see, e.g., Stagg and Smyth, 2010, Oncogene, 29:5346-5358; Salmi and Jalkanen, 2012, OncoImmunology, 1:247-248, 2012; Stagg, 2012, OncoImmunology, 1:217-218; Zhang, 2012, OncoImmunology, 167-70). Overexpression of CD73 in cancer cells impairs adaptive anti-tumor immune responses and promotes tumor growth and metastasis (see, e.g., Niemela et al., 2004, J.Immunol., 172:1646-1653; Sadej et al., 2006, Nucleosides Nucleotides Nucleic Acids, 25:1119-1123; Braganhol et al., 2007, Biochim.Biophys.Acta., 1770:1352-1359; Zhang, 2010, Cancer Res., 70:6407-6411; Zhang, 2012, OncoImmunology, 1:67-70).

[0148] An exemplary amino acid sequence of the mature human CD73 protein (amino acids 27-549 of GenBank Accession No. NP_002517) is as follows:

[0149] (SEQ ID NO: 70).

[0150] An exemplary amino acid sequence of the mature mouse CD73 protein (amino acids 29-551 of GenBank Accession No. NP_035981) is as follows:

[0151] (SEQ ID NO: 71).

[0152] An exemplary amino acid sequence of a mature cynomolgus monkey CD73 protein is as follows:

[0153] (SEQ ID NO: 72).

[0154] The present disclosure provides anti-CD73 antibodies useful in combination with A2A and / or A2B adenosine receptor inhibitors and PD-1 / PD-L1 inhibitors in the treatment of diseases, such as cancer. The present disclosure further provides anti-CD73 antibodies useful in combination with PD-1 / PD-L1 inhibitors in the treatment of diseases, such as cancer. These anti-CD73 antibodies are capable of binding to human CD73.

[0155] In some cases, these antibodies bind to human CD73 and cynomolgus monkey CD73. In some cases, these antibodies bind to human CD73 and cynomolgus monkey CD73, but not to mouse CD73. Such anti-CD73 antibodies include the sequence of anti-CD73 monoclonal antibody CL25 and its humanized version, HzCL25 (i.e., antibody Y), which binds with high affinity to both human and cynomolgus monkey CD73 and has undetectable binding to mouse CD73.

[0156] In some instances, these antibodies bind to human CD73, cynomolgus monkey CD73, and mouse CD73. Such anti-CD73 antibodies include the sequence of 3-F03, a human anti-CD73 monoclonal antibody that binds with high affinity to the open conformations of human, cynomolgus monkey, and mouse CD73, respectively.

[0157] Antibody HzCL25 (i.e., antibody Y) The antibody HzCL25 is a humanized IgG1 / kappa monoclonal antibody with an alanine at asparagine 297 (N297 according to EU numbering) in the heavy chain constant region to reduce effector function. D It specifically binds to human and cynomolgus monkey CD73 at a concentration of 0.5 nM or less and has low effector function.

[0158] HzCL25 was constructed from a chimeric version of the murine CL25 antibody.

[0159] Table 2 below shows the amino acid sequences of the HzCL25 CDRs according to IMGT numbering. Table 2 below also shows the amino acid sequences of the HzCL25 mature VH, VL, heavy chain, and light chain. [Table 2-1] [Table 2-2]

[0160] An anti-CD73 antibody may comprise the VH CDR1, VH CDR2, and VH CDR3, and the VL CDR1, VL CDR2, and VL CDR3 of HzCL25. In some cases, the anti-CD73 antibody comprises a VH comprising the VH CDR1, VH CDR2, and VH CDR3 of HzCL25 (see Table 2). In some cases, the anti-CD73 antibody comprises a VL comprising the VL CDR1, VL CDR2, and VL CDR3 of HzCL25 (see Table 2). In some cases, the anti-CD73 antibody comprises a VH comprising the VH CDR1, VH CDR2, and VH CDR3 of HzCL25 (see Table 2), and a VL comprising the VL CDR1, VL CDR2, and VL CDR3 of HzCL25 (see Table 2). In some cases, the anti-CD73 antibody may have, for example, one, two, or three substitutions in one or more (ie, one, two, three, four, five, or six) of the six CDRs of HzCL25. In some cases, the antibody (i) inhibits cellular CD73 (e.g., cellular CD73 activity is reduced by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 97%, at least 99%, or 100% compared to an isotype control), and / or (ii) inhibits soluble CD73 (e.g., soluble CD73 activity is reduced by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 97%, at least 99%, or 100% compared to an isotype control), and / or (iii) has high affinity (e.g., K D ≤ 0.5 nM) but does not significantly bind to mouse CD73 in the open conformation, and / or (iv) has high affinity (e.g., K D≦0.5 nM), but does not significantly bind to mouse CD73 in the closed conformation; and / or (v) binds to an epitope within amino acids 40-53 of SEQ ID NO: 70 (i.e., TKVQQIRRAEPNVL (SEQ ID NO: 76)); and / or (vi) reduces AMP-mediated inhibition of T cell proliferation (e.g., a decrease in T cell proliferation of at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 97%, at least 99%, or 100% compared to an isotype control); and / or (vii) reduces the level of cell surface CD73 (e.g., on cancer cells, e.g., on melanoma cancer cells, e.g., a decrease in T cell proliferation of at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 97%, at least 99%, or 100% compared to an isotype control). (viii) reduce tumor growth (e.g., melanoma) by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 97%, at least 99%, or 100%, e.g., compared to an isotope control); and / or (ix) reduce free surface CD73 on cells (e.g., cancer cells, e.g., melanoma) by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 97%, at least 99%, or 100%, e.g., compared to an isotope control).

[0161] In certain embodiments, the anti-CD73 antibody comprises an amino acid sequence having at least 80%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the VH of HzCL25 (i.e., the amino acid sequence set forth in SEQ ID NO: 22). In certain embodiments, the anti-CD73 antibody comprises a VH comprising the VH CDR1, VH CDR2, and VH CDR3 of HzCL25 (i.e., the amino acid sequences set forth in SEQ ID NOs: 16-18, respectively), wherein the VH comprises an amino acid sequence having at least 80%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the VH of HzCL25 (i.e., the amino acid sequence set forth in SEQ ID NO: 22). In certain specific embodiments, the anti-CD73 antibody comprises a VH comprising the amino acid sequence set forth in SEQ ID NO: 22. In some embodiments, the anti-CD73 antibody comprises an amino acid sequence having at least 80%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the heavy chain of HzCL25 (i.e., the amino acid sequence set forth in SEQ ID NO:24).In some embodiments, the anti-CD73 antibody comprises a heavy chain comprising a VH comprising the VH CDR1, VH CDR2, and VH CDR3 of HzCL25 (i.e., the amino acid sequences set forth in SEQ ID NOs: 16-18, respectively), wherein the VH has an amino acid sequence that is at least 80%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity (i.e., In some embodiments, the anti-CD73 antibody comprises a heavy chain comprising the amino acid sequence set forth in SEQ ID NO:24, wherein the heavy chain comprises an amino acid sequence having at least 80%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the heavy chain of HzCL25 (i.e., the amino acid sequence set forth in SEQ ID NO:24). In certain embodiments, the anti-CD73 antibody comprises an amino acid sequence having at least 80%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the VH of HzCL25 (i.e., the amino acid sequence set forth in SEQ ID NO: 23).In certain embodiments, the anti-CD73 antibody comprises a VH comprising the VL CDR1, VL CDR2, and VL CDR3 of HzCL25 (i.e., the amino acid sequences set forth in SEQ ID NOs: 19-21, respectively), wherein the VH comprises an amino acid sequence having at least 80%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the VH of HzCL25 (i.e., the amino acid sequence set forth in SEQ ID NO: 23). In certain embodiments, the anti-CD38 antibody comprises a VL comprising the amino acid sequence set forth in SEQ ID NO: 23. In some embodiments, the anti-CD73 antibody comprises an amino acid sequence having at least 80%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the light chain of HzCL25 (i.e., the amino acid sequence set forth in SEQ ID NO:25).In some embodiments, the anti-CD73 antibody comprises a light chain comprising a VL comprising the VL CDR1, VL CDR2, and VL CDR3 of HzCL25 (i.e., the amino acid sequences set forth in SEQ ID NOs: 19-21, respectively), wherein the VL has an amino acid sequence that is at least 80%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the VL of HzCL25 (i.e., In some embodiments, the anti-CD73 antibody comprises a light chain comprising the amino acid sequence set forth in SEQ ID NO:25, wherein the light chain comprises an amino acid sequence having at least 80%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the light chain of HzCL25 (i.e., the amino acid sequence set forth in SEQ ID NO:25). In certain embodiments, the anti-CD73 antibody comprises (i) an amino acid sequence having at least 80%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the VH of HzCL25 (i.e., the amino acid sequence set forth in SEQ ID NO:22); and (ii) an amino acid sequence having at least 80%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the VL of HzCL25 (i.e., the amino acid sequence set forth in SEQ ID NO:23).In some embodiments, the anti-CD73 antibody comprises (i) a VH comprising the VH CDR1, VH CDR2, and VH CDR3 of HzCL25 (i.e., the amino acid sequences set forth in SEQ ID NOs: 16-18, respectively), wherein the VH comprises an amino acid sequence having at least 80%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the VH of HzCL25 (i.e., the amino acid sequence set forth in SEQ ID NO: 22); and (ii) a VL CDR1, VL CDR2, and VL CDR3 of HzCL25. and (ii) a VL comprising the amino acid sequence set forth in SEQ ID NOs: 19-21, respectively, that has at least 80%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the VL of HzCL25 (i.e., the amino acid sequence set forth in SEQ ID NO: 23). In a specific embodiment, the anti-CD38 antibody comprises (i) the amino acid sequence set forth in SEQ ID NO: 22, and (ii) a VL comprising the amino acid sequence set forth in SEQ ID NO: 23.In some embodiments, the anti-CD73 antibody comprises (i) an amino acid sequence having at least 80%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the heavy chain of HzCL25 (i.e., the amino acid sequence set forth in SEQ ID NO:24), and (ii) an amino acid sequence having at least 80%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the light chain of HzCL25 (i.e., the amino acid sequence set forth in SEQ ID NO:25).In some embodiments, the anti-CD73 antibody comprises: (i) a heavy chain comprising a VH that comprises the VH CDR1, VH CDR2, and VH CDR3 of HzCL25 (i.e., the amino acid sequences set forth in SEQ ID NOs: 16-18, respectively), where the heavy chain comprises an amino acid sequence that has at least 80%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the heavy chain of HzCL25 (i.e., the amino acid sequence set forth in SEQ ID NO: 24); and (ii) a VL CDR1, VL CDR2, and VL CDR3 of HzCL25. a light chain comprising a VL comprising a CDR3 (i.e., the amino acid sequence set forth in SEQ ID NOs: 19-21, respectively), wherein the light chain comprises an amino acid sequence having at least 80%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the light chain of HzCL25 (i.e., the amino acid sequence set forth in SEQ ID NO: 25). In some embodiments, the anti-CD73 antibody comprises (i) a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 24, and (ii) a light chain comprising the amino acid sequence set forth in SEQ ID NO: 25.

[0162] The CD73-binding epitope of HzCL25 is within the amino acid sequence TKVQQIRRAEPNVL (SEQ ID NO: 76) (i.e., amino acids 40-53 of the amino acid sequence set forth in SEQ ID NO: 70). The present disclosure features antibodies that bind to CD73 within the sequence TKVQQIRRAEPNVL (SEQ ID NO: 76). The present disclosure features antibodies that bind to the same epitope as HzCL25. The present disclosure also features antibodies that competitively inhibit the binding of HzCL25 to human CD73.

[0163] In some embodiments, the VH of HzCL25 is linked to a heavy chain constant region comprising a CH1 domain and a hinge region. In some embodiments, the VH of HzCL25 is linked to a heavy chain constant region comprising a CH3 domain. In some embodiments, the CH3 domain lacks a C-terminal lysine (K) amino acid residue. In some embodiments, the CH3 domain comprises a C-terminal lysine (K) amino acid residue. In a specific embodiment, the VH of HzCL25 is linked to a heavy chain constant region comprising a CH1 domain, a hinge region, a CH2 domain, and a CH3 domain from human IgG1. In some embodiments, the CH3 domain from human IgG1 lacks a C-terminal lysine (K) amino acid residue. In some embodiments, the CH3 domain from human IgG1 comprises a C-terminal lysine (K) amino acid residue. In certain embodiments, such antibodies comprise one or more additional mutations in the heavy chain constant region that increase the stability of the antibody. In certain embodiments, the heavy chain constant region comprises substitutions that alter the properties of the antibody (e.g., decreased Fc receptor binding, increased or decreased glycosylation of the antibody, decreased binding to C1q). In a specific embodiment, the heavy chain constant region comprises an alanine at asparagine 297 (N297 according to EU numbering) of the heavy chain constant region to reduce effector function.

[0164] In certain embodiments, the anti-CD73 antibody is an IgG antibody. In one embodiment, the antibody is an IgG1 antibody. In one embodiment, the antibody is an IgG4 antibody. In another embodiment, the antibody is an IgG2 antibody. In certain embodiments, the anti-CD73 antibody comprises a heavy chain constant region that lacks one or more lysine (K) amino acid residues compared to a wild-type heavy chain constant region. For example, in certain embodiments, the antibody comprises a heavy chain constant region that lacks a C-terminal lysine (K) amino acid residue in the CH3 domain of the heavy chain constant region.

[0165] Antibody 3-F03 Antibody 3-F03 is a human IgG1 / kappa monoclonal antibody with an alanine at asparagine position 297 (N297 according to EU numbering) in the heavy chain constant region to reduce effector function. 3-F03 has high affinity (K D It specifically binds to human, cynomolgus monkey, and mouse CD73 at a concentration of ≤2 nM and has low effector function.

[0166] Table 3 below shows the amino acid sequences of the 3-F03 CDRs according to IMGT numbering. Table 3 below also shows the amino acid sequences of the 3-F03 mature VH, VL, heavy chain, and light chain. [Table 3-1] [Table 3-2]

[0167] Variants of 3-F03 are also described herein. 3-F03_411 is identical to 3-F03, except that the 3-F03_411 heavy chain (i) contains an N-terminal glutamic acid (E) that is absent in 3-F03, and (ii) does not contain a C-terminal lysine that is present in 3-F03. Table 4 below shows the amino acid sequences of the 3-F03_411 mature VH, VL, heavy chain, and light chain. 3-F03_413 is identical to 3-F03_411, except that it contains a glutamic acid (E) instead of an aspartic acid (D) at position H53 of VH Kabat (position 54 of SEQ ID NO: 60). Table 5 below shows the amino acid sequences of the 3-F03_413 CDRs according to the IMGT, Chothia, AbM, Kabat, and contact numbering. Table 5 below also shows the amino acid sequences of the 3-F03_413 mature VH, VL, heavy chain, and light chain. [Table 4] [Table 5-1] [Table 5-2]

[0168] An anti-CD73 antibody may comprise the VH CDR1, VH CDR2, and VH CDR3, and the VL CDR1, VL CDR2, and VL CDR3, of 3-F03 or 3-F03_413. In some cases, the anti-CD73 antibody comprises a VH comprising the VH CDR1, VH CDR2, and VH CDR3 of 3-F03 (see Table 3). In some cases, the anti-CD73 antibody comprises a VL comprising the VL CDR1, VL CDR2, and VL CDR3 of 3-F03 (see Table 3). In some cases, the anti-CD73 antibody comprises a VH comprising the VH CDR1, VH CDR2, and VH CDR3 of 3-F03 (see Table 3), and a VL comprising the VL CDR1, VL CDR2, and VL CDR3 of 3-F03 (see Table 3). In some cases, the anti-CD73 antibody comprises a VH that comprises the VH CDR1, VH CDR2, and VH CDR3 of 3-F03_413 (see Table 5). In some cases, the anti-CD73 antibody comprises a VL that comprises the VL CDR1, VL CDR2, and VL CDR3 of 3-F03_413 (see Table 5). In some cases, the anti-CD73 antibody comprises a VH that comprises the VH CDR1, VH CDR2, and VH CDR3 of 3-F03_413 (see Table 5), and a VL that comprises the VL CDR1, VL CDR2, and VL CDR3 of 3-F03_413 (see Table 5). In some cases, the anti-CD73 antibody may have, for example, one, two, or three substitutions in one or more (i.e., one, two, three, four, five, or six) of the six CDRs of 3-F03 or 3-F03_413.In some cases, these antibodies (i) inhibit cellular CD73 (e.g., at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 97%, at least 99%, or 100% reduction in cellular CD73 activity compared to an isotype control), and / or (ii) inhibit soluble CD73 (e.g., at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 97%, at least 99%, or 100% reduction in soluble CD73 activity compared to an isotype control), and / or (iii) have high affinity (e.g., K D≦2 nM) and / or (iv) does not bind to human, cynomolgus, or mouse CD73 in the open conformation, and / or (v) binds to an epitope within amino acids 386-399 of SEQ ID NO: 70 (i.e., within amino acids 470-489 of SEQ ID NO: 70 (i.e., within AAVLPFGGTFDLVQ (SEQ ID NO: 78) and ILPNFLANGGDGFQMIKDEL (SEQ ID NO: 79))), and / or (vi) reduces AMP-mediated inhibition of T cell proliferation (e.g., reduces T cell proliferation by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 97%, at least 99%, or or 100% reduction), and / or (vii) reducing the level of cell surface CD73 (e.g., on cancer cells, e.g., on melanoma cancer cells, e.g., by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 97%, at least 99%, or 100%, e.g., compared to an isotope control), and / or (viii) reducing tumor growth (e.g., malignant melanoma, e.g., by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 97%, at least 99%, or 100%, e.g., compared to an isotope control).

[0169] In specific embodiments, the anti-CD73 antibody comprises an amino acid sequence having at least 80%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the VH of 3-F03_411 or 3-F03_413 (i.e., the amino acid sequence set forth in SEQ ID NO: 62 or 63, respectively). In certain embodiments, the anti-CD73 antibody comprises a VH comprising the VH CDR1, VH CDR2, and VH CDR3 of 3-F03_411 (see Table 3, e.g., according to the IMGT definition, i.e., the amino acid sequences set forth in SEQ ID NOs: 34-36, respectively), wherein the VH comprises an amino acid sequence having at least 80%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the VH of 3-F03_411 (i.e., the amino acid sequence set forth in SEQ ID NO: 62). In certain embodiments, the anti-CD73 antibody comprises a VH comprising the VH CDR1, VH CDR2, and VH CDR3 of 3-F03_413 (see Table 5, e.g., according to the IMGT definition, i.e., the amino acid sequences set forth in SEQ ID NOs: 34, 40, and 36, respectively), wherein the VH comprises an amino acid sequence having at least 80%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the VH of 3-F03_411 (i.e., the amino acid sequence set forth in SEQ ID NO: 63). In some embodiments, the anti-CD73 antibody is an antibody comprising a VH having the amino acid sequence set forth in SEQ ID NO: 62.In some embodiments, the anti-CD73 antibody comprises a VH comprising the amino acid sequence set forth in SEQ ID NO: 63. In some embodiments, the anti-CD73 antibody comprises an amino acid sequence having at least 80%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the heavy chain of 3-F03_411 or 3-F03_413 (i.e., the amino acid sequence set forth in SEQ ID NO: 30 or 33, respectively). In some embodiments, the anti-CD73 antibody comprises a heavy chain comprising a VH comprising the VH CDR1, VH CDR2, and VH CDR3 of 3-F03_411 (see Table 3, e.g., according to the IMGT definition, i.e., the amino acid sequences set forth in SEQ ID NOs: 34-36, respectively), wherein the heavy chain comprises an amino acid sequence having at least 80%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the heavy chain of 3-F03_411 (i.e., the amino acid sequence set forth in SEQ ID NO: 30). In some embodiments, the anti-CD73 antibody comprises a heavy chain comprising a VH that comprises the VH CDR1, VH CDR2, and VH CDR3 of 3-F03_413 (see Table 5, e.g., according to the IMGT definition, i.e., the amino acid sequences set forth in SEQ ID NOs: 34, 40, and 36, respectively), wherein the heavy chain comprises an amino acid sequence having at least 80%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the heavy chain of 3-F03_413 (i.e., the amino acid sequence set forth in SEQ ID NO: 33).In some embodiments, the anti-CD73 antibody comprises a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 30. In some embodiments, the anti-CD73 antibody comprises a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 33. In specific embodiments, the anti-CD73 antibody comprises an amino acid sequence having at least 80%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the VL of 3-F03_411 or 3-F03_413 (i.e., the amino acid sequence set forth in SEQ ID NO: 61). In certain embodiments, the anti-CD73 antibody comprises a VL comprising the VL CDR1, VL CDR2, and VL CDR3 of 3-F03_411 (see Table 3, e.g., according to the IMGT definition, i.e., the amino acid sequences set forth in SEQ ID NOs: 37-39, respectively), wherein the VL comprises an amino acid sequence having at least 80%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the VL of 3-F03_411 or 3-F03_413 (i.e., the amino acid sequence set forth in SEQ ID NO: 61). In some embodiments, the anti-CD38 antibody comprises a VL having the amino acid sequence set forth in SEQ ID NO: 61. In some embodiments, the anti-CD73 antibody comprises an amino acid sequence having at least 80%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the light chain of F03_411 or 3-F03_413 (i.e., the amino acid sequence set forth in SEQ ID NO: 31).In some embodiments, the anti-CD73 antibody comprises a light chain comprising a VL that includes the VL CDR1, VL CDR2, and VL CDR3 of 3-F03_411 or 3-F03_413 (see Table 5, e.g., according to the IMGT definition, i.e., the amino acid sequences set forth in SEQ ID NOs: 37-39, respectively), wherein the light chain comprises an amino acid sequence having at least 80%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the light chain of 3-F03_411 or 3-F03_413 (i.e., the amino acid sequence set forth in SEQ ID NO: 31). In some embodiments, the anti-CD73 antibody comprises a light chain comprising the amino acid sequence set forth in SEQ ID NO: 31. In certain embodiments, the anti-CD73 antibody has an amino acid sequence having at least 80%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the VH of 3-F03_411 or 3-F03_413 (i.e., SEQ ID NO: 62 or 63, respectively). and an amino acid sequence having at least 80%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the VL of 3-F03_411 or 3-F03_413 (i.e., the amino acid sequence set forth in SEQ ID NO: 61).In some embodiments, the anti-CD73 antibody comprises (i) a VH comprising the VH CDR1, VH CDR2, and VH CDR3 of 3-F03_411 (see Table 3, e.g., according to the IMGT definition, i.e., the amino acid sequences set forth in SEQ ID NOs: 34-36, respectively), wherein the VH comprises an amino acid sequence having at least 80%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the VH of 3-F03 (i.e., the amino acid sequence set forth in SEQ ID NO: 62); and (ii) the VL CDR1, VL CDR2, and VL CDR3 of 3-F03_411. A VL comprising a CDR3 (see Table 3, e.g., according to the IMGT definition, i.e., the amino acid sequences set forth in SEQ ID NOs: 37-39, respectively), wherein the VL comprises an amino acid sequence having at least 80%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the VL of 3-F03 (i.e., the amino acid sequence set forth in SEQ ID NO: 61).In some embodiments, the anti-CD73 antibody comprises (i) a VH comprising the VH CDR1, VH CDR2, and VH CDR3 of 3-F03_413 (see Table 5, e.g., according to the IMGT definition, i.e., the amino acid sequences set forth in SEQ ID NOs: 34, 40, and 36, respectively), wherein the VH comprises an amino acid sequence having at least 80%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the VH of 3-F03_413 (i.e., the amino acid sequence set forth in SEQ ID NO: 63); and (ii) the VL CDR1, VL CDR2, and VL CDR3 of 3-F03_413. A VL comprising a CDR3 (see Table 5, e.g., according to the IMGT definition, i.e., the amino acid sequences set forth in SEQ ID NOS: 37-39, respectively), wherein the VL comprises an amino acid sequence having at least 80%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the VL of 3-F03_413 (i.e., the amino acid sequence set forth in SEQ ID NO: 61). In some embodiments, the anti-CD73 antibody comprises (i) a VH having the amino acid sequence set forth in SEQ ID NO: 62, and (ii) a VL comprising the amino acid sequence set forth in SEQ ID NO: 61. In some embodiments, the anti-CD73 antibody comprises (i) a VH having the amino acid sequence set forth in SEQ ID NO: 63, and (ii) a VL comprising the amino acid sequence set forth in SEQ ID NO: 61. In some embodiments, the anti-CD73 antibody comprises an amino acid sequence having at least 80%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the heavy chain of 3-F03_411 or 3-F03_413 (i.e., SEQ ID NO: 30 or 33). and an amino acid sequence having at least 80%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the light chain of 3-F03_411 or 3-F03_413 (i.e., the amino acid sequence shown in SEQ ID NO: 31).In some embodiments, the anti-CD73 antibody comprises: (i) a heavy chain comprising the VH CDR1, VH CDR2, and VH CDR3 of 3-F03_411 (see Table 3, e.g., according to the IMGT definition, i.e., the amino acid sequences set forth in SEQ ID NOs: 34-36, respectively), where the heavy chain comprises an amino acid sequence having at least 80%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the heavy chain of 3-F03_411 (i.e., the amino acid sequence set forth in SEQ ID NO: 30); and (ii) the VL CDR1, VL CDR2, and VL CDR3 of 3-F03_411. A light chain comprising a CDR3 (see Table 3, e.g., according to the IMGT definition, i.e., the amino acid sequences set forth in SEQ ID NOS: 37-39, respectively), wherein the light chain comprises an amino acid sequence having at least 80%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the light chain of 3-F03 (i.e., the amino acid sequence set forth in SEQ ID NO: 31).In some embodiments, the anti-CD73 antibody comprises (i) a heavy chain comprising the VH CDR1, VH CDR2, and VH CDR3 of 3-F03_413 (see Table 5, e.g., according to the IMGT definition, i.e., the amino acid sequences set forth in SEQ ID NOs: 34, 40, and 36, respectively), wherein the heavy chain comprises an amino acid sequence having at least 80%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the heavy chain of 3-F03 (i.e., the amino acid sequence set forth in SEQ ID NO: 33); and (ii) the VL CDR1, VL CDR2, and VL CDR3 of 3-F03_413. and a light chain comprising a CDR3 (see Table 5, e.g., according to the IMGT definition, i.e., the amino acid sequences set forth in SEQ ID NOS: 37-39, respectively), wherein the light chain comprises an amino acid sequence having at least 80%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the light chain of 3-F03_413 (i.e., the amino acid sequence set forth in SEQ ID NO: 31). In some embodiments, the anti-CD73 antibody comprises (i) a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 30, and (ii) a light chain comprising the amino acid sequence set forth in SEQ ID NO: 31. In some embodiments, the anti-CD73 antibody comprises (i) a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 33, and (ii) a light chain comprising the amino acid sequence set forth in SEQ ID NO: 31.

[0170] The CD73-binding epitope of 3-F03 (and its variants, e.g., 3-F03_411 and 3-F03_413) includes AAVLPFGGTFDLVQ (SEQ ID NO: 78) (i.e., amino acids 386 to 399 of the amino acid sequence set forth in SEQ ID NO: 70) and ILPNFLANGGDGFQMIKDEL (SEQ ID NO: 79) (i.e., amino acids 470 to 489 of the amino acid sequence set forth in SEQ ID NO: 70). The present disclosure features antibodies that bind to CD73 epitopes within AAVLPFGGTFDLVQ (SEQ ID NO: 78) and ILPNFLANGGDGFQMIKDEL (SEQ ID NO: 79). The present disclosure features antibodies that bind to the same epitope as 3-F03 (or variants thereof, e.g., 3-F03_411 or 3-F03_413). The present disclosure also features antibodies that competitively inhibit the binding of 3-F03 (or a variant thereof, e.g., 3-F03_411 or 3-F03_413) to human CD73.

[0171] In some embodiments, the VH of 3-F03 (or a variant thereof, such as 3-F03_411 or 3-F03_413) is linked to a heavy chain constant region comprising a CH1 domain and a hinge region. In some embodiments, the VH of 3-F03 (or a variant thereof, such as 3-F03_411 or 3-F03_413) is linked to a heavy chain constant region comprising a CH3 domain. In some embodiments, the CH3 domain lacks a C-terminal lysine (K) amino acid residue. In some embodiments, the CH3 domain comprises a C-terminal lysine (K) amino acid residue. In a specific embodiment, the VH of 3-F03 (or a variant thereof, such as 3-F03_411 or 3-F03_413) is linked to a heavy chain constant region comprising a CH1 domain, a hinge region, a CH2 domain, and a CH3 domain from human IgG1. In some embodiments, the CH3 domain from human IgG1 lacks a C-terminal lysine (K) amino acid residue. In some embodiments, the CH3 domain from human IgG1 comprises a C-terminal lysine (K) amino acid residue. In certain embodiments, such antibodies comprise one or more additional mutations in the heavy chain constant region that increase the stability of the antibody. In certain embodiments, the heavy chain constant region comprises a substitution that alters the properties of the antibody (e.g., reduced Fc receptor binding, increased or decreased glycosylation of the antibody, decreased binding to C1q). In certain embodiments, the heavy chain constant region comprises an alanine at asparagine 297 (N297 according to EU numbering) of the heavy chain constant region to reduce effector function.

[0172] In certain embodiments, the anti-CD73 antibody is an IgG antibody. In one embodiment, the antibody is an IgG1 antibody. In one embodiment, the antibody is an IgG4 antibody. In another embodiment, the antibody is an IgG2 antibody. In certain embodiments, the anti-CD73 antibody comprises a heavy chain constant region that lacks one or more lysine (K) amino acid residues compared to a wild-type heavy chain constant region. For example, in certain embodiments, the antibody comprises a heavy chain constant region that lacks a C-terminal lysine (K) amino acid residue in the CH3 domain of the heavy chain constant region.

[0173] Additional anti-CD73 antibodies and inhibitors The present disclosure provides additional anti-CD73 antibodies and anti-CD73 inhibitors useful in combination with A2A and / or A2B adenosine receptor inhibitors in the treatment of diseases, such as cancer. The present disclosure provides anti-CD73 antibodies and anti-CD73 inhibitors useful in combination with A2A and / or A2B adenosine receptor inhibitors and / or in combination with PD-1 / PD-L1 inhibitors in the treatment of diseases, such as cancer. The disclosure further provides anti-CD73 antibodies and anti-CD73 inhibitors useful in combination with PD-1 / PD-L1 inhibitors in the treatment of diseases, such as cancer.

[0174] Other anti-CD73 antibodies useful in combination with inhibitors of A2A and / or A2B adenosine receptors in the methods described herein are known in the art. Other anti-CD73 antibodies useful in combination with inhibitors of A2A and / or A2B adenosine receptors and / or in combination with inhibitors of PD-1 / PD-L1 in the treatment of diseases in the methods described herein are known in the art. Other anti-CD73 antibodies useful in combination with inhibitors of PD-1 / PD-L1 in the treatment of diseases in the methods described herein are known in the art. See, for example, U.S. Patent Nos. 9,090,697, 9,388,249, 9,605,080, 9,938,356, 10,100,129, and 10,287,362, U.S. Patent Application Publication Nos. 2004 / 0142342 and 2007 / 0009518, each of which is incorporated herein by reference in its entirety. , 2011 / 0300136, 2018 / 0009899, ​​2018 / 0030144, 2018 / 0237536, 2018 / 0264107, 2019 / 0031766, 2019 / 0225703, 2019 / 0077873, and 2019 / 0256598, International Publication No. WO See WO 2004 / 079013, WO 2011 / 089004, WO 2014 / 153424, WO 2017 / 100670, WO 2001 / 080884, WO 2018 / 110555, WO 2018 / 137598, WO 2018 / 187512, WO 2018 / 215535, WO 2018 / 237173, WO 2019 / 170131, WO 2019 / 173692, and WO 2019 / 173291.

[0175] In some examples, the anti-CD73 antibody comprises a VH comprising a VH CDR1, a VH CDR2, and a VH CDR3 of a VH comprising the amino acid sequence EIQLQQSGPELVKPGASVKVSCKASGYAFTSYNMYWVKQSHGKSLEWIGYIDPYNGGTSYNQKFKGKATLTVDKSSSTAYMHLNSLTSEDSAVYYCARGYGNYKAWFAYWGQGTLVTVSA (SEQ ID NO: 100), and a VL comprising a VL CDR1, a VL CDR2, and a VL CDR3 of a VL comprising the amino acid sequence DAVMTQTPKFLLVSAGDRVTITCKASQSVTNDVAWYQQKPGQSPKLLIYYASNRYTGVPDRFTGSGYGTDFTFTISTVQAEDLAVYFCQQDYSSLTFGAGTKLELK (SEQ ID NO: 101). In some cases, the anti-CD73 antibody comprises a VH comprising the amino acid sequence set forth in SEQ ID NO: 100 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 101. In some cases, the anti-CD73 antibody is 11E1 (see U.S. Patent Application Publication No. 2018 / 0237536, which is incorporated by reference herein in its entirety). In some cases, the anti-CD73 antibody comprises a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 102. In some cases, the anti-CD73 antibody comprises a light chain comprising the amino acid sequence set forth in SEQ ID NO: 103. In some cases, the anti-CD73 antibody comprises a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 102 and a light chain comprising the amino acid sequence set forth in SEQ ID NO: 103.

[0176] In some instances, the anti-CD73 antibody comprises a VH comprising a VH CDR1, a VH CDR2, and a VH CDR3 of the VH comprising the amino acid sequence EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAYSWVRQAPGKGLEWVSAISGSGGRTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARLGYGRVDEWGRGTLVTVSS (SEQ ID NO: 96), and a VL comprising a VL CDR1, a VL CDR2, and a VL CDR3 of the VL comprising the amino acid sequence QSVLTQPPSASGTPGQRVTISCSGSLSNIGRNPVNWYQQLPGTAPKLLIYLDNLRLSGVPDRFSGSSKSGTSASLAISGLQSEDEADYYCATWDDSHPGWTFGGGTKLTVL (SEQ ID NO: 97). In some cases, the anti-CD73 antibody comprises a VH comprising the amino acid sequence set forth in SEQ ID NO: 96 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 97. In some cases, the anti-CD73 antibody is Medi9447 (see U.S. Patent No. 10,287,362, incorporated herein by reference in its entirety). In some cases, the anti-CD73 antibody comprises a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 98. In some cases, the anti-CD73 antibody comprises a light chain comprising the amino acid sequence set forth in SEQ ID NO: 99. In some cases, the anti-CD73 antibody comprises a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 98 and a light chain comprising the amino acid sequence set forth in SEQ ID NO: 99.

[0177] In some cases, the CD73 inhibitor is CPI-006 (Corvus, see U.S. Patent Application Publication No. 2018 / 0009899A1 and International Publication No. WO2017 / 100670 AI, each of which is incorporated by reference in its entirety).

[0178] In some cases, the CD73 inhibitor is CB-708 SM (Calithera).

[0179] In some cases, the CD73 inhibitor is AB680 (Arcus).

[0180] In some cases, the CD73 inhibitor is BMS-986179 (BMS).

[0181] antibody fragment In some cases, the anti-CD73 antibody is an antibody fragment. The antibody fragments described herein (e.g., Fab, Fab', F(ab')2, Facb, and Fv) can be prepared by proteolysis of an intact antibody. For example, antibody fragments can be obtained by treating a whole antibody with an enzyme such as papain, pepsin, or plasmin. Papain digestion of a whole antibody produces F(ab)2 or Fab fragments, pepsin digestion of a whole antibody produces F(ab')2 or Fab', and plasmin digestion of a whole antibody produces Facb fragments.

[0182] Alternatively, antibody fragments can be produced recombinantly: for example, a nucleic acid encoding the antibody fragment of interest can be constructed, introduced into an expression vector, and expressed in a suitable host cell. See, e.g., Co, M. et al., J. Immunol., 152:2968-2976 (1994); Better, M. and Horwitz, A.H., Methods in Enzymology, 178:476-496 (1989); Plueckthun, A. and Skerra, A., Methods in Enzymology, 178:476-496 (1989); Lamoyi, E., Methods in Enzymology, 121:652-663 (1989); Rousseaux, J. et al., Methods in Enzymology, (1989) 121:663-669 (1989); and Bird, R. et al., TIBTECH, 9:132-137 (1991)). All antibody fragments can be expressed in and secreted from E. coli, allowing for the facile production of large amounts of these fragments. Antibody fragments can be isolated from antibody phage libraries. Alternatively, Fab'-SH fragments can be directly recovered from E. coli and chemically coupled to form F(ab)2 fragments (Carter et al., Bio / Technology, 10:163-167 (1992)). According to another approach, F(ab')2 fragments can be directly isolated from recombinant host cell culture. Fab and F(ab')2 fragments containing salvage receptor-binding epitope residues and having increased in vivo half-lives are described in U.S. Patent No. 5,869,046.

