RU2787157C2 - Compositions containing naphthyridine derivatives and aluminum-containing auxiliary agent, intended for use in treatment of solid tumors - Google Patents

Abstract

FIELD: pharmaceutics.

SUBSTANCE: invention relates to the field of pharmaceutics, namely to a pharmaceutical combination for the treatment of solid tumor, containing: a) effective amount of the first pharmaceutical compositions containing 3-(5-amino-2-(4-(2-(3,3-difluor-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridine-8-yl)propanoic acid or its pharmaceutically acceptable salt, aluminum-containing particles, a buffer agent, and one or several pharmaceutically acceptable auxiliary substances, where the buffer agent is tris-buffer; pharmaceutically acceptable auxiliary substance is mannitol; the composition has pH in the range from 6.5 to 9.0, and aluminum-containing particles are a suspension of aluminum hydroxide particles, and b) effective amount of the second pharmaceutical composition containing an antibody to PD-L1. The invention also relates to a pharmaceutical combination for the treatment of solid tumor, such as defined above, additionally containing c) effective amount of the third pharmaceutical composition containing an antibody to CTLA-4.

EFFECT: effective treatment of solid tumors.

7 cl, 10 dwg, 17 tbl, 15 ex

Description

SEQUENCE LIST

This application contains a sequence listing that has been filed electronically in ASCII format and is incorporated by reference in its entirety. The specified ASCII copy, created on May 17, 207, is named PAT057568-US-PSP_ST25.txt and is 73200 bytes in size.

FIELD OF TECHNOLOGY TO WHICH THE INVENTION RELATES

The present invention provides methods for treating tumors by intratumoral administration of TLR7 agonists and the use of such agonists for the treatment of tumors.

BACKGROUND OF THE INVENTION

Toll-like receptors (TLRs) are pattern recognition receptors that play an important role in innate immunity by recognizing invading microbial pathogens and initiating intracellular signaling pathways to initiate the expression of genes whose products can control innate immune responses. In particular, toll-like receptor (TLR) agonists activate innate immune cells through the TLR-MyD88-NFkβ and IRF3/7 pathways. TLR7, TLR8 and TLR9 belong to the TLR subfamily based on their genomic structure, sequence similarity and homology. TLR7, TLR8 and TLR9 are located in intracellular endolysosomal compartments and exhibit a unique cell type-specific expression pattern that is believed to be responsible for different pathogen response profiles.

Small molecule TLR7 and/or TLR8 agonists have been reported and demonstrated to activate innate immune responses by inducing the biosynthesis of selected cytokines, inducing co-stimulatory molecules, and by increasing the antigen presenting capacity of cells. Such compounds include imidazoquinoline amine derivatives (US Patent No. 4,689,338), imidazopyridine amine derivative (US Patent No. 5,446,153), imidazonaphthyridine derivative (US Patent No. 6,194,425), oxazoloquinoline amine derivatives (US Patent No. 6,110,929); thiazoloquinolineamine derivatives (US Patent No. 6110929), selenazoloquinolineamine derivatives (US Patent No. 6110929), pyrazolopyridine derivatives (US Patent No. 9145410) and benzonaphthyridineamine derivatives (US Patent Nos. 8466167 and 9045470).

The synthetic TLR7 agonist imiquimod (1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline-4-amine) is FDA approved for the topical treatment of cutaneous basal cell carcinoma, actinic keratosis, and genital warts with a cream formulation. and has limited activity against skin melanoma and breast tumors (J. Immunol. 2014, 193(9): 4722-4731). Systemic administration of imiquimod and structurally similar resiquimod is limited by cytokine-mediated side effects, including severe flu-like symptoms (Expert Opin. Emerging Drugs (2010), 15:544-555). Therefore, imiquimod is used exclusively for topical application and is not used to treat deep, non-cutaneous tumors such as melanoma or solid tumors.

A lipid-modified imidazoquinoline injectable (dual TLR7/8 agonist) has been described that forms a slow sustained release tissue depot that provides local TLR triggering activity without systemic release of cytokines (J. Immunol. 2014, 193(9): 4722 -4731). However, this compound has been shown to be ineffective against large tumors and, in addition, the serum concentration of this compound has decreased by about 50% within 24 hours after subcutaneous administration (Journal for ImmunoTherapy of Cancer, 2014, 2:12). Therefore, there remains a need for intratumoral administration of a sustained sustained release TLR7 agonist, which may aid in the treatment of large tumors.

BRIEF DESCRIPTION OF THE INVENTION

There remains a need for new treatments and therapies for solid tumors and hemoblastoses. The present invention provides pharmaceutical compositions and pharmaceutical combinations containing a TLR7 agonist and a suspension of particles containing aluminum. The present invention also provides pharmaceutical compositions and pharmaceutical combinations containing a TLR7 agonist and a suspension of particles containing aluminum, intended for use in the treatment of solid tumors or hemoblastoses. The present invention further provides methods for treating a solid tumor or hemoblastosis by administering to a subject in need thereof such pharmaceutical compositions or pharmaceutical combinations, and using such pharmaceutical compositions or pharmaceutical combinations in the treatment of a solid tumor or hematological malignancy.