[0183] Mini Body In some instances, the anti-CD3 antibody is a minibody. Minibodies of anti-CD73 antibodies include diabodies, single-chain Fvs, and single-chain Fv2s (sc(Fv)2s). Minibodies of antibodies that bind to human PD-1 or human PD-L1 include diabodies, single-chain Fvs, and single-chain Fv2s (sc(Fv)2s).

[0184] A "diabody" is a bivalent minibody constructed by gene fusion (see, e.g., Holliger, P. et al., Proc. Natl. Acad. Sci. USA, 90:6444-6448 (1993), EP 404,097, and WO 93 / 11161). Diabodies are dimers consisting of two polypeptide chains. The VL and VH domains of each polypeptide chain of a diabody are connected by a linker. The number of amino acid residues constituting the linker can be 2 to 12 residues (e.g., 3 to 10 residues, or 5 or about 5 residues). The linker between polypeptides in a diabody is typically too short to allow the VL and VH to bind to each other. Therefore, the VL and VH encoded by the same polypeptide chain cannot form a single-chain variable region fragment, but instead form a dimer with different single-chain variable region fragments. As a result, a diabody has two antigen-binding sites.

[0185] scFv is a single-chain polypeptide antibody obtained by linking VH and VL with a linker (see, for example, Huston et al. Proc. Natl. Acad. Sci. USA, 85:5879-5883 (1988) and Plickthun, "The Pharmacology of Monoclonal Antibodies," Vol. 113, Ed Resenburg and Moore, Springer Verlag, New York, pp. 269-315, (1994)). The order of the linked VH and VL is not particularly limited, and they can be arranged in any order. Examples of arrangements include [VH] linker [VL] or [VL] linker [VH]. The heavy chain variable domain and light chain variable domain in scFv may be derived from any anti-CD73 antibody described herein. The heavy chain V region and light chain V region in the ScFv can be derived from any antibody that binds to human PD-1 or human PD-L1, or an antigen-binding fragment thereof, described herein.

[0186] sc(Fv)2 is a minibody in which two VHs and two VLs are linked by a linker to form a single chain (Hudson, et al., J. Immunol. Methods, (1999) 231:177-189 (1999)). sc(Fv)2 can be prepared, for example, by connecting scFvs with a linker. In the Sc(Fv)2 of the present invention, the two VHs and two VLs are preferably arranged in the order of VH, VL, VH, and VL ([VH] linker[VL] linker[VH] linker[VL]) starting from the N-terminus of the single-chain polypeptide. However, the order of the two VHs and two VLs is not limited to the above arrangement, and they can be arranged in any order.

[0187] bispecific antibody In some cases, the anti-CD73b antibody is a bispecific antibody. A bispecific antibody is an antibody that has binding specificities for at least two different epitopes. Exemplary bispecific antibodies may bind to two different epitopes of the CD73 protein. Other such antibodies may combine a CD73-binding site with a binding site of another protein. Exemplary bispecific antibodies may bind to two different epitopes of the PD-1 protein. Other such antibodies may combine a PD-1-binding site with a binding site of another protein. Bispecific antibodies can be prepared as full-length antibodies or lower molecular weight forms thereof (e.g., F(ab')2 bispecific antibodies, sc(Fv)2 bispecific antibodies, diabody bispecific antibodies).

[0188] Traditional production of full-length bispecific antibodies is based on the coexpression of two immunoglobulin heavy-chain-light chain pairs, where these two chains have different specificities (Millstein et al., Nature, 305:537-539 (1983)). According to a different approach, antibody variable domains with the desired binding specificities are fused to immunoglobulin constant domain sequences. DNA encoding the immunoglobulin heavy chain fusions and, if desired, the immunoglobulin light chain, are inserted into separate expression vectors and cotransfected into suitable host cells. This provides greater flexibility in adjusting the ratio of the three polypeptide fragments. However, if expression of at least two polypeptide chains in equal ratios results in high yields, it is possible to insert the coding sequences for two or all three polypeptide chains into a single expression vector.

[0189] According to another approach described in U.S. Patent No. 5,731,168, the interface between a pair of antibody molecules can be engineered to maximize the percentage of heterodimers recovered from recombinant cell culture. A preferred interface comprises at least a portion of the CH3 domain. In this method, one or more small amino acid side chains from the interface of a first antibody molecule are replaced with larger side chains (e.g., tyrosine or tryptophan). By replacing the large amino acid side chains with smaller ones (e.g., alanine or threonine), compensatory "cavities" of identical or similar size to the large side chain(s) are created on the interface of the second antibody molecule. This provides a mechanism for increasing the yield of heterodimers over other unwanted end-products, such as homodimers.

[0190] Bispecific antibodies include cross-linked or "heteroconjugate" antibodies. For example, one of the antibodies in the heteroconjugate can be coupled to avidin, the other to biotin. Heteroconjugate antibodies can be made using any convenient cross-linking method.

[0191] "Diabody" technology provides an alternative mechanism for making bispecific antibody fragments. These fragments comprise a VH connected to a VL by a linker that is too short to allow pairing between the two domains on the same chain. The VH and VL domains of one fragment are thus forced to pair with the complementary VL and VH domains of another fragment, thereby forming two antigen-binding sites.

[0192] Multivalent antibodies In some cases, the anti-CD3 antibody is a multivalent antibody. Multivalent antibodies may be internalized (and / or catabolized) more quickly than bivalent antibodies by cells expressing the antigen to which the antibody binds. The antibodies provided herein may be multivalent antibodies (e.g., tetravalent antibodies) having three or more antigen-binding sites, which can be readily produced by recombinant expression of nucleic acids encoding antibody polypeptide chains. The multivalent antibody can comprise a dimerization domain and three or more antigen-binding sites. Exemplary dimerization domains comprise (or consist of) an Fc region or a hinge region. The multivalent antibody can comprise (or consist of) from three to about eight (e.g., four) antigen-binding sites. The multivalent antibody optionally comprises at least one polypeptide chain (e.g., at least two polypeptide chains), wherein the polypeptide chain(s) comprise two or more variable domains. For example, the polypeptide chain(s) may comprise a VD1-(X1) variable domain. n -VD2-(X2) n -Fc, where VD1 is a first variable domain, VD2 is a second variable domain, Fc is one polypeptide chain of an Fc region, X1 and X2 represent amino acids or peptide spacers, and n is 0 or 1.

[0193] Conjugated antibodies In some cases, the anti-CD3 antibody is a conjugated antibody. The antibodies disclosed herein can be conjugated to a polymer (e.g., polyethylene glycol (PEG), polyethyleneimine (PEI) modified with PEG (PEI-PEG), polyglutamic acid (PGA) (N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer), hyaluronic acid, radioactive materials (e.g., 90 Y, 131 I), and may be conjugated antibodies bound to a variety of molecules, including macromolecular substances such as fluorescent substances, luminescent substances, haptens, enzymes, metal chelates, drugs, and toxins (e.g., calcheamicin, Pseudomonas exotoxin A, ricin (e.g., deglycosylated ricin A chain)).

[0194] In one embodiment, to improve the cytotoxicity of anti-CD73 antibodies and thereby improve their therapeutic efficacy, the antibodies are conjugated to highly toxic substances, including radioisotopes and cytotoxic agents. In one embodiment, to improve the cytotoxicity of anti-PD-L1 antibodies and thereby improve their therapeutic efficacy, the antibodies are conjugated to highly toxic substances, including radioisotopes and cytotoxic agents. These conjugates can selectively deliver a toxic load to the target site (i.e., cells expressing the antigen recognized by the antibody), while sparing cells not recognized by the antibody. To minimize toxicity, conjugates are generally engineered based on molecules with short serum half-lives (hence the use of murine sequences and IgG3 or IgG4 isotypes).

[0195] In certain embodiments, an anti-CD73 antibody is modified with a moiety that improves its stabilization and / or retention in the circulation, e.g., by at least 1.5, 2, 5, 10, or 50-fold, e.g., in blood, serum, or other tissues. For example, an anti-CD73 antibody can be associated (e.g., conjugated) with a polymer, e.g., a substantially non-antigenic polymer such as a polyalkylene oxide or polyethylene oxide. In certain embodiments, an antibody, or antigen-binding fragment thereof, that binds human PD-1 or human PD-L1 is modified with a moiety that improves its stabilization and / or retention in the circulation, e.g., by at least 1.5, 2, 5, 10, or 50-fold, e.g., in blood, serum, or other tissues. For example, an antibody, or antigen-binding fragment thereof, that binds human PD-1 or human PD-L1 can be associated (e.g., conjugated) with a polymer, e.g., a substantially non-antigenic polymer such as a polyalkylene oxide or polyethylene oxide. Suitable polymers vary substantially by weight. Polymers having molecular number-average weights ranging from about 200 to about 35,000 daltons (or about 1,000 to about 15,000, and 2,000 to about 12,500) can be used. For example, an anti-CD73 antibody, anti-PD-1 antibody, or antigen-binding fragment thereof can be conjugated to a water-soluble polymer, e.g., a hydrophilic polyvinyl polymer, e.g., polyvinyl alcohol or polyvinylpyrrolidone. Examples of such polymers include polyalkylene oxide homopolymers such as polyethylene glycol (PEG) or polypropylene glycol, polyoxyethylated polyols, copolymers thereof, and block copolymers thereof, provided that the water solubility of the block copolymers is maintained. Additional useful polymers include polyoxyalkylenes such as polyoxyethylene and polyoxypropylene, and block copolymers of polyoxyethylene and polyoxypropylene, polymethacrylates, carbomers, and branched or unbranched polysaccharides.

[0196] The conjugated antibodies described above can be prepared by chemically modifying each of the antibodies described herein or their lower molecular weight forms. Methods for modifying antibodies are well known in the art (e.g., US 5,057,313 and US 5,156,840).

[0197] Polynucleotides, expression vectors, and cells The present disclosure also provides polynucleotides and vectors encoding the anti-CD73 antibodies or portions thereof (e.g., VH, VL, HC, or LC) described herein. The polynucleotides of the present disclosure can be in the form of RNA or DNA. In some cases, the polynucleotide is DNA. In some cases, the polynucleotide is complementary DNA (cDNA). In some cases, the polynucleotide is RNA.

[0198] In some cases, the polynucleotide encodes a VH comprising a VH CDR1, a VH CDR2, and a VH CDR3 of any antibody described herein (see, e.g., Tables 3, 4, and 6). In some cases, the polynucleotide encodes a VL comprising a VL CDR1, a VL CDR2, and a VL CDR3 of any antibody described herein (see, e.g., Tables 3, 4, and 6). In some cases, the polynucleotide encodes a heavy chain comprising a VH comprising a VH CDR1, a VH CDR2, and a VH CDR3 of any antibody described herein (see, e.g., Tables 3, 4, and 6). In some cases, the polynucleotide encodes a light chain comprising a VL comprising a VL CDR1, a VL CDR2, and a VL CDR3 of any antibody described herein (see, e.g., Tables 3, 4, and 6). In some cases, the polynucleotide is operably linked to a promoter.

[0199] In some cases, the polynucleotide comprises: (i) a first nucleic acid sequence encoding a first polypeptide, wherein the first polypeptide comprises a VH comprising a VH CDR1, a VH CDR2, and a VH CDR3 of any antibody described herein (see, e.g., Tables 3, 4, and 6); and (ii) a second nucleic acid sequence encoding a second polypeptide, wherein the second polypeptide comprises a VL comprising a VL CDR1, a VL CDR2, and a VL CDR3 of any antibody described herein (see, e.g., Tables 3, 4, and 6). In some cases, the polynucleotide comprises (i) a first nucleic acid sequence encoding a first polypeptide, wherein the first polypeptide comprises a VH comprising a VH CDR1, a VH CDR2, and a VH CDR3 of any antibody described herein (see, e.g., Tables 3, 4, and 6), and (ii) a second nucleic acid sequence encoding a second polypeptide, wherein the second polypeptide comprises a light chain comprising a VL comprising a VL CDR1, a VL CDR2, and a VL CDR3 of any antibody described herein (see, e.g., Tables 3, 4, and 6). In some cases, the first nucleic acid is operably linked to a first promoter and the second nucleic acid is operably linked to a second promoter.

[0200] In some cases, the polynucleotide encodes the VH of CL25 or a variant thereof (e.g., a humanized version thereof, e.g., HzCL25). In some cases, the polynucleotide encodes a polypeptide comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, or 100% identity to the set of amino acid sequences set forth in SEQ ID NO: 22. In some cases, the polynucleotide encodes a polypeptide comprising one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10) amino acid substitutions, additions, and / or deletions relative to the set of amino acid sequences set forth in any one of SEQ ID NOs: 22, 26, and 82-84. In some cases, the polynucleotide encodes a polypeptide comprising the amino acid sequence set forth in SEQ ID NO: 22. In some cases, the polynucleotide is operably linked to a promoter.

[0201] In some cases, the polynucleotide encodes the VL of CL25 or a variant thereof (e.g., a humanized version thereof, e.g., HzCL25). In some cases, the polynucleotide encodes a polypeptide comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, or 100% identity to the amino acid sequence set forth in SEQ ID NO:23. In some cases, the polynucleotide encodes a polypeptide comprising one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10) amino acid substitutions, additions, and / or deletions relative to the amino acid sequence set forth in SEQ ID NO:23. In some cases, the polynucleotide encodes a polypeptide comprising the amino acid sequence set forth in SEQ ID NO:23. In some cases, the polynucleotide is operably linked to a promoter.

[0202] In some cases, the polynucleotide encodes the VH of 3-F03 or a variant thereof (e.g., 3-F03_411 or 3-F03_413). In some cases, the polynucleotide encodes a polypeptide comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, or 100% identity to the set of amino acid sequences set forth in SEQ ID NOs: 62 or 63. In some cases, the polynucleotide encodes a polypeptide comprising one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10) amino acid substitutions, additions, and / or deletions relative to the set of amino acid sequences set forth in SEQ ID NOs: 62 or 63. In some cases, the polynucleotide encodes a polypeptide comprising the amino acid sequence set forth in SEQ ID NO: 62. In some cases, the polynucleotide encodes a polypeptide comprising the amino acid sequence set forth in SEQ ID NO: 63. In some cases, the polynucleotide is operably linked to a promoter.

[0203] In some cases, the polynucleotide encodes the VL of 3-F03 or a variant thereof (e.g., 3-F03_411 or 3-F03_413). In some cases, the polynucleotide encodes a polypeptide comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, or 100% identity to the amino acid sequence set forth in SEQ ID NO:61. In some cases, the polynucleotide encodes a polypeptide comprising one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10) amino acid substitutions, additions, and / or deletions relative to the amino acid sequence set forth in SEQ ID NO:61. In some cases, the polynucleotide encodes a polypeptide comprising the amino acid sequence set forth in SEQ ID NO:61. In some cases, the polynucleotide is operably linked to a promoter.

[0204] In some embodiments, the polynucleotides described herein are isolated.

[0205] Also provided herein are expression vectors encoding the anti-CD73 antibodies described herein, or portions thereof (e.g., VH, VL, HC, and / or LC). Also provided herein are expression vectors comprising one or more polynucleotides described herein. Various types of expression vectors are known in the art and described herein (see, e.g., the "Methods of Producing Antibodies" section herein).

[0206] Also provided herein are cells comprising the anti-CD73 antibodies described herein. Also provided herein are cells comprising one or more polynucleotides described herein. Also provided herein are cells comprising one or more expression vectors described herein. Various types of cells are known in the art and described herein (see, e.g., the "Methods of Producing Antibodies" section herein).

[0207] Anti-CD73 antibodies with altered glycosylation Different glycoforms can profoundly affect therapeutic drug properties, including pharmacokinetics, pharmacodynamics, receptor interactions, and tissue-specific targeting (Graddis et al., 2002, Curr Pharm Biotechnol. 3:285-297). In particular, for antibodies, oligosaccharide structures can affect antibody effector functions (e.g., binding to complement complex C1, which induces CDC, and binding to FcγR receptors, which regulate the ADCC pathway), as well as properties related to protease resistance, serum half-life of antibodies, phagocytosis, and antibody feedback mediated by the FcRn receptor (Nose and Wigzell, 1983; Leatherbarrow and Dwek, 1983; Leatherbarrow et al., 1985; Walker et al., 1989; Carter et al., 1992, PNAS, 89:4285-4289).

[0208] Thus, another means of modulating antibody effector function involves altering the glycosylation of the antibody constant region, including, for example, reducing or increasing the number of glycosylated residues, changing the pattern or location of glycosylated residues, and altering the sugar structure(s). The oligosaccharides found on human IgG influence the extent of their effector functions (Raju, TSBioProcess International April 2003.44-53), and the microheterogeneity of human IgG oligosaccharides can affect biological functions such as CDC and ADCC, binding to various Fc receptors, and binding to Clq proteins (Wright A. & Morrison SL. TIBTECH 1997, 15 26-32; Shields et al. J Biol Chem. 2001 276(9):6591-604; Shields et al. J Biol Chem. 2002;277(30):26733-40; Shinkawa et al. J Biol Chem. 2003 278(5):3466-73; Umana et al. Nat Biotechnol. 1999 Feb;17(2): 176-80). For example, the ability of IgG to bind C1q and activate the complement cascade can depend on the presence, absence, or modification of a carbohydrate moiety located between the two CH2 domains (usually anchored at Asn297) (Ward and Ghetie, Therapeutic Immunology 2:77-94 (1995)). Thus, in some cases, anti-CD73 antibodies contain an Asn297Ala substitution relative to the wild-type constant region.

[0209] Glycosylation sites within an Fc-containing polypeptide, e.g., an antibody, such as an IgG antibody, can be identified by standard techniques. Identification of glycosylation sites can be based on experimental or sequence analysis or modeling data. Consensus motifs, i.e., amino acid sequences recognized by various glycosyltransferases, have been described. For example, consensus motifs for N-linked glycosylation motifs are frequently NXT or NXS, where X can be any amino acid except proline. Several algorithms for finding potential glycosylation motifs have also been described. Thus, to identify potential glycosylation sites within an antibody or Fc-containing fragment, the sequence of the antibody is examined using publicly available databases, such as the website provided by the Center for Biological Sequence Analysis (see, for example, the NetNGlyc service for predicting N-linked glycosylation sites and the NetOGlyc service for predicting O-linked glycosylation sites).

[0210] In vivo studies have confirmed the reduced effector function of aglycosyl antibodies. For example, aglycosyl anti-CD8 antibodies cannot deplete CD8-bearing cells in mice (Isaacs, 1992 J. Immunol. 148:3062), and aglycosyl anti-CD3 antibodies do not induce cytokine release syndrome in mice or humans (Boyd, 1995 (supra); Friend, 1999 Transplantation 68:1632). The aglycosylated form of anti-CD73 antibodies also has reduced effector function.

[0211] Importantly, removal of glycans within the CH2 domain appears to significantly affect effector function, while other functional and physical properties of the antibody remain unchanged. Specifically, it has been shown that removal of glycans has little or no effect on serum half-life and antigen binding (Nose, 1983 (supra); Tao, 1989 (supra); Dorai, 1991 (supra); Hand, 1992 (supra); Hobbs, 1992 (supra); Mol. Immunol. 29:949).

[0212] The anti-CD73 antibodies of the invention may be modified or altered to elicit increased or decreased effector function(s) (compared to a second CD73-specific antibody). Methods for altering glycosylation sites of antibodies are described, for example, in US 6,350,861 and US 5,714,350, WO 05 / 18572 and WO 05 / 03175, and these methods can be used to produce anti-CD73 antibodies of the invention with altered, reduced, or no glycosylation.

[0213] Methods for producing antibodies Anti-CD73 antibody Antibodies can be produced in bacteria or eukaryotic cells. Some antibodies, such as Fab', can be produced in bacterial cells, such as E. coli cells. Antibodies can also be produced in eukaryotic cells, such as transformed cell lines (e.g., CHO, 293E, COS). In addition, antibodies (e.g., scFv') can be expressed in yeast cells, such as Pichia (e.g., Powers et al., J Immunol Methods. 251:123-35 (2001)), Hanseula, or Saccharomyces. To produce the antibody of interest, a polynucleotide encoding the antibody is constructed, introduced into an expression vector, and then expressed in a suitable host cell. Standard molecular biology techniques are used to prepare the recombinant expression vector, transfect the host cell, select for transformants, culture the host cell, and recover the antibody.

[0214] If the antibody is expressed in bacterial cells (eg, E. coli), the expression vector should have features that allow for amplification of the vector within the bacterial cell. Furthermore, when E. coli such as JM109, DH5α, HB101, or XL1-Blue is used as a host, the vector must have a promoter such as the lacZ promoter (Ward et al., 341:544-546 (1989)), the araB promoter (Better et al., Science, 240:1041-1043 (1988)), or a T7 promoter that can enable efficient expression in E. coli. Examples of such vectors include M13 series vectors, pUC series vectors, pBR322, pBluescript, pCR-Script, pGEX-5X-1 (Pharmacia), the "QIAexpress system" (QIAGEN), pEGFP, and pET (when this expression vector is used, the host is preferably BL21, which expresses T7 RNA polymerase). The expression vector may contain a signal sequence for antibody secretion. For production into the periplasm of E. coli, the pelB signal sequence (Lei et al., 2004) is used. al., J. Bacteriol., 169:4379 (1987)) may be used as a signal sequence for antibody secretion. For bacterial expression, the calcium chloride method or electroporation may be used to introduce the expression vector into bacterial cells.

[0215] When antibodies are expressed in animal cells such as CHO, COS, and NIH3T3 cells, the expression vector contains a promoter necessary for expression in these cells, such as the SV40 promoter (Mulligan et al., Nature, 277:108 (1979)), the MMLV-LTR promoter, the EF1α promoter (Mizushima et al., Nucleic Acids Res., 18:5322 (1990)), or the CMV promoter. In addition to the nucleic acid sequence encoding an immunoglobulin or a domain thereof, the recombinant expression vector can carry additional sequences, such as sequences that regulate replication of the vector in host cells (e.g., origins of replication) and selectable marker genes. The selectable marker gene can facilitate selection of host cells into which the vector has been introduced (see, e.g., U.S. Patent Nos. 4,399,216, 4,634,665, and 5,179,017). For example, typically, the selectable marker gene confers resistance to drugs such as G418, hygromycin, methotrexate, etc. to a host cell into which the vector has been introduced. Examples of vectors having selectable markers include pMAM, pDR2, pBK-RSV, pBK-CMV, pOPRSV, and pOP13.

[0216] In one embodiment, the antibody is produced in mammalian cells. Exemplary mammalian host cells for expressing the antibody include Chinese hamster ovary (CHO) cells (dhfr cells, as described in Urlaub and Chasin (1980) Proc. Natl. Acad. Sci. USA 77:4216-4220). - Examples of suitable cells include CHO cells (e.g., used with a DHFR selection marker as described in Kaufman and Sharp (1982) Mol. Biol. 159:601-621), human embryonic kidney 293 cells (e.g., 293, 293E, 293T), COS cells, NIH3T3 cells, lymphoid cell lines such as NS0 myeloma cells and SP2 cells, and cells derived from transgenic animals, e.g., transgenic mammals. For example, the cell is a mammary epithelial cell.

[0217] In an exemplary system for antibody expression, recombinant expression vectors encoding both the antibody heavy chain and the antibody light chain of an anti-CD73 antibody (e.g., CL25, HzCL25, 3-F03, 3-F03_411, or 3-F03_413) are transfected into dhfr - The antibody is then introduced into CHO cells. In an exemplary system for antibody expression, a recombinant expression vector encoding both the antibody heavy and light chains of an antibody that binds to human PD-1 or human PD-L1 antibody (e.g., antibody X) is introduced into dhfr-CHO cells by calcium phosphate-mediated transfection. Within the recombinant expression vector, the antibody heavy and light chain genes are each operably linked to enhancer / promoter regulatory elements (e.g., derived from SV40, CMV, adenovirus, etc., such as the CMV enhancer / AdMLP promoter regulatory element or the SV40 enhancer / AdMLP promoter regulatory element) to drive high levels of gene transcription. The recombinant expression vector also carries a DHFR gene, which allows for selection of CHO cells transfected with the vector using methotrexate selection / amplification. The selected transformed host cells are cultured to allow expression of the antibody heavy and light chains, and the antibody is recovered from the culture medium.

[0218] Antibodies can also be produced by transgenic animals. For example, U.S. Patent No. 5,849,992 describes a method for expressing an antibody in the mammary gland of a transgenic mammal. A transgene is constructed containing a milk-specific promoter, a nucleic acid encoding the antibody of interest, and a signal sequence for secretion. Milk produced by female transgenic mammals contains the antibody of interest secreted therein. The antibody can be purified from the milk or used directly for several applications. Animals containing one or more of the nucleic acids described herein are also provided.

[0219] The antibodies of the present disclosure can be isolated from the inside or outside of host cells (such as the culture medium) and purified as substantially pure and homogeneous antibodies. Isolation and purification methods commonly used for antibody purification may be used for antibody isolation and purification, and are not limited to any particular method. Antibodies can be isolated and purified by appropriately selecting and combining, for example, column chromatography, filtration, ultrafiltration, salting out, solvent precipitation, solvent extraction, distillation, immunoprecipitation, SDS-polyacrylamide gel electrophoresis, isoelectric focusing, dialysis, and recrystallization. Examples of chromatography include affinity chromatography, ion exchange chromatography, hydrophobic chromatography, gel filtration, reversed-phase chromatography, and adsorption chromatography (Strategies for Protein Purification and Characterization: A Laboratory Course Manual, Ed. Daniel R. Marshak et al., Cold Spring Harbor Laboratory Press, 1996). Chromatography can be performed using liquid-phase chromatography such as HPLC and FPLC. Columns used for affinity chromatography include protein A columns and protein G columns. Examples of columns that use Protein A columns include Hyper D, POROS, and Sepharose FF (GE Healthcare Biosciences). The present disclosure also includes antibodies that are highly purified using these purification methods.

[0220] Anti-PD-1 antibody Anti-PD-1 antibodies, such as retifanlimab, can be made, for example, by preparing and expressing a synthetic gene encoding the recited amino acid sequence, or by mutating a human germline gene to provide a gene encoding the recited amino acid sequence. Additionally, this and other anti-PD-1 antibodies can be obtained, for example, using one or more of the following methods:

[0221] Humanized antibodies can be generated by replacing Fv variable region sequences not directly involved in antigen binding with equivalent sequences from human Fv variable regions. General methods for generating humanized antibodies are provided by Morrison, SL, Science, 229:1202-1207 (1985); Oi et al., BioTechniques, 4:214 (1986); and US Pat. Nos. 5,585,089, 5,693,761, 5,693,762, 5,859,205, and 6,407,213. These methods involve isolating, manipulating, and expressing nucleic acid sequences encoding all or part of immunoglobulin Fv variable regions from at least one of the heavy or light chains. Sources of such nucleic acids are well known to those of skill in the art and can be obtained, for example, from hybridomas producing antibodies against a predetermined target, from germline immunoglobulin genes, or from synthetic constructs, as described above. The recombinant DNA encoding the humanized antibody can then be cloned into an appropriate expression vector.

[0222] For example, human germline sequences are described in Tomlinson, IA et al., J. Mol. Biol., 227:776-798 (1992); Cook, GP et al., Immunol. Today, 16: 237-242 (1995); Chothia, D. et al., J. Mol. Biol., 227:799-817 (1992); and Tomlinson et al., EMBO J., 14:4628-4638 (1995). The V BASE directory provides a comprehensive directory of human immunoglobulin variable region sequences (compiled by Tomlinson, IA et al. MRC Centre for Protein Engineering, Cambridge, UK). These sequences can be used, for example, as a source of human sequences for framework regions and CDRs. Consensus human framework regions can also be used, for example, as described in U.S. Patent No. 6,300,064.

[0223] Other methods for humanizing antibodies can also be used. For example, other methods can account for the three-dimensional structure of the antibody, framework positions three-dimensionally adjacent to binding determinants, and immunogenic peptide sequences. See, for example, WO 90 / 07861, U.S. Patent Nos. 5,693,762, 5,693,761, 5,585,089, 5,530,101, and 6,407,213, and Tempest et al. (1991) Biotechnology 9:266-271. Yet another method, referred to as "humaneering," is described, for example, in U.S. Patent No. 2005-008625.

[0224] The antibody can comprise a human Fc region, e.g., a wild-type Fc region or an Fc region containing one or more modifications. In one embodiment, the constant region is modified, e.g., mutated, to modify the properties of the antibody (e.g., to increase or decrease one or more of Fc receptor binding, antibody glycosylation, the number of cysteine ​​residues, effector cell function, or complement function). For example, a human IgG1 constant region can be mutated at one or more residues, e.g., one or more of residues 234 and 237 (based on Kabat numbering). The antibody can have mutations in the CH2 region of the heavy chain that reduce or modify effector function, e.g., Fc receptor binding and complement activation. For example, the antibody can have mutations as described in U.S. Patent Nos. 5,624,821 and 5,648,260. The antibody may also have mutations that stabilize the disulfide bonds between the two heavy chains of the immunoglobulin, such as mutations in the hinge region of IgG4 (e.g., Angal et al. (1993) Mol. Immunol. 30:105-08), as disclosed in the art. See also, e.g., US2005 / 0037000.

[0225] Anti-PD-L1 antibodies can be in the form of full-length antibodies or in the form of lower molecular weight forms (e.g., biologically active antibody fragments or minibodies) of anti-PD-1 antibodies, such as Fab, Fab', F(ab')2, Fv, Fd, dAb, scFv, and sc(Fv)2. Other anti-PD-1 antibodies encompassed by the present disclosure include single-domain antibodies (sdAbs) containing a single variable chain, such as VH or VL, or a biologically active fragment thereof. See, e.g., Moller et al., J. Biol. Chem., 285(49):38348-38361 (2010); Harmsen et al., Appl. Microbiol. Biotechnol., 77(1):13-22 (2007); US2005 / 0079574 and Davieset al. (1996) Protein Eng., 9(6):531-7. Like whole antibodies, sdAbs can selectively bind to specific antigens. With a molecular weight of only 12-15 kDa, sdAbs are much smaller than typical antibodies, even smaller than Fab fragments and single-chain variable fragments.

[0226] Provided herein are compositions comprising a mixture of an anti-PD-1 antibody, or antigen-binding fragment thereof, and one or more acidic variants, e.g., the amount of acidic variant(s) is less than about 80%, 70%, 60%, 60%, 50%, 40%, 30%, 30%, 20%, 10%, 5%, or 1%. Also provided are compositions comprising an anti-PD-1 antibody, or antigen-binding fragment thereof, that contain at least one deamidation site, wherein the pH of the composition is, for example, about 5.0 to about 6.5, such that at least about 90% of the antibody is not deamidated (i.e., less than about 10% of the antibody is deamidated). In certain embodiments, less than about 5%, 3%, 2%, or 1% of the antibody is deamidated. The pH may be 5.0 to 6.0, such as 5.5 or 6.0. In certain embodiments, the pH of the composition is 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, or 6.5.

[0227] An "acidic variant" is a variant of a polypeptide of interest that is more acidic than the polypeptide of interest (e.g., as determined by cation exchange chromatography). An example of an acidic variant is a deamidated variant.

[0228] "Deamidated" variants of a polypeptide molecule are polypeptides in which one or more asparagine residue(s) of the original polypeptide have been converted to aspartic acid, i.e., the neutral amide side chains have been converted to residues with overall acidic properties.

[0229] As used herein, the term "mixture" refers to a composition comprising an anti-PD-1 antibody or antigen-binding fragment thereof and refers to the presence of both the desired antibody or antigen-binding fragment thereof that binds to human PD-1 or human PD-L1, and one or more acidic variants thereof. The acidic variants may include primarily deamidated antibodies that bind to human PD-1 or human PD-L1, along with minor amounts of other acidic variant(s).

[0230] In certain embodiments, the binding affinity (K) of antibodies mutated to eliminate deamidation is D ), on-rate (K D on) and / or off-rate (K D Off) is similar to that of a wild-type antibody, for example, with a difference of less than about 5-fold, 2-fold, 1-fold (100%), 50%, 30%, 20%, 10%, 5%, 3%, 2%, or 1%.

[0231] Dosage and route of administration The anti-CD73 antibody, the inhibitor of the A2A and / or A2B adenosine receptor, and the inhibitor of PD-1 / PD-L1 described herein can be administered to a subject, e.g., a subject in need thereof, e.g., a human subject, in a variety of ways. In some cases, the anti-CD73 antibody, the inhibitor of the A2A and / or A2B adenosine receptor, and the inhibitor of PD-1 / PD-L1 are administered to a subject by the same route. In some cases, the anti-CD73 antibody and the inhibitor of PD-1 / PD-L1 are administered to a subject by the same route. In some cases, the inhibitor of the A2A and / or A2B adenosine receptor and the inhibitor of PD-1 / PD-L1 are administered to a subject by different routes. In some cases, the anti-CD73 antibody and the inhibitor of PD-1 / PD-L1 are administered to a subject by different routes. In many applications, the route of administration is one of intravenous injection or infusion (IV), subcutaneous injection (SC), intraperitoneal (IP), or intramuscular injection. Intra-articular delivery can also be used. Other methods of parenteral administration can also be used. Examples of such modes include intra-arterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, transtracheal, subcutaneous, intra-articular, subcapsular, subarachnoid, intraspinal, and epidural and intrasternal injection. In some cases, administration can be oral.

[0232] The route and / or mode of administration of the anti-CD73 antibody, the inhibitor of the A2A and / or A2B adenosine receptor, and the inhibitor of PD-1 / PD-L1 may be tailored to the individual case, e.g., by monitoring the subject, e.g., using tomography to visualize the tumor. The route and / or mode of administration of the anti-CD73 antibody and the inhibitor of PD-1 / PD-L1 may also be tailored to the individual case, e.g., by monitoring the subject, e.g., using tomography to visualize the tumor.

[0233] The anti-CD73 antibody, the A2A and / or A2B adenosine receptor inhibitor, and the PD-1 / PD-L1 inhibitor can each be administered as a fixed dose or in mg / kg doses based on the patient's body weight. For example, in dual combination therapy, the anti-CD73 antibody and the PD-1 / PD-L1 inhibitor can each be administered as a fixed dose or in mg / kg doses based on the patient's body weight. Doses can also be selected to reduce or avoid the production of antibodies against the anti-CD73 antibody, the A2A and / or A2B adenosine receptor inhibitor, and / or the PD-1 / PD-L1 inhibitor. Dosage regimens can be adjusted to provide a desired response (e.g., a therapeutic response) or combined therapeutic effect. Generally, doses of the anti-CD73 antibody, the A2A and / or A2B adenosine receptor inhibitor, and the PD-1 / PD-L1 inhibitor can be used to provide a bioavailable amount of the agent to the subject. For example, doses ranging from 0.1 to 100 mg / kg, 0.5 to 100 mg / kg, 1 mg / kg to 100 mg / kg, 0.5 to 20 mg / kg, 0.1 to 10 mg / kg, or 1 to 10 mg / kg can be administered. Other doses can also be used.

[0234] In some embodiments, the anti-CD73 antibody, the inhibitor of A2A and / or A2B adenosine receptors, and / or the inhibitor of PD-1 / PD-L1 are administered simultaneously. In some embodiments, the anti-CD73 antibody and the inhibitor of PD-1 / PD-L1 are administered simultaneously.

[0235] In some embodiments, the anti-CD73 antibody, the inhibitor of A2A and / or A2B adenosine receptors, and / or the inhibitor of PD-1 / PD-L1 are administered sequentially, hi some embodiments, the anti-CD73 antibody and the PD-1 / PD-L1 inhibitor are administered sequentially.

[0236] As used herein, dosage unit form or "fixed dose" or "uniform dose" refers to physically discrete units suitable as unitary dosages for treating a subject, each unit containing a predetermined amount of active compound calculated to produce a desired therapeutic effect in association with the necessary pharmaceutical carriers, and optionally in association with other agents. Single or multiple doses may be administered. Alternatively, or in addition, the antibody and / or inhibitor may be administered via continuous infusion. Exemplary fixed doses include 375 mg, 500 mg, and 750 mg.

[0237] A2A / A2B adenosine receptor inhibitors In some embodiments, the A2A / A2B inhibitor or a pharmaceutically acceptable salt thereof is administered to a subject at a dose of about 0.1 mg to about 1000 mg of the free base. In some embodiments, the A2A / A2B inhibitor or a pharmaceutically acceptable salt thereof is administered to a subject at a dose of about 1 mg to about 500 mg of the free base. In some embodiments, the A2A / A2B inhibitor or a pharmaceutically acceptable salt thereof is administered to a subject at a dose of about 5 mg to about 250 mg of the free base. In some embodiments, the A2A / A2B inhibitor or a pharmaceutically acceptable salt thereof is administered to a subject at a dose of about 10 mg to about 100 mg of the free base.

[0238] In some embodiments, the inhibitor of A2A / A2B, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 0.5 mg, about 1 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg, about 150 mg, about 160 mg, about 165 mg, about 170 mg, about 175 mg, about 180 mg, about 185 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 245 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, about 350 mg, about 360 mg, about 370 mg, about 380 mg, about 390 mg, about 400 mg, about 410 mg, about 420 mg, about 430 mg, about 440 mg, about 450 mg, about 460 mg, about 470 mg, about 480 mg, about 490 mg, about 500 mg, about 510 mg, 50mg, about 155mg, about 160mg, about 165mg, about 170mg, about 175mg, about 180mg, about 185mg, about 190mg, about 195mg, about 200mg, about 205mg, about 210mg, about 215mg, about 220mg, about 225mg, about 230mg, about 235mg, About 240mg, about 245mg, about 250mg, about 255mg, about 260mg, about 265mg, about 270mg, about 275mg, about 280mg, about 285mg, about 290mg, about 295mg, about 300mg, about 305mg, about 310mg, about 315mg, about 320mg, about 325mg , about 330mg, about 335mg, about 340mg, about 345mg, about 350mg, about 355mg, about 360mg, about 365mg, about 370mg, about 375mg, about 380mg, about 385mg, about 390mg, about 395mg, about 400mg, about 405mg, about 410mg, about 415 mg, approx. 420 mg, approx. 425 mg, approx. 430 mg, approx. 435 mg, approx. 440 mg, approx. 445 mg, approx. 450 mg, approx. 455 mg, approx. 460 mg, approx. 5mg, approx. 510mg, approx. 515mg, approx. 520mg, approx. 525mg, approx. 530mg, approx. 535mg, approx. 540mg, approx. 545mg, approx. 550mg, approx. 595mg, about 600mg, about 605mg, about 610mg, about 615mg, about 620mg, about 625mg, about 630mg, about 635mg, about 640mg, about 645mg, about 650mg, about 655mg, about 660mg, about 665mg, about 670mg, about 675mg, about 680mg,Approx. 685 mg, approx. 690 mg, approx. 695 mg, approx. 700 mg, approx. 705 mg, approx. 710 mg, approx. 715 mg, approx. 720 mg, approx. 725 mg, approx. 730 mg, approx. g, approx. 770 mg, approx. 775 mg, approx. 780 mg, approx. 785 mg, approx. 790 mg, approx. 795 mg, approx. 800 mg, approx. 805 mg, approx. 810 mg, approx. mg, about 855 mg, about 860 mg, about 865 mg, about 870 mg, about 875 mg, about 880 mg, about 885 mg, about 890 mg, about 895 mg, about 900 mg, about 905 mg, about 910 mg, about 915 mg, about 920 mg, about 925 mg, about 930 mg, about 935 mg, about 940 mg, about 945 mg, about 950 mg, about 955 mg, about 960 mg, about 965 mg, about 970 mg, about 975 mg, about 980 mg, about 985 mg, about 990 mg, about 995 mg, and about 1000 mg. In some embodiments, the A2A / A2B inhibitor, or a pharmaceutically acceptable salt thereof, is administered to a subject at a dose ranging from about 0.1 mg to about 500 mg of the free base, or any dose value therebetween. In some embodiments, the A2A / A2B inhibitor, or a pharmaceutically acceptable salt thereof, is administered to a subject at a dose ranging from about 1 mg to about 100 mg of the free base, or any dose value therebetween. In some embodiments, the A2A / A2B inhibitor is administered to a subject at a dose of about 0.1 mg to about 500 mg of the free base, and the A2A / A2B inhibitor is administered once daily or every other day.

[0239] In some embodiments, the A2A / A2B inhibitor, or a pharmaceutically acceptable salt thereof, is administered to the subject once daily, every other day, once weekly, or any time interval therebetween. In some embodiments, the A2A / A2B inhibitor, or a pharmaceutically acceptable salt thereof, is administered to the subject once daily. In some embodiments, the A2A / A2B inhibitor, or a pharmaceutically acceptable salt thereof, is administered to the subject every other day. In some embodiments, the A2A / A2B inhibitor, or a pharmaceutically acceptable salt thereof, is administered to the subject once weekly.

[0240] In some embodiments, the inhibitor of A2A / A2B or a pharmaceutically acceptable salt thereof is administered to a subject at a dosage of about 1 mg to about 50 mg QD on a free base basis.

[0241] In some embodiments, the inhibitor of A2A / A2B or a pharmaceutically acceptable salt thereof is administered to a subject at a dosage of about 1 mg to about 50 mg BID on a free base basis.

[0242] In some embodiments, the inhibitor of A2A / A2B or a pharmaceutically acceptable salt thereof is administered to a subject at a dosage of about 10 mg QD on a free base basis.

[0243] In some embodiments, the inhibitor of A2A / A2B or a pharmaceutically acceptable salt thereof is administered to a subject at a dosage of about 10 mg BID on a free base basis.

[0244] In some embodiments, the inhibitor of A2A / A2B or a pharmaceutically acceptable salt thereof is administered to a subject at a dosage of about 40 mg QD on a free base basis.

[0245] In some embodiments, the inhibitor of A2A / A2B or a pharmaceutically acceptable salt thereof is administered to a subject at a dosage of about 40 mg BID on a free base basis.

[0246] In some embodiments, each of the doses is administered as a single, once-daily dose. In some embodiments, each of the doses is administered as a single, once-daily oral dose.

[0247] In some embodiments, the provided methods include a first dose of an inhibitor of A2A / A2B or a pharmaceutically acceptable salt thereof as defined herein, and a second dose of the inhibitor of A2A / A2B or a pharmaceutically acceptable salt thereof, wherein the second dose is greater than the first dose (i.e., the methods include dose escalation of the inhibitor of A2A / A2B or a pharmaceutically acceptable salt thereof, such as compound 9).

[0248] In some embodiments, the method comprises dose-escalation of an A2A / A2B inhibitor or a pharmaceutically acceptable salt thereof, where the A2A / A2B inhibitor or a pharmaceutically acceptable salt thereof is administered to a subject in combination with a PD-1 / PD-L1 inhibitor and an anti-CD73 antibody, or antigen-binding fragment thereof.

[0249] In some embodiments, the methods include dose escalation of compound 9 when compound 9 is administered to a subject in combination with a PD-1 / PD-L1 inhibitor (e.g., retifanlimab) and in combination with an anti-CD73 antibody, or antigen-binding antibody thereof (e.g., antibody Y).

[0250] PD-1 / PD-L1 inhibitors In some embodiments, the PD-1 / PD-L1 inhibitor, or a pharmaceutically acceptable salt thereof, is administered to a subject at a dose of about 0.1 mg to about 1000 mg, based on the free base. In some embodiments, the PD-1 / PD-L1 inhibitor, or a pharmaceutically acceptable salt thereof, is administered to a subject at a dose of about 1 mg to about 500 mg, based on the free base. In some embodiments, the PD-1 / PD-L1 inhibitor, or a pharmaceutically acceptable salt thereof, is administered to a subject at a dose of about 5 mg to about 250 mg, based on the free base. In some embodiments, the PD-1 / PD-L1 inhibitor, or a pharmaceutically acceptable salt thereof, is administered to a subject at a dose of about 10 mg to about 100 mg, based on the free base.

[0251] The composition may comprise about 1 mg / mL to 100 mg / mL, or about 10 mg / mL to 100 mg / mL, or about 50 to 250 mg / mL, or about 100 to 150 mg / mL, or about 100 to 250 mg / mL of an anti-PD-1 / PD-L1 inhibitor (e.g., an anti-PD-1 antibody or antigen-binding fragment thereof).

[0252] Doses of a PD-1 / PD-L1 inhibitor (e.g., an anti-PD-1 antibody or antigen-binding fragment thereof) can be administered, for example, at least two doses, three doses, five doses, ten doses, or more, e.g., once or twice daily, or about 1 to 4 times per week, or preferably once weekly, every other week (every two weeks), every three weeks, or once monthly, at periodic intervals over a period sufficient to encompass, for example, about 1 to 12 weeks, preferably 2 to 8 weeks, more preferably about 3 to 7 weeks, and even more preferably about 4, 5, or 6 weeks (course of treatment). Factors that may affect the dosage and timing required to effectively treat a subject include, for example, the severity of the disease or disorder, the formulation, the route of delivery, previous treatments, the general health and / or age of the subject, and other diseases present. Moreover, treatment of a subject with a therapeutically effective amount of a compound can include a single treatment or, preferably, include a series of treatments.

[0253] In some embodiments, the inhibitor of PD-1 / PD-L1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 0.5 mg, about 1 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg, About 150mg, about 155mg, about 160mg, about 165mg, about 170mg, about 175mg, about 180mg, about 185mg, about 190mg, about 195mg, about 200mg, about 205mg, about 210mg, about 215mg, about 220mg, about 225mg, about 230mg, about 235mg , about 240mg, about 245mg, about 250mg, about 255mg, about 260mg, about 265mg, about 270mg, about 275mg, about 280mg, about 285mg, about 290mg, about 295mg, about 300mg, about 305mg, about 310mg, about 315mg, about 320mg, about 325m g, approx. 330 mg, approx. 335 mg, approx. 340 mg, approx. 345 mg, approx. 350 mg, approx. 355 mg, approx. 360 mg, approx. 365 mg, approx. 370 mg, approx. 375 mg, approx. 5mg, approx. 420mg, approx. 425mg, approx. 430mg, approx. 435mg, approx. 440mg, approx. 445mg, approx. 450mg, approx. 455mg, approx. 460mg, approx. 05mg, approx. 510mg, approx. 515mg, approx. 520mg, approx. 525mg, approx. 530mg, approx. 535mg, approx. 540mg, approx. 545mg, approx. 550mg, approx. 595mg, about 600mg, about 605mg, about 610mg, about 615mg, about 620mg, about 625mg, about 630mg, about 635mg, about 640mg, about 645mg, about 650mg, about 655mg, about 660mg, about 665mg, about 670mg, about 675mg, about 680mg,Approx. 685 mg, approx. 690 mg, approx. 695 mg, approx. 700 mg, approx. 705 mg, approx. 710 mg, approx. 715 mg, approx. 720 mg, approx. 725 mg, approx. 730 mg, approx. g, approx. 770 mg, approx. 775 mg, approx. 780 mg, approx. 785 mg, approx. 790 mg, approx. 795 mg, approx. 800 mg, approx. 805 mg, approx. 810 mg, approx. mg, about 855 mg, about 860 mg, about 865 mg, about 870 mg, about 875 mg, about 880 mg, about 885 mg, about 890 mg, about 895 mg, about 900 mg, about 905 mg, about 910 mg, about 915 mg, about 920 mg, about 925 mg, about 930 mg, about 935 mg, about 940 mg, about 945 mg, about 950 mg, about 955 mg, about 960 mg, about 965 mg, about 970 mg, about 975 mg, about 980 mg, about 985 mg, about 990 mg, about 995 mg, and about 1000 mg. In some embodiments, the PD-1 / PD-L1 inhibitor, or a pharmaceutically acceptable salt thereof, is administered to a subject at a dose ranging from about 0.1 mg to about 500 mg, on a free base basis, or any dose value therebetween. In some embodiments, the PD-1 / PD-L1 inhibitor, or a pharmaceutically acceptable salt thereof, is administered to a subject at a dose ranging from about 1 mg to about 100 mg, on a free base basis, or any dose value therebetween.

[0254] In some embodiments, the PD-1 / PD-L1 inhibitor is administered to a subject at a dose of about 1 mg / kg to about 10 mg / kg. In some embodiments, the PD-1 / PD-L1 inhibitor is administered to a subject at a dose of about 2 mg / kg, about 3 mg / kg, about 4 mg / kg, about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, or about 10 mg / kg. In some embodiments, the PD-1 / PD-L1 inhibitor is administered to a subject at a dose of about 200 mg to about 1000 mg. In some embodiments, the inhibitor of PD-1 / PD-L1 is administered to a subject at a dose of about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, about 500 mg, about 525 mg, about 550 mg, about 575 mg, about 600 mg, about 625 mg, about 650 mg, about 675 mg, about 700 mg, about 725 mg, about 750 mg, about 775 mg, about 800 mg, about 825 mg, about 850 mg, about 875 mg, about 900 mg, about 925 mg, about 950 mg, about 975 mg, or about 1000 mg.

[0255] In some embodiments, the PD-1 / PD-L1 inhibitor is administered to the subject once daily, every other day, once weekly, or any time interval therebetween. In some embodiments, the PD-1 / PD-L1 inhibitor is administered to the subject once daily. In some embodiments, the PD-1 / PD-L1 inhibitor is administered to the subject every other day. In some embodiments, the PD-1 / PD-L1 inhibitor is administered to the subject once weekly.

[0256] In some embodiments, each of the doses is administered as a single, once-daily dose. In some embodiments, each of the doses is administered as a single, once-daily oral dose.

[0257] In some embodiments, the PD-1 / PD-L1 inhibitor is administered to the subject every two weeks, every three weeks, or every four weeks. In some embodiments, the PD-1 / PD-L1 inhibitor is administered to the subject monthly or quarterly. In some embodiments, the PD-1 / PD-L1 inhibitor is administered to the subject by intravenous administration.

[0258] In some embodiments, the inhibitor of PD-1 / PD-L1 is administered to the subject at a dosage of 1 mg / kg Q2W.

[0259] In some embodiments, the PD-1 / PD-L1 inhibitor is administered to the subject at a dosage of 3 mg / kg Q2W.

[0260] In some embodiments, the PD-1 / PD-L1 inhibitor is administered to the subject at a dosage of 3 mg / kg Q4W.

[0261] In some embodiments, the PD-1 / PD-L1 inhibitor is administered to the subject at a dosage of 10 mg / kg Q2W.

[0262] In some embodiments, the inhibitor of PD-1 / PD-L1 is administered to the subject at a dosage of 10 mg / kg Q4W.

[0263] In some embodiments, the PD-1 / PD-L1 inhibitor is administered to the subject at a dosage of 200 mg Q3W.

[0264] In some embodiments, the PD-1 / PD-L1 inhibitor is administered to the subject at a dosage of 250 mg Q3W.

[0265] In some embodiments, the PD-1 / PD-L1 inhibitor is administered to a subject at a dosage of 375 mg Q3W.

[0266] In some embodiments, the PD-1 / PD-L1 inhibitor is administered to a subject at a dosage of 500 mg Q4W.

[0267] In some embodiments, the PD-1 / PD-L1 inhibitor is administered to a subject at a dosage of 750 mg Q4W.

[0268] In some embodiments, the PD-1 / PD-L1 inhibitor is retifanlimab. In some embodiments, retifanlimab is administered to a subject at a dose of about 250 mg to about 850 mg. In some embodiments, retifanlimab is administered to a subject at a dose of about 375 mg to about 850 mg. In some embodiments, retifanlimab is administered to a subject at a dose of about 450 mg to about 850 mg. In some embodiments, retifanlimab is administered to a subject at a dose of about 500 mg to about 750 mg. In some embodiments, retifanlimab is administered to a subject at a dose of about 500 mg. In some embodiments, retifanlimab is administered to a subject at a dose of about 750 mg. In some embodiments, retifanlimab is administered to a subject every four weeks. In some embodiments, retifanlimab is administered to a subject by intravenous administration.

[0269] In some embodiments, retifanlimab is administered to a subject at a dosage of 1 mg / kg Q2W.

[0270] In some embodiments, retifanlimab is administered to a subject at a dosage of 3 mg / kg Q2W.

[0271] In some embodiments, retifanlimab is administered to a subject at a dosage of 3 mg / kg Q4W.

[0272] In some embodiments, retifanlimab is administered to a subject at a dosage of 10 mg / kg Q2W.

[0273] In some embodiments, retifanlimab is administered to a subject at a dosage of 10 mg / kg Q4W.

[0274] In some embodiments, retifanlimab is administered to a subject at a dosage of 200 mg Q3W.

[0275] In some embodiments, retifanlimab is administered to a subject at a dosage of 250 mg Q3W.

[0276] In some embodiments, retifanlimab is administered to a subject at a dosage of 375 mg Q3W.

[0277] In some embodiments, retifanlimab is administered to a subject at a dosage of 500 mg Q4W.

[0278] In some embodiments, retifanlimab is administered to a subject at a dosage of 750 mg Q4W.

[0279] In some embodiments, retifanlimab is administered to a subject at a dosage of about 100 mg to about 1000 mg Q4W.

[0280] In some embodiments, the methods provided comprise a first dose of an inhibitor of PD-1 / PD-L1 as defined herein and a second dose of the PD-1 / PD-L1 inhibitor, where the second dose is greater than the first dose (i.e., the methods comprise dose escalation of the PD-1 / PD-L1 inhibitor, such as retifanlimab).

[0281] In some embodiments, the methods include dose escalation of the PD-1 / PD-L1 inhibitor when the PD-1 / PD-L1 inhibitor is administered to the subject in combination with an A2A and / or A2B inhibitor, and / or in combination with an anti-CD73 antibody, or antigen-binding fragment thereof.

[0282] In some embodiments, the methods include dose escalation of the PD-1 / PD-L1 inhibitor when the PD-1 / PD-L1 inhibitor is administered to the subject in combination with an anti-CD73 antibody, or antigen-binding fragment thereof.

[0283] In some embodiments, the methods include dose escalation of retifanlimab when said retifanlimab is administered to a subject in combination with an inhibitor of A2A and / or A2B and / or in combination with an anti-CD73 antibody, or antigen-binding fragment thereof.

[0284] In some embodiments, the methods include dose escalation of retifanlimab when said retifanlimab is administered to a subject in combination with an anti-CD73 antibody, or antigen-binding fragment thereof (eg, antibody Y).

[0285] Anti-CD73 antibody In some embodiments, the anti-CD73 antibody, or antigen-binding fragment thereof, is administered to a subject at a dose of about 0.1 mg to about 1000 mg. In some embodiments, the anti-CD73 antibody, or antigen-binding fragment thereof, is administered to a subject at a dose of about 0.1 mg to about 500 mg. In some embodiments, the anti-CD73 antibody, or antigen-binding fragment thereof, is administered to a subject at a dose of about 0.1 mg to about 100 mg. In some embodiments, the anti-CD73 antibody, or antigen-binding fragment thereof, is administered to a subject at a dose of about 1 mg to about 100 mg. In some embodiments, the anti-CD73 antibody, or antigen-binding fragment thereof, is administered to a subject at a dose of about 50 mg to about 100 mg.

[0286] The composition may contain about 1 mg / mL to 100 mg / mL, or about 10 mg / mL to 100 mg / mL, or about 50 to 250 mg / mL, or about 100 to 150 mg / mL, or about 100 to 250 mg / mL of an anti-CD73 antibody (e.g., an anti-CD73 antibody or antigen-binding fragment thereof). In some embodiments, the composition contains 50 mg / mL of an anti-CD73 antibody (e.g., an anti-CD73 antibody or antigen-binding fragment thereof).

[0287] Anti-CD73 antibody doses can be administered, for example, at least two doses, three doses, five doses, ten doses, or more, e.g., once or twice daily, or about 1 to 4 times per week, or preferably once weekly, every other week (every two weeks), every three weeks, or once monthly, at periodic intervals over a period sufficient to encompass, for example, about 1 to 12 weeks, preferably 2 to 8 weeks, more preferably about 3 to 7 weeks, and even more preferably about 4, 5, or 6 weeks (course of treatment). Factors that can affect the dosage and timing required to effectively treat a subject include, for example, the severity of the disease or disorder, the formulation, the route of delivery, previous treatments, the general health and / or age of the subject, and other diseases present. Furthermore, treatment of a subject with a therapeutically effective amount of a compound can include a single treatment or, preferably, a series of treatments.

[0288] In some embodiments, the inhibitor of PD-1 / PD-L1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 0.5 mg, about 1 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg, About 150mg, about 155mg, about 160mg, about 165mg, about 170mg, about 175mg, about 180mg, about 185mg, about 190mg, about 195mg, about 200mg, about 205mg, about 210mg, about 215mg, about 220mg, about 225mg, about 230mg, about 235mg , about 240mg, about 245mg, about 250mg, about 255mg, about 260mg, about 265mg, about 270mg, about 275mg, about 280mg, about 285mg, about 290mg, about 295mg, about 300mg, about 305mg, about 310mg, about 315mg, about 320mg, about 325m g, approx. 330 mg, approx. 335 mg, approx. 340 mg, approx. 345 mg, approx. 350 mg, approx. 355 mg, approx. 360 mg, approx. 365 mg, approx. 370 mg, approx. 375 mg, approx. 5mg, approx. 420mg, approx. 425mg, approx. 430mg, approx. 435mg, approx. 440mg, approx. 445mg, approx. 450mg, approx. 455mg, approx. 460mg, approx. 05mg, approx. 510mg, approx. 515mg, approx. 520mg, approx. 525mg, approx. 530mg, approx. 535mg, approx. 540mg, approx. 545mg, approx. 550mg, approx. 595mg, about 600mg, about 605mg, about 610mg, about 615mg, about 620mg, about 625mg, about 630mg, about 635mg, about 640mg, about 645mg, about 650mg, about 655mg, about 660mg, about 665mg, about 670mg, about 675mg, about 680mg,Approx. 685 mg, approx. 690 mg, approx. 695 mg, approx. 700 mg, approx. 705 mg, approx. 710 mg, approx. 715 mg, approx. 720 mg, approx. 725 mg, approx. 730 mg, approx. 775mg, about 780mg, about 785mg, about 790mg, about 795mg, about 800mg, about 805mg, about 810mg, about 815mg, about 820mg, about 825mg, about 830mg, about 835mg, about 840mg, about 845mg, about 850mg, about 855mg, about 860mg, about 86 The compound is administered to a subject at a dose selected from about 5 mg, about 870 mg, about 875 mg, about 880 mg, about 885 mg, about 890 mg, about 895 mg, about 900 mg, about 905 mg, about 910 mg, about 915 mg, about 920 mg, about 925 mg, about 930 mg, about 935 mg, about 940 mg, about 945 mg, about 950 mg, about 955 mg, about 960 mg, about 965 mg, about 970 mg, about 975 mg, about 980 mg, about 985 mg, about 990 mg, about 995 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, or about 1500 mg.

[0289] In some embodiments, the anti-CD73 antibody, or antigen-binding fragment thereof, is administered to the subject once daily, every other day, once weekly, or any time interval therebetween. In some embodiments, the anti-CD73 antibody, or antigen-binding fragment thereof, is administered to the subject once daily. In some embodiments, the anti-CD73 antibody, or antigen-binding fragment thereof, is administered to the subject every other day. In some embodiments, the anti-CD73 antibody, or antigen-binding fragment thereof, is administered to the subject once weekly.

[0290] In some embodiments, the anti-CD73 antibody, or antigen-binding fragment thereof, is administered to the subject every two weeks, every three weeks, or every four weeks. In some embodiments, the anti-CD73 antibody, or antigen-binding fragment thereof, is administered to the subject every other month or every three months. In some embodiments, the anti-CD73 antibody, or antigen-binding fragment thereof, is administered to the subject intravenously.

[0291] In some embodiments, each of the doses is administered as a single, once-daily dose. In some embodiments, each of the doses is administered as a single, once-daily intravenous dose.

[0292] In some embodiments, the anti-CD73 antibody, or antigen-binding fragment thereof, is administered to the subject at a dose of about 70 mg Q2W.

[0293] In some embodiments, the anti-CD73 antibody, or antigen-binding fragment thereof, is administered to the subject at a dosage of about 100 mg Q2W.

[0294] In some embodiments, the anti-CD73 antibody, or antigen-binding fragment thereof, is administered to the subject at a dosage of about 250 mg Q2W.

[0295] In some embodiments, the anti-CD73 antibody, or antigen-binding fragment thereof, is administered to the subject at a dosage of about 500 mg Q2W.

[0296] In some embodiments, the anti-CD73 antibody, or antigen-binding fragment thereof, is administered to the subject at a dose of about 750 mg Q2W.

[0297] In some embodiments, the anti-CD73 antibody, or antigen-binding fragment thereof, is administered to the subject at a dosage of about 1500 mg Q2W.

[0298] In some embodiments, the anti-CD73 antibody, or antigen-binding fragment thereof, is administered to the subject at a dose of about 70 mg Q4W.

[0299] In some embodiments, the anti-CD73 antibody, or antigen-binding fragment thereof, is administered to the subject at a dosage of about 100 mg Q4W.

[0300] In some embodiments, the anti-CD73 antibody, or antigen-binding fragment thereof, is administered to the subject at a dosage of about 250 mg Q4W.

[0301] In some embodiments, the anti-CD73 antibody, or antigen-binding fragment thereof, is administered to the subject at a dosage of about 500 mg Q4W.

[0302] In some embodiments, the anti-CD73 antibody, or antigen-binding fragment thereof, is administered to the subject at a dosage of about 750 mg Q4W.

[0303] In some embodiments, the anti-CD73 antibody, or antigen-binding fragment thereof, is administered to the subject at a dosage of about 1500 mg Q4W.

[0304] In some embodiments, the provided methods comprise administering a first dose of an anti-CD73 antibody, or antigen-binding fragment thereof, as defined herein, and a second dose of the anti-CD73 antibody, or antigen-binding fragment thereof, wherein the second dose is greater than the first dose (i.e., the methods comprise dose escalation of the anti-CD73 antibody, or antigen-binding fragment thereof, such as antibody Y).

[0305] In some embodiments, the methods include dose escalation of an anti-CD73 antibody, or antigen-binding fragment thereof, when the anti-CD73 antibody, or antigen-binding fragment thereof, is administered to a subject in combination with an inhibitor of A2A and / or A2B and / or in combination with an inhibitor of PD-1 / PD-L1.

[0306] In some embodiments, the methods include dose escalation of the anti-CD73 antibody, or antigen-binding fragment thereof, when the anti-CD73 antibody, or antigen-binding fragment thereof, is administered to the subject in combination with an inhibitor of PD-1 / PD-L1.

[0307] In some embodiments, the methods include dose escalation of antibody Y when antibody Y is administered to a subject in combination with an inhibitor of A2A and / or A2B and / or in combination with an inhibitor of PD-1 / PD-L1.

[0308] In some embodiments, the method comprises dose escalation of antibody Y when antibody Y is administered to a subject in combination with an inhibitor of PD-1 / PD-L1.

[0309] How to use The anti-CD73 antibodies of the present disclosure can modulate the activity of CD73. Accordingly, the anti-CD73 antibodies described herein can be used in methods of inhibiting CD73 by contacting CD73 with any one or more of the antibodies or compositions thereof described herein. The A2A and / or A2B inhibitors of the present disclosure can modulate the activity of the A2A and / or A2B adenosine receptor. Accordingly, the A2A and / or A2B adenosine receptor inhibitors, salts, or stereoisomers described herein can be used in methods of inhibiting the A2A and / or A2B adenosine receptor by contacting the A2A and / or A2B adenosine receptor with any one or more of the A2A and / or A2B adenosine receptor inhibitors or compositions thereof described herein, respectively. Similarly, the PD-1 / PD-L1 inhibitors of the present disclosure can modulate the activity of PD-1 / PD-L1. Thus, the PD-1 / PD-L1 inhibitors, salts, or stereoisomers described herein can be used in methods of inhibiting PD-1 / PD-L1 by contacting PD-1 / PD-L1 with any one or more of the PD-1 / PD-L1 inhibitors or compositions thereof described herein, respectively. In some embodiments, the contacting is in vivo. In some embodiments, the contacting is ex vivo or in vitro.

[0310] Another aspect of the present disclosure relates to methods of treating a CD73, A2A and / or A2B adenosine receptor, and / or PD-1 / PD-L1 associated disease or disorder in an individual (e.g., a patient), comprising administering to the individual in need of such treatment one or more anti-CD73 antibodies of the present disclosure, or pharmaceutical compositions thereof, in a therapeutically effective amount or dose; administering one or more inhibitors of the A2A and / or A2B adenosine receptor of the present disclosure, or pharmaceutical compositions thereof, in a therapeutically effective amount or dose; and administering one or more inhibitors of the PD-1 / PD-L1 of the present disclosure, or pharmaceutical compositions thereof, in a therapeutically effective amount.

[0311] Another aspect of the present disclosure relates to a method of treating a CD73- and / or PD-1 / PD-L1-associated disease or disorder in an individual (e.g., a patient), comprising administering to the individual in need of such treatment one or more anti-CD73 antibodies or pharmaceutical compositions thereof in a therapeutically effective amount or dose, and one or more PD-1 / PD-L1 inhibitors of the present disclosure, or pharmaceutical compositions thereof, in a therapeutically effective amount.

[0312] CD73-related diseases or disorders may include any disease, disorder, or condition directly or indirectly associated with CD73 expression or activity, including overexpression and / or abnormal activity levels. A2A and / or A2B adenosine receptor-related diseases or disorders may include any disease, disorder, or condition directly or indirectly associated with A2A and / or A2B adenosine receptor expression or activity, including overexpression and / or abnormal activity levels. PD-1 / PD-L1-related diseases or disorders may include any disease, disorder, or condition directly or indirectly associated with PD-1 / PD-L1 expression or activity, including overexpression and / or abnormal activity levels.

[0313] A CD73 and / or A2A and / or A2B adenosine receptor, and / or PD-1 / PD-L1 associated disease or disorder may include any disease, disorder, or condition that is directly or indirectly linked to the expression or activity of CD73 and / or A2A and / or A2B adenosine receptor, and / or PD-1, and / or PD-L1, including overexpression and / or abnormal activity levels of CD73 and / or A2A and / or A2B adenosine receptor, and / or PD-1, and / or PD-L1.

[0314] Another aspect of the present disclosure relates to a method of treating a disease or disorder (e.g., cancer) in an individual (e.g., a patient), comprising administering to the individual in need of such treatment one or more anti-CD73 antibodies or pharmaceutical compositions thereof of the present disclosure in a therapeutically effective amount or dose, one or more inhibitors of the A2A and / or A2B adenosine receptors or pharmaceutical compositions thereof of the present disclosure in a therapeutically effective amount or dose, and one or more inhibitors of PD-1 / PD-L1 of the present disclosure or pharmaceutical compositions thereof in a therapeutically effective amount, wherein the disease or disorder is characterized by elevated adenosine. Methods for determining whether a disease or disorder is characterized by elevated adenosine are known in the art. For example, gene expression analysis of tumor tissue may be performed using a defined panel of adenosine-responsive genes.

[0315] The anti-CD73 antibodies of the present disclosure, inhibitors of A2A and / or A2B adenosine receptors, and inhibitors of PD-1 / PD-L1 may function synergistically, e.g., to treat a disease or disorder, e.g., cancer. For example, in a dual combination therapy, the anti-CD73 antibodies of the present disclosure and inhibitors of PD-1 / PD-L1 may function synergistically, e.g., to treat a disease or disorder, e.g., cancer. Thus, the anti-CD73 antibodies, inhibitors of A2A and / or A2B adenosine receptors, and inhibitors of PD-1 / PD-L1 described herein can be used in combination with methods of inhibiting CD73, A2A and / or A2B adenosine receptors, and / or PD-1 / PD-L1 by contacting CD73 with any one or more of the anti-CD73 antibodies, or compositions thereof, described herein, contacting the A2A and / or A2B adenosine receptors with any one or more of the A2A and / or A2B adenosine receptors, or compositions thereof, described herein, and contacting PD-1 / PD-L1 with any one or more of the inhibitors of PD-1 / PD-L1, or compositions thereof, described herein. In some embodiments, the anti-CD73 antibodies and PD-1 / PD-L1 inhibitors described herein can be used in combination with methods of inhibiting CD73 and / or PD-1 / PD-L1 by contacting CD73 with any one or more of the anti-CD73 antibodies or compositions thereof described herein, and contacting PD-1 / PD-L1 with any one or more of the PD-1 / PD-L1 inhibitors or compositions thereof described herein.

[0316] The anti-CD73 antibodies, inhibitors of A2A and / or A2B adenosine receptors, and inhibitors of PD-1 / PD-L1 of the present disclosure are useful in combination with the treatment of diseases associated with CD73 and / or A2A and / or A2B adenosine receptor, and / or PD-1 / PD-L1 activity, including, for example, cancer, inflammatory diseases, cardiovascular diseases, neurodegenerative diseases, immune dysregulation, central nervous system diseases, and diabetes. The anti-CD73 antibodies and inhibitors of PD-1 / PD-L1 of the present disclosure are useful in combination with the treatment of diseases associated with CD73 and / or PD-1 / PD-L1 activity, including, for example, cancer, inflammatory diseases, cardiovascular diseases, neurodegenerative diseases, immune dysregulation, central nervous system diseases, and diabetes.

[0317] Based on the compelling roles of CD73, A2A and / or A2B adenosine receptors, and / or PD-1 / PD-L1 in multiple immunosuppressive mechanisms, combination therapies can strengthen the immune system and suppress tumor progression. Anti-CD73 antibodies, A2A and / or A2B adenosine receptor inhibitors, and PD-1 / PD-L1 inhibitors, optionally further combined with other treatments, can be used in combination with the treatment of bladder cancer, lung cancer (e.g., non-small cell lung cancer (NSCLC), lung metastasis), melanoma (e.g., metastatic melanoma), breast cancer (e.g., breast adenocarcinoma), cervical cancer, ovarian cancer, colorectal cancer, pancreatic cancer, esophageal cancer, prostate cancer, kidney cancer, skin cancer, thyroid cancer, liver cancer (e.g., hepatocellular carcinoma), uterine cancer, head and neck cancer (e.g., head and neck squamous cell carcinoma), and renal cell carcinoma.

[0318] Examples of cancers treatable using the therapeutic methods and regimens of the present disclosure include, but are not limited to, bone cancer, spleen cancer, skin cancer, head and neck cancer, cutaneous or intraocular malignant melanoma, uterine cancer, ovarian cancer, rectal cancer, anal cancer, stomach cancer, testicular cancer, uterine cancer, fallopian tube cancer, carcinoma of the endometrium, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, non-Hodgkin's lymphoma, esophageal cancer, small intestine cancer, endocrine system cancer, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, ureteral cancer, urethral cancer, urachal cancer, gastric cancer, Cancers include penile cancer, chronic or acute leukemia, including acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, and chronic lymphocytic leukemia, childhood solid tumors, lymphocytic lymphoma, bladder cancer, kidney or urethral cancer, renal pelvis cancer, neoplasms of the central nervous system (CNS), primary CNS lymphoma, tumor angiogenesis, spinal axis tumors, brainstem glioma, pituitary adenoma, Kaposi's sarcoma, epidermoid carcinoma, squamous cell carcinoma, T-cell lymphoma, environmentally induced cancers, including asbestos-induced cancers, and combinations of the above cancers. The methods of the present disclosure are also useful for treating metastatic cancers, particularly metastatic cancers that express PD-L1.

[0319] In some embodiments, cancers treatable by the methods of the present disclosure include melanoma (e.g., metastatic malignant melanoma), renal carcinoma (e.g., clear cell carcinoma), prostate cancer (e.g., hormone-refractory prostate adenocarcinoma), breast cancer (e.g., breast adenocarcinoma), colon cancer, lung cancer (e.g., non-small cell lung cancer and small cell lung cancer), head and neck squamous cell carcinoma, urothelial carcinoma (e.g., bladder), and microsatellite instability-high cancer (MSI-high). Additionally, the present disclosure includes refractory or recurrent malignancies whose growth may be inhibited using the methods of the present disclosure.

[0320] In some embodiments, cancers treatable using the methods of the present disclosure include, but are not limited to, solid tumors (e.g., prostate cancer, colon cancer, esophageal cancer, endometrial cancer, ovarian cancer, uterine cancer, renal cancer, liver cancer, pancreatic cancer, gastric cancer, breast cancer (e.g., mammary gland cancer), lung cancer, head and neck cancer, thyroid cancer, glioblastoma, sarcoma, bladder cancer, etc.), blood cancers (e.g., lymphoma, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma, non-Hodgkin's lymphoma (including relapsed or refractory NHL and relapsed follicular), lymphomas such as Hodgkin's lymphoma or multiple myeloma, leukemia), and combinations of such cancers.

[0321] In some embodiments, cancers treatable using the methods of the present disclosure include, but are not limited to, cholangiocarcinoma, bile duct cancer, triple-negative breast cancer, rhabdomyosarcoma, small cell lung cancer, leiomyosarcoma, hepatocellular carcinoma, Ewing's sarcoma, brain cancer, brain tumor, astrocytoma, neuroblastoma, neurofibroma, basal cell carcinoma, chondrosarcoma, epithelioid sarcoma, eye cancer, fallopian tube cancer, gastrointestinal cancer, gastrointestinal stromal tumor, hairy cell leukemia, intestinal cancer, pancreatic islet cell carcinoma, oral cavity cancer (oral cancer), mouth cancer, pharyngeal cancer, laryngeal cancer, lip cancer, mesothelioma, cervical cancer, nasal cavity cancer, ocular cancer, ocular melanoma, pelvic cancer, rectal cancer, renal cell carcinoma, salivary gland cancer, paranasal sinus cancer, spinal cancer, tongue cancer, tubular cancer, urethral cancer, and ureteral cancer.