The present invention provides the following aspects, advantageous features, and specific embodiments, respectively, individually or in combination, as indicated in the following paragraphs.

The present invention provides the following aspects, advantageous features, and specific embodiments, respectively, individually or in combination, as indicated in the following paragraphs.

Claim 1. A pharmaceutical composition containing a compound having the structure of formula (A) or a pharmaceutically acceptable salt thereof, aluminum particles, a buffer agent and one or more pharmaceutically acceptable excipients,

formula (A),

where

R ¹ is -L ₁ R ⁴ , -L ₁ R ⁵ , -OL ₁ R ⁴ , -OL ₁ R ⁵ , CH ₃ , -C(=O)P(O)(OH) ₂ or -C(= O)CF ₂ P(O)(OH) ₂ ;

R² represents -L₂R^four, -L₂R⁶, -L₂L₃L₂R⁶, -L₂L₃R^four, -L₂L₃L₂R^four, -OL₂R^four, -OR^four, -OL₂R⁶, -OL₂L₃R⁶, -OL₂L₃L₂R⁶, -OL₂L_3R ^four -OL₂L₃L₂R^four or -OCH₃;

each R ³ is independently selected from H and fluorine;

R ⁴ is -P(O)(OH) ₂ ,

R ⁵ is -CF ₂ P(O)(OH) ₂ or -C(O)OH;

R ⁶ is -CF ₂ P(O)(OH) ₂ or -C(O)OH;

L₁ represents C₁-C₆alkylene, C₂-C₆alkenylene or -((CR^fourR^four)_pO)_q(CH₂)_p-, where C₁-C₆alkylene and C₂-C₆alkenylene in L₁ substituted with 0-4 fluoro groups;

each L ₂ is independently selected from C ₁ -C ₆ alkylene and -((CR ³ R ³ ) _p O) _q (CH ₂ ) _p - wherein the C ₁ -C ₆ alkylene in L ₂ is substituted with 0-4 fluoro groups;

L ₃ is arylene or 5-6 membered heteroarylene;

each p is independently selected from 1, 2, 3, 4, 5, and 6, and

q is 1, 2, 3, or 4.

Item 2. The pharmaceutical composition according to item 1, where the composition contains a compound characterized by the structure of formula (A), or a pharmaceutically acceptable salt thereof, a buffer agent, a pharmaceutically acceptable excipient selected from mannitol and sucrose, where the composition has a pH in the range of 6 .5-9.0, and the aluminum-containing particles are a suspension of aluminum-containing particles.

Item 3. A pharmaceutical composition according to item 1 or item 2, where the composition contains a compound characterized by the structure of formula (A), or a pharmaceutically acceptable salt thereof, a buffer agent, mannitol, where the composition is characterized by a pH in the range of 6.5-9.0 , and the aluminum-containing particles are a suspension of aluminum-containing particles.

Item 4. A pharmaceutical composition according to any one of items 1-3, wherein the composition has a pH in the range of 7.0-8.0.

Item 5. A pharmaceutical composition according to any one of items 1-4, wherein the composition has a pH in the range of 7.2-7.8.

Item 6. The pharmaceutical composition according to any one of items 1 to 5, wherein the aluminum-containing particles are aluminum hydroxide particles, aluminum oxyhydroxide particles, or aluminum hydroxyphosphate particles, and the suspension of aluminum-containing particles is a suspension of aluminum hydroxide particles, aluminum oxyhydroxide particles, or aluminum hydroxyphosphate particles .

Item 7. The pharmaceutical composition according to any one of items 1 to 6, wherein the aluminum-containing particles are aluminum hydroxide particles and the suspension of aluminum-containing particles is a suspension of aluminum hydroxide particles.

Item 8. The pharmaceutical composition according to any one of items 1-7, wherein the composition comprises a compound having the structure of formula (A) or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles, Tris buffer and mannitol.

Item 9. Pharmaceutical composition according to any one of items 1-8, where the composition contains 0.5-2 mg/ml of a compound characterized by the structure of formula (A), or a pharmaceutically acceptable salt thereof, 5-100 mM Tris buffer, 5 -10% (w/v) mannitol and a suspension of aluminum hydroxide particles characterized by an aluminum content of 1-4 mg/ml.

Item 10. The pharmaceutical composition according to any one of items 1-9, wherein the composition contains 0.5-2 mg/ml of a compound having the structure of formula (A) or a pharmaceutically acceptable salt thereof, 5-50 mM Tris buffer, 5 -10% (w/v) mannitol and a suspension of aluminum hydroxide particles characterized by an aluminum content of 1-4 mg/ml.

Item 11. A pharmaceutical composition according to any one of items 1-10, wherein the composition contains 0.5-2 mg/ml of a compound having the structure of formula (A) or a pharmaceutically acceptable salt thereof, 5-20 mM Tris buffer, 5 -10% (w/v) mannitol and a suspension of aluminum hydroxide particles characterized by an aluminum content of 1-4 mg/ml.