[0322] In some embodiments, the disease or disorder is lung cancer (e.g., non-small cell lung cancer), melanoma, pancreatic cancer, breast cancer (e.g., breast adenocarcinoma), prostate cancer, liver cancer, colon cancer, endometrial cancer, bladder cancer, skin cancer, uterine cancer, kidney cancer, gastric cancer, or sarcoma. In some embodiments, the cancer is selected from acute lymphoblastic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, diffuse large B-cell lymphoma, mantle cell lymphoma, non-Hodgkin's lymphoma, Hodgkin's lymphoma, multiple myeloma, multiple myelogenous leukemia, essential thrombocythemia, chronic myelogenous leukemia, myelofibrosis, primary myelofibrosis, post-polycythemia / essential thrombocythemia myelofibrosis, post-essential thrombocythemia myelofibrosis, and post-polycythemia myelofibrosis. In some embodiments, the cancer is selected from melanoma, endometrial cancer, lung cancer, renal cell carcinoma, urothelial cancer, bladder cancer, breast cancer (eg, breast adenocarcinoma), and pancreatic cancer.

[0323] In some embodiments, the cancer is selected from bladder cancer, lung cancer (e.g., non-small cell lung cancer (NSCLC), small cell lung cancer, or lung metastasis), melanoma (e.g., metastatic melanoma), breast cancer (e.g., breast adenocarcinoma), cervical cancer, ovarian cancer, colon cancer, rectal cancer, colorectal cancer, pancreatic cancer, esophageal cancer, prostate cancer, kidney cancer, skin cancer, thyroid cancer, liver cancer, uterine cancer, head and neck cancer, renal cell carcinoma, endometrial cancer, anal cancer, bile duct cancer, oral cancer, non-melanoma skin cancer, and Merkel cell carcinoma.

[0324] In some embodiments, the prostate cancer is metastatic castration-resistant prostate cancer (mCRPC).

[0325] In some embodiments, the colon cancer is colorectal cancer (CRC).

[0326] In some embodiments, the disease or disorder is lung cancer (e.g., non-small cell lung cancer), melanoma, pancreatic cancer, breast cancer (e.g., breast adenocarcinoma), head and neck squamous cell carcinoma, prostate cancer, liver cancer, color cancer, endometrial cancer, bladder cancer, skin cancer, uterine cancer, kidney cancer, gastric cancer, or sarcoma. In some embodiments, the sarcoma is Askin tumor, botryoid sarcoma, chondrosarcoma, Ewing's sarcoma, malignant hemangioendothelioma, malignant schwannoma, osteosarcoma, alveolar soft part sarcoma, angiosarcoma, cystosarcoma phyllodes, dermatofibrosarcoma protuberans, desmoid tumor, desmoplastic small round cell tumor, epithelioid sarcoma, extraskeletal chondrosarcoma, extraskeletal osteosarcoma, fibrosarcoma, gastrointestinal stromal tumor (GIST), hemangiopericytoma, angiosarcoma, Kaposi's sarcoma, leiomyosarcoma, liposarcoma, lymphangiosarcoma, lymphosarcoma, malignant peripheral nerve sheath tumor (MPNST), neurofibrosarcoma, rhabdomyosarcoma, synovial sarcoma, or undifferentiated pleomorphic sarcoma.

[0327] In some embodiments, the disease or disorder is head and neck cancer (e.g., head and neck squamous cell carcinoma), colorectal cancer (e.g., non-small cell lung cancer (NSCLC)), melanoma, ovarian cancer, bladder cancer, liver cancer (e.g., hepatocellular carcinoma), or renal cell carcinoma.

[0328] In some embodiments, the cancer is mesothelioma or adenocarcinoma. In some embodiments, the disease or disorder is mesothelioma. In some embodiments, the cancer is adenocarcinoma.

[0329] MDSCs (myeloid-derived suppressor cells) are a heterogeneous group of immune cells from the myeloid lineage (a family of cells originating from bone marrow stem cells). MDSCs are strongly expanded in pathological situations, such as chronic infections and cancer, as a result of altered hematopoiesis. MDSCs are distinct from other myeloid cell types in that they possess potent immunosuppressive rather than immunostimulatory properties. Like other myeloid cells, MDSCs interact with and regulate the function of other types of immune cells, including T cells, dendritic cells, macrophages, and natural killer cells. In some embodiments, for example, the compounds described herein can be used in methods related to cancerous tissues (e.g., tumors) with high MDSC infiltration, including solid tumors with high basal levels of macrophage and / or MDSC infiltration. In some embodiments, the combination therapies described herein can be used in methods related to cancerous tissues (e.g., tumors) with tumors or tumor-infiltrating lymphocytes (TILs) that express PD-1 or PD-L1.

[0330] In some embodiments, the cancer is head and neck cancer, lung cancer, ovarian cancer, prostate cancer, breast cancer, bladder cancer, colorectal cancer, gastric cancer, gastroesophageal cancer (e.g., gastroesophageal junction cancer), anal cancer, liver cancer, or pancreatic cancer.

[0331] In some embodiments, the cancer is head and neck cancer, lung cancer, ovarian cancer, prostate cancer, breast cancer, bladder cancer, colorectal cancer, or pancreatic cancer.

[0332] In some embodiments, the cancer is squamous cell carcinoma of the head and neck (SCCNH), non-small cell lung cancer (NSCLC), ovarian cancer, castration-resistant prostate cancer (CRPC), triple-negative breast cancer (TNBC), bladder cancer, metastatic colorectal cancer (mCRC), pancreatic ductal adenocarcinoma (PDAC), gastric / gastroesophageal junction (GEJ) cancer, hepatocellular carcinoma (HCC), or squamous cell carcinoma of the anal canal (SCAC).

[0333] In some embodiments, the cancer is squamous cell carcinoma of the head and neck (SCCNH), non-small cell lung cancer (NSCLC), ovarian cancer, castration-resistant prostate cancer (CRPC), triple-negative breast cancer (TNBC), bladder cancer, metastatic colorectal cancer (mCRC), or pancreatic cancer.

[0334] In some embodiments, the cancer is head and neck squamous cell carcinoma (HNSCC), non-small cell lung cancer (NSCLC), colorectal cancer (e.g., colon cancer), melanoma, ovarian cancer, bladder cancer, renal cell carcinoma, liver cancer, or hepatocellular carcinoma.

[0335] In some embodiments, the cancer is head and neck cancer.

[0336] In some embodiments, the cancer is squamous cell carcinoma of the head and neck (SCCNH).

[0337] In some embodiments, the cancer is lung cancer.

[0338] In some embodiments, the cancer is non-small cell lung cancer (NSCLC).

[0339] In some embodiments, the cancer is ovarian cancer.

[0340] In some embodiments, the cancer is prostate cancer.

[0341] In some embodiments, the cancer is castration-resistant prostate cancer (CRPC).

[0342] In some embodiments, the cancer is breast cancer.

[0343] In some embodiments, the cancer is triple-negative breast cancer (TNBC).

[0344] In some embodiments, the cancer is bladder cancer.

[0345] In some embodiments, the cancer is colorectal cancer.

[0346] In some embodiments, the cancer is metastatic colorectal cancer (mCRC).

[0347] In some embodiments, the cancer is lung cancer.

[0348] In some embodiments, the cancer is gastric cancer.

[0349] In some embodiments, the cancer is esophageal cancer.

[0350] In some embodiments, the cancer is gastroesophageal junction (GEJ) cancer.

[0351] In some embodiments, the cancer is hepatocellular carcinoma (HCC).

[0352] In some embodiments, the cancer is pancreatic ductal adenocarcinoma (PDAC).

[0353] In some embodiments, the cancer is squamous cell carcinoma of the anal canal (SCAC).

[0354] In some embodiments, the cancer is selected from bladder cancer, breast cancer (e.g., breast adenocarcinoma), cervical cancer, colon cancer, rectal cancer, colorectal cancer, anal cancer, endometrial cancer, kidney cancer, oral cancer, head and neck cancer, liver cancer, melanoma, mesothelioma, non-small cell lung cancer, small cell lung cancer, non-melanoma skin cancer, ovarian cancer, pancreatic cancer, prostate cancer, sarcoma, thyroid cancer, renal cell carcinoma, and Merkel cell carcinoma.

[0355] In some embodiments, the cancer is selected from bladder cancer, breast cancer (e.g., breast cancer), cervical cancer, colon cancer, rectal cancer, anal cancer, endometrial cancer, kidney cancer, oral cancer, head and neck cancer, liver cancer, melanoma, mesothelioma, non-small cell lung cancer, small cell lung cancer, non-melanoma skin cancer, ovarian cancer, pancreatic cancer, prostate cancer, sarcoma, thyroid cancer, and Merkel cell carcinoma.

[0356] In some embodiments, the cancer is selected from melanoma, endometrial cancer, lung cancer, kidney cancer, bladder cancer, breast cancer (e.g., breast adenocarcinoma), pancreatic cancer, colon cancer, head and neck cancer, colorectal cancer, ovarian cancer, liver cancer, or renal cell carcinoma.

[0357] In some embodiments, the cancer is selected from melanoma, endometrial cancer, lung cancer, kidney cancer, bladder cancer, breast cancer (eg, mammary gland cancer), pancreatic cancer, and colon cancer.

[0358] In some embodiments, the cancer is selected from endometrial cancer, anal cancer, and bile duct cancer.

[0359] In some embodiments, the cancer is a tumor that exhibits high adenosine levels in the tumor microenvironment. These tumors may be enriched by a gene expression signature or by high expression levels of CD73 and / or other alkaline phosphatases, including tissue-nonspecific alkaline phosphatases (i.e., TNAP and PAP).

[0360] In some embodiments, the cancer is rectal cancer. In some embodiments, the cancer is melanoma. In some embodiments, the cancer is endometrial cancer. In some embodiments, the endometrial cancer is endometrial adenocarcinoma. In some embodiments, the cancer is lung cancer. In some embodiments, the lung cancer is small cell lung cancer or non-small cell lung cancer. In some embodiments, the cancer is renal clear cell carcinoma. In some embodiments, the cancer is squamous cell carcinoma. In some embodiments, the cancer is bladder cancer. In some embodiments, the cancer is breast cancer. In certain embodiments, the breast cancer is breast adenocarcinoma. In some embodiments, the cancer is triple-negative breast cancer. In some embodiments, the cancer is lung cancer. In some embodiments, the pancreatic cancer is pancreatic ductal adenocarcinoma. In some embodiments, the cancer is a sarcoma. In some embodiments, the sarcoma is Askin tumor, botryoid sarcoma, chondrosarcoma, Ewing's sarcoma, malignant hemangioendothelioma, malignant schwannoma, osteosarcoma, alveolar soft part sarcoma, angiosarcoma, cystosarcoma phyllodes, dermatofibrosarcoma protuberans, desmoid tumor, desmoplastic small round cell tumor, epithelioid sarcoma, extraskeletal chondrosarcoma, extraskeletal osteosarcoma, fibrosarcoma, gastrointestinal stromal tumor (GIST), hemangiopericytoma, angiosarcoma, Kaposi's sarcoma, leiomyosarcoma, liposarcoma, lymphangiosarcoma, lymphosarcoma, malignant peripheral nerve sheath tumor (MPNST), neurofibrosarcoma, rhabdomyosarcoma, synovial sarcoma, or undifferentiated pleomorphic sarcoma.

[0361] In some embodiments, the disclosed anti-CD73 antibodies, inhibitors of A2A and / or A2B adenosine receptors, and inhibitors of PD-1 / PD-L1 may be used in combination to treat pulmonary inflammation, including bleomycin-induced pulmonary fibrosis and injuries associated with adenosine deaminase deficiency. In some embodiments, the disclosed anti-CD73 antibodies and inhibitors of PD-1 / PD-L1 may be used in combination to treat pulmonary inflammation, including bleomycin-induced pulmonary fibrosis and injuries associated with adenosine deaminase deficiency.

[0362] In some embodiments, the disclosed anti-CD73 antibodies, inhibitors of A2A and / or A2B adenosine receptors, and inhibitors of PD-1 / PD-L1 can be used in combination to treat inflammatory diseases, such as allergic reactions (e.g., CD73- and / or A2A and / or A2B adenosine receptor- and / or PD-1 / PD-L1-dependent allergic reactions) and other CD73- and / or A2A and / or A2B adenosine receptor- and / or PD-1 / PD-L1 immune responses. Additional inflammatory diseases that may be treated with a combination of the disclosed anti-CD73 antibodies, inhibitors of A2A and / or A2B adenosine receptors, and inhibitors of PD-1 / PD-L1 include respiratory diseases, sepsis, reperfusion injury, and thrombosis.

[0363] In some embodiments, the disclosed anti-CD73 antibodies and PD-1 / PD-L1 inhibitors can be used in combination to treat inflammatory diseases, such as allergic reactions (e.g., CD73- and / or PD-1 / PD-L1-dependent allergic reactions) and other CD73- and / or PD-1 / PD-L1 immune responses. Additional inflammatory diseases that may be treated with a combination of the disclosed anti-CD73 antibodies and PD-1 / PD-L1 inhibitors include respiratory diseases, sepsis, reperfusion injury, and thrombosis.

[0364] In some embodiments, the disclosed anti-CD73 antibodies, inhibitors of A2A and / or A2B adenosine receptors, and inhibitors of PD-1 / PD-L1 can be used in combination to treat cardiovascular diseases such as coronary artery disease (myocardial infarction, angina pectoris, heart failure), cerebrovascular disease (stroke, transient ischemic attack), peripheral artery disease, and large artery atherosclerosis and aneurysms. Atherosclerosis is the underlying etiology of many types of cardiovascular disease. Atherosclerosis manifests as fatty streaks in adolescence and progresses to plaques in adulthood, ultimately leading to thrombotic events that cause vessel occlusion and contribute to clinically significant morbidity and mortality.

[0365] In some embodiments, the disclosed anti-CD73 antibodies and PD-1 / PD-L1 inhibitors can be used in combination to treat cardiovascular diseases such as coronary artery disease (myocardial infarction, angina pectoris, heart failure), cerebrovascular disease (stroke, transient ischemic attack), peripheral artery disease, and large artery atherosclerosis and aneurysms. Atherosclerosis is the underlying etiology of many types of cardiovascular disease. Atherosclerosis manifests as fatty streaks in adolescence and progresses to plaques in adulthood, ultimately leading to thrombotic events that cause vessel occlusion and contribute to clinically significant morbidity and mortality.

[0366] In some embodiments, the disclosed anti-CD73 antibodies, inhibitors of A2A and / or A2B adenosine receptors, and inhibitors of PD-1 / PD-L1 can be used in combination as a treatment for motor activity disorders such as deficiencies caused by degeneration of the striatonigral dopamine system, Parkinson's disease, and some motivational symptoms of depression.

[0367] In some embodiments, the disclosed anti-CD73 antibodies and PD-1 / PD-L1 inhibitors can be used in combination as a treatment for motor activity disorders such as deficiencies caused by degeneration of the striatonigral dopamine system, Parkinson's disease, and some motivational symptoms of depression.

[0368] In some embodiments, the disclosed anti-CD73 antibodies, inhibitors of A2A and / or A2B adenosine receptors, and inhibitors of PD-1 / PD-L1 can be used in combination to treat diabetes and related disorders, such as insulin resistance. Diabetes affects adenosine production and expression of the A2B adenosine receptor (A2BR), which stimulates IL-6 and CRP production, insulin resistance, and the association between A2BR gene single nucleotide polymorphisms (ADORA2B SNPs) and inflammatory markers. Increased A2BR signaling in diabetes may increase insulin resistance, in part, through elevated pro-inflammatory mediators. Selective CD73 inhibitors may be useful in treating insulin resistance.

[0369] In some embodiments, the disclosed anti-CD73 antibodies and PD-1 / PD-L1 inhibitors can be used in combination as a treatment for diabetes and related disorders, such as insulin resistance.

[0370] Further provided herein, in some embodiments, is a method of treating a cancer selected from bladder cancer, breast cancer (e.g., breast adenocarcinoma tumors), cervical cancer, colon cancer, rectal cancer, anal cancer, endometrial cancer, kidney cancer, oral cancer, head and neck cancer, liver cancer, melanoma, mesothelioma, non-small cell lung cancer, small cell lung cancer, non-melanoma skin cancer, ovarian cancer, pancreatic cancer, prostate cancer, sarcoma, thyroid cancer, and Merkel cell carcinoma in a subject, comprising administering to the subject: (i) an inhibitor of A2A / A2B that is 3-(8-amino-5-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-2-(pyridin-2-ylmethyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile, or a pharmaceutically acceptable salt thereof; (ii) an inhibitor of PD-1 / PD-L1 that is an antibody or antigen-binding fragment thereof that binds to human PD-1, wherein the antibody or antigen-binding fragment thereof comprises a variable heavy (VH) domain comprising VH complementarity-determining region (CDR) 1, VH CDR2, and VH CDR3, wherein: the VH CDR1 comprises the amino acid sequence SYWMN (SEQ ID NO: 6); the VH CDR2 comprises the amino acid sequence VIHPSDSETWLDQKFKD (SEQ ID NO: 7); the VH CDR3 comprises the amino acid sequence EHYGTSPFAY (SEQ ID NO: 8); wherein the antibody comprises a variable light (VL) domain comprising a VL CDR1, a VL CDR2, and a VL CDR3, wherein: the VL CDR1 comprises the amino acid sequence RASESVDNYGMSFMNW (SEQ ID NO: 9); the VL CDR2 comprises the amino acid sequence AASNQGS (SEQ ID NO: 10); the inhibitor of PD-1 / PD-L1, wherein the VL CDR3 comprises the amino acid sequence QQSKEVPYT (SEQ ID NO: 11); and (iii) an antibody that binds to human CD73, wherein the antibody that binds to human CD73 is (a) a variable heavy (VH) domain comprising a VH complementarity-determining region (CDR) 1, a VH CDR2, and a VH CDR3, wherein: the VH CDR1 comprises the amino acid sequence GYTFTSYG (SEQ ID NO: 16); the VH CDR2 comprises the amino acid sequence IYPGSGNT (SEQ ID NO: 17); the VH domain, wherein the VH CDR3 comprises the amino acid sequence ARYDYLGSSYGFDY (SEQ ID NO: 18); a variable light (VL) domain comprising a VL CDR1, a VL CDR2, and a VL CDR3, wherein: the VL CDR1 comprises the amino acid sequence QDVSTA (SEQ ID NO: 19); the VL CDR2 comprises the amino acid sequence SAS (SEQ ID NO: 20); the VL domain, wherein the VL CDR3 comprises the amino acid sequence QQHYNTPYT (SEQ ID NO: 21); (b) binds to human CD73 at an epitope within amino acids 40 to 53 of SEQ ID NO: 70; (c) binds to human CD73 and competes for binding to human CD73 with an antibody having a heavy chain comprising the amino acid sequence of SEQ ID NO: 24 and a light chain comprising the amino acid sequence of SEQ ID NO: 25; (d) a VH domain comprising a VH CDR1, a VH CDR2, and a VH CDR3; the VH CDR1 comprises the amino acid sequence GFTFSSYD (SEQ ID NO: 34); the VH CDR2 comprises the amino acid sequence MSYDGSNK (SEQ ID NO: 35) or MSYEGSNK (SEQ ID NO: 40); the VH CDR3 comprises the amino acid sequence ATEIAAKGDY (SEQ ID NO: 36), wherein the antibody comprises a VL domain comprising a VL CDR1, a VL CDR2, and a VL CDR3, wherein: the VL CDR1 comprises the amino acid sequence QGISNY (SEQ ID NO: 37); the VL CDR2 comprises the amino acid sequence AAS (SEQ ID NO: 38); the VH domain, wherein the VL CDR3 comprises the amino acid sequence QQSYSTPH (SEQ ID NO: 39); (e) binds to human CD73 at an epitope within amino acids 386 to 399 and 470 to 489 of SEQ ID NO: 70; (f) binds to human CD73 and competes for binding to human CD73 with an antibody having a heavy chain comprising the amino acid sequence of SEQ ID NO: 30 and a light chain comprising the amino acid sequence of SEQ ID NO: 31; or (g) competing for binding to human CD73 with an antibody that binds to human CD73 and has a heavy chain comprising the amino acid sequence of SEQ ID NO: 33 and a light chain comprising the amino acid sequence of SEQ ID NO: 31.

[0371] In some embodiments, provided herein are methods of treating breast cancer (e.g., breast adenocarcinoma tumors) in a subject, the method comprising administering to the subject: (i) an inhibitor of A2A / A2B that is 3-(8-amino-5-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-2-(pyridin-2-ylmethyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile, or a pharmaceutically acceptable salt thereof; (ii) an inhibitor of PD-1 / PD-L1 that is an antibody or antigen-binding fragment thereof that binds to human PD-1, wherein the antibody or antigen-binding fragment thereof comprises a variable heavy (VH) domain comprising VH complementarity-determining region (CDR) 1, VH CDR2, and VH CDR3, wherein: the VH CDR1 comprises the amino acid sequence SYWMN (SEQ ID NO: 6); the VH CDR2 comprises the amino acid sequence VIHPSDSETWLDQKFKD (SEQ ID NO: 7); the VH CDR3 comprises the amino acid sequence EHYGTSPFAY (SEQ ID NO: 8); wherein the antibody comprises a variable light (VL) domain comprising a VL CDR1, a VL CDR2, and a VL CDR3, wherein: the VL CDR1 comprises the amino acid sequence RASESVDNYGMSFMNW (SEQ ID NO: 9); the VL CDR2 comprises the amino acid sequence AASNQGS (SEQ ID NO: 10); the inhibitor of PD-1 / PD-L1, wherein the VL CDR3 comprises the amino acid sequence QQSKEVPYT (SEQ ID NO: 11); and (iii) an antibody that binds to human CD73, wherein the antibody that binds to human CD73 is (a) a variable heavy (VH) domain comprising a VH complementarity-determining region (CDR) 1, a VH CDR2, and a VH CDR3, wherein: the VH CDR1 comprises the amino acid sequence GYTFTSYG (SEQ ID NO: 16); the VH CDR2 comprises the amino acid sequence IYPGSGNT (SEQ ID NO: 17); the VH domain, wherein the VH CDR3 comprises the amino acid sequence ARYDYLGSSYGFDY (SEQ ID NO: 18); a variable light (VL) domain comprising a VL CDR1, a VL CDR2, and a VL CDR3, wherein: the VL CDR1 comprises the amino acid sequence QDVSTA (SEQ ID NO: 19); the VL CDR2 comprises the amino acid sequence SAS (SEQ ID NO: 20); the VL domain, wherein the VL CDR3 comprises the amino acid sequence QQHYNTPYT (SEQ ID NO: 21); (b) binds to human CD73 at an epitope within amino acids 40 to 53 of SEQ ID NO: 70; (c) binds to human CD73 and competes for binding to human CD73 with an antibody having a heavy chain comprising the amino acid sequence of SEQ ID NO: 24 and a light chain comprising the amino acid sequence of SEQ ID NO: 25; (d) a VH domain comprising a VH CDR1, a VH CDR2, and a VH CDR3; the VH CDR1 comprises the amino acid sequence GFTFSSYD (SEQ ID NO: 34); the VH CDR2 comprises the amino acid sequence MSYDGSNK (SEQ ID NO: 35) or MSYEGSNK (SEQ ID NO: 40); the VH CDR3 comprises the amino acid sequence ATEIAAKGDY (SEQ ID NO: 36), wherein the antibody comprises a VL domain comprising a VL CDR1, a VL CDR2, and a VL CDR3, wherein: the VL CDR1 comprises the amino acid sequence QGISNY (SEQ ID NO: 37); the VL CDR2 comprises the amino acid sequence AAS (SEQ ID NO: 38); the VH domain, wherein the VL CDR3 comprises the amino acid sequence QQSYSTPH (SEQ ID NO: 39); (e) binds to human CD73 at an epitope within amino acids 386 to 399 and 470 to 489 of SEQ ID NO: 70; (f) binds to human CD73 and competes for binding to human CD73 with an antibody having a heavy chain comprising the amino acid sequence of SEQ ID NO: 30 and a light chain comprising the amino acid sequence of SEQ ID NO: 31; or (g) competing for binding to human CD73 with an antibody that binds to human CD73 and has a heavy chain comprising the amino acid sequence of SEQ ID NO: 33 and a light chain comprising the amino acid sequence of SEQ ID NO: 31.

[0372] Further provided herein, in some embodiments, is a method of treating a cancer selected from bladder cancer, breast cancer (e.g., breast adenocarcinoma tumors), cervical cancer, colon cancer, rectal cancer, anal cancer, endometrial cancer, kidney cancer, oral cancer, head and neck cancer, liver cancer, melanoma, mesothelioma, non-small cell lung cancer, small cell lung cancer, non-melanoma skin cancer, ovarian cancer, pancreatic cancer, prostate cancer, sarcoma, thyroid cancer, and Merkel cell carcinoma in a subject, comprising administering to the subject: (i) an inhibitor of A2A / A2B that is 3-(8-amino-5-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-2-(pyridin-2-ylmethyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile, or a pharmaceutically acceptable salt thereof; (ii) a PD-1 / PD-L1 inhibitor, which is retifanlimab; (iii) antibody Y, an antibody that binds to human CD73.

[0373] In some embodiments, provided herein are methods of treating breast cancer (e.g., breast adenocarcinoma tumors) in a subject, the method comprising administering to the subject: (i) an inhibitor of A2A / A2B that is 3-(8-amino-5-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-2-(pyridin-2-ylmethyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile, or a pharmaceutically acceptable salt thereof; (ii) a PD-1 / PD-L1 inhibitor, which is retifanlimab; (iii) antibody Y, an antibody that binds to human CD73.

[0374] Further provided herein, in some embodiments, is a method of treating a cancer selected from bladder cancer, breast cancer (e.g., breast adenocarcinoma tumors), cervical cancer, colon cancer, rectal cancer, anal cancer, endometrial cancer, kidney cancer, oral cancer, head and neck cancer, liver cancer, melanoma, mesothelioma, non-small cell lung cancer, small cell lung cancer, non-melanoma skin cancer, ovarian cancer, pancreatic cancer, prostate cancer, sarcoma, thyroid cancer, and Merkel cell carcinoma in a subject, comprising administering to the subject: (i) an inhibitor of A2A / A2B that is 3-(8-amino-5-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-2-(pyridin-2-ylmethyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile, or a pharmaceutically acceptable salt thereof; (ii) an inhibitor of PD-1 / PD-L1 which is (R)-1-((7-cyano-2-(3'-(3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylic acid, or a pharmaceutically acceptable salt thereof; (iii) an antibody that binds to human CD73, wherein the antibody that binds to human CD73 is (a) a variable heavy (VH) domain comprising a VH complementarity-determining region (CDR) 1, a VH CDR2, and a VH CDR3, wherein: the VH CDR1 comprises the amino acid sequence GYTFTSYG (SEQ ID NO: 16); the VH CDR2 comprises the amino acid sequence IYPGSGNT (SEQ ID NO: 17); the VH domain, wherein the VH CDR3 comprises the amino acid sequence ARYDYLGSSYGFDY (SEQ ID NO: 18); a variable light (VL) domain comprising a VL CDR1, a VL CDR2, and a VL CDR3, wherein: the VL CDR1 comprises the amino acid sequence QDVSTA (SEQ ID NO: 19); the VL CDR2 comprises the amino acid sequence SAS (SEQ ID NO: 20); the VL domain, wherein the VL CDR3 comprises the amino acid sequence QQHYNTPYT (SEQ ID NO: 21); (b) binds to human CD73 at an epitope within amino acids 40 to 53 of SEQ ID NO: 70; (c) binds to human CD73 and competes for binding to human CD73 with an antibody having a heavy chain comprising the amino acid sequence of SEQ ID NO: 24 and a light chain comprising the amino acid sequence of SEQ ID NO: 25; (d) a VH domain comprising a VH CDR1, a VH CDR2, and a VH CDR3; the VH CDR1 comprises the amino acid sequence GFTFSSYD (SEQ ID NO: 34); the VH CDR2 comprises the amino acid sequence MSYDGSNK (SEQ ID NO: 35) or MSYEGSNK (SEQ ID NO: 40); the VH CDR3 comprises the amino acid sequence ATEIAAKGDY (SEQ ID NO: 36), wherein the antibody comprises a VL domain comprising a VL CDR1, a VL CDR2, and a VL CDR3, wherein: the VL CDR1 comprises the amino acid sequence QGISNY (SEQ ID NO: 37); the VL CDR2 comprises the amino acid sequence AAS (SEQ ID NO: 38); the VH domain, wherein the VL CDR3 comprises the amino acid sequence QQSYSTPH (SEQ ID NO: 39); (e) binds to human CD73 at an epitope within amino acids 386 to 399 and 470 to 489 of SEQ ID NO: 70; (f) binds to human CD73 and competes for binding to human CD73 with an antibody having a heavy chain comprising the amino acid sequence of SEQ ID NO: 30 and a light chain comprising the amino acid sequence of SEQ ID NO: 31; or (g) competing for binding to human CD73 with an antibody that binds to human CD73 and has a heavy chain comprising the amino acid sequence of SEQ ID NO: 33 and a light chain comprising the amino acid sequence of SEQ ID NO: 31.

[0375] In some embodiments, provided herein are methods of treating breast cancer (e.g., breast adenocarcinoma tumors) in a subject, the method comprising administering to the subject: (i) an inhibitor of A2A / A2B that is 3-(8-amino-5-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-2-(pyridin-2-ylmethyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile, or a pharmaceutically acceptable salt thereof; (ii) an inhibitor of PD-1 / PD-L1 which is (R)-1-((7-cyano-2-(3'-(3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylic acid, or a pharmaceutically acceptable salt thereof; (iii) an antibody that binds to human CD73, wherein the antibody that binds to human CD73 is (a) a variable heavy (VH) domain comprising a VH complementarity-determining region (CDR) 1, a VH CDR2, and a VH CDR3, wherein: the VH CDR1 comprises the amino acid sequence GYTFTSYG (SEQ ID NO: 16); the VH CDR2 comprises the amino acid sequence IYPGSGNT (SEQ ID NO: 17); the VH domain, wherein the VH CDR3 comprises the amino acid sequence ARYDYLGSSYGFDY (SEQ ID NO: 18); a variable light (VL) domain comprising a VL CDR1, a VL CDR2, and a VL CDR3, wherein: the VL CDR1 comprises the amino acid sequence QDVSTA (SEQ ID NO: 19); the VL CDR2 comprises the amino acid sequence SAS (SEQ ID NO: 20); the VL domain, wherein the VL CDR3 comprises the amino acid sequence QQHYNTPYT (SEQ ID NO: 21); (b) binds to human CD73 at an epitope within amino acids 40 to 53 of SEQ ID NO: 70; (c) binds to human CD73 and competes for binding to human CD73 with an antibody having a heavy chain comprising the amino acid sequence of SEQ ID NO: 24 and a light chain comprising the amino acid sequence of SEQ ID NO: 25; (d) a VH domain comprising a VH CDR1, a VH CDR2, and a VH CDR3; the VH CDR1 comprises the amino acid sequence GFTFSSYD (SEQ ID NO: 34); the VH CDR2 comprises the amino acid sequence MSYDGSNK (SEQ ID NO: 35) or MSYEGSNK (SEQ ID NO: 40); the VH CDR3 comprises the amino acid sequence ATEIAAKGDY (SEQ ID NO: 36), wherein the antibody comprises a VL domain comprising a VL CDR1, a VL CDR2, and a VL CDR3, wherein: the VL CDR1 comprises the amino acid sequence QGISNY (SEQ ID NO: 37); the VL CDR2 comprises the amino acid sequence AAS (SEQ ID NO: 38); the VH domain, wherein the VL CDR3 comprises the amino acid sequence QQSYSTPH (SEQ ID NO: 39); (e) binds to human CD73 at an epitope within amino acids 386 to 399 and 470 to 489 of SEQ ID NO: 70; (f) binds to human CD73 and competes for binding to human CD73 with an antibody having a heavy chain comprising the amino acid sequence of SEQ ID NO: 30 and a light chain comprising the amino acid sequence of SEQ ID NO: 31; or (g) competing for binding to human CD73 with an antibody that binds to human CD73 and has a heavy chain comprising the amino acid sequence of SEQ ID NO: 33 and a light chain comprising the amino acid sequence of SEQ ID NO: 31.

[0376] Further provided herein, in some embodiments, is a method of treating a cancer selected from bladder cancer, breast cancer (e.g., breast adenocarcinoma tumors), cervical cancer, colon cancer, rectal cancer, anal cancer, endometrial cancer, kidney cancer, oral cancer, head and neck cancer, liver cancer, melanoma, mesothelioma, non-small cell lung cancer, small cell lung cancer, non-melanoma skin cancer, ovarian cancer, pancreatic cancer, prostate cancer, sarcoma, thyroid cancer, and Merkel cell carcinoma in a subject, comprising administering to the subject: (i) an inhibitor of A2A / A2B that is 3-(8-amino-5-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-2-(pyridin-2-ylmethyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile, or a pharmaceutically acceptable salt thereof; (ii) an inhibitor of PD-1 / PD-L1 which is (R)-1-((7-cyano-2-(3'-(3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylic acid, or a pharmaceutically acceptable salt thereof; (iii) antibody Y, an antibody that binds to human CD73.

[0377] In some embodiments, provided herein are methods of treating breast cancer (e.g., breast adenocarcinoma tumors) in a subject, the method comprising administering to the subject: (i) an inhibitor of A2A / A2B that is 3-(8-amino-5-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-2-(pyridin-2-ylmethyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile, or a pharmaceutically acceptable salt thereof; (ii) an inhibitor of PD-1 / PD-L1 which is (R)-1-((7-cyano-2-(3'-(3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylic acid, or a pharmaceutically acceptable salt thereof; (iii) antibody Y, an antibody that binds to human CD73.

[0378] Further provided herein, in some embodiments, is a method of treating a cancer selected from head and neck cancer, lung cancer, ovarian cancer, prostate cancer, breast cancer, bladder cancer, colorectal cancer, stomach cancer, gastroesophageal junction cancer, anal cancer, liver cancer, or pancreatic cancer in a subject, comprising administering to the subject: (i) An inhibitor of PD-1 / PD-L1 that is an antibody or antigen-binding fragment thereof that binds to human PD-1, wherein the antibody or antigen-binding fragment thereof comprises a variable heavy (VH) domain comprising VH complementarity-determining region (CDR) 1, VH CDR2, and VH CDR3, wherein: the VH CDR1 comprises the amino acid sequence SYWMN (SEQ ID NO: 6); the VH CDR2 comprises the amino acid sequence VIHPSDSETWLDQKFKD (SEQ ID NO: 7); the VH CDR3 comprises the amino acid sequence EHYGTSPFAY (SEQ ID NO: 8); wherein the antibody comprises a variable light (VL) domain comprising a VL CDR1, a VL CDR2, and a VL CDR3, wherein: the VL CDR1 comprises the amino acid sequence RASESVDNYGMSFMNW (SEQ ID NO: 9); the VL CDR2 comprises the amino acid sequence AASNQGS (SEQ ID NO: 10); the inhibitor of PD-1 / PD-L1, wherein the VL CDR3 comprises the amino acid sequence QQSKEVPYT (SEQ ID NO: 11); and (ii) an antibody that binds to human CD73, wherein the antibody that binds to human CD73 is (a) a variable heavy (VH) domain comprising a VH complementarity-determining region (CDR) 1, a VH CDR2, and a VH CDR3, wherein: the VH CDR1 comprises the amino acid sequence GYTFTSYG (SEQ ID NO: 16); the VH CDR2 comprises the amino acid sequence IYPGSGNT (SEQ ID NO: 17); the VH domain, wherein the VH CDR3 comprises the amino acid sequence ARYDYLGSSYGFDY (SEQ ID NO: 18); a variable light (VL) domain comprising a VL CDR1, a VL CDR2, and a VL CDR3, wherein: the VL CDR1 comprises the amino acid sequence QDVSTA (SEQ ID NO: 19); the VL CDR2 comprises the amino acid sequence SAS (SEQ ID NO: 20); the VL domain, wherein the VL CDR3 comprises the amino acid sequence QQHYNTPYT (SEQ ID NO: 21); (b) binds to human CD73 at an epitope within amino acids 40 to 53 of SEQ ID NO: 70; (c) binds to human CD73 and competes for binding to human CD73 with an antibody having a heavy chain comprising the amino acid sequence of SEQ ID NO: 24 and a light chain comprising the amino acid sequence of SEQ ID NO: 25; (d) a VH domain comprising a VH CDR1, a VH CDR2, and a VH CDR3; the VH CDR1 comprises the amino acid sequence GFTFSSYD (SEQ ID NO: 34); the VH CDR2 comprises the amino acid sequence MSYDGSNK (SEQ ID NO: 35) or MSYEGSNK (SEQ ID NO: 40); the VH CDR3 comprises the amino acid sequence ATEIAAKGDY (SEQ ID NO: 36), wherein the antibody comprises a VL domain comprising a VL CDR1, a VL CDR2, and a VL CDR3, wherein: the VL CDR1 comprises the amino acid sequence QGISNY (SEQ ID NO: 37); the VL CDR2 comprises the amino acid sequence AAS (SEQ ID NO: 38); the VH domain, wherein the VL CDR3 comprises the amino acid sequence QQSYSTPH (SEQ ID NO: 39); (e) binds to human CD73 at an epitope within amino acids 386 to 399 and 470 to 489 of SEQ ID NO: 70; (f) binds to human CD73 and competes for binding to human CD73 with an antibody having a heavy chain comprising the amino acid sequence of SEQ ID NO: 30 and a light chain comprising the amino acid sequence of SEQ ID NO: 31; or (g) competing for binding to human CD73 with an antibody that binds to human CD73 and has a heavy chain comprising the amino acid sequence of SEQ ID NO: 33 and a light chain comprising the amino acid sequence of SEQ ID NO: 31.