Item 12. A pharmaceutical composition according to any one of items 1-11, wherein the composition contains 1 mg/ml of a compound having the structure of formula (A) or a pharmaceutically acceptable salt thereof, 5-20 mM Tris buffer, 5-10% ( weight/volume) mannitol and a suspension of aluminum hydroxide particles, characterized by an aluminum content of 2 mg/ml, and where the composition is characterized by a pH in the range of 7.0-8.0.

Item 13. A pharmaceutical composition according to any of items 1-12, wherein the composition contains 1 mg/ml of a compound having the structure of formula (A) or a pharmaceutically acceptable salt thereof, 16 mM Tris buffer, 7.5% (w/w) volume) mannitol and a suspension of aluminum hydroxide particles, characterized by an aluminum content of 2 mg/ml, and where the composition is characterized by a pH in the range of 7.0-8.0.

Item 14. A pharmaceutical composition according to any one of items 1-12, wherein the composition contains 1 mg/ml of a compound having the structure of formula (A) or a pharmaceutically acceptable salt thereof, 5 mM Tris buffer, 8.25% (w/w). volume) mannitol and a suspension of aluminum hydroxide particles, characterized by an aluminum content of 2 mg/ml, and where the composition is characterized by a pH in the range of 7.0-8.0.

Item 15. A pharmaceutical composition according to any one of items 1-12, wherein the composition contains 1 mg/ml of a compound having the structure of formula (A) or a pharmaceutically acceptable salt thereof, 5 mM Tris buffer, 5.5% (w/w). volume) mannitol and a suspension of aluminum hydroxide particles, characterized by an aluminum content of 2 mg/ml, and where the composition is characterized by a pH in the range of 7.0-8.0.

Item 16 A pharmaceutical composition according to any one of items 1 to 7, wherein the composition comprises a compound having the structure of formula (A) or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles, Tris buffer and sucrose.

Item 17. The pharmaceutical composition according to any one of items 1-7 or 16, wherein the composition contains 0.5-2 mg/ml of a compound having the structure of formula (A) or a pharmaceutically acceptable salt thereof, 5-100 mM Tris buffer , 5-10% (w/v) sucrose and a suspension of aluminum hydroxide particles characterized by an aluminum content of 1-4 mg/ml.

Item 18. The pharmaceutical composition according to any one of items 1-7 or 16-17, wherein the composition contains 0.5-2 mg/ml of a compound having the structure of formula (A) or a pharmaceutically acceptable salt thereof, 5-50 mM Tris buffer, 5-10% (w/v) sucrose and a suspension of aluminum hydroxide particles, characterized by an aluminum content of 1-4 mg/ml.

Item 19 A pharmaceutical composition according to any one of items 1-7 or 15-17, wherein the composition contains 0.5-2 mg/mL of a compound having the structure of formula (A) or a pharmaceutically acceptable salt thereof, 5-20 mM Tris buffer, 5-10% (w/v) sucrose and a suspension of aluminum hydroxide particles, characterized by an aluminum content of 1-4 mg/ml.

Item 20. The pharmaceutical composition according to any one of items 1-7 or 16-20, wherein the composition contains 1 mg/ml of a compound having the structure of formula (A) or a pharmaceutically acceptable salt thereof, 5-20 mM Tris buffer, 5 -10% (w/v) sucrose and a suspension of aluminum hydroxide particles, characterized by an aluminum content of 2 mg/ml, and where the composition is characterized by a pH in the range of 7.0-8.0.

Item 21 A pharmaceutical composition according to any one of items 1-7 or 16-20, wherein the composition contains 1 mg/mL of a compound having the structure of formula (A) or a pharmaceutically acceptable salt thereof, 16 mM Tris buffer, 7.5 % (w/v) sucrose and a suspension of aluminum hydroxide particles, characterized by an aluminum content of 2 mg/ml, and where the composition is characterized by a pH in the range of 7.0-8.0.

Item 22 A pharmaceutical composition according to any one of items 1-7 or 16-21, wherein the composition contains 1 mg/mL of a compound having the structure of formula (A) or a pharmaceutically acceptable salt thereof, 5 mM Tris buffer, 8.25 % (w/v) sucrose and a suspension of aluminum hydroxide particles, characterized by an aluminum content of 2 mg/ml, and where the composition is characterized by a pH in the range of 7.0-8.0.

Item 23. A pharmaceutical composition according to any one of items 1-22, wherein the ratio (w/w) of the weight of the compound of formula A and the weight of aluminum in the suspension of aluminum-containing particles is in the range from 1:1 to 1:20.

Item 24. The pharmaceutical composition according to any one of items 1-23, wherein the ratio (w/w) of the weight of the compound of formula A and the weight of aluminum in the suspension of aluminum-containing particles is in the range from 1:1.5 to 1:2.5.

Item 25. The pharmaceutical composition according to any one of items 1-22, wherein the ratio (w/w) of the weight of the compound of formula A to the weight of aluminum in the suspension of aluminum-containing particles is 1:1.5.

Item 26. The pharmaceutical composition according to any one of items 1-22, wherein the ratio (w/w) of the weight of the compound of formula A and the weight of aluminum in the suspension of aluminum-containing particles is 1:2.

Item 27. A pharmaceutical composition according to any one of items 1-15 or 23, wherein the composition contains a compound having the structure of formula (A) or a pharmaceutically acceptable salt thereof, 5-20 mM Tris buffer, 5-10% (w/w). volume) mannitol and a suspension of particles of aluminum hydroxide, and where the ratio (weight/weight) of the weight of the compound of formula A and the weight of aluminum in the suspension of particles is 1:20.

Item 28. Pharmaceutical composition according to any one of items 1-15 or 23, where the composition contains a compound characterized by the structure of formula (A), or a pharmaceutically acceptable salt thereof, 5-20 mm Tris buffer, 5-10% (weight / volume) mannitol and a suspension of particles of aluminum hydroxide, and where the ratio (weight/weight) of the weight of the compound of formula A and the weight of aluminum in the suspension of particles is 1:2, and the composition has a pH in the range of 7.0-8.0.

Item 29 A pharmaceutical composition according to any one of items 1-15 or 23, wherein the composition comprises a compound having the structure of formula (A) or a pharmaceutically acceptable salt thereof, 16 mM Tris buffer, 7.5% (w/v) mannitol and a suspension of particles of aluminum hydroxide, and where the ratio (weight/weight) of the weight of the compound of formula A and the weight of aluminum in the suspension of particles is 1:2, and the composition has a pH in the range of 7.0-8.0.

Item 30 A pharmaceutical composition according to any one of items 1-15 or 23, wherein the composition comprises a compound having the structure of formula (A) or a pharmaceutically acceptable salt thereof, 5 mM Tris buffer, 8.25% (w/v) mannitol and a suspension of particles of aluminum hydroxide, and where the ratio (weight/weight) of the weight of the compound of formula A and the weight of aluminum in the suspension of particles is 1:2, and the composition has a pH in the range of 7.0-8.0.

Item 31 A pharmaceutical composition according to any one of items 1-15 or 23, wherein the composition comprises a compound having the structure of formula (A) or a pharmaceutically acceptable salt thereof, 5 mM Tris buffer, 5.5% (w/v) mannitol and a suspension of particles of aluminum hydroxide, and where the ratio (weight/weight) of the weight of the compound of formula A and the weight of aluminum in the suspension of particles is 1:2, and the composition has a pH in the range of 7.0-8.0.

Item 32 A pharmaceutical composition according to any one of items 16-23, wherein the composition comprises a compound having the structure of formula (A), or a pharmaceutically acceptable salt thereof, 5-20 mM Tris buffer, 5-10% (w/v) sucrose and a suspension of particles of aluminum hydroxide, and where the ratio (weight/weight) of the compounds of formula A and aluminum in the suspension of particles is 1:20.

Item 33 A pharmaceutical composition according to any one of items 16-23, wherein the composition comprises a compound having the structure of formula (A), or a pharmaceutically acceptable salt thereof, 5-20 mM Tris buffer, 5-10% (w/v) sucrose and a suspension of particles of aluminum hydroxide, and where the ratio (weight/weight) of the compound of formula A and aluminum in the suspension of particles is 1:2, and the composition has a pH in the range of 7.0-8.0.

Item 34 A pharmaceutical composition according to any one of items 16-23, wherein the composition comprises a compound having the structure of formula (A) or a pharmaceutically acceptable salt thereof, 16 mM Tris buffer, 7.5% (w/v) sucrose, and suspension of particles of aluminum hydroxide, and where the ratio (weight/weight) of the compounds of formula A and aluminum in the suspension of particles is 1:2, and the composition has a pH in the range of 7.0-8.0.

Item 35. A pharmaceutical composition according to any one of items 16-23, wherein the composition comprises a compound having the structure of formula (A), or a pharmaceutically acceptable salt thereof, 5 mM Tris buffer, 8.25% (w/v) sucrose, and suspension of particles of aluminum hydroxide, and where the ratio (weight/weight) of the compounds of formula A and aluminum in the suspension of particles is 1:2, and the composition has a pH in the range of 7.0-8.0.

Item 36 A pharmaceutical composition according to any one of items 1-34, wherein the compound having the structure of formula (A) is:

3-(5-Amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid ;

3-(5-amino-2-(2-methyl-4-(2-(2-(2-phosphonoethoxy)ethoxy)ethoxy)phenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid ;

3-(5-amino-2-(4-(4,4-difluoro-4-phosphonobutoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid;

3-(5-Amino-2-(2-methyl-4-(3-phosphonopropoxy)phenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid;

3-(5-amino-2-(4-(2-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridine-8 -yl) propanoic acid;

3-(5-Amino-2-(2-methyl-4-(2-(2-(2-(2-phosphonoethoxy)ethoxy)ethoxy)ethoxy)phenethyl)benzo[f][1,7]naphthyridine-8 -yl) propanoic acid and

3-(5-amino-2-(2-methyl-4-(2-(2-phosphonoethoxy)ethoxy)phenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid;

(3-(4-(2-(5-Amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenoxy)propyl)phosphonic acid;