[0379] In some embodiments, provided herein is a method of treating a cancer selected from squamous cell carcinoma of the head and neck (SCCNH), non-small cell lung cancer (NSCLC), ovarian cancer, castration-resistant prostate cancer (CRPC), triple-negative breast cancer (TNBC), bladder cancer, metastatic colorectal cancer (mCRC), pancreatic ductal adenocarcinoma (PDAC), gastric / gastroesophageal junction (GEJ) cancer, hepatocellular carcinoma (HCC), and squamous cell carcinoma of the anal canal (SCAC) in a subject, comprising administering to the subject: (i) An inhibitor of PD-1 / PD-L1 that is an antibody or antigen-binding fragment thereof that binds to human PD-1, wherein the antibody or antigen-binding fragment thereof comprises a variable heavy (VH) domain comprising VH complementarity-determining region (CDR) 1, VH CDR2, and VH CDR3, wherein: the VH CDR1 comprises the amino acid sequence SYWMN (SEQ ID NO: 6); the VH CDR2 comprises the amino acid sequence VIHPSDSETWLDQKFKD (SEQ ID NO: 7); the VH CDR3 comprises the amino acid sequence EHYGTSPFAY (SEQ ID NO: 8); wherein the antibody comprises a variable light (VL) domain comprising a VL CDR1, a VL CDR2, and a VL CDR3, wherein: the VL CDR1 comprises the amino acid sequence RASESVDNYGMSFMNW (SEQ ID NO: 9); the VL CDR2 comprises the amino acid sequence AASNQGS (SEQ ID NO: 10); the inhibitor of PD-1 / PD-L1, wherein the VL CDR3 comprises the amino acid sequence QQSKEVPYT (SEQ ID NO: 11); and (ii) an antibody that binds to human CD73, wherein the antibody that binds to human CD73 is (a) a variable heavy (VH) domain comprising a VH complementarity-determining region (CDR) 1, a VH CDR2, and a VH CDR3, wherein: the VH CDR1 comprises the amino acid sequence GYTFTSYG (SEQ ID NO: 16); the VH CDR2 comprises the amino acid sequence IYPGSGNT (SEQ ID NO: 17); the VH domain, wherein the VH CDR3 comprises the amino acid sequence ARYDYLGSSYGFDY (SEQ ID NO: 18); a variable light (VL) domain comprising a VL CDR1, a VL CDR2, and a VL CDR3, wherein: the VL CDR1 comprises the amino acid sequence QDVSTA (SEQ ID NO: 19); the VL CDR2 comprises the amino acid sequence SAS (SEQ ID NO: 20); the VL domain, wherein the VL CDR3 comprises the amino acid sequence QQHYNTPYT (SEQ ID NO: 21); (b) binds to human CD73 at an epitope within amino acids 40 to 53 of SEQ ID NO: 70; (c) binds to human CD73 and competes for binding to human CD73 with an antibody having a heavy chain comprising the amino acid sequence of SEQ ID NO: 24 and a light chain comprising the amino acid sequence of SEQ ID NO: 25; (d) a VH domain comprising a VH CDR1, a VH CDR2, and a VH CDR3; the VH CDR1 comprises the amino acid sequence GFTFSSYD (SEQ ID NO: 34); the VH CDR2 comprises the amino acid sequence MSYDGSNK (SEQ ID NO: 35) or MSYEGSNK (SEQ ID NO: 40); the VH CDR3 comprises the amino acid sequence ATEIAAKGDY (SEQ ID NO: 36), wherein the antibody comprises a VL domain comprising a VL CDR1, a VL CDR2, and a VL CDR3, wherein: the VL CDR1 comprises the amino acid sequence QGISNY (SEQ ID NO: 37); the VL CDR2 comprises the amino acid sequence AAS (SEQ ID NO: 38); the VH domain, wherein the VL CDR3 comprises the amino acid sequence QQSYSTPH (SEQ ID NO: 39); (e) binds to human CD73 at an epitope within amino acids 386 to 399 and 470 to 489 of SEQ ID NO: 70; (f) binds to human CD73 and competes for binding to human CD73 with an antibody having a heavy chain comprising the amino acid sequence of SEQ ID NO: 30 and a light chain comprising the amino acid sequence of SEQ ID NO: 31; or (g) competing for binding to human CD73 with an antibody that binds to human CD73 and has a heavy chain comprising the amino acid sequence of SEQ ID NO: 33 and a light chain comprising the amino acid sequence of SEQ ID NO: 31.

[0380] Further provided herein, in some embodiments, is a method of treating a cancer selected from head and neck cancer, lung cancer, ovarian cancer, prostate cancer, breast cancer, bladder cancer, colorectal cancer, stomach cancer, gastroesophageal junction cancer, anal cancer, liver cancer, and pancreatic cancer in a subject, comprising administering to the subject: (i) a PD-1 / PD-L1 inhibitor, which is retifanlimab; and (ii) antibody Y, an antibody that binds to human CD73.

[0381] In some embodiments, provided herein is a method of treating a cancer selected from squamous cell carcinoma of the head and neck (SCCNH), non-small cell lung cancer (NSCLC), ovarian cancer, castration-resistant prostate cancer (CRPC), triple-negative breast cancer (TNBC), bladder cancer, metastatic colorectal cancer (mCRC), and pancreatic cancer in a subject, comprising administering to the subject: (i) a PD-1 / PD-L1 inhibitor, which is retifanlimab; and (ii) antibody Y, an antibody that binds to human CD73.

[0382] Further provided herein, in some embodiments, is a method of treating a cancer selected from head and neck cancer, lung cancer, ovarian cancer, prostate cancer, breast cancer, bladder cancer, colorectal cancer, and pancreatic cancer in a subject, comprising administering to the subject: (i) an inhibitor of PD-1 / PD-L1 which is (R)-1-((7-cyano-2-(3'-(3-(((R)-3-hydroxypyrrolidin-1-yl)methyl-1,7-naphthyridin-8-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylic acid, or a pharmaceutically acceptable salt thereof; (ii) an antibody that binds to human CD73, wherein the antibody that binds to human CD73 is (a) a variable heavy (VH) domain comprising a VH complementarity-determining region (CDR) 1, a VH CDR2, and a VH CDR3, wherein: the VH CDR1 comprises the amino acid sequence GYTFTSYG (SEQ ID NO: 16); the VH CDR2 comprises the amino acid sequence IYPGSGNT (SEQ ID NO: 17); the VH domain, wherein the VH CDR3 comprises the amino acid sequence ARYDYLGSSYGFDY (SEQ ID NO: 18); a variable light (VL) domain comprising a VL CDR1, a VL CDR2, and a VL CDR3, wherein: the VL CDR1 comprises the amino acid sequence QDVSTA (SEQ ID NO: 19); the VL CDR2 comprises the amino acid sequence SAS (SEQ ID NO: 20); the VL domain, wherein the VL CDR3 comprises the amino acid sequence QQHYNTPYT (SEQ ID NO: 21); (b) binds to human CD73 at an epitope within amino acids 40 to 53 of SEQ ID NO: 70; (c) binds to human CD73 and competes for binding to human CD73 with an antibody having a heavy chain comprising the amino acid sequence of SEQ ID NO: 24 and a light chain comprising the amino acid sequence of SEQ ID NO: 25; (d) a VH domain comprising a VH CDR1, a VH CDR2, and a VH CDR3; the VH CDR1 comprises the amino acid sequence GFTFSSYD (SEQ ID NO: 34); the VH CDR2 comprises the amino acid sequence MSYDGSNK (SEQ ID NO: 35) or MSYEGSNK (SEQ ID NO: 40); the VH CDR3 comprises the amino acid sequence ATEIAAKGDY (SEQ ID NO: 36), wherein the antibody comprises a VL domain comprising a VL CDR1, a VL CDR2, and a VL CDR3, wherein: the VL CDR1 comprises the amino acid sequence QGISNY (SEQ ID NO: 37); the VL CDR2 comprises the amino acid sequence AAS (SEQ ID NO: 38); the VH domain, wherein the VL CDR3 comprises the amino acid sequence QQSYSTPH (SEQ ID NO: 39); (e) binds to human CD73 at an epitope within amino acids 386 to 399 and 470 to 489 of SEQ ID NO: 70; (f) binds to human CD73 and competes for binding to human CD73 with an antibody having a heavy chain comprising the amino acid sequence of SEQ ID NO: 30 and a light chain comprising the amino acid sequence of SEQ ID NO: 31; or (g) competing for binding to human CD73 with an antibody that binds to human CD73 and has a heavy chain comprising the amino acid sequence of SEQ ID NO: 33 and a light chain comprising the amino acid sequence of SEQ ID NO: 31.

[0383] In some embodiments, provided herein is a method of treating a cancer selected from squamous cell carcinoma of the head and neck (SCCNH), non-small cell lung cancer (NSCLC), ovarian cancer, castration-resistant prostate cancer (CRPC), triple-negative breast cancer (TNBC), bladder cancer, metastatic colorectal cancer (mCRC), pancreatic ductal adenocarcinoma (PDAC), gastric / gastroesophageal junction (GEJ) cancer, hepatocellular carcinoma (HCC), and squamous cell carcinoma of the anal canal (SCAC) in a subject, comprising administering to the subject: (i) an inhibitor of PD-1 / PD-L1 which is (R)-1-((7-cyano-2-(3'-(3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylic acid, or a pharmaceutically acceptable salt thereof; (ii) an antibody that binds to human CD73, wherein the antibody that binds to human CD73 is (a) a variable heavy (VH) domain comprising a VH complementarity-determining region (CDR) 1, a VH CDR2, and a VH CDR3, wherein: the VH CDR1 comprises the amino acid sequence GYTFTSYG (SEQ ID NO: 16); the VH CDR2 comprises the amino acid sequence IYPGSGNT (SEQ ID NO: 17); the VH domain, wherein the VH CDR3 comprises the amino acid sequence ARYDYLGSSYGFDY (SEQ ID NO: 18); a variable light (VL) domain comprising a VL CDR1, a VL CDR2, and a VL CDR3, wherein: the VL CDR1 comprises the amino acid sequence QDVSTA (SEQ ID NO: 19); the VL CDR2 comprises the amino acid sequence SAS (SEQ ID NO: 20); the VL domain, wherein the VL CDR3 comprises the amino acid sequence QQHYNTPYT (SEQ ID NO: 21); (b) binds to human CD73 at an epitope within amino acids 40 to 53 of SEQ ID NO: 70; (c) binds to human CD73 and competes for binding to human CD73 with an antibody having a heavy chain comprising the amino acid sequence of SEQ ID NO: 24 and a light chain comprising the amino acid sequence of SEQ ID NO: 25; (d) a VH domain comprising a VH CDR1, a VH CDR2, and a VH CDR3; the VH CDR1 comprises the amino acid sequence GFTFSSYD (SEQ ID NO: 34); the VH CDR2 comprises the amino acid sequence MSYDGSNK (SEQ ID NO: 35) or MSYEGSNK (SEQ ID NO: 40); the VH CDR3 comprises the amino acid sequence ATEIAAKGDY (SEQ ID NO: 36), wherein the antibody comprises a VL domain comprising a VL CDR1, a VL CDR2, and a VL CDR3, wherein: the VL CDR1 comprises the amino acid sequence QGISNY (SEQ ID NO: 37); the VL CDR2 comprises the amino acid sequence AAS (SEQ ID NO: 38); the VH domain, wherein the VL CDR3 comprises the amino acid sequence QQSYSTPH (SEQ ID NO: 39); (e) binds to human CD73 at an epitope within amino acids 386 to 399 and 470 to 489 of SEQ ID NO: 70; (f) binds to human CD73 and competes for binding to human CD73 with an antibody having a heavy chain comprising the amino acid sequence of SEQ ID NO: 30 and a light chain comprising the amino acid sequence of SEQ ID NO: 31; or (g) the method, comprising an antibody that binds to human CD73 and competes for binding to human CD73 with an antibody having a heavy chain comprising the amino acid sequence of SEQ ID NO: 33 and a light chain comprising the amino acid sequence of SEQ ID NO: 31.

[0384] Further provided herein, in some embodiments, is a method of treating a cancer selected from head and neck cancer, lung cancer, ovarian cancer, prostate cancer, breast cancer, bladder cancer, colorectal cancer, stomach cancer, gastroesophageal junction cancer, anal cancer, liver cancer, and pancreatic cancer in a subject, comprising administering to the subject: (i) an inhibitor of PD-1 / PD-L1 which is (R)-1-((7-cyano-2-(3'-(3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylic acid, or a pharmaceutically acceptable salt thereof; (ii) antibody Y, an antibody that binds to human CD73.

[0385] In some embodiments, provided herein is a method of treating a cancer selected from squamous cell carcinoma of the head and neck (SCCNH), non-small cell lung cancer (NSCLC), ovarian cancer, castration-resistant prostate cancer (CRPC), triple-negative breast cancer (TNBC), bladder cancer, metastatic colorectal cancer (mCRC), pancreatic ductal adenocarcinoma (PDAC), gastric / gastroesophageal junction (GEJ) cancer, hepatocellular carcinoma (HCC), and squamous cell carcinoma of the anal canal (SCAC) in a subject, comprising administering to the subject: (i) an inhibitor of PD-1 / PD-L1 which is (R)-1-((7-cyano-2-(3'-(3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylic acid, or a pharmaceutically acceptable salt thereof; (ii) antibody Y, an antibody that binds to human CD73.

[0386] In some embodiments in which an inhibitor of PD-1 / PD-L1 and an antibody that binds human CD73 are administered, the cancer is head and neck cancer, lung cancer, ovarian cancer, prostate cancer, breast cancer, bladder cancer, colorectal cancer, or pancreatic cancer.

[0387] In some embodiments in which an inhibitor of PD-1 / PD-L1 and an antibody that binds human CD73 are administered, the cancer is head and neck squamous cell carcinoma (HNSCC), non-small cell lung cancer (NSCLC), colorectal cancer, melanoma, ovarian cancer, bladder cancer, renal cell carcinoma, or hepatocellular carcinoma.

[0388] In some embodiments in which an inhibitor of PD-1 / PD-L1 and an antibody that binds human CD73 are administered, the cancer is head and neck cancer.

[0389] In some embodiments in which an inhibitor of PD-1 / PD-L1 and an antibody that binds human CD73 are administered, the cancer is squamous cell carcinoma of the head and neck (SCCNH).

[0390] In some embodiments in which an inhibitor of PD-1 / PD-L1 and an antibody that binds human CD73 are administered, the cancer is lung cancer.

[0391] In some embodiments in which an inhibitor of PD-1 / PD-L1 and an antibody that binds human CD73 are administered, the cancer is non-small cell lung cancer (NSCLC).

[0392] In some embodiments in which an inhibitor of PD-1 / PD-L1 and an antibody that binds human CD73 are administered, the cancer is ovarian cancer.

[0393] In some embodiments in which an inhibitor of PD-1 / PD-L1 and an antibody that binds human CD73 are administered, the cancer is prostate cancer.

[0394] In some embodiments in which an inhibitor of PD-1 / PD-L1 and an antibody that binds human CD73 are administered, the cancer is castration-resistant prostate cancer (CRPC).

[0395] In some embodiments in which an inhibitor of PD-1 / PD-L1 and an antibody that binds human CD73 are administered, the cancer is breast cancer.

[0396] In some embodiments in which an inhibitor of PD-1 / PD-L1 and an antibody that binds human CD73 are administered, the cancer is triple-negative breast cancer (TNBC).

[0397] In some embodiments in which an inhibitor of PD-1 / PD-L1 and an antibody that binds human CD73 are administered, the cancer is bladder cancer.

[0398] In some embodiments in which an inhibitor of PD-1 / PD-L1 and an antibody that binds human CD73 are administered, the cancer is colorectal cancer.

[0399] In some embodiments in which an inhibitor of PD-1 / PD-L1 and an antibody that binds human CD73 are administered, the cancer is metastatic colorectal cancer (mCRC).

[0400] In some embodiments in which an inhibitor of PD-1 / PD-L1 and an antibody that binds human CD73 are administered, the cancer is pancreatic cancer.

[0401] In some embodiments in which an inhibitor of PD-1 / PD-L1 and an antibody that binds human CD73 are administered, the cancer is gastric cancer.

[0402] In some embodiments in which an inhibitor of PD-1 / PD-L1 and an antibody that binds human CD73 are administered, the cancer is gastroesophageal cancer.

[0403] In some embodiments in which an inhibitor of PD-1 / PD-L1 and an antibody that binds human CD73 are administered, the cancer is gastric / gastroesophageal junction (GEJ) cancer.

[0404] In some embodiments in which an inhibitor of PD-1 / PD-L1 and an antibody that binds human CD73 are administered, the cancer is hepatocellular carcinoma (HCC).

[0405] In some embodiments in which an inhibitor of PD-1 / PD-L1 and an antibody that binds human CD73 are administered, the cancer is pancreatic ductal adenocarcinoma (PDAC).

[0406] In some embodiments in which an inhibitor of PD-1 / PD-L1 and an antibody that binds human CD73 are administered, the cancer is squamous cell carcinoma of the anal canal (SCAC).

[0407] As used herein, the term "contacting" refers to bringing the indicated moieties together in an in vitro system or in an in vivo system. For example, "contacting" A2A / A2B with a compound described herein includes administering a compound of the invention to an individual or patient, such as a human, having A2A / A2B, and introducing a compound described herein into a sample, including, for example, a cell preparation or purified preparation containing A2A / A2B.

[0408] The terms "individual" or "patient" or "subject," used interchangeably, refer to any animal, including a mammal, preferably a mouse, rat, other rodent, rabbit, dog, cat, pig, cow, sheep, horse, or primate, most preferably a human (i.e., a human subject).

[0409] As used herein, the phrase "therapeutically effective amount" refers to that amount of an active compound or pharmaceutical agent that elicits the biological or medicinal response that a researcher, veterinarian, physician, or other clinician is seeking in a tissue, system, animal, individual, or human.

[0410] As used herein, the term "treating" or "treatment" refers to one or more of: 1) inhibiting a disease, e.g., inhibiting a disease, condition, or disorder (i.e., preventing further progression of the condition or symptom) in an individual experiencing or exhibiting the pathology or symptom of the disease, condition, or disorder; and 2) ameliorating a disease, e.g., ameliorating a disease, condition, or disorder (i.e., reversing the condition or symptom) in an individual experiencing or exhibiting the pathology or symptom of the disease, condition, or disorder, e.g., reducing the severity of the disease.

[0411] As used herein, "QD" is understood to mean a dose administered to a subject once daily. "QOD" is understood to mean a dose administered to a subject once every other day. "QW" is understood to mean a dose administered to a subject once weekly. "Q2W" is understood to mean a dose administered to a subject once every two weeks. "Q3W" is understood to mean a dose administered to a subject once every three weeks. "Q4W" is understood to mean a dose administered to a subject once every four weeks.

[0412] In some embodiments, the disclosed anti-CD73 antibodies, inhibitors of A2A and / or A2B adenosine receptors, and inhibitors of PD-1 / PD-L1 are useful in combination to prevent or reduce the risk of developing any of the diseases mentioned herein, for example, to prevent or reduce the risk of developing a disease, condition, or disorder in an individual who may be predisposed to the disease, condition, or disorder, but who has not yet experienced or exhibited the pathology or symptoms of the disease.

[0413] Pharmaceutical Compositions and Formulations The anti-CD73 antibodies, inhibitors of A2A and / or A2B adenosine receptors, and inhibitors of PD-1 / PD-L1 described herein can be formulated as pharmaceutical compositions for administration to a subject, e.g., to treat a disorder described herein. In some cases, the pharmaceutical composition comprises an anti-CD73 antibody as a single agent. In some cases, the pharmaceutical composition comprises an inhibitor of A2A and / or A2B adenosine receptors as a single agent.

[0414] In some cases, the pharmaceutical composition comprises a PD-1 / PD-L1 inhibitor as a single agent. In some cases, the pharmaceutical composition comprises one or more of an anti-CD73 antibody, an inhibitor of A2A and / or A2B adenosine receptors, and an inhibitor of PD-1 / PD-L1 described herein. In some cases, the pharmaceutical composition comprises one or more of an anti-CD73 antibody and a PD-1 / PD-L1 inhibitor described herein.

[0415] When used as a pharmaceutical, the compounds of the present disclosure can be administered in the form of pharmaceutical compositions. These compositions can be prepared in a manner well known in the pharmaceutical arts and can be administered by various routes, depending on whether local or systemic treatment is desired and the area to be treated. Administration can be topical (including transdermal, epidermal, ophthalmic, and mucosal delivery, including intranasal, vaginal, and rectal delivery), pulmonary (e.g., by inhalation or insufflation of powders or aerosols, including by nebulizer; intratracheal or intranasal), oral, or parenteral. Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular, or injection or infusion, or intracranial, e.g., intrathecal or intraventricular, administration. Parenteral administration can be in the form of a single bolus dose or, for example, by a continuous perfusion pump. Pharmaceutical compositions and formulations for topical administration can include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids, and powders. Conventional pharmaceutical carriers, aqueous, powder or oily bases, thickeners and the like may be necessary or desirable.

[0416] The pharmaceutical composition may contain a "therapeutically effective amount" of the agent described herein. Such an effective amount may be determined based on the effect of the administered agent or the combined effect of the agents when two or more agents are used. The "therapeutically effective amount" of an agent may also vary depending on factors such as the individual's disease state, age, sex, and weight, as well as the ability of the compound to elicit a desired response in the individual, for example, improvement of at least one disorder parameter or improvement of at least one disorder symptom. A therapeutically effective amount is also one in which the therapeutically beneficial effects outweigh any toxic or adverse effects of the composition.

[0417] Typically, pharmaceutical compositions contain a pharmaceutically acceptable carrier. As used herein, "pharmaceutically acceptable carrier" includes any and all physiologically compatible solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, etc. The composition may contain a pharmaceutically acceptable salt, for example, an acid addition salt or a base addition salt (see, for example, Berge, SM, et al. (1977) J.Pharm.Sci.66:1-19).

[0418] Pharmaceutical formulation is a well-established art and is further described, for example, in The Science and Practice of Pharmacy, 20th ed., Lippincott, Williams & Wilkins (2000) (ISBN: 0683306472); Ansel et al., Pharmaceutical Dosage Forms and Drug Delivery Systems, 7th Ed., Lippincott Williams & Wilkins Publishers (1999) (ISBN: 0683305727); and Kibbe (ed.), Handbook of Pharmaceutical Excipients American Pharmaceutical Association, 3rd ed. (2000) (ISBN: 091733096X).

[0419] Pharmaceutical compositions can be in various forms. These include, for example, liquid, semi-solid and solid dosage forms such as liquid solutions (e.g., injectable and infusible solutions), dispersions or suspensions, tablets, pills, powders, liposomes and suppositories. The preferred form can depend on the intended mode of administration and therapeutic application. Typically, the compositions for the pharmaceuticals described herein are in the form of injectable or infusible solutions.

[0420] The compositions can be formulated as solutions, microemulsions, dispersions, liposomes, or other ordered structures suitable for stable storage at high concentrations. Sterile injectable solutions can be prepared by incorporating the required amount of the agent described herein in an appropriate solvent with one or a combination of the ingredients listed above, followed by filter sterilization, as needed. Generally, dispersions are prepared by incorporating the agent described herein into a sterile vehicle containing a basic dispersion medium and the required other ingredients from those listed above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and freeze-drying, which yield a powder of the agent described herein plus any additional desired ingredients from a previously sterile-filtered solution of the agent. The proper fluidity of the solution can be maintained, for example, by the use of a coating such as lecithin, by maintaining the required particle size in the case of dispersions, and by the use of surfactants. Prolonged absorption of injectable compositions can be achieved by including in the composition an agent that delays absorption, such as monostearate salts and gelatin.

[0421] The present disclosure also includes pharmaceutical compositions comprising the compounds of the present disclosure or pharmaceutically acceptable salts thereof as an active ingredient in combination with one or more pharmaceutically acceptable carriers (excipients). In some embodiments, the compositions are suitable for topical administration. When preparing the disclosed compositions, typically, one or more active ingredients are mixed with an excipient, diluted by the excipient, or enclosed in such a carrier, for example, in the form of a capsule, sachet, paper, or other container. When the excipient serves as a diluent, it can be a solid, semi-solid, or liquid material that acts as a vehicle, carrier, or medium for the active ingredient. Thus, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as solid or liquid media), for example, ointments containing up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.

[0422] When preparing formulation, one or more active ingredients can be milled to obtain suitable particle size before being combined with other ingredients.If active compound is substantially insoluble, it can be milled to a particle size of less than 200 mesh.If active compound is substantially water-soluble, particle size can be adjusted by milling to obtain substantially uniform distribution in formulation, for example, about 40 mesh.

[0423] The compounds of the present disclosure can be milled using known milling procedures, such as wet milling, to obtain a particle size suitable for tableting and other formulation types. Finely divided (nanoparticulate) preparations of the compounds of the present disclosure can be prepared by processes known in the art, see, for example, the disclosure of International Application No. WO2002 / 000196.

[0424] Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starch, gum arabic, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methylcellulose.The formulation may further include lubricants such as talc, magnesium stearate, and mineral oil, wetting agents, emulsifying and suspending agents, preservatives such as methylbenzoate and propylhydroxybenzoate, sweeteners, and flavoring agents.The compositions of the present disclosure can be formulated to provide quick, sustained, or delayed release of the active ingredient after administration to a patient by using procedures known in the art.

[0425] The compositions may be formulated in unit dosage form. The term "unit dosage form" refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce a desired therapeutic effect, in association with a suitable pharmaceutical excipient.

[0426] To prepare solid compositions such as tablets, the primary active ingredient is mixed with pharmaceutical excipients to form a solid preformulation composition containing a homogeneous mixture of the compounds of the present disclosure. When these preformulation compositions are referred to as homogeneous, the active ingredient is typically dispersed evenly throughout the composition, allowing the composition to be easily subdivided into equally effective unit dosage forms such as tablets, pills, and capsules. This solid preformulation is then subdivided into unit dosage forms.

[0427] The tablets or pills of the present disclosure can be coated or otherwise compounded to provide a dosage form that provides the advantage of prolonged action.For example, the tablets or pills can comprise an inner dose and an outer dose component, the latter being in the form of an envelope over the former.The two components can be separated by an enteric layer that resists disintegration in the stomach and allows the inner component to pass intact into the duodenum or be delayed in release.A variety of materials can be used as such enteric layers or coatings, including numerous polymeric acids and mixtures of polymeric acids with materials such as shellac, cetyl alcohol, and cellulose acetate.

[0428] Liquid forms into which the compounds and compositions of the present invention may be incorporated for oral or injectable administration include aqueous solutions, suitably flavored syrups, aqueous or oily suspensions, and emulsions flavored with edible oils such as cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical vehicles.

[0429] Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents, or mixtures thereof, as well as powders. Liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described above. In some embodiments, compositions are administered by the oral or nasal respiratory route for local or systemic effect. Compositions may be nebulized by use of inert gases. Nebulized solutions may be inhaled directly from the nebulizing device, or the nebulizing device may be attached to a face mask, tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions may be administered orally or nasally from devices that deliver the formulation in an appropriate manner.

[0430] Topical formulations may contain one or more conventional carriers. In some embodiments, ointments may contain water and one or more hydrophobic carriers selected from, for example, liquid paraffin, polyoxyethylene alkyl ether, propylene glycol, white Vaseline® (petrolatum), etc. Cream carrier compositions may be based on a combination of water with glycerol and one or more other components, such as glycerol monostearate, PEG-glycerol monostearate, and cetylstearyl alcohol. Gels may be formulated using isopropyl alcohol and water, preferably in combination with other components such as glycerol and hydroxyethylcellulose. In some embodiments, topical formulations contain at least about 0.1, at least about 0.25, at least about 0.5, at least about 1, at least about 2, or at least about 5% by weight of a compound of the present disclosure. Topical formulations may be suitably packaged in 100g tubes, optionally accompanied by instructions for treating a selected indication, such as psoriasis or other skin conditions.

[0431] The amount of compound or composition administered to a patient will vary depending on what is being administered, the purpose of the administration, such as prophylaxis or treatment, the condition of the patient, the method of administration, etc. In therapeutic applications, compositions can be administered to a patient already suffering from a disease in an amount sufficient to cure or at least partially arrest the symptoms of the disease and its complications. The effective dose will depend on the disease state being treated and the judgment of the attending physician based on factors such as the severity of the disease, the age, weight, and general condition of the patient.

[0432] The compositions administered to patients may be in the form of pharmaceutical compositions described above. These compositions may be sterilized by conventional sterilization techniques or may be sterile filtered. Aqueous solutions may be packaged for immediate use or lyophilized, with the lyophilized preparation being combined with a sterile aqueous carrier prior to administration. The pH of the compound preparation will typically be 3-11, more preferably 5-9, and most preferably 7-8. It will be appreciated that the use of certain of the aforementioned excipients, carriers, or stabilizers may result in the formulation of pharmaceutical salts.

[0433] Therapeutic amounts of compounds of the present disclosure can vary according to, for example, the particular therapeutic application, the method of administration of the compound, the health and condition of the patient, and the judgment of the prescribing physician. The proportion or concentration of a compound of the present disclosure in a pharmaceutical composition can vary depending on several factors, including dosage, chemical characteristics (e.g., hydrophobicity), and the route of administration. For example, compounds of the present disclosure can be provided in an aqueous physiological buffer solution containing about 0.1 to about 10% w / v of the compound for parenteral administration.

[0434] The compositions of the present invention can further comprise one or more additional pharmaceutical agents, such as chemotherapeutic agents, steroids, anti-inflammatory compounds, or immunosuppressants, examples of which are listed herein.

[0435] In certain embodiments, anti-CD73 antibodies, inhibitors of A2A and / or A2B adenosine receptors, and / or inhibitors of PD-1 / PD-L1 can be prepared with carriers that protect the compound against rapid release, such as sustained-release formulations, including implants, and microencapsulated delivery systems. Biodegradable, biocompatible polymers, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid, can be used. Many methods for the preparation of such formulations are patented or generally known. See, for example, *Sustained and Controlled Release Drug Delivery Systems*, J.R. Robinson, ed., Marcel Dekker, Inc., New York (1978).

[0436] Labeled Compounds and Assay Methods The present disclosure further includes isotopically labeled compounds of the present disclosure. An "isotopically labeled" or "radiolabeled" compound is a compound of the present disclosure in which one or more atoms have been replaced, i.e., substituted, with an atom having an atomic mass or mass number different from that normally found in nature (i.e., naturally occurring). Suitable radionuclides that may be incorporated into compounds of the present disclosure include: 2 H (also written as D for deuterium), 3 H (also written as T for tritium), 11 C. 13 C. 14 C. 13 N, 15 N, 15 O. 17 O. 18 O. 18 F, 35 S, 36 Cl, 82 Br, 75 Br, 76 Br, 77 Br, 123 I, 124 I, 125 I and 131For example, one or more hydrogen atoms in the compounds of the present disclosure can be replaced with deuterium atoms (e.g., one or more hydrogen atoms in the alkyl groups of the compounds can be optionally replaced with deuterium atoms, e.g., -CH3 can be replaced with -CD3).

[0437] One or more constituent atoms of the compounds presented herein can be replaced or substituted with natural or non-natural abundance isotopes of the atoms. In some embodiments, the compounds contain at least one deuterium atom. In some embodiments, the compounds contain two or more deuterium atoms. In some embodiments, the compounds contain 1-2, 1-3, 1-4, 1-5, or 1-6 deuterium atoms. In some embodiments, all hydrogen atoms in the compounds can be replaced or substituted with deuterium atoms.

[0438] In some embodiments, 1, 2, 3, 4, 5, 6, 7, or 8 hydrogen atoms bonded to carbon atoms of any Formula A substituent are each optionally replaced by a deuterium atom.

[0439] Synthetic methods for incorporating isotopes into organic compounds are known in the art (Deuterium Labeling in Organic Chemistry by Alan F. Thomas (New York, NY, Appleton-Century-Crofts, 1971); The Renaissance of H / D Exchange by Jens Atzrodt, Volker Derdau, Thorsten Fey and Jochen Zimmermann, Angew. Chem. Int. Ed. 2007, 7744-7765; The Organic Chemistry of Isotopic Labelling by James R. Hanson, Royal Society of Chemistry, 2011). Isotopically labeled compounds can be used in a variety of studies, such as NMR spectroscopy, metabolic experiments, and / or assays.

[0440] Substitution with heavier isotopes, such as deuterium, can confer certain therapeutic advantages due to greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements, and therefore may be preferable in some cases (see, e.g., A. Kerekes et al. J. Med. Chem. 2011, 54, 201-210; R. Xu et al. J. Label Compd. Radiopharm. 2015, 58, 308-312). In particular, substitution at one or more metabolic sites may confer one or more therapeutic advantages.

[0441] The radionuclide incorporated into the radiolabeled compound will depend on the particular application of the radiolabeled compound. For example, for in vitro A2A / A2B labeling and competition assays: 3 H, 14 C. 82 Br, 125 I, 131 I, or 35 Compounds incorporating S may be useful. For radioimaging applications, 11 C. 18 F, 125 I, 123 I, 124 I, 131 I, 75 Br, 76 Br, or 77 Br may be useful.

[0442] A "radiolabel" or "labeled compound" is understood to be a compound that incorporates at least one radionuclide. In some embodiments, the radionuclide is 3 H, 14 C. 125 I, 35 S, and 82 Br.

[0443] The present disclosure can further include synthetic methods for incorporating radioisotopes into the compounds of the present disclosure. Synthetic methods for incorporating radioisotopes into organic compounds are well known in the art, and one of ordinary skill in the art will readily recognize methods applicable to the compounds of the present disclosure.

[0444] The disclosed labeled agents can be used in screening assays to identify / evaluate agents. For example, a labeled newly synthesized or identified agent (i.e., a test agent) can be evaluated for its ability to bind to adenosine receptors, CD73, or PD-1 / PD-L1 by monitoring its concentration change upon contact with adenosine receptors, CD73, or PD-1 / PD-L1, respectively, through label tracking. For example, a (labeled) test agent can be evaluated for its ability to reduce the binding of another agent (i.e., a standard agent) known to bind to adenosine receptors, CD73, or PD-1 / PD-L1. Thus, the ability of a test agent to compete with the standard agent for binding to adenosine receptors, CD73, or PD-1 / PD-L1 directly correlates to its binding affinity. Conversely, in some other screening assays, the standard agent is labeled and the test agent is unlabeled. Thus, the concentration of the labeled standard agent is monitored to assess competition between the standard agent and the test agent, thereby ascertaining the relative binding affinity of the test agent.

[0445] Accordingly, another aspect of the present disclosure relates to the disclosed labeled agents (i.e., labeled anti-CD73 antibodies, inhibitors of A2A and / or A2B adenosine receptors, and inhibitors of PD-1 / PD-L1) that may be useful in both in vitro and in vivo assays, as well as imaging techniques, for localizing and quantifying CD73, A2A and / or A2B, and / or PD-1 / PD-L1 receptors in tissue samples, including human tissues, through the binding of labeled compounds, and for identifying CD73, A2A and / or A2B, and / or PD-1 / PD-L1 antagonists. Substitution of one or more atoms of the disclosed compounds may also be useful in generating differentiated ADME (adsorption, distribution, metabolism, and excretion). Accordingly, the present disclosure includes adenosine receptor (e.g., A2A and / or A2B) assays containing such labeled or substituted compounds.

[0446] kit The present disclosure also includes pharmaceutical kits useful, for example, in the treatment or prevention of diseases or disorders described herein, which include one or more containers housing a pharmaceutical composition comprising a therapeutically effective amount of one or more of the disclosed compounds / antibodies. As will be apparent to those skilled in the art, such kits can optionally further include one or more of a variety of conventional pharmaceutical kit components, such as, for example, a container with one or more pharmaceutically acceptable carriers, additional containers, etc. Instructions, either as an insert or label, indicating the amounts of components to be administered, administration guidelines, and / or guidelines for mixing the components, can also be included in the kit.