4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenyl dihydrogen phosphate;

((4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenoxy)methyl)phosphonic acid;

5-(4-(2-(5-Amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenoxy)-1,1-difluoropentylphosphonic acid;

(4-(4-(2-(5-Amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenoxy)-1,1-difluorobutyl)phosphonic acid;

(3-(2-(2-(4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenoxy)ethoxy)ethoxy)-1 ,1-difluoropropyl)phosphonic acid;

3-(2-(4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenoxy)ethoxy)-1,1-difluoropropylphosphonic acid;

2-(4-((4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenoxy)methyl)phenyl)-1,1- difluoroethylphosphonic acid;

(3-((4-(2-(5-Amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenoxy)methyl)phenyl)phosphonic acid;

(2-(4-(2-(5-Amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenoxy)ethyl)phosphonic acid;

(6-(4-(2-(5-Amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenoxy)hexyl)phosphonic acid;

(6-(4-(2-(5-Amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenoxy)-1,1-difluorohexyl)phosphonic acid;

(4-((4-(2-(5-Amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenoxy)methyl)benzyl)phosphonic acid;

(2-(2-(2-(4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenoxy)ethoxy)ethoxy)ethyl) phosphonic acid;

(5-(4-(2-(5-Amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenoxy)pentyl)phosphonic acid and

(4-(4-(2-(5-Amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenoxy)butyl)phosphonic acid;

2-(5-amino-2-(4-methoxy-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)-1,1-difluoro-2-oxoethylphosphonic acid;

(E)-(2-(5-amino-2-(4-methoxy-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)vinyl)phosphonic acid;

2-(5-Amino-2-(4-methoxy-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)ethylphosphonic acid;

(E)-(2-(5-amino-2-(4-methoxy-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)-1-fluorovinyl)phosphonic acid or

(5-Amino-2-(4-methoxy-2-methylphenethyl)benzo[f][1,7]naphthyridine-8-carbonyl)phosphonic acid.

Item 37 A pharmaceutical composition according to any one of items 1-36, wherein the compound is 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2- methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid.

Item 38 A pharmaceutical composition according to any one of items 1-36 wherein the compound is 3-(5-amino-2-(2-methyl-4-(2-(2-(2-phosphonoethoxy)ethoxy)ethoxy) phenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid.

Item 39. The pharmaceutical composition according to any one of items 1-8, wherein the composition contains 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl )benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles, Tris buffer and mannitol.

Item 40. The pharmaceutical composition according to any one of items 1-8 or 39, wherein the composition contains 0.5-2 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro- 3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, 5-100 mM Tris buffer, 5-10% (w/v) ) mannitol and a suspension of particles of aluminum hydroxide, characterized by an aluminum content of 1-4 mg/ml.

Item 41. The pharmaceutical composition according to any one of items 1-8 or 39-40, wherein the composition contains 0.5-2 mg/ml 3-(5-amino-2-(4-(2-(3,3- difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, 5-50 mM Tris buffer, 5-10% (w/w) /volume) mannitol and a suspension of particles of aluminum hydroxide, characterized by an aluminum content of 1-4 mg/ml.

Item 42. The pharmaceutical composition according to any one of items 1-8 or 39-41, wherein the composition contains 0.5-2 mg/ml 3-(5-amino-2-(4-(2-(3,3- difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, 5-20 mM Tris buffer, 5-10% (w/w /volume) mannitol and a suspension of particles of aluminum hydroxide, characterized by an aluminum content of 1-4 mg/ml.

Item 43 A pharmaceutical composition according to any one of items 1-8 or 39-42, wherein the composition contains 1 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3- phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, 5-20 mM Tris buffer, 5-10% (w/v) mannitol and a suspension of particles of aluminum hydroxide, characterized by an aluminum content of 2 mg/ml, and where the composition is characterized by a pH in the range of 7.0-8.0.

Item 44. The pharmaceutical composition according to any one of items 1-8 or 39-43, wherein the composition contains 1 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3- phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, 16 mM Tris buffer, 7.5% (w/v) mannitol and suspension particles of aluminum hydroxide, characterized by an aluminum content of 2 mg/ml, and where the composition is characterized by a pH in the range of 7.0-8.0.

Item 45. The pharmaceutical composition according to any one of items 1-8 or 39-43, wherein the composition contains 1 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3- phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, 5 mM Tris buffer, 8.25% (w/v) mannitol and suspension particles of aluminum hydroxide, characterized by an aluminum content of 2 mg/ml, and where the composition is characterized by a pH in the range of 7.0-8.0.

Item 46. A pharmaceutical composition according to any one of items 1-8 or 39-43, wherein the composition contains 1 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3- phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, 5 mM Tris buffer, 5.5% (w/v) mannitol and suspension particles of aluminum hydroxide, characterized by an aluminum content of 2 mg/ml, and where the composition is characterized by a pH in the range of 7.0-8.0.

Item 47. The pharmaceutical composition according to any one of items 1-7, wherein the composition contains 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl )benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles, Tris buffer and sucrose.