[0447] The present invention will be described in more detail by specific examples. The following examples are provided for illustrative purposes and are not intended to limit the present invention in any way. Those skilled in the art will readily recognize a variety of non-critical parameters that can be changed or modified to achieve essentially the same results. It is understood that certain features of the present invention that are described for clarity in the context of separate embodiments can also be provided in a single embodiment in combination. Conversely, various features of the present invention that are described for brevity in the context of a single embodiment can also be provided separately or in any suitable subcombination.

[0448]

[0013] Various modifications of the present invention, in addition to those described herein, will be apparent to those skilled in the art from the foregoing description. Such modifications are intended to fall within the scope of the appended claims. Each reference cited in this application, including all patents, patent applications, and patent publications, is hereby incorporated by reference in its entirety. [Example]

[0449] The following are examples of the practice of the present invention, which should not be construed in any way as limiting the scope of the invention.

[0450] Example 1. Antitumor effect of antibody Y in combination with retifanlimab and compound 9.

[0451] Antibody Y, an anti-CD73 antibody, Compound 9 (3-(8-amino-5-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-2-(pyridin-2-ylmethyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile, see Table 1), and / or the anti-PD-1 antibody, retifanlimab, as single agents and in combination with A2A / A2B small molecule receptor antagonists, were analyzed in a humanized mouse host bearing the human breast adenocarcinoma tumor, MDA-MB-231, a high expresser of CD73 and an established responder to PD-1 / PD-L1 blockade. Female human CD34+ reconstituted mice (29 weeks old, The Jackson Laboratory, Bar Harbor, ME) were injected with 3x10 cells suspended in Matrigel (Corning Life Sciences). 6 MDA-MB-231 cells (ATCC# HTB-26) were inoculated subcutaneously into the shaved left flank. On day 7, and every 3-4 days thereafter, tumors were measured with calipers and tumor volumes were calculated using the formula: Volume = [L (longitudinal dimension) × W 2 Based on these measurements, mice were assigned to a group with a mean starting tumor volume of 180 mm 3 Mice were randomly assigned to eight treatment groups of 10 mice each. The tested agents were formulated and administered as follows: Antibody Y was diluted in phosphate-buffered saline to a final concentration of 1 mg / mL and administered to mice at a dose of 10 mg / kg every 5 days via intraperitoneal (ip) injection at 10 mL / kg. Retifanlimab (MacroGenics) was diluted to 1 mg / mL and administered intraperitoneally every 5 days. For combination treatment, the two antibodies were co-formulated at a concentration of 1 mg / mL each. The oral vehicle was 5% N,N-dimethylacetamide in 0.5% methylcellulose in 50 mM citrate buffer, pH 3.0 (all reagents obtained from Sigma) and was administered by oral gavage (po) twice daily (bid). Compound 9 (Incyte Corporation) was formulated in the latter vehicle at a concentration of 1 mg / mL and administered orally at 10 mg / mL twice daily for an effective dose of 10 mg / kg. The following treatments and combinations were tested:

[0452] 1) Vehicle and IgG isotype control; 2) Retifanlimab, 3) Antibody Y, 4) compound 9, 5) Retifanlimab + antibody Y, 6 retifanlimab + compound 9, 7) Antibody Y + Compound 9, and 8) Retifanlimab + antibody Y + compound 9.

[0453] Treatment began on day 7 and continued for 28 days until day 35. Animals continued to be followed individually after treatment ended until the humane endpoint of the study, which was achieved when tumor volume reached 10% or more of the mouse's body weight.

[0454] By day 35, when treatment was discontinued, all combinations exhibited superior tumor growth inhibition compared with their component single agents and vehicle. Tumor growth inhibition (TGI), defined as (1 - treatment group volume) / control group volume) x 100, was analyzed for the entire study on day 47, the last day before some animals were terminated for this endpoint. Significance was determined by nonparametric post-hoc tests (Kruskal-Wallis). Data are summarized in Table A and Figure 1. [Table 6]

[0455] For survival analysis, mice were followed to endpoint until day 90. As shown in Figure 2, all combinations with antibody Y promoted survival compared to the control group, which had a median survival of 60 days; the combination with retifanlimab (62 days), the combination with compound 9 (74 days), and the combination of retifanlimab, compound 9, and antibody Y (72 days). This data demonstrates that blockade of both CD73 with antibody Y and A2A / A2B receptors with compound 9 improves disease control and mortality compared to single-agent treatment. Furthermore, the best control of tumor growth occurred with the triple combination of antibody Y, compound 9, and retifanlimab.

[0456] Example 2. Phase I, Open-Label, Multicenter Study of Antibody Y as Monotherapy or in Combination with Immunotherapy in Participants with Advanced Solid Tumors I. Purpose This is an open-label, non-randomized, multicenter, dose-escalation and dose-expansion, first-in-human (FIH), Phase 1 study to determine the safety, tolerability, pharmacokinetics (PK), pharmacodynamics, and preliminary efficacy of antibody Y, administered alone or in combination with compound 9 and / or retifanlimab, in participants with certain advanced solid tumors, including squamous cell carcinoma of the head and neck (SCCHN) and certain gastrointestinal (GI) malignancies. Participants with CD8 T-cell-positive tumors are being selected because these tumors are more likely to respond to immunotherapy.

[0457] II. Overall Design Phase Ia consists of dose escalation for each treatment group using a hybrid design, which allows for evaluation of safety and tolerability following investigational treatment in participants with advanced solid tumors (limited to CD8 T-cell-positive advanced SCCHN or specified gastrointestinal malignancies, defined herein as colorectal cancer (CRC), gastric / gastroesophageal junction (GEJ) cancer, hepatocellular carcinoma (HCC), pancreatic ductal adenocarcinoma (PDAC), or squamous cell carcinoma of the anal canal (SCAC) after the initial dose-escalation cohort).

[0458] Treatment group A (TGA): Antibody Y as monotherapy Treatment arm B1 (TGB1): Antibody Y in combination with retifanlimab Treatment arm B2 (TGB2): Antibody Y in combination with compound 9 Treatment Group C (TGC): Antibody Y in combination with retifanlimab and Compound 9 Following the initial dose-escalation cohort in each treatment arm, which will enroll participants with advanced solid tumors, enrollment in subsequent dose-escalation cohorts will be limited to participants with CD8 T-cell-positive advanced SCCHN or certain gastrointestinal malignancies (i.e., the same inclusion criteria as in Phase 1b will apply), and will require pre- and on-treatment biopsies, which may be performed before initiating enrollment in the second dose level or any time thereafter, based on emerging PK data (i.e., saturation of target-mediated pharmacokinetics (TMDD)).

[0459] Phase 1b is a dose expansion to better characterize the safety, tolerability, PK, pharmacodynamic effects, and preliminary tumor activity of antibody Y as monotherapy or in combination with retifanlimab and / or Compound 9 at the monotherapy recommended expansion dose (RDE), with a total of approximately 120 evaluable participants for each combination. Phase 1b participants will be limited to patients with select CD8 T cell-positive advanced or metastatic SCCHN or specified gastrointestinal malignancies (defined herein as colorectal cancer (CRC), gastric / gastroesophageal junction (GEJ) cancer, hepatocellular carcinoma (HCC), pancreatic ductal adenocarcinoma (PDAC), or squamous cell carcinoma of the anal canal (SCAC)).

[0460] TGA (antibody Y monotherapy) - SCCHN: 10 participants - Specific gastrointestinal malignancies: 10 participants TGB1 (antibody Y + retifanlimab) - SCCHN: 10 participants - Specific gastrointestinal malignancies: 10 participants · TGB2 (antibody Y + compound 9) - SCCHN: 20 participants - Specific gastrointestinal malignancies: 20 participants TGC (antibody Y + retifanlimab + compound 9) - SCCHN: 20 participants - Specific gastrointestinal malignancies: 20 participants The study includes a 28-day screening period to determine eligibility, a treatment period of up to two years, an end-of-treatment (EOT) visit, and safety follow-up visits at 30 and 90 days. Participants who discontinue study treatment for reasons other than disease progression will continue to receive assessments of their disease status during the follow-up phase and will be required to continue receiving tumor assessments every 8 weeks for the first 12 months, and every 12 weeks thereafter until initiation of new anti-cancer therapy, disease progression, death, withdrawal of consent, or study termination, whichever occurs first.

[0461] Tumor assessments will be performed at baseline according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, reviewed by the investigator every 8 weeks for the first year of treatment, and every 12 weeks thereafter. The guidelines for Response Criteria for Use in Investigational Immunotherapy (iRECIST) may be used to determine discontinuation of study treatment due to radiological progressive disease (PD).

[0462] Safety will be assessed from the time participants sign the informed consent until the 90-day safety follow-up visit. Safety data will be reviewed regularly by a safety assessment committee.

[0463] Mandatory pre- and on-treatment biopsies will be collected from all participants, except at the initial dose level of each treatment arm in the dose-escalation Phase Ia study. If adequate on-treatment tumor tissue is not available, participants will be allowed to continue in the study.

[0464] In Phase Ia, up to six additional participants may be enrolled at one dose level if there are insufficient evaluable paired biopsy specimens.

[0465] The objective of Phase 1b is to obtain at least 10 evaluable paired biopsy specimens within each cohort. If 10 evaluable paired specimens are not obtained after the initial enrollment of a participant, up to 6 additional participants may be enrolled in the cohort (i.e., SCCHN or specific GI malignancies).

[0466] All participants must have CD8 T-cell positive tumors to enter the study (except for participants at the initial dose level of each treatment arm in the dose-escalation Phase Ia). Mandatory pre-treatment biopsies collected from all participants will be analyzed for the presence of CD8+ T-cell lymphocytes as part of pre-screening. Pre-screening allows for the pre-selection of participants with CD8 T-cell positive tumors outside the 28-day screening period and before signing the study's main informed consent form (ICF). Participants are required to sign a specific pre-screening consent form, but no other protocol assessments based on the pre-screening consent form will be conducted.

[0467] Participants in the Phase Ia and Ib TGAs with available archival tissue may submit archival tissue for this prescreening analysis, but eligible participants will be required to undergo a new biopsy during screening for biomarker analysis. These fresh biopsies during screening are required to obtain frozen tissue samples necessary for evaluation of CD73 enzyme activity.

[0468] Paired tumor biopsies collected in this study will be used to demonstrate the pharmacodynamic activity of Antibody Y (versus fresh paired biopsy specimens), assess changes in the tumor and tumor microenvironment (TME), identify potential biomarkers, and develop and evaluate an adenosine-regulated gene expression signature.

[0469] III. Phase Ia - Dose Escalation An open-label hybrid design will be used to assess safety and tolerability and identify the RDE of TGA and combination treatment arms TGB1, TGB2, and TGC in participants with advanced solid tumors (limited to CD8 T-cell positive advanced SCCHN or specific gastrointestinal malignancies (CRC, GEJ cancer, HCC, PDAC, or SCAC) after the initial dose-escalation cohort). Details of each treatment arm are provided in the relevant subsections that follow.

[0470] Dose escalation will begin with TGA. The decision to begin enrollment in dose escalation cohorts for TGB1, TGB2, and TGC will be based on observed safety, tolerability, clinical activity, PK, and pharmacodynamics of antibody Y.

[0471] Hybrid statistical designs to guide dose escalation The hybrid design is a hybrid of the modified toxicity probability interval design and the dose-toxicity model and has three steps.

[0472] Step 1. Target dose-limiting toxicity (DLT) rate of 28% T The modified toxicity probability interval (mTPI) design (see, e.g., Ji et al. Clin.Trials. 2010;7:653-663) with p = 0.001 is first calculated as the posterior probability (p T + ε2,1) is used to modify the mTPI to control overdose toxicity to be less than 0.8. With this rule, if 3 out of 6 participants experience a DLT, the DLT rate is approximately 50%, and if the observed toxicity rate is high, the modified mTPI warrants dose de-escalation rather than remaining at the current dose level. Table B shows the dose escalation rules based on the number of DLTs observed in a dose level cohort: E = escalate to the next higher dose, D = de-escalate to the next lower dose, DU = current dose unacceptably toxic, and S = maintain current dose. The target toxicity rate p T : 28%. A flat, non-informative prior distribution, Beta(1,1), was used with ε1 = ε2 = 0.05 (see, e.g., Ji et al., Clin.Trials 2010, 7:653-663; and Ji et al., J.Clin.Oncol. 2013, 31:1785-1791). Posterior toxicity probability cutoff: 0.8. [Table 7]

[0473] Step 2. The second step of the hybrid design is to use a dose-toxicity model, pooling all observed safety information at all previous doses, to estimate the DLT rate at the current dose level and predict the DLT rate at the next dose level in the interim dose list. The estimated DLT rate at the current dose level is used with the decision rule from the modified mTPI in Table B to jointly make decisions about dose escalation. If the dose-toxicity model is infeasible (e.g., if no DLTs are observed at the doses tested), no action is required in this step.

[0474] Step 3. If the decision in Table B results in a dose escalation (E) to the next dose level in the interim dose list, the predicted DLT rate using the dose-toxicity model in Step 2 is used to determine whether the next dose level is feasible by verifying whether the predicted DLT rate at the next dose level exceeds the pre-specified target DLT rate. If the predicted DLT rate exceeds the target DLT rate, the next dose level in the interim dose list cannot be used. Instead, the intermediate dose from the dose-toxicity model is calibrated to ensure that the DLT rate is below the target DLT rate. If the decision in Table B results in a dose de-escalation (D) to a lower dose level in the interim dose list, the intermediate dose from the previously used dose-toxicity model is calibrated to ensure that the DLT rate is below the target DLT rate. Note that selecting an intermediate dose level requires consideration of what is clinically and operationally feasible (e.g., based on variability in exposure among participants). If the decision in Table B results in maintaining the current dose (S), the estimated DLT rate at the current dose using the dose-toxicity model in Step 2 is used to make the decision. If the estimated DLT at the current dose exceeds a pre-specified target DLT rate, a decision to taper the dose (D) is made, otherwise maintenance (S).

[0475] At least three evaluable participants are required at each dose level; however, three, four, five, or six participants may be enrolled depending on the funding rate. Approximately 30 evaluable participants may be treated in each treatment arm during the dose escalation phase; the dose escalation procedure may be stopped if the number of evaluable participants treated at any dose level is nine or more. If new data support an intolerable dose (D or DU) de-escalation at the lowest dose level, the trial will evaluate the data to determine whether a lower dose (or alternative schedule) should be considered.

[0476] When adding participants in response to a "maintenance (S)" decision, the number of additional participants enrolled is limited to minimize exposure to doses that may have unacceptable toxicity (labeled "Unacceptable Dose (DU)" in Table B). Next, to determine how many more participants can be enrolled at that dose level, the steps can be counted diagonally (downward to the right) from the current cell to the first cell marked DU. For example, if one of three participants experiences a DLT at a particular dose level, no more than three additional participants should be enrolled at this dose level until additional DLT data are available. This is because if all three additional participants experience a DLT (i.e., four of six participants in Table B experience a DLT), that dose level is considered to have unacceptable toxicity.

[0477] If no DLTs are observed at all proposed doses and there is no clear efficacy-related signal at the highest dose level, the dose escalation procedure may continue by enrolling additional participants at higher dose levels.

[0478] At the end of the dose-escalation procedure, DLT rates at all dose levels tested will be estimated based on the dose-toxicity model described above, if feasible, or based on a pooled adjacent violation algorithm if a parametric dose-toxicity model is not feasible. The dose with an estimated DLT rate closest to 28% will be treated as the MTD. However, the totality of available data, including new safety, PK, progressive disease (PD), and other biomarker information, will be considered before determining the dose to proceed to Phase 1b.

[0479] Treatment group A: Antibody Y monotherapy Dose-escalation enrollment will begin with antibody Y monotherapy, administered intravenously (IV) at a dose of 70 mg every 2 weeks (Q2W) on days 1 and 2 of each 28-day cycle. The DLT assessment period will be 28 days. Once evaluable participants in a dose-level cohort have completed the 28-day DLT period, safety and tolerability will be assessed before initiating the next dose-level cohort. The proposed dose (70 mg Q2W) attempts to minimize late-stage cancer patients' exposure to subtherapeutic antibody Y while balancing the safety risks associated with the nonclinical pharmacological and toxicological profiles. This dose was determined from a weight-of-evidence (WOE) of all nonclinical data and is believed to provide an acceptable risk-benefit profile.

[0480] Planned dose levels of antibody Y to be investigated in this study may include 70 mg, 250 mg, 750 mg, and 1500 mg, with doses selected based on emerging data. Doses above 250 mg will not be increased by more than three-fold. Intermediate dose levels may be considered if supported by safety, PK, or pharmacodynamic data.

[0481] Participants must have received two doses of antibody Y at the level assigned to Q2W dosing, or one dose of antibody Y at the level assigned to Q4W dosing, or experienced a DLT evaluable for dose tolerability during the 28-day DLT observation period. Participants deemed unevaluable for reasons other than toxic...

Claims

1. (i) an inhibitor of A2A / A2B; (ii) a PD-1 / PD-L1 inhibitor; and (iii) an inhibitor of human CD73 A pharmaceutical combination for treating cancer in a subject, comprising: the A2A / A2B inhibitor, the PD-1 / PD-L1 inhibitor, and the human CD73 inhibitor are administered simultaneously or sequentially to the subject; and The A2A / A2B inhibitor is (a) A compound of formula (I): 【Chemistry 1】 [During the ceremony, Cy 1 is phenyl substituted by 1 or 2 substituents independently selected from halo and CN; Cy 2 is a 5-6 membered heteroaryl or a 4-7 membered heterocycloalkyl, wherein the 5-6 membered heteroaryl or the 4-7 membered heterocycloalkyl of Cy 2 are each optionally substituted with 1, 2, or 3 groups independently selected from C 1-3 alkyl, C 1-3 alkoxy, NH 2 , NH(C 1-3 alkyl) and N(C 1-3 alkyl) 2 ; R 2 is selected from phenyl-C 1-3 alkyl, C 3-7 cycloalkylC 1-3 alkyl, (5- to 7-membered heteroaryl)-C 1-3 alkyl, (4- to 7-membered heterocycloalkyl)-C 1-3 alkyl, and OR a2 , wherein the phenyl-C 1-3 alkyl, C 3-7 cycloalkylC 1-3 alkyl, (5- to 7-membered heteroaryl)-C 1-3 alkyl, and (4- to 7-membered heterocycloalkyl)-C 1-3 alkyl of R 2 are each optionally substituted with 1, 2, or 3 independently selected R C substituents; R a2 is (5- to 7-membered heteroaryl)-C 1-3 alkyl optionally substituted with 1 or 2 independently selected R C substituents; each R C is independently selected from halo, C 1-6 alkyl, C 6 aryl, 5- to 7-membered heteroaryl, (4- to 7-membered heterocycloalkyl)-C 1-3 alkyl, OR a4 , and NR c4 R d4 ; and Each R a4 , R c4 , and R d4 is independently selected from H and C 1-6 alkyl. or a pharma- ceutically acceptable salt thereof; (b) A compound of formula (II): 【Chemistry 2】 [During the ceremony, R 2 is selected from H and CN; Cy 1 is phenyl substituted by 1 or 2 substituents independently selected from halo and CN; L is C 1-3 alkylene, where said alkylene is optionally substituted with 1, 2, or 3 independently selected R 8D substituents; Cy 4 is selected from phenyl, cyclohexyl, pyridyl, pyrrolidinonyl, and imidazolyl, wherein phenyl, cyclohexyl, pyridyl, pyrrolidinonyl, and imidazolyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R 8D and R 8 ; Each R 8 is independently selected from halo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl, phenyl, C 3-7 cycloalkyl, 5- to 6-membered heteroaryl, 4- to 7-membered heterocycloalkyl, phenyl-C 1-3 alkyl, C 3-7 cycloalkylC 1-3 alkyl, (5- to 6-membered heteroaryl)-C 1-3 alkyl, and (4- to 7-membered heterocycloalkyl)-C 1-3 alkyl, wherein the C 1-6 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, phenyl, C 3-7 cycloalkyl, 5- to 6-membered heteroaryl, 4- to 7-membered heterocycloalkyl, phenyl-C 1-3 alkyl, C 3-7 cycloalkylC 1-3 alkyl, (5- to 6-membered heteroaryl)-C 1-3 alkyl of said R 8 . alkyl, and (4 to 7 membered heterocycloalkyl)-C 1-3 alkyl are each optionally substituted with 1, 2, or 3 independently selected R 8A substituents; each R 8A is independently selected from halo, C 1-6 alkyl, 5- to 6-membered heteroaryl, 4- to 7-membered heterocycloalkyl, CN, OR a81 , and NR c81 R d81 , wherein the C 1-6 alkyl, 5- to 6-membered heteroaryl, and 4- to 7-membered heterocycloalkyl of said R 8A are each optionally substituted with 1, 2, or 3 independently selected R 8B substituents; each R a81 , R c81 , and R d81 is independently selected from H, C 1-6 alkyl, and 4- to 7-membered heterocycloalkyl, wherein the C 1-6 alkyl and 4- to 7-membered heterocycloalkyl of said R a81 , R c81 , and R d81 are each optionally substituted with 1, 2, or 3 independently selected R 8B substituents; each R 8B is independently selected from halo and C 1-3 alkyl; and each R 8D is independently selected from OH, CN, halo, C 1-6 alkyl, and C 1-6 haloalkyl; or a pharma- ceutically acceptable salt thereof; (c) A compound of formula (III): 【Chemistry 3】 [During the ceremony, Cy 1 is phenyl substituted by 1 or 2 substituents independently selected from halo and CN; R 2 is selected from 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl, wherein said 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl of R 2 are each optionally substituted with 1, 2, or 3 independently selected R 2A substituents; each R 2A is independently selected from D, halo, C 1-6 alkyl, and C 1-6 haloalkyl; R 4 is selected from phenyl-C 1-3 alkyl-, C 3-7 cycloalkyl-C 1-3 alkyl-, (5- to 6-membered heteroaryl)-C 1-3 alkyl-, and (4- to 7-membered heterocycloalkyl)-C 1-3 alkyl, wherein the phenyl-C 1-3 alkyl-, C 3-7 cycloalkyl-C 1-3 alkyl-, (5- to 6-membered heteroaryl)-C 1-3 alkyl, and (4- to 7-membered heterocycloalkyl)-C 1-3 alkyl- of R 4 are each optionally substituted with 1, 2, or 3 independently selected R 4A substituents; each R 4A is independently selected from halo, C 1-6 alkyl, C 1-6 haloalkyl, CN, OR a41 , and NR c41 R d41 ; and Each R a41 , R c41 , and R d41 is independently selected from H and C 1-6 alkyl. or a pharma- ceutically acceptable salt thereof; or (d) A compound of formula (IV): 【Chemistry 4】 [During the ceremony, Cy 1 is phenyl substituted by 1 or 2 substituents independently selected from halo and CN; Cy 2 is selected from 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl, wherein said 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl of Cy 2 are each optionally substituted with 1, 2, or 3 independently selected R 6 substituents; each R 6 is independently selected from halo, C 1-6 alkyl, and C 1-6 haloalkyl; R 2 is phenyl-C 1-3 alkyl- or (5- to 6-membered heteroaryl)-C 1-3 alkyl-, wherein said phenyl-C 1-3 alkyl- and (5- to 6-membered heteroaryl)-C 1-3 alkyl- of R 2 are each optionally substituted by 1, 2, or 3 independently selected R 2A substituents; each R 2A is independently selected from halo, C 1-6 alkyl, and C 1-6 haloalkyl; or a pharma- ceutically acceptable salt thereof, The combination drug,

2. A pharmaceutical for treating cancer in a subject, comprising an inhibitor of A2A / A2B, the medicament is administered to the subject in combination with an inhibitor of PD-1 / PD-L1 and an inhibitor of human CD73; and The A2A / A2B inhibitor is 【Chemistry 5】 [During the ceremony, Cy 1 is phenyl substituted by 1 or 2 substituents independently selected from halo and CN; Cy 2 is a 5-6 membered heteroaryl or a 4-7 membered heterocycloalkyl, wherein the 5-6 membered heteroaryl or the 4-7 membered heterocycloalkyl of Cy 2 are each optionally substituted with 1, 2, or 3 groups independently selected from C 1-3 alkyl, C 1-3 alkoxy, NH 2 , NH(C 1-3 alkyl) and N(C 1-3 alkyl) 2 ; R 2 is selected from phenyl-C 1-3 alkyl, C 3-7 cycloalkylC 1-3 alkyl, (5- to 7-membered heteroaryl)-C 1-3 alkyl, (4- to 7-membered heterocycloalkyl)-C 1-3 alkyl, and OR a2 , wherein the phenyl-C 1-3 alkyl, C 3-7 cycloalkylC 1-3 alkyl, (5- to 7-membered heteroaryl)-C 1-3 alkyl, and (4- to 7-membered heterocycloalkyl)-C 1-3 alkyl of R 2 are each optionally substituted with 1, 2, or 3 independently selected R C substituents; R a2 is (5- to 7-membered heteroaryl)-C 1-3 alkyl optionally substituted with 1 or 2 independently selected R C substituents; each R C is independently selected from halo, C 1-6 alkyl, C 6 aryl, 5- to 7-membered heteroaryl, (4- to 7-membered heterocycloalkyl)-C 1-3 alkyl, OR a4 , and NR c4 R d4 ; and Each R a4 , R c4 , and R d4 is independently selected from H and C 1-6 alkyl. or a pharma- ceutically acceptable salt thereof; (b) A compound of formula (II): 【Chemistry 6】 [During the ceremony, R 2 is selected from H and CN; Cy 1 is phenyl substituted by 1 or 2 substituents independently selected from halo and CN; L is C 1-3 alkylene, where said alkylene is optionally substituted with 1, 2, or 3 independently selected R 8D substituents; Cy 4 is selected from phenyl, cyclohexyl, pyridyl, pyrrolidinonyl, and imidazolyl, wherein phenyl, cyclohexyl, pyridyl, pyrrolidinonyl, and imidazolyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R 8D and R 8 ; Each R 8 is independently selected from halo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl, phenyl, C 3-7 cycloalkyl, 5- to 6-membered heteroaryl, 4- to 7-membered heterocycloalkyl, phenyl-C 1-3 alkyl, C 3-7 cycloalkylC 1-3 alkyl, (5- to 6-membered heteroaryl)-C 1-3 alkyl, and (4- to 7-membered heterocycloalkyl)-C 1-3 alkyl, wherein the C 1-6 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, phenyl, C 3-7 cycloalkyl, 5- to 6-membered heteroaryl, 4- to 7-membered heterocycloalkyl, phenyl-C 1-3 alkyl, C 3-7 cycloalkylC 1-3 alkyl, (5- to 6-membered heteroaryl)-C 1-3 alkyl of said R 8 . alkyl, and (4 to 7 membered heterocycloalkyl)-C 1-3 alkyl are each optionally substituted with 1, 2, or 3 independently selected R 8A substituents; each R 8A is independently selected from halo, C 1-6 alkyl, 5- to 6-membered heteroaryl, 4- to 7-membered heterocycloalkyl, CN, OR a81 , and NR c81 R d81 , wherein the C 1-6 alkyl, 5- to 6-membered heteroaryl, and 4- to 7-membered heterocycloalkyl of said R 8A are each optionally substituted with 1, 2, or 3 independently selected R 8B substituents; each R a81 , R c81 , and R d81 is independently selected from H, C 1-6 alkyl, and 4- to 7-membered heterocycloalkyl, wherein the C 1-6 alkyl and 4- to 7-membered heterocycloalkyl of said R a81 , R c81 , and R d81 are each optionally substituted with 1, 2, or 3 independently selected R 8B substituents; each R 8B is independently selected from halo and C 1-3 alkyl; and each R 8D is independently selected from OH, CN, halo, C 1-6 alkyl, and C 1-6 haloalkyl; or a pharma- ceutically acceptable salt thereof; (c) A compound of formula (III): 【Chemistry 7】 [During the ceremony, Cy 1 is phenyl substituted by 1 or 2 substituents independently selected from halo and CN; R 2 is selected from 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl, wherein said 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl of R 2 are each optionally substituted with 1, 2, or 3 independently selected R 2A substituents; each R 2A is independently selected from D, halo, C 1-6 alkyl, and C 1-6 haloalkyl; R 4 is selected from phenyl-C 1-3 alkyl-, C 3-7 cycloalkyl-C 1-3 alkyl-, (5- to 6-membered heteroaryl)-C 1-3 alkyl-, and (4- to 7-membered heterocycloalkyl)-C 1-3 alkyl, wherein the phenyl-C 1-3 alkyl-, C 3-7 cycloalkyl-C 1-3 alkyl-, (5- to 6-membered heteroaryl)-C 1-3 alkyl, and (4- to 7-membered heterocycloalkyl)-C 1-3 alkyl- of R 4 are each optionally substituted with 1, 2, or 3 independently selected R 4A substituents; each R 4A is independently selected from halo, C 1-6 alkyl, C 1-6 haloalkyl, CN, OR a41 , and NR c41 R d41 ; and Each R a41 , R c41 , and R d41 is independently selected from H and C 1-6 alkyl. or a pharma- ceutically acceptable salt thereof; or (d) A compound of formula (IV): 【Chemistry 8】 [During the ceremony, Cy 1 is phenyl substituted by 1 or 2 substituents independently selected from halo and CN; Cy 2 is selected from 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl, wherein said 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl of Cy 2 are each optionally substituted with 1, 2, or 3 independently selected R 6 substituents; each R 6 is independently selected from halo, C 1-6 alkyl, and C 1-6 haloalkyl; R 2 is phenyl-C 1-3 alkyl- or (5- to 6-membered heteroaryl)-C 1-3 alkyl-, wherein said phenyl-C 1-3 alkyl- and (5- to 6-membered heteroaryl)-C 1-3 alkyl- of R 2 are each optionally substituted by 1, 2, or 3 independently selected R 2A substituents; each R 2A is independently selected from halo, C 1-6 alkyl, and C 1-6 haloalkyl; or a pharma- ceutically acceptable salt thereof, The pharmaceutical composition according to the present invention,

3. A pharmaceutical for treating cancer in a subject, comprising an inhibitor of PD-1 / PD-L1, the medicament is administered to the subject in combination with an inhibitor of A2A / A2B and an inhibitor of human CD73; and The A2A / A2B inhibitor is (a) A compound of formula (I): 【Chemistry 9】 [During the ceremony, Cy 1 is phenyl substituted by 1 or 2 substituents independently selected from halo and CN; Cy 2 is a 5-6 membered heteroaryl or a 4-7 membered heterocycloalkyl, wherein the 5-6 membered heteroaryl or the 4-7 membered heterocycloalkyl of Cy 2 are each optionally substituted with 1, 2, or 3 groups independently selected from C 1-3 alkyl, C 1-3 alkoxy, NH 2 , NH(C 1-3 alkyl) and N(C 1-3 alkyl) 2 ; R 2 is selected from phenyl-C 1-3 alkyl, C 3-7 cycloalkylC 1-3 alkyl, (5- to 7-membered heteroaryl)-C 1-3 alkyl, (4- to 7-membered heterocycloalkyl)-C 1-3 alkyl, and OR a2 , wherein the phenyl-C 1-3 alkyl, C 3-7 cycloalkylC 1-3 alkyl, (5- to 7-membered heteroaryl)-C 1-3 alkyl, and (4- to 7-membered heterocycloalkyl)-C 1-3 alkyl of R 2 are each optionally substituted with 1, 2, or 3 independently selected R C substituents; R a2 is (5- to 7-membered heteroaryl)-C 1-3 alkyl optionally substituted with 1 or 2 independently selected R C substituents; each R C is independently selected from halo, C 1-6 alkyl, C 6 aryl, 5- to 7-membered heteroaryl, (4- to 7-membered heterocycloalkyl)-C 1-3 alkyl, OR a4 , and NR c4 R d4 ; and Each R a4 , R c4 , and R d4 is independently selected from H and C 1-6 alkyl. or a pharma- ceutically acceptable salt thereof; (b) A compound of formula (II): 【Chemistry 10】 [During the ceremony, R 2 is selected from H and CN; Cy 1 is phenyl substituted by 1 or 2 substituents independently selected from halo and CN; L is C 1-3 alkylene, where said alkylene is optionally substituted with 1, 2, or 3 independently selected R 8D substituents; Cy 4 is selected from phenyl, cyclohexyl, pyridyl, pyrrolidinonyl, and imidazolyl, wherein phenyl, cyclohexyl, pyridyl, pyrrolidinonyl, and imidazolyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R 8D and R 8 ; Each R 8 is independently selected from halo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl, phenyl, C 3-7 cycloalkyl, 5- to 6-membered heteroaryl, 4- to 7-membered heterocycloalkyl, phenyl-C 1-3 alkyl, C 3-7 cycloalkylC 1-3 alkyl, (5- to 6-membered heteroaryl)-C 1-3 alkyl, and (4- to 7-membered heterocycloalkyl)-C 1-3 alkyl, wherein the C 1-6 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, phenyl, C 3-7 cycloalkyl, 5- to 6-membered heteroaryl, 4- to 7-membered heterocycloalkyl, phenyl-C 1-3 alkyl, C 3-7 cycloalkylC 1-3 alkyl, (5- to 6-membered heteroaryl)-C 1-3 alkyl of said R 8 . alkyl, and (4 to 7 membered heterocycloalkyl)-C 1-3 alkyl are each optionally substituted with 1, 2, or 3 independently selected R 8A substituents; each R 8A is independently selected from halo, C 1-6 alkyl, 5- to 6-membered heteroaryl, 4- to 7-membered heterocycloalkyl, CN, OR a81 , and NR c81 R d81 , wherein the C 1-6 alkyl, 5- to 6-membered heteroaryl, and 4- to 7-membered heterocycloalkyl of said R 8A are each optionally substituted with 1, 2, or 3 independently selected R 8B substituents; each R a81 , R c81 , and R d81 is independently selected from H, C 1-6 alkyl, and 4- to 7-membered heterocycloalkyl, wherein the C 1-6 alkyl and 4- to 7-membered heterocycloalkyl of said R a81 , R c81 , and R d81 are each optionally substituted with 1, 2, or 3 independently selected R 8B substituents; each R 8B is independently selected from halo and C 1-3 alkyl; and each R 8D is independently selected from OH, CN, halo, C 1-6 alkyl, and C 1-6 haloalkyl; or a pharma- ceutically acceptable salt thereof; (c) A compound of formula (III): 【Chemistry 11】 [During the ceremony, Cy 1 is phenyl substituted by 1 or 2 substituents independently selected from halo and CN; R 2 is selected from 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl, wherein said 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl of R 2 are each optionally substituted with 1, 2, or 3 independently selected R 2A substituents; each R 2A is independently selected from D, halo, C 1-6 alkyl, and C 1-6 haloalkyl; R 4 is selected from phenyl-C 1-3 alkyl-, C 3-7 cycloalkyl-C 1-3 alkyl-, (5- to 6-membered heteroaryl)-C 1-3 alkyl-, and (4- to 7-membered heterocycloalkyl)-C 1-3 alkyl, wherein the phenyl-C 1-3 alkyl-, C 3-7 cycloalkyl-C 1-3 alkyl-, (5- to 6-membered heteroaryl)-C 1-3 alkyl, and (4- to 7-membered heterocycloalkyl)-C 1-3 alkyl- of R 4 are each optionally substituted with 1, 2, or 3 independently selected R 4A substituents; each R 4A is independently selected from halo, C 1-6 alkyl, C 1-6 haloalkyl, CN, OR a41 , and NR c41 R d41 ; and Each R a41 , R c41 , and R d41 is independently selected from H and C 1-6 alkyl. or a pharma- ceutically acceptable salt thereof; or (d) A compound of formula (IV): 【Chemistry 12】 [During the ceremony, Cy 1 is phenyl substituted by 1 or 2 substituents independently selected from halo and CN; Cy 2 is selected from 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl, wherein said 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl of Cy 2 are each optionally substituted with 1, 2, or 3 independently selected R 6 substituents; each R 6 is independently selected from halo, C 1-6 alkyl, and C 1-6 haloalkyl; R 2 is phenyl-C 1-3 alkyl- or (5- to 6-membered heteroaryl)-C 1-3 alkyl-, wherein said phenyl-C 1-3 alkyl- and (5- to 6-membered heteroaryl)-C 1-3 alkyl- of R 2 are each optionally substituted by 1, 2, or 3 independently selected R 2A substituents; each R 2A is independently selected from halo, C 1-6 alkyl, and C 1-6 haloalkyl; or a pharma- ceutically acceptable salt thereof, The pharmaceutical composition according to the present invention,