Item 48 A pharmaceutical composition according to any one of items 1-7 or 47, wherein the composition contains 0.5-2 mg/mL of 3-(5-amino-2-(4-(2-(3,3-difluoro- 3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, 5-100 mM Tris buffer, 5-10% (w/v) ) sucrose and a suspension of particles of aluminum hydroxide, characterized by an aluminum content of 1-4 mg/ml.

Item 49 A pharmaceutical composition according to any one of items 1-7 or 47-48, wherein the composition contains 0.5-2 mg/mL of 3-(5-amino-2-(4-(2-(3,3- difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, 5-50 mM Tris buffer, 5-10% (w/w) /volume) sucrose and a suspension of particles of aluminum hydroxide, characterized by an aluminum content of 1-4 mg/ml.

Item 50. A pharmaceutical composition according to any one of items 1-7 or 47-49, wherein the composition contains 0.5-2 mg/ml 3-(5-amino-2-(4-(2-(3,3- difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, 5-20 mM Tris buffer, 5-10% (w/w /volume) sucrose and a suspension of particles of aluminum hydroxide, characterized by an aluminum content of 1-4 mg/ml.

Item 51. The pharmaceutical composition according to any one of items 1-7 or 47-50, wherein the composition contains 1 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3- phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, 5-20 mM Tris buffer, 5-10% (w/v) sucrose and a suspension of particles of aluminum hydroxide, characterized by an aluminum content of 2 mg/ml, and where the composition is characterized by a pH in the range of 7.0-8.0.

Item 52. The pharmaceutical composition according to any one of items 1-7 or 47-51, wherein the composition contains 1 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3- phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, 16 mM Tris buffer, 7.5% (w/v) sucrose and suspension particles of aluminum hydroxide, characterized by an aluminum content of 2 mg/ml, and where the composition is characterized by a pH in the range of 7.0-8.0.

Item 53 A pharmaceutical composition according to any one of items 1-7 or 47-52, wherein the composition contains 1 mg/mL of 3-(5-amino-2-(4-(2-(3,3-difluoro-3- phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, 5 mM Tris buffer, 8.25% (w/v) sucrose and suspension particles of aluminum hydroxide, characterized by an aluminum content of 2 mg/ml, and where the composition is characterized by a pH in the range of 7.0-8.0.

Item 54. Pharmaceutical composition according to any one of paragraphs. 1-8 or paragraphs. 39-53, where the ratio (w/w) of the weight of 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][ 1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof and the weight of aluminum in the suspension of aluminum-containing particles is in the range from 1:1 to 1:20.

Item 55. Pharmaceutical composition according to any one of paragraphs. 1-8 or 39-53, where the ratio (w/w) of the weight of 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo [f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof and the weight of aluminum in the suspension of aluminum-containing particles is in the range from 1:1.5 to 1:2.5.

Item 56. Pharmaceutical composition according to any one of paragraphs. 1-8 or 39-53, where the ratio (w/w) of the weight of 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo [f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof and the weight of aluminum in the suspension of aluminum-containing particles is 1:1.5.

Item 57. Pharmaceutical composition according to any one of paragraphs. 1-8 or paragraphs. 39-53, where the ratio (w/w) of the weight of 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][ 1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof and the weight of aluminum in the suspension of aluminum-containing particles is 1:2.

Item 58 A pharmaceutical composition according to any one of items 1-8 or 39-45, wherein the composition contains 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy) -2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, 5-100 mM Tris buffer, 5-10% (w/v) mannitol and hydroxide particle suspension aluminum, and where the ratio (w/w) of the weight of 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1 ,7]naphthyridin-8-yl)propanoic acid and the weight of aluminum in the particle suspension is 1:20.

Item 59. A pharmaceutical composition according to any one of items 1-8 or 39-45, wherein the composition contains 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy) -2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, 5-20 mM tris buffer, 5-10% (w/v) mannitol and hydroxide particle suspension aluminum, and where the ratio (w/w) of the weight of 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1 ,7]naphthyridin-8-yl)propanoic acid and the weight of aluminum in the suspension of particles is 1:2, and the composition is characterized by a pH in the range of 7.0-8.0.

Item 60. A pharmaceutical composition according to any one of items 1-8 or 39-45, wherein the composition contains 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy) -2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid, or a pharmaceutically acceptable salt thereof, 16 mM Tris buffer, 7.5 (w/v) mannitol, and a suspension of aluminum hydroxide particles, and where the ratio (w/w) of the weight of 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1.7] naphthyridin-8-yl)propanoic acid and the weight of aluminum in the suspension of particles is 1:2, and the composition is characterized by a pH in the range of 7.0-8.0.

Item 61 A pharmaceutical composition according to any one of items 1-8 or 39-45, wherein the composition contains 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy) -2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid, or a pharmaceutically acceptable salt thereof, 5 mM tris buffer, 8.25 (w/v) mannitol, and a suspension of aluminum hydroxide particles, and where the ratio (w/w) of the weight of 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1.7] naphthyridin-8-yl)propanoic acid and the weight of aluminum in the suspension of particles is 1:2, and the composition is characterized by a pH in the range of 7.0-8.0.