4. A pharmaceutical for treating cancer in a subject, comprising an inhibitor of human CD73, the medicament is administered to the subject in combination with an A2A / A2B inhibitor and a PD-1 / PD-L1 inhibitor; and The A2A / A2B inhibitor is (a) A compound of formula (I): 【Chemistry 13】 [During the ceremony, Cy 1 is phenyl substituted by 1 or 2 substituents independently selected from halo and CN; Cy 2 is a 5-6 membered heteroaryl or a 4-7 membered heterocycloalkyl, wherein the 5-6 membered heteroaryl or the 4-7 membered heterocycloalkyl of Cy 2 are each optionally substituted with 1, 2, or 3 groups independently selected from C 1-3 alkyl, C 1-3 alkoxy, NH 2 , NH(C 1-3 alkyl) and N(C 1-3 alkyl) 2 ; R 2 is selected from phenyl-C 1-3 alkyl, C 3-7 cycloalkylC 1-3 alkyl, (5- to 7-membered heteroaryl)-C 1-3 alkyl, (4- to 7-membered heterocycloalkyl)-C 1-3 alkyl, and OR a2 , wherein the phenyl-C 1-3 alkyl, C 3-7 cycloalkylC 1-3 alkyl, (5- to 7-membered heteroaryl)-C 1-3 alkyl, and (4- to 7-membered heterocycloalkyl)-C 1-3 alkyl of R 2 are each optionally substituted with 1, 2, or 3 independently selected R C substituents; R a2 is (5- to 7-membered heteroaryl)-C 1-3 alkyl optionally substituted with 1 or 2 independently selected R C substituents; each R C is independently selected from halo, C 1-6 alkyl, C 6 aryl, 5- to 7-membered heteroaryl, (4- to 7-membered heterocycloalkyl)-C 1-3 alkyl, OR a4 , and NR c4 R d4 ; and Each R a4 , R c4 , and R d4 is independently selected from H and C 1-6 alkyl. or a pharma- ceutically acceptable salt thereof; (b) A compound of formula (II): 【Chemistry 14】 [During the ceremony, R 2 is selected from H and CN; Cy 1 is phenyl substituted by 1 or 2 substituents independently selected from halo and CN; L is C 1-3 alkylene, where said alkylene is optionally substituted with 1, 2, or 3 independently selected R 8D substituents; Cy 4 is selected from phenyl, cyclohexyl, pyridyl, pyrrolidinonyl, and imidazolyl, wherein phenyl, cyclohexyl, pyridyl, pyrrolidinonyl, and imidazolyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R 8D and R 8 ; Each R 8 is independently selected from halo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl, phenyl, C 3-7 cycloalkyl, 5- to 6-membered heteroaryl, 4- to 7-membered heterocycloalkyl, phenyl-C 1-3 alkyl, C 3-7 cycloalkylC 1-3 alkyl, (5- to 6-membered heteroaryl)-C 1-3 alkyl, and (4- to 7-membered heterocycloalkyl)-C 1-3 alkyl, wherein the C 1-6 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, phenyl, C 3-7 cycloalkyl, 5- to 6-membered heteroaryl, 4- to 7-membered heterocycloalkyl, phenyl-C 1-3 alkyl, C 3-7 cycloalkylC 1-3 alkyl, (5- to 6-membered heteroaryl)-C 1-3 alkyl of said R 8 . alkyl, and (4 to 7 membered heterocycloalkyl)-C 1-3 alkyl are each optionally substituted with 1, 2, or 3 independently selected R 8A substituents; each R 8A is independently selected from halo, C 1-6 alkyl, 5- to 6-membered heteroaryl, 4- to 7-membered heterocycloalkyl, CN, OR a81 , and NR c81 R d81 , wherein the C 1-6 alkyl, 5- to 6-membered heteroaryl, and 4- to 7-membered heterocycloalkyl of said R 8A are each optionally substituted with 1, 2, or 3 independently selected R 8B substituents; each R a81 , R c81 , and R d81 is independently selected from H, C 1-6 alkyl, and 4- to 7-membered heterocycloalkyl, wherein the C 1-6 alkyl and 4- to 7-membered heterocycloalkyl of said R a81 , R c81 , and R d81 are each optionally substituted with 1, 2, or 3 independently selected R 8B substituents; each R 8B is independently selected from halo and C 1-3 alkyl; and each R 8D is independently selected from OH, CN, halo, C 1-6 alkyl, and C 1-6 haloalkyl; or a pharma- ceutically acceptable salt thereof; (c) A compound of formula (III): 【Chemistry 15】 [During the ceremony, Cy 1 is phenyl substituted by 1 or 2 substituents independently selected from halo and CN; R 2 is selected from 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl, wherein said 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl of R 2 are each optionally substituted with 1, 2, or 3 independently selected R 2A substituents; each R 2A is independently selected from D, halo, C 1-6 alkyl, and C 1-6 haloalkyl; R 4 is selected from phenyl-C 1-3 alkyl-, C 3-7 cycloalkyl-C 1-3 alkyl-, (5- to 6-membered heteroaryl)-C 1-3 alkyl-, and (4- to 7-membered heterocycloalkyl)-C 1-3 alkyl, wherein the phenyl-C 1-3 alkyl-, C 3-7 cycloalkyl-C 1-3 alkyl-, (5- to 6-membered heteroaryl)-C 1-3 alkyl, and (4- to 7-membered heterocycloalkyl)-C 1-3 alkyl- of R 4 are each optionally substituted with 1, 2, or 3 independently selected R 4A substituents; each R 4A is independently selected from halo, C 1-6 alkyl, C 1-6 haloalkyl, CN, OR a41 , and NR c41 R d41 ; and Each R a41 , R c41 , and R d41 is independently selected from H and C 1-6 alkyl. or a pharma- ceutically acceptable salt thereof; or (d) A compound of formula (IV): 【Chemistry 16】 [During the ceremony, Cy 1 is phenyl substituted by 1 or 2 substituents independently selected from halo and CN; Cy 2 is selected from 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl, wherein said 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl of Cy 2 are each optionally substituted with 1, 2, or 3 independently selected R 6 substituents; each R 6 is independently selected from halo, C 1-6 alkyl, and C 1-6 haloalkyl; R 2 is phenyl-C 1-3 alkyl- or (5- to 6-membered heteroaryl)-C 1-3 alkyl-, wherein said phenyl-C 1-3 alkyl- and (5- to 6-membered heteroaryl)-C 1-3 alkyl- of R 2 are each optionally substituted by 1, 2, or 3 independently selected R 2A substituents; each R 2A is independently selected from halo, C 1-6 alkyl, and C 1-6 haloalkyl; or a pharma- ceutically acceptable salt thereof, The pharmaceutical composition according to the present invention, 5. The A2A / A2B inhibitor, comprising: (a) a compound of formula (I): 【Chemistry 17】 [During the ceremony, Cy 1 is phenyl substituted by 1 or 2 substituents independently selected from halo and CN; Cy 2 is a 5-6 membered heteroaryl or a 4-7 membered heterocycloalkyl, wherein the 5-6 membered heteroaryl or the 4-7 membered heterocycloalkyl of Cy 2 are each optionally substituted with 1, 2, or 3 groups independently selected from C 1-3 alkyl, C 1-3 alkoxy, NH 2 , NH(C 1-3 alkyl) and N(C 1-3 alkyl) 2 ; R 2 is selected from phenyl-C 1-3 alkyl, C 3-7 cycloalkylC 1-3 alkyl, (5- to 7-membered heteroaryl)-C 1-3 alkyl, (4- to 7-membered heterocycloalkyl)-C 1-3 alkyl, and OR a2 , wherein the phenyl-C 1-3 alkyl, C 3-7 cycloalkylC 1-3 alkyl, (5- to 7-membered heteroaryl)-C 1-3 alkyl, and (4- to 7-membered heterocycloalkyl)-C 1-3 alkyl of R 2 are each optionally substituted with 1, 2, or 3 independently selected R C substituents; R a2 is (5- to 7-membered heteroaryl)-C 1-3 alkyl optionally substituted with 1 or 2 independently selected R C substituents; each R C is independently selected from halo, C 1-6 alkyl, C 6 aryl, 5- to 7-membered heteroaryl, (4- to 7-membered heterocycloalkyl)-C 1-3 alkyl, OR a4 , and NR c4 R d4 ; and Each R a4 , R c4 , and R d4 is independently selected from H and C 1-6 alkyl. or a pharma- ceutically acceptable salt thereof, The A2A / A2B inhibitor is 3-(5-amino-2-(pyridin-2-ylmethyl)-8-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-2-((2,6-difluorophenyl)(hydroxy)methyl)-8-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-2-((5-(pyridin-2-yl)-2H-tetrazol-2-yl)methyl)-8-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-2-((3-methylpyridin-2-yl)methoxy)-8-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; and 3-(2-((5-(1H-pyrazol-1-yl)-2H-tetrazol-2-yl)methyl)-5-amino-8-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; and pharma- ceutically acceptable salts of any of the foregoing. may be selected from The combination pharmaceutical according to claim 1 or the pharmaceutical according to any one of claims 2 to 4.

6. The A2A / A2B inhibitor, (b) a compound of formula (II): 【Chemistry 18】 [During the ceremony, R 2 is selected from H and CN; Cy 1 is phenyl substituted by 1 or 2 substituents independently selected from halo and CN; L is C 1-3 alkylene, where said alkylene is optionally substituted with 1, 2, or 3 independently selected R 8D substituents; Cy 4 is selected from phenyl, cyclohexyl, pyridyl, pyrrolidinonyl, and imidazolyl, wherein phenyl, cyclohexyl, pyridyl, pyrrolidinonyl, and imidazolyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R 8D and R 8 ; Each R 8 is independently selected from halo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl, phenyl, C 3-7 cycloalkyl, 5- to 6-membered heteroaryl, 4- to 7-membered heterocycloalkyl, phenyl-C 1-3 alkyl, C 3-7 cycloalkylC 1-3 alkyl, (5- to 6-membered heteroaryl)-C 1-3 alkyl, and (4- to 7-membered heterocycloalkyl)-C 1-3 alkyl, wherein the C 1-6 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, phenyl, C 3-7 cycloalkyl, 5- to 6-membered heteroaryl, 4- to 7-membered heterocycloalkyl, phenyl-C 1-3 alkyl, C 3-7 cycloalkylC 1-3 alkyl, (5- to 6-membered heteroaryl)-C 1-3 alkyl of said R 8 . alkyl, and (4 to 7 membered heterocycloalkyl)-C 1-3 alkyl are each optionally substituted with 1, 2, or 3 independently selected R 8A substituents; each R 8A is independently selected from halo, C 1-6 alkyl, 5- to 6-membered heteroaryl, 4- to 7-membered heterocycloalkyl, CN, OR a81 , and NR c81 R d81 , wherein the C 1-6 alkyl, 5- to 6-membered heteroaryl, and 4- to 7-membered heterocycloalkyl of said R 8A are each optionally substituted with 1, 2, or 3 independently selected R 8B substituents; each R a81 , R c81 , and R d81 is independently selected from H, C 1-6 alkyl, and 4- to 7-membered heterocycloalkyl, wherein the C 1-6 alkyl and 4- to 7-membered heterocycloalkyl of said R a81 , R c81 , and R d81 are each optionally substituted with 1, 2, or 3 independently selected R 8B substituents; each R 8B is independently selected from halo and C 1-3 alkyl; and each R 8D is independently selected from OH, CN, halo, C 1-6 alkyl, and C 1-6 haloalkyl; or a pharma- ceutically acceptable salt thereof, The A2A / A2B inhibitor is 3-(5-amino-2-(hydroxy(phenyl)methyl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-2-((2,6-difluorophenyl)(hydroxy)methyl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)-2-fluorobenzonitrile; 5-amino-7-(3-cyano-2-fluorophenyl)-2-((2,6-difluorophenyl)(hydroxy)methyl)-[1,2,4]triazolo[1,5-c]pyrimidine-8-carbonitrile; and 3-(5-amino-2-((2-fluoro-6-(((1-methyl-2-oxopyrrolidin-3-yl)amino)methyl)phenyl)(hydroxy)methyl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)-2-fluorobenzonitrile; and pharma- ceutically acceptable salts of any of the foregoing. may be selected from The combination pharmaceutical according to claim 1 or the pharmaceutical according to any one of claims 2 to 4.

7. The A2A / A2B inhibitor, (c) a compound of formula (III): 【Chemistry 19】 [During the ceremony, Cy 1 is phenyl substituted by 1 or 2 substituents independently selected from halo and CN; R 2 is selected from 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl, wherein said 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl of R 2 are each optionally substituted with 1, 2, or 3 independently selected R 2A substituents; each R 2A is independently selected from D, halo, C 1-6 alkyl, and C 1-6 haloalkyl; R 4 is selected from phenyl-C 1-3 alkyl-, C 3-7 cycloalkyl-C 1-3 alkyl-, (5- to 6-membered heteroaryl)-C 1-3 alkyl-, and (4- to 7-membered heterocycloalkyl)-C 1-3 alkyl, wherein the phenyl-C 1-3 alkyl-, C 3-7 cycloalkyl-C 1-3 alkyl-, (5- to 6-membered heteroaryl)-C 1-3 alkyl, and (4- to 7-membered heterocycloalkyl)-C 1-3 alkyl- of R 4 are each optionally substituted with 1, 2, or 3 independently selected R 4A substituents; each R 4A is independently selected from halo, C 1-6 alkyl, C 1-6 haloalkyl, CN, OR a41 , and NR c41 R d41 ; and Each R a41 , R c41 , and R d41 is independently selected from H and C 1-6 alkyl. or a pharma- ceutically acceptable salt thereof, The A2A / A2B inhibitor is 3-(8-amino-5-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-2-(pyridin-2-ylmethyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile; 3-(8-amino-2-((2,6-difluorophenyl)(hydroxy)methyl)-5-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile; 3-(8-amino-2-(amino(2,6-difluorophenyl)methyl)-5-(4-methyloxazol-5-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile; and 3-(8-amino-2-((2,6-difluorophenyl)(hydroxy)methyl)-5-(2,6-dimethylpyridin-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile; and pharma- ceutically acceptable salts of any of the foregoing. may be selected from The combination pharmaceutical according to claim 1 or the pharmaceutical according to any one of claims 2 to 4.

8. The A2A / A2B inhibitor, (d) a compound of formula (IV): 【Chemistry 20】 [During the ceremony, Cy 1 is phenyl substituted by 1 or 2 substituents independently selected from halo and CN; Cy 2 is selected from 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl, wherein said 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl of Cy 2 are each optionally substituted with 1, 2, or 3 independently selected R 6 substituents; each R 6 is independently selected from halo, C 1-6 alkyl, and C 1-6 haloalkyl; R 2 is phenyl-C 1-3 alkyl- or (5- to 6-membered heteroaryl)-C 1-3 alkyl-, wherein said phenyl-C 1-3 alkyl- and (5- to 6-membered heteroaryl)-C 1-3 alkyl- of R 2 are each optionally substituted by 1, 2, or 3 independently selected R 2A substituents; each R 2A is independently selected from halo, C 1-6 alkyl, and C 1-6 haloalkyl; or a pharma- ceutically acceptable salt thereof, The A2A / A2B inhibitor is 3-(4-amino-2-(pyridin-2-ylmethyl)-7-(pyrimidin-4-yl)-2H-[1,2,3]triazolo[4,5-c]pyridin-6-yl)benzonitrile; 3-(4-amino-2-((3-fluoropyridin-2-yl)methyl)-7-(pyrimidin-4-yl)-2H-[1,2,3]triazolo[4,5-c]pyridin-6-yl)benzonitrile; 3-(4-amino-2-((3-fluoropyridin-2-yl)methyl)-7-(pyridin-4-yl)-2H-[1,2,3]triazolo[4,5-c]pyridin-6-yl)benzonitrile; and 3-(4-amino-7-(1-methyl-1H-pyrazol-5-yl)-2-(pyridin-2-ylmethyl)-2H-[1,2,3]triazolo[4,5-c]pyridin-6-yl)-2-fluorobenzonitrile; and pharma- ceutically acceptable salts of any of the foregoing. may be selected from The combination pharmaceutical according to claim 1 or the pharmaceutical according to any one of claims 2 to 4.

9. The PD-1 / PD-L1 inhibitor, (i) (R)-1-((7-cyano-2-(3'-(3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylic acid, or a pharma- ceutically acceptable salt thereof; (ii) pembrolizumab; (iii) atezolizumab; or (iv) an antibody or antigen-binding fragment thereof that binds to human PD-1, the antibody or antigen-binding fragment thereof Variable heavy (VH) complementarity determining region (CDR) 1 comprising the amino acid sequence SYWMN (SEQ ID NO: 6), VH CDR2 comprising the amino acid sequence VIHPSDSETWLDQKFKD (SEQ ID NO:7), and VH CDR3 comprising the amino acid sequence EHYGTSPFAY (SEQ ID NO:8) and The antibody, Variable light (VL) CDR1 comprising the amino acid sequence RASESVDNYGMSFMNW (SEQ ID NO:9), a VL CDR2 comprising the amino acid sequence AASNQGS (SEQ ID NO: 10); and The VL CDR3 comprises the amino acid sequence QQSKEVPYT (SEQ ID NO:11). A VL domain comprising the antibody or antigen-binding fragment thereof that binds to human PD-1; The combination drug according to claim 1, the drug according to any one of claims 2 to 4, or the combination drug or drug according to any one of claims 5 to 8, (i) the VH domain comprises the amino acid sequence set forth in SEQ ID NO:4 and the VL domain comprises the amino acid sequence set forth in SEQ ID NO:5; (ii) the antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence set forth in SEQ ID NO:2 and the light chain comprises the amino acid sequence set forth in SEQ ID NO:3; or (iii) the antibody or antigen-binding fragment thereof that binds to human PD-1 is a humanized antibody; 10. The pharmaceutical combination or medicament according to claim 9.

11. The human CD73 inhibitor, (a) an antibody that binds to human CD73, Variable heavy (VH) complementarity determining region (CDR) 1 comprising the amino acid sequence GYTFTSYG (SEQ ID NO: 16), VH CDR2 comprising the amino acid sequence IYPGSGNT (SEQ ID NO: 17), and VH CDR3 comprising the amino acid sequence ARYDYLGSSYGFDY (SEQ ID NO: 18) and a VH domain comprising Variable light (VL) CDR1 comprising the amino acid sequence QDVSTA (SEQ ID NO: 19), VL CDR2 comprising the amino acid sequence SAS (SEQ ID NO:20), and VL CDR3 comprising the amino acid sequence QQHYNTPYT (SEQ ID NO:21) and a VL domain comprising The antibody, (b) an antibody that binds to human CD73 at an epitope within amino acids 40-53 of SEQ ID NO:70; (c) an antibody that binds to human CD73 and competes for binding to human CD73 with an antibody having a heavy chain comprising the amino acid sequence of SEQ ID NO:24 and a light chain comprising the amino acid sequence of SEQ ID NO:25; (d) an antibody that binds to human CD73, VH CDR1 comprising the amino acid sequence GFTFSSYD (SEQ ID NO:34), a VH CDR2 comprising the amino acid sequence MSYDGSNK (SEQ ID NO: 35) or MSYEGSNK (SEQ ID NO: 40); and VH CDR3 comprising the amino acid sequence ATEIAAKGDY (SEQ ID NO:36) and a VH domain comprising VL CDR1 comprising the amino acid sequence QGISNY (SEQ ID NO:37), VL CDR2 comprising the amino acid sequence AAS (SEQ ID NO:38), and VL CDR3 comprising the amino acid sequence QQSYSTPH (SEQ ID NO:39) and a VL domain comprising The antibody, (e) an antibody that binds to human CD73 at an epitope within amino acids 386-399 and 470-489 of SEQ ID NO: 70; (f) an antibody that binds to human CD73 and competes for binding to human CD73 with an antibody having a heavy chain comprising the amino acid sequence of SEQ ID NO: 30 and a light chain comprising the amino acid sequence of SEQ ID NO: 31; (g) an antibody that binds to human CD73 and competes for binding to human CD73 with an antibody having a heavy chain comprising the amino acid sequence of SEQ ID NO: 33 and a light chain comprising the amino acid sequence of SEQ ID NO: 31; (h) an antibody selected from the group consisting of 11E1, Medi9447, CPI-006, and BMS-986179, or (i) an inhibitor selected from the group consisting of CB-708 and AB680; Including, A combination pharmaceutical according to claim 1, a pharmaceutical according to any one of claims 2 to 4, or a combination pharmaceutical or pharmaceutical according to any one of claims 5 to 10.

12. The inhibitor of human CD73, (i) an antibody that binds to human CD73, An antibody that binds to human CD73, Variable heavy (VH) complementarity determining region (CDR) 1 comprising the amino acid sequence GYTFTSYG (SEQ ID NO: 16), VH CDR2 comprising the amino acid sequence IYPGSGNT (SEQ ID NO: 17), and VH CDR3 comprising the amino acid sequence ARYDYLGSSYGFDY (SEQ ID NO: 18) and a VH domain comprising Variable light (VL) CDR1 comprising the amino acid sequence QDVSTA (SEQ ID NO: 19), VL CDR2 comprising the amino acid sequence SAS (SEQ ID NO:20), and VL CDR3 comprising the amino acid sequence QQHYNTPYT (SEQ ID NO:21) and a VL domain comprising or the antibody comprising: (ii) an antibody that binds to human CD73 at an epitope within amino acids 40-53 of SEQ ID NO:70; (iii) an antibody that binds to human CD73 and competes for binding to human CD73 with an antibody having a heavy chain comprising the amino acid sequence of SEQ ID NO:24 and a light chain comprising the amino acid sequence of SEQ ID NO:25; (iv) an antibody that binds to human CD73, VH CDR1 comprising the amino acid sequence GFTFSSYD (SEQ ID NO:34), a VH CDR2 comprising the amino acid sequence MSYDGSNK (SEQ ID NO: 35) or MSYEGSNK (SEQ ID NO: 40); and VH CDR3 comprising the amino acid sequence ATEIAAKGDY (SEQ ID NO:36) and a VH domain comprising VL CDR1 comprising the amino acid sequence QGISNY (SEQ ID NO:37), VL CDR2 comprising the amino acid sequence AAS (SEQ ID NO:38), and VL CDR3 comprising the amino acid sequence QQSYSTPH (SEQ ID NO:39) and a VL domain comprising or (v) an antibody that binds to human CD73 at an epitope within amino acids 386-399 and 470-489 of SEQ ID NO:70; (vi) an antibody that binds to human CD73 and competes for binding to human CD73 with an antibody having a heavy chain comprising the amino acid sequence of SEQ ID NO: 30 and a light chain comprising the amino acid sequence of SEQ ID NO: 31; (vii) an antibody that binds to human CD73 and competes for binding to human CD73 with an antibody having a heavy chain comprising the amino acid sequence of SEQ ID NO:33 and a light chain comprising the amino acid sequence of SEQ ID NO:31; (viii) an antibody selected from the group consisting of 11E1, Medi9447, CPI-006, and BMS-986179; or (ix) selected from the group consisting of CB-708 and AB680; A combination pharmaceutical according to claim 1, a pharmaceutical according to any one of claims 2 to 4, or a combination pharmaceutical or pharmaceutical according to any one of claims 5 to 11. (i) the VH domain comprises the amino acid sequence set forth in SEQ ID NO:22 and the VL domain comprises the amino acid sequence set forth in SEQ ID NO:23; or (ii) the antibody comprises a heavy chain and a light chain, the heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 24 and the light chain comprising the amino acid sequence set forth in SEQ ID NO: 25; 13. A pharmaceutical combination or medicament according to claim 12.

14. (i) the VH domain comprises the amino acid sequence set forth in SEQ ID NO:62 and the VL domain comprises the amino acid sequence set forth in SEQ ID NO:61; (ii) the antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence set forth in SEQ ID NO:30 and the light chain comprises the amino acid sequence set forth in SEQ ID NO:31; (iii) the VH domain comprises the amino acid sequence set forth in SEQ ID NO:63 and the VL domain comprises the amino acid sequence set forth in SEQ ID NO:61; or (iv) the antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence set forth in SEQ ID NO: 33 and the light chain comprises the amino acid sequence set forth in SEQ ID NO: 31; 13. A pharmaceutical combination or medicament according to claim 12.

15. 15. The combination pharmaceutical of claim 1, the pharmaceutical of any one of claims 2 to 4, or the combination pharmaceutical or pharmaceutical of any one of claims 5 to 14, wherein the cancer is selected from bladder cancer, breast cancer, cervical cancer, colon cancer, rectal cancer, anal cancer, colorectal cancer, endometrial cancer, kidney cancer, oral cancer, head and neck cancer, liver cancer, melanoma, mesothelioma, non-small cell lung cancer, small cell lung cancer, non-melanoma skin cancer, ovarian cancer, pancreatic cancer, prostate cancer, sarcoma, thyroid cancer, renal cell carcinoma, and Merkel cell carcinoma.

16. A pharmaceutical combination for treating a cancer selected from bladder cancer, breast cancer, cervical cancer, colon cancer, rectal cancer, anal cancer, colorectal cancer, endometrial cancer, renal cancer, oral cancer, head and neck cancer, liver cancer, melanoma, mesothelioma, non-small cell lung cancer, small cell lung cancer, non-melanoma skin cancer, ovarian cancer, pancreatic cancer, prostate cancer, sarcoma, thyroid cancer, and Merkel cell carcinoma in a subject, comprising an inhibitor of A2A / A2B, an inhibitor of PD-1 / PD-L1, and an antibody that binds to human CD73, To the subject, (i) an inhibitor of A2A / A2B; (ii) the PD-1 / PD-L1 inhibitor, which is an antibody or an antigen-binding fragment thereof that binds to human PD-1, the antibody or antigen-binding fragment thereof Variable heavy (VH) complementarity determining region (CDR) 1 comprising the amino acid sequence SYWMN (SEQ ID NO: 6), VH CDR2 comprising the amino acid sequence VIHPSDSETWLDQKFKD (SEQ ID NO:7), and VH CDR3 comprising the amino acid sequence EHYGTSPFAY (SEQ ID NO:8) and The antibody, Variable light (VL) CDR1 comprising the amino acid sequence RASESVDNYGMSFMNW (SEQ ID NO:9), a VL CDR2 comprising the amino acid sequence AASNQGS (SEQ ID NO: 10); and VL CDR3 comprising the amino acid sequence QQSKEVPYT (SEQ ID NO:11) A VL domain comprising said PD-1 / PD-L1 inhibitor; and (iii) the antibody that binds to human CD73, (a) Variable heavy (VH) complementarity determining region (CDR) 1 comprising the amino acid sequence GYTFTSYG (SEQ ID NO: 16), VH CDR2 comprising the amino acid sequence IYPGSGNT (SEQ ID NO: 17), and VH CDR3 comprising the amino acid sequence ARYDYLGSSYGFDY (SEQ ID NO: 18) and a VH domain comprising Variable light (VL) CDR1 comprising the amino acid sequence QDVSTA (SEQ ID NO: 19), VL CDR2 comprising the amino acid sequence SAS (SEQ ID NO:20), and VL CDR3 comprising the amino acid sequence QQHYNTPYT (SEQ ID NO:21) and a VL domain comprising Contains or (b) binds to human CD73 at an epitope within amino acids 40-53 of SEQ ID NO:70; (c) binds to human CD73 and competes for binding to human CD73 with an antibody having a heavy chain comprising the amino acid sequence of SEQ ID NO:24 and a light chain comprising the amino acid sequence of SEQ ID NO:25; (d) VH CDR1 comprising the amino acid sequence GFTFSSYD (SEQ ID NO:34), a VH CDR2 comprising the amino acid sequence MSYDGSNK (SEQ ID NO: 35) or MSYEGSNK (SEQ ID NO: 40); and VH CDR3 comprising the amino acid sequence ATEIAAKGDY (SEQ ID NO:36) and a VH domain comprising VL CDR1 comprising the amino acid sequence QGISNY (SEQ ID NO:37), VL CDR2 comprising the amino acid sequence AAS (SEQ ID NO:38), and VL CDR3 comprising the amino acid sequence QQSYSTPH (SEQ ID NO:39) and a VL domain comprising Contains or (e) binds to human CD73 at an epitope within amino acids 386-399 and 470-489 of SEQ ID NO: 70; (f) binds to human CD73 and competes for binding to human CD73 with an antibody having a heavy chain comprising the amino acid sequence of SEQ ID NO:30 and a light chain comprising the amino acid sequence of SEQ ID NO:31; or (g) binds to human CD73 and competes for binding to human CD73 with an antibody having a heavy chain comprising the amino acid sequence of SEQ ID NO: 33 and a light chain comprising the amino acid sequence of SEQ ID NO: 31; The antibody that binds to human CD73 are administered simultaneously or sequentially.

17. A pharmaceutical agent for treating a cancer selected from bladder cancer, breast cancer, cervical cancer, colon cancer, rectal cancer, anal cancer, colorectal cancer, endometrial cancer, renal cancer, oral cancer, head and neck cancer, liver cancer, melanoma, mesothelioma, non-small cell lung cancer, small cell lung cancer, non-melanoma skin cancer, ovarian cancer, pancreatic cancer, prostate cancer, sarcoma, thyroid cancer, and Merkel cell carcinoma in a subject, comprising an inhibitor of A2A / A2B, To the subject, (i) an inhibitor of PD-1 / PD-L1 that is an antibody or antigen-binding fragment thereof that binds to human PD-1, the antibody or antigen-binding fragment thereof Variable heavy (VH) complementarity determining region (CDR) 1 comprising the amino acid sequence SYWMN (SEQ ID NO: 6), VH CDR2 comprising the amino acid sequence VIHPSDSETWLDQKFKD (SEQ ID NO:7), and VH CDR3 comprising the amino acid sequence EHYGTSPFAY (SEQ ID NO:8) and The antibody, Variable light (VL) CDR1 comprising the amino acid sequence RASESVDNYGMSFMNW (SEQ ID NO:9), a VL CDR2 comprising the amino acid sequence AASNQGS (SEQ ID NO: 10); and VL CDR3 comprising the amino acid sequence QQSKEVPYT (SEQ ID NO:11) A VL domain comprising said PD-1 / PD-L1 inhibitor; and (ii) an antibody that binds to human CD73, wherein the antibody that binds to human CD73 is (a) Variable heavy (VH) complementarity determining region (CDR) 1 comprising the amino acid sequence GYTFTSYG (SEQ ID NO: 16), VH CDR2 comprising the amino acid sequence IYPGSGNT (SEQ ID NO: 17), and VH CDR3 comprising the amino acid sequence ARYDYLGSSYGFDY (SEQ ID NO: 18) and a VH domain comprising Variable light (VL) CDR1 comprising the amino acid sequence QDVSTA (SEQ ID NO: 19), VL CDR2 comprising the amino acid sequence SAS (SEQ ID NO:20), and VL CDR3 comprising the amino acid sequence QQHYNTPYT (SEQ ID NO:21) and a VL domain comprising Contains or (b) binds to human CD73 at an epitope within amino acids 40-53 of SEQ ID NO:70; (c) binds to human CD73 and competes for binding to human CD73 with an antibody having a heavy chain comprising the amino acid sequence of SEQ ID NO:24 and a light chain comprising the amino acid sequence of SEQ ID NO:25; (d) VH CDR1 comprising the amino acid sequence GFTFSSYD (SEQ ID NO:34), a VH CDR2 comprising the amino acid sequence MSYDGSNK (SEQ ID NO: 35) or MSYEGSNK (SEQ ID NO: 40); and VH CDR3 comprising the amino acid sequence ATEIAAKGDY (SEQ ID NO:36) and a VH domain comprising VL CDR1 comprising the amino acid sequence QGISNY (SEQ ID NO:37), VL CDR2 comprising the amino acid sequence AAS (SEQ ID NO:38), and VL CDR3 comprising the amino acid sequence QQSYSTPH (SEQ ID NO:39) and a VL domain comprising Contains or (e) binds to human CD73 at an epitope within amino acids 386-399 and 470-489 of SEQ ID NO: 70; (f) binds to human CD73 and competes for binding to human CD73 with an antibody having a heavy chain comprising the amino acid sequence of SEQ ID NO:30 and a light chain comprising the amino acid sequence of SEQ ID NO:31; or (g) binds to human CD73 and competes for binding to human CD73 with an antibody having a heavy chain comprising the amino acid sequence of SEQ ID NO: 33 and a light chain comprising the amino acid sequence of SEQ ID NO: 31; The antibody that binds to human CD73 The said medicament administered in combination with.

18. A pharmaceutical agent for treating a cancer selected from bladder cancer, breast cancer, cervical cancer, colon cancer, rectal cancer, anal cancer, colorectal cancer, endometrial cancer, renal cancer, oral cancer, head and neck cancer, liver cancer, melanoma, mesothelioma, non-small cell lung cancer, small cell lung cancer, non-melanoma skin cancer, ovarian cancer, pancreatic cancer, prostate cancer, sarcoma, thyroid cancer, and Merkel cell carcinoma in a subject, comprising an inhibitor of PD-1 / PD-L1, To the subject, (i) an inhibitor of A2A / A2B; and (ii) an antibody that binds to human CD73, wherein the antibody that binds to human CD73 is (a) Variable heavy (VH) complementarity determining region (CDR) 1 comprising the amino acid sequence GYTFTSYG (SEQ ID NO: 16), VH CDR2 comprising the amino acid sequence IYPGSGNT (SEQ ID NO: 17), and VH CDR3 comprising the amino acid sequence ARYDYLGSSYGFDY (SEQ ID NO: 18) and a VH domain comprising Variable light (VL) CDR1 comprising the amino acid sequence QDVSTA (SEQ ID NO: 19), VL CDR2 comprising the amino acid sequence SAS (SEQ ID NO:20), and VL CDR3 comprising the amino acid sequence QQHYNTPYT (SEQ ID NO:21) and a VL domain comprising Contains or (b) binds to human CD73 at an epitope within amino acids 40-53 of SEQ ID NO:70; (c) binds to human CD73 and competes for binding to human CD73 with an antibody having a heavy chain comprising the amino acid sequence of SEQ ID NO:24 and a light chain comprising the amino acid sequence of SEQ ID NO:25; (d) VH CDR1 comprising the amino acid sequence GFTFSSYD (SEQ ID NO:34), a VH CDR2 comprising the amino acid sequence MSYDGSNK (SEQ ID NO: 35) or MSYEGSNK (SEQ ID NO: 40); and VH CDR3 comprising the amino acid sequence ATEIAAKGDY (SEQ ID NO:36) and a VH domain comprising VL CDR1 comprising the amino acid sequence QGISNY (SEQ ID NO:37), VL CDR2 comprising the amino acid sequence AAS (SEQ ID NO:38), and VL CDR3 comprising the amino acid sequence QQSYSTPH (SEQ ID NO:39) and a VL domain comprising Contains or (e) binds to human CD73 at an epitope within amino acids 386-399 and 470-489 of SEQ ID NO: 70; (f) binds to human CD73 and competes for binding to human CD73 with an antibody having a heavy chain comprising the amino acid sequence of SEQ ID NO:30 and a light chain comprising the amino acid sequence of SEQ ID NO:31; or (g) binds to human CD73 and competes for binding to human CD73 with an antibody having a heavy chain comprising the amino acid sequence of SEQ ID NO: 33 and a light chain comprising the amino acid sequence of SEQ ID NO: 31; The antibody that binds to human CD73 The said medicament administered in combination with.

19. A pharmaceutical agent for treating a cancer selected from bladder cancer, breast cancer, cervical cancer, colon cancer, rectal cancer, anal cancer, colorectal cancer, endometrial cancer, renal cancer, oral cancer, head and neck cancer, liver cancer, melanoma, mesothelioma, non-small cell lung cancer, small cell lung cancer, non-melanoma skin cancer, ovarian cancer, pancreatic cancer, prostate cancer, sarcoma, thyroid cancer, and Merkel cell carcinoma in a subject, comprising an antibody that binds to human CD73, To the subject, (i) an inhibitor of A2A / A2B; and (ii) An inhibitor of PD-1 / PD-L1 that is an antibody or antigen-binding fragment thereof that binds to human PD-1, the antibody or antigen-binding fragment thereof Variable heavy (VH) complementarity determining region (CDR) 1 comprising the amino acid sequence SYWMN (SEQ ID NO: 6), VH CDR2 comprising the amino acid sequence VIHPSDSETWLDQKFKD (SEQ ID NO:7), and VH CDR3 comprising the amino acid sequence EHYGTSPFAY (SEQ ID NO:8) and The antibody, Variable light (VL) CDR1 comprising the amino acid sequence RASESVDNYGMSFMNW (SEQ ID NO:9), a VL CDR2 comprising the amino acid sequence AASNQGS (SEQ ID NO: 10); and VL CDR3 comprising the amino acid sequence QQSKEVPYT (SEQ ID NO:11) A VL domain comprising The PD-1 / PD-L1 inhibitor The said medicament administered in combination with.

20. The antibody that binds to human CD73, Variable heavy (VH) complementarity determining region (CDR) 1 comprising the amino acid sequence GYTFTSYG (SEQ ID NO: 16), VH CDR2 comprising the amino acid sequence IYPGSGNT (SEQ ID NO: 17), and VH CDR3 comprising the amino acid sequence ARYDYLGSSYGFDY (SEQ ID NO: 18) and a VH domain comprising Variable light (VL) CDR1 comprising the amino acid sequence QDVSTA (SEQ ID NO: 19), VL CDR2 comprising the amino acid sequence SAS (SEQ ID NO:20), and VL CDR3 comprising the amino acid sequence QQHYNTPYT (SEQ ID NO:21) and a VL domain comprising Including, A combination pharmaceutical according to claim 16 or a pharmaceutical according to any one of claims 17 to 19.