Item 62. A pharmaceutical composition according to any one of items 1-8 or 39-45, wherein the composition contains 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy) -2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid, or a pharmaceutically acceptable salt thereof, 5 mM Tris buffer, 5.5 (w/v) mannitol, and a suspension of aluminum hydroxide particles, and where the ratio (w/w) of the weight of 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1.7] naphthyridin-8-yl)propanoic acid and the weight of aluminum in the suspension of particles is 1:2, and the composition is characterized by a pH in the range of 7.0-8.0.

Item 63 A pharmaceutical composition according to any one of items 1-7 or 47-53, wherein the composition contains 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy) -2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, 5-100 mM Tris buffer, 5-10% (w/v) sucrose and hydroxide particle suspension aluminum, and where the ratio (w/w) of the weight of 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1 ,7]naphthyridin-8-yl)propanoic acid and the weight of aluminum in the particle suspension is 1:20.

Item 64 A pharmaceutical composition according to any one of items 1-7 or 47-53, wherein the composition contains 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy) -2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, 5-20 mM Tris buffer, 5-10% (w/v) sucrose and hydroxide particle suspension aluminum, and where the ratio (w/w) of the weight of 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1 ,7]naphthyridin-8-yl)propanoic acid and the weight of aluminum in the suspension of particles is 1:2, and the composition is characterized by a pH in the range of 7.0-8.0.

Item 65 A pharmaceutical composition according to any one of items 1-7 or 47-53, wherein the composition contains 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy) -2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, 16 mM Tris buffer, 7.5 (w/v) sucrose and a suspension of aluminum hydroxide particles, and where the ratio (w/w) of the weight of 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1.7] naphthyridin-8-yl)propanoic acid and the weight of aluminum in the suspension of particles is 1:2, and the composition is characterized by a pH in the range of 7.0-8.0.

Item 66 A pharmaceutical composition according to any one of items 1-7 or 47-53, wherein the composition contains 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy) -2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, 5 mM Tris buffer, 8.25 (w/v) sucrose and a suspension of aluminum hydroxide particles, and where the ratio (w/w) of the weight of 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1.7] naphthyridin-8-yl)propanoic acid and the weight of aluminum in the suspension of particles is 1:2, and the composition is characterized by a pH in the range of 7.0-8.0.

Item 67. A pharmaceutical composition according to any one of items 1-66, further comprising an additional therapeutic agent.

Item 68. The pharmaceutical composition according to item 67, wherein the additional therapeutic agents are a checkpoint inhibitor, a TLR9 agonist, a TLR8 agonist, a TLR7 agonist, a STING agonist, or a chemotherapeutic agent.

Item 69. A pharmaceutical combination comprising a first pharmaceutical composition according to any one of items 1-66 and a second pharmaceutical composition containing a checkpoint inhibitor, a TLR9 agonist, a TLR8 agonist, a TLR7 agonist, a STING agonist, or a chemotherapeutic agent.

Item 70. A pharmaceutical combination comprising a first pharmaceutical composition according to any one of items 1-66, a second pharmaceutical composition containing a checkpoint inhibitor, a TLR9 agonist, a TLR8 agonist, a TLR7 agonist, a STING agonist, or a chemotherapeutic agent, and a third pharmaceutical composition containing a checkpoint inhibitor, a TLR9 agonist, a TLR8 agonist, a TLR7 agonist, a STING agonist, or a chemotherapeutic agent.

Item 71. Pharmaceutical combination containing:

a) a first pharmaceutical composition according to any one of paragraphs 1-66 and

b) a second pharmaceutical composition comprising a checkpoint inhibitor selected from a CTLA-4 receptor inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor inhibitor, a TIM-3 receptor inhibitor, a BTLA receptor inhibitor, a KIR receptor inhibitor, a PD-L1 inhibitor, or PD-L2 inhibitor.

Item 72. Pharmaceutical combination containing:

a) a first pharmaceutical composition according to any one of paragraphs 1-66 and

b) a second pharmaceutical composition containing a PD-1 receptor inhibitor.

Item 73. Pharmaceutical combination containing:

a) a first pharmaceutical composition according to any one of paragraphs 1-66 and

b) a second pharmaceutical composition containing a PD-L1 inhibitor.

Item 74. Pharmaceutical combination containing:

a) a first pharmaceutical composition according to any one of paragraphs 1-66 and

b) a second pharmaceutical composition containing an anti-PD-L1 antibody.

Item 75. Pharmaceutical combination containing:

a) a first pharmaceutical composition according to any one of paragraphs 1-66 and

b) a second pharmaceutical composition containing an anti-PD-1 antibody.

Item 76. Pharmaceutical combination containing:

a) a first pharmaceutical composition according to any one of paragraphs 1-66,

b) a second pharmaceutical composition comprising a checkpoint inhibitor selected from a CTLA-4 receptor inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor inhibitor, a TIM-3 receptor inhibitor, a BTLA receptor inhibitor, a KIR receptor inhibitor, a PD-L1 inhibitor, or a PD-L2 inhibitor, and

c) a third pharmaceutical composition comprising a checkpoint inhibitor selected from a CTLA-4 receptor inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor inhibitor, a TIM-3 receptor inhibitor, a BTLA receptor inhibitor, a KIR receptor inhibitor, a PD-L1 inhibitor, or PD-L2 inhibitor,

wherein the checkpoint of the third composition is different from the checkpoint inhibitor of the second composition.