21. (i) the VH domain comprises the amino acid sequence set forth in SEQ ID NO:22; (ii) the antibody comprises a heavy chain, and the heavy chain comprises the amino acid sequence set forth in SEQ ID NO:24; (iii) the anti-VL domain comprises the amino acid sequence set forth in SEQ ID NO:23; (iv) the antibody comprises a light chain, and the light chain comprises the amino acid sequence set forth in SEQ ID NO:25; (v) the VH domain is at least 80% identical to the amino acid sequence set forth in SEQ ID NO:22 and the VL domain is at least 80% identical to the amino acid sequence set forth in SEQ ID NO:23; (vi) the VH domain comprises the amino acid sequence set forth in SEQ ID NO: 22 and the VL domain comprises the amino acid sequence set forth in SEQ ID NO: 23; or (vii) the antibody comprises a heavy chain and a light chain, the heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 24 and the light chain comprising the amino acid sequence set forth in SEQ ID NO:

25.

21. The pharmaceutical combination or medicament of claim 20.

22. (i) the antibody that binds to human CD73 binds to an epitope within amino acids 40-53 of SEQ ID NO:70; (ii) the antibody binds to human CD73 and competes for binding to human CD73 with an antibody having a heavy chain comprising the amino acid sequence of SEQ ID NO:24 and a light chain comprising the amino acid sequence of SEQ ID NO:25; or (iii) the antibody that binds to human CD73, VH CDR1 comprising the amino acid sequence GFTFSSYD (SEQ ID NO:34), a VH CDR2 comprising the amino acid sequence MSYDGSNK (SEQ ID NO: 35) or MSYEGSNK (SEQ ID NO: 40); and VH CDR3 comprising the amino acid sequence ATEIAAKGDY (SEQ ID NO:36) and a VH domain comprising VL CDR1 comprising the amino acid sequence QGISNY (SEQ ID NO:37), VL CDR2 comprising the amino acid sequence AAS (SEQ ID NO:38), and VL CDR3 comprising the amino acid sequence QQSYSTPH (SEQ ID NO:39) and a VL domain comprising Including, The combination pharmaceutical according to claim 16 or the pharmaceutical according to any one of claims 17 to 19.

23. The VH CDR1 comprises the amino acid sequence GFTFSSYD (SEQ ID NO:34), the VH CDR2 comprises the amino acid sequence MSYDGSNK (SEQ ID NO:35); the VH CDR3 comprises the amino acid sequence ATEIAAKGDY (SEQ ID NO:36); the VL CDR1 comprises the amino acid sequence QGISNY (SEQ ID NO:37); the VL CDR2 comprises the amino acid sequence AAS (SEQ ID NO:38); and the VL CDR3 comprises the amino acid sequence QQSYSTPH (SEQ ID NO:39); (i) the VH domain may comprise the amino acid sequence set forth in SEQ ID NO:62; (ii) the antibody comprises a heavy chain, and the heavy chain may comprise the amino acid sequence set forth in SEQ ID NO:30; (iii) the VL domain may comprise the amino acid sequence set forth in SEQ ID NO:61; (iv) the antibody comprises a light chain, and optionally the light chain comprises the amino acid sequence set forth in SEQ ID NO:31; (v) the VH domain may be at least 80% identical to the amino acid sequence set forth in SEQ ID NO:62 and the VL domain may be at least 80% identical to the amino acid sequence set forth in SEQ ID NO:61; (vi) the VH domain comprises the amino acid sequence set forth in SEQ ID NO: 62 and the VL domain comprises the amino acid sequence set forth in SEQ ID NO: 61; or (vii) the antibody comprises a heavy chain and a light chain, the heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 30, and the light chain comprising the amino acid sequence set forth in SEQ ID NO: 31; 23. The pharmaceutical combination or medicament of claim 22.

24. The VH CDR1 comprises the amino acid sequence GFTFSSYD (SEQ ID NO:34), the VH CDR2 comprises the amino acid sequence MSYEGSNK (SEQ ID NO:40); the VH CDR3 comprises the amino acid sequence ATEIAAKGDY (SEQ ID NO:36); the VL CDR1 comprises the amino acid sequence QGISNY (SEQ ID NO:37); the VL CDR2 comprises the amino acid sequence AAS (SEQ ID NO:38); and the VL CDR3 comprises the amino acid sequence QQSYSTPH (SEQ ID NO:39); (i) the VH domain may comprise the amino acid sequence set forth in SEQ ID NO:63; (ii) the antibody comprises a heavy chain, and the heavy chain may comprise the amino acid sequence set forth in SEQ ID NO:33; (iii) the VL domain may comprise the amino acid sequence set forth in SEQ ID NO:61; (iv) the antibody comprises a light chain, and optionally the light chain comprises the amino acid sequence set forth in SEQ ID NO:31; (v) the VH domain may be at least 80% identical to the amino acid sequence set forth in SEQ ID NO:63 and the VL domain may be at least 80% identical to the amino acid sequence set forth in SEQ ID NO:61; (vi) the VH domain comprises the amino acid sequence set forth in SEQ ID NO: 63 and the VL domain comprises the amino acid sequence set forth in SEQ ID NO: 61; or (vii) the antibody comprises a heavy chain and a light chain, the heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 33, and the light chain comprising the amino acid sequence set forth in SEQ ID NO: 31; 23. The pharmaceutical combination or medicament of claim 22.

25. (i) the antibody that binds to human CD73 binds to an epitope within amino acids 386-399 and 470-489 of SEQ ID NO:70; (ii) the antibody binds to human CD73 and competes for binding to human CD73 with an antibody having a heavy chain comprising the amino acid sequence of SEQ ID NO:30 and a light chain comprising the amino acid sequence of SEQ ID NO:31; or (iii) The combination pharmaceutical of claim 16 or the pharmaceutical of any one of claims 17 to 19, wherein the antibody binds to human CD73 and competes for binding to human CD73 with an antibody having a heavy chain comprising the amino acid sequence of SEQ ID NO: 33 and a light chain comprising the amino acid sequence of SEQ ID NO:

31.

26. (i) the A2A / A2B inhibitor is 3-(5-amino-2-(pyridin-2-ylmethyl)-8-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-2-((2,6-difluorophenyl)(hydroxy)methyl)-8-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-2-((5-(pyridin-2-yl)-2H-tetrazol-2-yl)methyl)-8-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-2-((5-(pyridin-2-yl)-1H-tetrazol-1-yl)methyl)-8-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-2-((3-methylpyridin-2-yl)methoxy)-8-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(2-((5-(1H-pyrazol-1-yl)-2H-tetrazol-2-yl)methyl)-5-amino-8-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(2-((5-(1H-pyrazol-1-yl)-1H-tetrazol-1-yl)methyl)-5-amino-8-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-2-(hydroxy(phenyl)methyl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile 3-(5-amino-2-((2,6-difluorophenyl)(hydroxy)methyl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)-2-fluorobenzonitrile; 5-Amino-7-(3-cyano-2-fluorophenyl)-2-((2,6-difluorophenyl)(hydroxy)methyl)-[1,2,4]triazolo[1,5-c]pyrimidine-8-carbonitrile 3-(5-amino-2-((2-fluoro-6-(((1-methyl-2-oxopyrrolidin-3-yl)amino)methyl)phenyl)(hydroxy)methyl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)-2-fluorobenzonitrile 3-(8-amino-5-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-2-(pyridin-2-ylmethyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile; 3-(8-amino-2-((2,6-difluorophenyl)(hydroxy)methyl)-5-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile; 3-(8-amino-2-(amino(2,6-difluorophenyl)methyl)-5-(4-methyloxazol-5-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile 3-(8-amino-2-((2,6-difluorophenyl)(hydroxy)methyl)-5-(2,6-dimethylpyridin-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile; 3-(4-amino-2-(pyridin-2-ylmethyl)-7-(pyrimidin-4-yl)-2H-[1,2,3]triazolo[4,5-c]pyridin-6-yl)benzonitrile; 3-(4-amino-2-((3-fluoropyridin-2-yl)methyl)-7-(pyrimidin-4-yl)-2H-[1,2,3]triazolo[4,5-c]pyridin-6-yl)benzonitrile; 3-(4-amino-2-((3-fluoropyridin-2-yl)methyl)-7-(pyridin-4-yl)-2H-[1,2,3]triazolo[4,5-c]pyridin-6-yl)benzonitrile; and 3-(4-amino-7-(1-methyl-1H-pyrazol-5-yl)-2-(pyridin-2-ylmethyl)-2H-[1,2,3]triazolo[4,5-c]pyridin-6-yl)-2-fluorobenzonitrile; and a pharma- ceutically acceptable salt of any of the foregoing; or (ii) the A2A / A2B inhibitor is 7-(5-methylfuran-2-yl)-3-[[6-[[(3S)-oxolan-3-yl]oxymethyl]pyridin-2-yl]methyl]triazolo[4,5-d]pyrimidin-5-amine; 3-(5-amino-2-((5-(pyridin-2-yl)-2H-tetrazol-2-yl)methyl)-8-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-[2-amino-6-[1-[[6-(2-hydroxypropan-2-yl)pyridin-2-yl]methyl]triazol-4-yl]pyrimidin-4-yl]-2-methylbenzonitrile; 6-(2-chloro-6-methylpyridin-4-yl)-5-(4-fluorophenyl)-1,2,4-triazin-3-amine; and 5-bromo-2,6-di(1H-pyrazol-1-yl)pyrimidin-4-amine; and pharma- ceutically acceptable salts of any of the foregoing. Selected from: A pharmaceutical combination according to claim 16, a pharmaceutical according to any one of claims 17 to 19, or a pharmaceutical combination or pharmaceutical according to any one of claims 20 to 25.

27. The A2A / A2B inhibitor comprising: (i) 3-(8-amino-5-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-2-(pyridin-2-ylmethyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile, or a pharma- ceutically acceptable salt thereof; or (ii) 3-(5-amino-2-((5-(pyridin-2-yl)-2H-tetrazol-2-yl)methyl)-8-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile, or a pharma- ceutically acceptable salt thereof. A pharmaceutical combination according to claim 1 or 16, a pharmaceutical according to any one of claims 2 to 4 and 17 to 19, or a pharmaceutical combination or pharmaceutical according to any one of claims 20 to 25.

28. (i) the cancer is selected from melanoma, endometrial cancer, lung cancer, kidney cancer, bladder cancer, breast cancer, pancreatic cancer, colon cancer, head and neck cancer, colorectal cancer, ovarian cancer, liver cancer, and renal cell carcinoma; (ii) the cancer is melanoma; or (iii) the cancer is breast cancer; A pharmaceutical combination according to claim 1 or 16, a pharmaceutical according to any one of claims 2 to 4 and 17 to 19, or a pharmaceutical combination or pharmaceutical according to any one of claims 5 to 15 and 20 to 27.

29. A pharmaceutical combination for treating breast cancer in a subject, comprising an inhibitor of A2A / A2B, an inhibitor of PD-1 / PD-L1, and an antibody that binds to human CD73, To the subject, (i) the A2A / A2B inhibitor which is 3-(8-amino-5-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-2-(pyridin-2-ylmethyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile or a pharma- ceutically acceptable salt thereof; (ii) the PD-1 / PD-L1 inhibitor, which is an antibody or an antigen-binding fragment thereof that binds to human PD-1, the antibody or antigen-binding fragment thereof Variable heavy (VH) complementarity determining region (CDR) 1 comprising the amino acid sequence SYWMN (SEQ ID NO: 6), VH CDR2 comprising the amino acid sequence VIHPSDSETWLDQKFKD (SEQ ID NO:7), and VH CDR3 comprising the amino acid sequence EHYGTSPFAY (SEQ ID NO:8) and The antibody, Variable light (VL) CDR1 comprising the amino acid sequence RASESVDNYGMSFMNW (SEQ ID NO:9), a VL CDR2 comprising the amino acid sequence AASNQGS (SEQ ID NO: 10); and VL CDR3 comprising the amino acid sequence QQSKEVPYT (SEQ ID NO:11) A VL domain comprising said PD-1 / PD-L1 inhibitor; and (iii) the antibody that binds to human CD73, (a) Variable heavy (VH) complementarity determining region (CDR) 1 comprising the amino acid sequence GYTFTSYG (SEQ ID NO: 16), VH CDR2 comprising the amino acid sequence IYPGSGNT (SEQ ID NO: 17), and VH CDR3 comprising the amino acid sequence ARYDYLGSSYGFDY (SEQ ID NO: 18) and a VH domain comprising Variable light (VL) CDR1 comprising the amino acid sequence QDVSTA (SEQ ID NO: 19), VL CDR2 comprising the amino acid sequence SAS (SEQ ID NO:20), and VL CDR3 comprising the amino acid sequence QQHYNTPYT (SEQ ID NO:21) and a VL domain comprising Contains or (b) binds to human CD73 at an epitope within amino acids 40-53 of SEQ ID NO:70; (c) binds to human CD73 and competes for binding to human CD73 with an antibody having a heavy chain comprising the amino acid sequence of SEQ ID NO:24 and a light chain comprising the amino acid sequence of SEQ ID NO:25; (d) VH CDR1 comprising the amino acid sequence GFTFSSYD (SEQ ID NO:34), a VH CDR2 comprising the amino acid sequence MSYDGSNK (SEQ ID NO: 35) or MSYEGSNK (SEQ ID NO: 40); and VH CDR3 comprising the amino acid sequence ATEIAAKGDY (SEQ ID NO:36) and a VH domain comprising VL CDR1 comprising the amino acid sequence QGISNY (SEQ ID NO:37), VL CDR2 comprising the amino acid sequence AAS (SEQ ID NO:38), and VL CDR3 comprising the amino acid sequence QQSYSTPH (SEQ ID NO:39) and a VL domain comprising Contains or (e) binds to human CD73 at an epitope within amino acids 386-399 and 470-489 of SEQ ID NO: 70; (f) binds to human CD73 and competes for binding to human CD73 with an antibody having a heavy chain comprising the amino acid sequence of SEQ ID NO:30 and a light chain comprising the amino acid sequence of SEQ ID NO:31; or (g) binds to human CD73 and competes for binding to human CD73 with an antibody having a heavy chain comprising the amino acid sequence of SEQ ID NO: 33 and a light chain comprising the amino acid sequence of SEQ ID NO: 31; The antibody that binds to human CD73 are administered simultaneously or sequentially.

30. A medicament for treating breast cancer in a subject, comprising an inhibitor of A2A / A2B, which is 3-(8-amino-5-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-2-(pyridin-2-ylmethyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile or a pharma- ceutically acceptable salt thereof, To the subject, (i) an inhibitor of PD-1 / PD-L1 that is an antibody or antigen-binding fragment thereof that binds to human PD-1, the antibody or antigen-binding fragment thereof Variable heavy (VH) complementarity determining region (CDR) 1 comprising the amino acid sequence SYWMN (SEQ ID NO: 6), VH CDR2 comprising the amino acid sequence VIHPSDSETWLDQKFKD (SEQ ID NO:7), and VH CDR3 comprising the amino acid sequence EHYGTSPFAY (SEQ ID NO:8) and The antibody, Variable light (VL) CDR1 comprising the amino acid sequence RASESVDNYGMSFMNW (SEQ ID NO:9), a VL CDR2 comprising the amino acid sequence AASNQGS (SEQ ID NO: 10); and VL CDR3 comprising the amino acid sequence QQSKEVPYT (SEQ ID NO:11) A VL domain comprising said PD-1 / PD-L1 inhibitor; and (ii) the antibody that binds to human CD73, (a) Variable heavy (VH) complementarity determining region (CDR) 1 comprising the amino acid sequence GYTFTSYG (SEQ ID NO: 16), VH CDR2 comprising the amino acid sequence IYPGSGNT (SEQ ID NO: 17), and VH CDR3 comprising the amino acid sequence ARYDYLGSSYGFDY (SEQ ID NO: 18) and a VH domain comprising Variable light (VL) CDR1 comprising the amino acid sequence QDVSTA (SEQ ID NO: 19), VL CDR2 comprising the amino acid sequence SAS (SEQ ID NO:20), and VL CDR3 comprising the amino acid sequence QQHYNTPYT (SEQ ID NO:21) and a VL domain comprising Contains or (b) binds to human CD73 at an epitope within amino acids 40-53 of SEQ ID NO:70; (c) binds to human CD73 and competes for binding to human CD73 with an antibody having a heavy chain comprising the amino acid sequence of SEQ ID NO:24 and a light chain comprising the amino acid sequence of SEQ ID NO:25; (d) VH CDR1 comprising the amino acid sequence GFTFSSYD (SEQ ID NO:34), a VH CDR2 comprising the amino acid sequence MSYDGSNK (SEQ ID NO: 35) or MSYEGSNK (SEQ ID NO: 40); and VH CDR3 comprising the amino acid sequence ATEIAAKGDY (SEQ ID NO:36) and a VH domain comprising VL CDR1 comprising the amino acid sequence QGISNY (SEQ ID NO:37), VL CDR2 comprising the amino acid sequence AAS (SEQ ID NO:38), and VL CDR3 comprising the amino acid sequence QQSYSTPH (SEQ ID NO:39) and a VL domain comprising Contains or (e) binds to human CD73 at an epitope within amino acids 386-399 and 470-489 of SEQ ID NO: 70; (f) binds to human CD73 and competes for binding to human CD73 with an antibody having a heavy chain comprising the amino acid sequence of SEQ ID NO:30 and a light chain comprising the amino acid sequence of SEQ ID NO:31; or (g) binds to human CD73 and competes for binding to human CD73 with an antibody having a heavy chain comprising the amino acid sequence of SEQ ID NO: 33 and a light chain comprising the amino acid sequence of SEQ ID NO: 31; The antibody that binds to human CD73 The said medicament administered in combination with.

31. A PD-1 / PD-L1 inhibitor which is an antibody or antigen-binding fragment thereof that binds to human PD-1, the antibody or antigen-binding fragment thereof Variable heavy (VH) complementarity determining region (CDR) 1 comprising the amino acid sequence SYWMN (SEQ ID NO: 6), VH CDR2 comprising the amino acid sequence VIHPSDSETWLDQKFKD (SEQ ID NO:7), and VH CDR3 comprising the amino acid sequence EHYGTSPFAY (SEQ ID NO:8) and The antibody, Variable light (VL) CDR1 comprising the amino acid sequence RASESVDNYGMSFMNW (SEQ ID NO:9), a VL CDR2 comprising the amino acid sequence AASNQGS (SEQ ID NO: 10); and VL CDR3 comprising the amino acid sequence QQSKEVPYT (SEQ ID NO:11) A VL domain comprising A medicament for treating breast cancer in a subject, comprising the PD-1 / PD-L1 inhibitor, To the subject, (i) an inhibitor of A2A / A2B which is 3-(8-amino-5-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-2-(pyridin-2-ylmethyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile, or a pharma- ceutically acceptable salt thereof; and (ii) an antibody that binds to human CD73, wherein the antibody that binds to human CD73 is (a) Variable heavy (VH) complementarity determining region (CDR) 1 comprising the amino acid sequence GYTFTSYG (SEQ ID NO: 16), VH CDR2 comprising the amino acid sequence IYPGSGNT (SEQ ID NO: 17), and VH CDR3 comprising the amino acid sequence ARYDYLGSSYGFDY (SEQ ID NO: 18) and a VH domain comprising Variable light (VL) CDR1 comprising the amino acid sequence QDVSTA (SEQ ID NO: 19), VL CDR2 comprising the amino acid sequence SAS (SEQ ID NO:20), and VL CDR3 comprising the amino acid sequence QQHYNTPYT (SEQ ID NO:21) and a VL domain comprising Contains or (b) binds to human CD73 at an epitope within amino acids 40-53 of SEQ ID NO:70; (c) binds to human CD73 and competes for binding to human CD73 with an antibody having a heavy chain comprising the amino acid sequence of SEQ ID NO:24 and a light chain comprising the amino acid sequence of SEQ ID NO:25; (d) VH CDR1 comprising the amino acid sequence GFTFSSYD (SEQ ID NO:34), a VH CDR2 comprising the amino acid sequence MSYDGSNK (SEQ ID NO: 35) or MSYEGSNK (SEQ ID NO: 40); and VH CDR3 comprising the amino acid sequence ATEIAAKGDY (SEQ ID NO:36) and a VH domain comprising VL CDR1 comprising the amino acid sequence QGISNY (SEQ ID NO:37), VL CDR2 comprising the amino acid sequence AAS (SEQ ID NO:38), and VL CDR3 comprising the amino acid sequence QQSYSTPH (SEQ ID NO:39) and a VL domain comprising Contains or (e) binds to human CD73 at an epitope within amino acids 386-399 and 470-489 of SEQ ID NO: 70; (f) binds to human CD73 and competes for binding to human CD73 with an antibody having a heavy chain comprising the amino acid sequence of SEQ ID NO:30 and a light chain comprising the amino acid sequence of SEQ ID NO:31; or (g) binds to human CD73 and competes for binding to human CD73 with an antibody having a heavy chain comprising the amino acid sequence of SEQ ID NO: 33 and a light chain comprising the amino acid sequence of SEQ ID NO: 31; The antibody that binds to human CD73 The said medicament administered in combination with.

32. The antibody that binds to human CD73, wherein the antibody that binds to human CD73 comprises: (a) Variable heavy (VH) complementarity determining region (CDR) 1 comprising the amino acid sequence GYTFTSYG (SEQ ID NO: 16), VH CDR2 comprising the amino acid sequence IYPGSGNT (SEQ ID NO: 17), and VH CDR3 comprising the amino acid sequence ARYDYLGSSYGFDY (SEQ ID NO: 18) and a VH domain comprising Variable light (VL) CDR1 comprising the amino acid sequence QDVSTA (SEQ ID NO: 19), VL CDR2 comprising the amino acid sequence SAS (SEQ ID NO:20), and VL CDR3 comprising the amino acid sequence QQHYNTPYT (SEQ ID NO:21) and a VL domain comprising Contains or (b) binds to human CD73 at an epitope within amino acids 40-53 of SEQ ID NO:70; (c) binds to human CD73 and competes for binding to human CD73 with an antibody having a heavy chain comprising the amino acid sequence of SEQ ID NO:24 and a light chain comprising the amino acid sequence of SEQ ID NO:25; (d) VH CDR1 comprising the amino acid sequence GFTFSSYD (SEQ ID NO:34), a VH CDR2 comprising the amino acid sequence MSYDGSNK (SEQ ID NO: 35) or MSYEGSNK (SEQ ID NO: 40); and VH CDR3 comprising the amino acid sequence ATEIAAKGDY (SEQ ID NO:36) and a VH domain comprising VL CDR1 comprising the amino acid sequence QGISNY (SEQ ID NO:37), VL CDR2 comprising the amino acid sequence AAS (SEQ ID NO:38), and VL CDR3 comprising the amino acid sequence QQSYSTPH (SEQ ID NO:39) and a VL domain comprising Contains or (e) binds to human CD73 at an epitope within amino acids 386-399 and 470-489 of SEQ ID NO: 70; (f) binds to human CD73 and competes for binding to human CD73 with an antibody having a heavy chain comprising the amino acid sequence of SEQ ID NO:30 and a light chain comprising the amino acid sequence of SEQ ID NO:31; or (g) binds to human CD73 and competes for binding to human CD73 with an antibody having a heavy chain comprising the amino acid sequence of SEQ ID NO: 33 and a light chain comprising the amino acid sequence of SEQ ID NO: 31; A medicament for treating breast cancer in a subject, comprising the antibody that binds to human CD73, To the subject, (i) an inhibitor of A2A / A2B which is 3-(8-amino-5-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-2-(pyridin-2-ylmethyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile or a pharma- ceutically acceptable salt thereof; and (ii) An inhibitor of PD-1 / PD-L1 that is an antibody or antigen-binding fragment thereof that binds to human PD-1, the antibody or antigen-binding fragment thereof Variable heavy (VH) complementarity determining region (CDR) 1 comprising the amino acid sequence SYWMN (SEQ ID NO: 6), VH CDR2 comprising the amino acid sequence VIHPSDSETWLDQKFKD (SEQ ID NO:7), and VH CDR3 comprising the amino acid sequence EHYGTSPFAY (SEQ ID NO:8) and The antibody, Variable light (VL) CDR1 comprising the amino acid sequence RASESVDNYGMSFMNW (SEQ ID NO:9), a VL CDR2 comprising the amino acid sequence AASNQGS (SEQ ID NO: 10); and VL CDR3 comprising the amino acid sequence QQSKEVPYT (SEQ ID NO:11) A VL domain comprising The PD-1 / PD-L1 inhibitor The said medicament administered in combination with.

33. A pharmaceutical combination for treating breast cancer in a subject, comprising an inhibitor of A2A / A2B, an inhibitor of PD-1 / PD-L1, and an antibody that binds to human CD73, To the subject, (i) the A2A / A2B inhibitor which is 3-(8-amino-5-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-2-(pyridin-2-ylmethyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile or a pharma- ceutically acceptable salt thereof; (ii) the PD-1 / PD-L1 inhibitor, which is (R)-1-((7-cyano-2-(3'-(3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-6-methyl-1,7-naphthyridin-8-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylic acid or a pharma- ceutically acceptable salt thereof; and (iii) the antibody that binds to human CD73, (a) Variable heavy (VH) complementarity determining region (CDR) 1 comprising the amino acid sequence GYTFTSYG (SEQ ID NO: 16), VH CDR2 comprising the amino acid sequence IYPGSGNT (SEQ ID NO: 17), and VH CDR3 comprising the amino acid sequence ARYDYLGSSYGFDY (SEQ ID NO: 18) and a VH domain comprising Variable light (VL) CDR1 comprising the amino acid sequence QDVSTA (SEQ ID NO: 19), VL CDR2 comprising the amino acid sequence SAS (SEQ ID NO:20), and VL CDR3 comprising the amino acid sequence QQHYNTPYT (SEQ ID NO:21) and a VL domain comprising Contains or (b) binds to human CD73 at an epitope within amino acids 40-53 of SEQ ID NO:70; (c) binds to human CD73 and competes for binding to human CD73 with an antibody having a heavy chain comprising the amino acid sequence of SEQ ID NO:24 and a light chain comprising the amino acid sequence of SEQ ID NO:25; (d) VH CDR1 comprising the amino acid sequence GFTFSSYD (SEQ ID NO:34), a VH CDR2 comprising the amino acid sequence MSYDGSNK (SEQ ID NO: 35) or MSYEGSNK (SEQ ID NO: 40); and VH CDR3 comprising the amino acid sequence ATEIAAKGDY (SEQ ID NO:36) and a VH domain comprising VL CDR1 comprising the amino acid sequence QGISNY (SEQ ID NO:37), VL CDR2 comprising the amino acid sequence AAS (SEQ ID NO:38), and VL CDR3 comprising the amino acid sequence QQSYSTPH (SEQ ID NO:39) and a VL domain comprising Contains or (e) binds to human CD73 at an epitope within amino acids 386-399 and 470-489 of SEQ ID NO: 70; (f) binds to human CD73 and competes for binding to human CD73 with an antibody having a heavy chain comprising the amino acid sequence of SEQ ID NO:30 and a light chain comprising the amino acid sequence of SEQ ID NO:31; or (g) binds to human CD73 and competes for binding to human CD73 with an antibody having a heavy chain comprising the amino acid sequence of SEQ ID NO: 33 and a light chain comprising the amino acid sequence of SEQ ID NO: 31; The antibody that binds to human CD73 are administered simultaneously or sequentially.

34. A medicament for treating breast cancer in a subject, comprising an inhibitor of A2A / A2B, which is 3-(8-amino-5-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-2-(pyridin-2-ylmethyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile or a pharma- ceutically acceptable salt thereof, To the subject, (i) an inhibitor of PD-1 / PD-L1 which is (R)-1-((7-cyano-2-(3'-(3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-6-methyl-1,7-naphthyridin-8-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylic acid or a pharma- ceutically acceptable salt thereof; and (ii) an antibody that binds to human CD73, wherein the antibody that binds to human CD73 is (a) Variable heavy (VH) complementarity determining region (CDR) 1 comprising the amino acid sequence GYTFTSYG (SEQ ID NO: 16), VH CDR2 comprising the amino acid sequence IYPGSGNT (SEQ ID NO: 17), and VH CDR3 comprising the amino acid sequence ARYDYLGSSYGFDY (SEQ ID NO: 18) and a VH domain comprising Variable light (VL) CDR1 comprising the amino acid sequence QDVSTA (SEQ ID NO: 19), VL CDR2 comprising the amino acid sequence SAS (SEQ ID NO:20), and VL CDR3 comprising the amino acid sequence QQHYNTPYT (SEQ ID NO:21) and a VL domain comprising Contains or (b) binds to human CD73 at an epitope within amino acids 40-53 of SEQ ID NO:70; (c) binds to human CD73 and competes for binding to human CD73 with an antibody having a heavy chain comprising the amino acid sequence of SEQ ID NO:24 and a light chain comprising the amino acid sequence of SEQ ID NO:25; (d) VH CDR1 comprising the amino acid sequence GFTFSSYD (SEQ ID NO:34), a VH CDR2 comprising the amino acid sequence MSYDGSNK (SEQ ID NO: 35) or MSYEGSNK (SEQ ID NO: 40); and VH CDR3 comprising the amino acid sequence ATEIAAKGDY (SEQ ID NO:36) and a VH domain comprising VL CDR1 comprising the amino acid sequence QGISNY (SEQ ID NO:37), VL CDR2 comprising the amino acid sequence AAS (SEQ ID NO:38), and VL CDR3 comprising the amino acid sequence QQSYSTPH (SEQ ID NO:39) and a VL domain comprising Contains or (e) binds to human CD73 at an epitope within amino acids 386-399 and 470-489 of SEQ ID NO: 70; (f) binds to human CD73 and competes for binding to human CD73 with an antibody having a heavy chain comprising the amino acid sequence of SEQ ID NO:30 and a light chain comprising the amino acid sequence of SEQ ID NO:31; or (g) binds to human CD73 and competes for binding to human CD73 with an antibody having a heavy chain comprising the amino acid sequence of SEQ ID NO: 33 and a light chain comprising the amino acid sequence of SEQ ID NO: 31; The antibody that binds to human CD73 The said medicament administered in combination with.

35. A pharmaceutical agent for treating breast cancer in a subject, comprising an inhibitor of PD-1 / PD-L1, which is (R)-1-((7-cyano-2-(3'-(3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-6-methyl-1,7-naphthyridin-8-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylic acid or a pharma- ceutically acceptable salt thereof, To the subject, (i) an inhibitor of A2A / A2B which is (3-(8-amino-5-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-2-(pyridin-2-ylmethyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile or a pharma- ceutically acceptable salt thereof; and (ii) an antibody that binds to human CD73, wherein the antibody that binds to human CD73 is (a) Variable heavy (VH) complementarity determining region (CDR) 1 comprising the amino acid sequence GYTFTSYG (SEQ ID NO: 16), VH CDR2 comprising the amino acid sequence IYPGSGNT (SEQ ID NO: 17), and VH CDR3 comprising the amino acid sequence ARYDYLGSSYGFDY (SEQ ID NO: 18) and a VH domain comprising Variable light (VL) CDR1 comprising the amino acid sequence QDVSTA (SEQ ID NO: 19), VL CDR2 comprising the amino acid sequence SAS (SEQ ID NO:20), and VL CDR3 comprising the amino acid sequence QQHYNTPYT (SEQ ID NO:21) and a VL domain comprising Contains or (b) binds to human CD73 at an epitope within amino acids 40-53 of SEQ ID NO:70; (c) binds to human CD73 and competes for binding to human CD73 with an antibody having a heavy chain comprising the amino acid sequence of SEQ ID NO:24 and a light chain comprising the amino acid sequence of SEQ ID NO:25; (d) VH CDR1 comprising the amino acid sequence GFTFSSYD (SEQ ID NO:34), a VH CDR2 comprising the amino acid sequence MSYDGSNK (SEQ ID NO: 35) or MSYEGSNK (SEQ ID NO: 40); and VH CDR3 comprising the amino acid sequence ATEIAAKGDY (SEQ ID NO:36) and a VH domain comprising VL CDR1 comprising the amino acid sequence QGISNY (SEQ ID NO:37), VL CDR2 comprising the amino acid sequence AAS (SEQ ID NO:38), and VL CDR3 comprising the amino acid sequence QQSYSTPH (SEQ ID NO:39) and a VL domain comprising Contains or (e) binds to human CD73 at an epitope within amino acids 386-399 and 470-489 of SEQ ID NO: 70; (f) binds to human CD73 and competes for binding to human CD73 with an antibody having a heavy chain comprising the amino acid sequence of SEQ ID NO:30 and a light chain comprising the amino acid sequence of SEQ ID NO:31; or (g) binds to human CD73 and competes for binding to human CD73 with an antibody having a heavy chain comprising the amino acid sequence of SEQ ID NO: 33 and a light chain comprising the amino acid sequence of SEQ ID NO: 31; The antibody that binds to human CD73 The said medicament administered in combination with.

36. An antibody that binds to human CD73, comprising: (a) Variable heavy (VH) complementarity determining region (CDR) 1 comprising the amino acid sequence GYTFTSYG (SEQ ID NO: 16), VH CDR2 comprising the amino acid sequence IYPGSGNT (SEQ ID NO: 17), and VH CDR3 comprising the amino acid sequence ARYDYLGSSYGFDY (SEQ ID NO: 18) and a VH domain comprising Variable light (VL) CDR1 comprising the amino acid sequence QDVSTA (SEQ ID NO: 19), VL CDR2 comprising the amino acid sequence SAS (SEQ ID NO:20), and VL CDR3 comprising the amino acid sequence QQHYNTPYT (SEQ ID NO:21) and a VL domain comprising Contains or (b) binds to human CD73 at an epitope within amino acids 40-53 of SEQ ID NO:70; (c) binds to human CD73 and competes for binding to human CD73 with an antibody having a heavy chain comprising the amino acid sequence of SEQ ID NO:24 and a light chain comprising the amino acid sequence of SEQ ID NO:25; (d) VH CDR1 comprising the amino acid sequence GFTFSSYD (SEQ ID NO:34), a VH CDR2 comprising the amino acid sequence MSYDGSNK (SEQ ID NO: 35) or MSYEGSNK (SEQ ID NO: 40); and VH CDR3 comprising the amino acid sequence ATEIAAKGDY (SEQ ID NO:36) and a VH domain comprising VL CDR1 comprising the amino acid sequence QGISNY (SEQ ID NO:37), VL CDR2 comprising the amino acid sequence AAS (SEQ ID NO:38), and VL CDR3 comprising the amino acid sequence QQSYSTPH (SEQ ID NO:39) and a VL domain comprising Contains or (e) binds to human CD73 at an epitope within amino acids 386-399 and 470-489 of SEQ ID NO: 70; (f) binds to human CD73 and competes for binding to human CD73 with an antibody having a heavy chain comprising the amino acid sequence of SEQ ID NO:30 and a light chain comprising the amino acid sequence of SEQ ID NO:31; or (g) binds to human CD73 and competes for binding to human CD73 with an antibody having a heavy chain comprising the amino acid sequence of SEQ ID NO: 33 and a light chain comprising the amino acid sequence of SEQ ID NO: 31; A medicament for treating breast cancer in a subject, comprising the antibody that binds to human CD73, To the subject, (i) an inhibitor of A2A / A2B which is 3-(8-amino-5-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-2-(pyridin-2-ylmethyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile or a pharma- ceutically acceptable salt thereof; and (ii) a PD-1 / PD-L1 inhibitor which is (R)-1-((7-cyano-2-(3'-(3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-6-methyl-1,7-naphthyridin-8-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylic acid or a pharma- ceutically acceptable salt thereof; The said medicament administered in combination with.

37. The combination pharmaceutical of claim 29 or 33, or the pharmaceutical of any one of claims 30 to 32 and 34 to 36, wherein the breast cancer is a breast adenocarcinoma tumor.

38. (i) the cancer has a high adenosine signature; (ii) the A2A / A2B inhibitor is administered to the subject at a dose of about 0.1 mg to about 1000 mg on a free base basis; (iii) the A2A / A2B inhibitor is administered to the subject once daily, every other day, or once weekly; (iv) the A2A / A2B inhibitor, the PD-1 / PD-L1 inhibitor, and the human CD73 inhibitor are administered simultaneously; and / or (v) The pharmaceutical combination of any one of claims 1, 16, 29 and 33, the pharmaceutical of any one of claims 2 to 4, 17 to 19, 30 to 32 and 34 to 36, or the pharmaceutical combination or pharmaceutical of any one of claims 5 to 15, 20 to 28 and 37, wherein the inhibitor of A2A / A2B, the inhibitor of PD-1 / PD-L1 and the inhibitor of human CD73 are administered sequentially.

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