Item 77. Pharmaceutical combination containing:

a) a first pharmaceutical composition according to any one of paragraphs 1-66,

b) a second pharmaceutical composition containing a PD-L1 inhibitor, and

c) a third pharmaceutical composition containing a CTLA-4 receptor inhibitor.

Item 78. Pharmaceutical combination containing:

a) a first pharmaceutical composition according to any one of paragraphs 1-66,

b) a second pharmaceutical composition containing a PD-1 inhibitor, and

c) a third pharmaceutical composition containing a CTLA-4 receptor inhibitor.

Item 79. Pharmaceutical combination containing:

a) a first pharmaceutical composition according to any one of paragraphs 1-66,

b) a second pharmaceutical composition comprising an anti-PD-L1 antibody, and

c) a third pharmaceutical composition containing an anti-CTLA-4 antibody.

Item 80. Pharmaceutical combination containing:

a) a first pharmaceutical composition according to any one of paragraphs 1-66,

b) a second pharmaceutical composition comprising an anti-PD-1 antibody, and

c) a third pharmaceutical composition containing an anti-CTLA-4 antibody.

Item 81. A method of treating a solid tumor, carried out by administering to a subject in need thereof a pharmaceutical composition according to any one of items 1-68 or a pharmaceutical combination according to any one of items 69-80.

Item 82. A method of treating a solid tumor, carried out by administering to a subject in need of it, a pharmaceutical combination containing:

a) a first pharmaceutical composition according to any one of paragraphs 1-66,

b) a second pharmaceutical composition comprising a checkpoint inhibitor selected from a CTLA-4 receptor inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor inhibitor, a TIM-3 receptor inhibitor, a BTLA receptor inhibitor, a KIR receptor inhibitor, a PD-L1 inhibitor, or a PD-L2 inhibitor, and

c) a third pharmaceutical composition comprising a checkpoint inhibitor selected from a CTLA-4 receptor inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor inhibitor, a TIM-3 receptor inhibitor, a BTLA receptor inhibitor, a KIR receptor inhibitor, a PD-L1 inhibitor, or PD-L2 inhibitor,

wherein the checkpoint of the third composition is different from the checkpoint inhibitor of the second composition, and

wherein the first pharmaceutical composition is administered intratumorally, and the second pharmaceutical composition and the third pharmaceutical composition are administered intratumorally, intramuscularly, intradermally, subcutaneously, intravenously, by intraperitoneal injection, by lavage, or by infusion.

Item 83. A method of treating a solid tumor, carried out by administering to a subject in need of it, a pharmaceutical combination containing:

a) a first pharmaceutical composition according to any one of paragraphs 1-66 and

b) a second pharmaceutical composition comprising a checkpoint inhibitor selected from a CTLA-4 receptor inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor inhibitor, a TIM-3 receptor inhibitor, a BTLA receptor inhibitor, a KIR receptor inhibitor, a PD-L1 inhibitor, or PD-L2 inhibitor,

wherein the first pharmaceutical composition is administered intratumorally and the second pharmaceutical composition is administered intratumorally, intramuscularly, intradermally, subcutaneously, intravenously, by intraperitoneal injection, by lavage, or by infusion.

Item 84. The method according to any one of items 81-33, wherein the solid tumor is head and neck squamous cell carcinoma (HNSCC), melanoma, or visceral tumor.

Item 85 Use of a pharmaceutical composition according to any of Items 1-68 or use of a pharmaceutical combination according to any of Items 69-80 in the treatment of a solid tumor.

Item 86 Use according to item 85, wherein the solid tumor is head and neck squamous cell carcinoma (HNSCC), melanoma, or visceral tumor.

Item 87 A pharmaceutical composition according to any one of items 1-68, or a pharmaceutical combination according to any one of items 69-80, for use in the treatment of a solid tumor.

Item 88. The pharmaceutical composition according to item 87, wherein the solid tumor is head and neck squamous cell carcinoma (HNSCC), melanoma, or visceral tumor.

Item 89. A lyophilisate containing a compound having the structure of formula (A) or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients,

formula (A),

where

R ¹ is -L ₁ R ⁴ , -L ₁ R ⁵ , -OL ₁ R ⁴ , -OL ₁ R ⁵ , CH ₃ , -C(=O)P(O)(OH) ₂ or -C(= O)CF ₂ P(O)(OH) ₂ ;

R² represents -L₂R^four, -L₂R⁶, -L₂L₃L₂R⁶, -L₂L₃R^four, -L₂L₃L₂R^four, -OL₂R^four, -OR^four, -OL₂R⁶, -OL₂L₃R⁶, -OL₂L₃L₂R⁶, -OL₂L_3R ^four -OL₂L₃L₂R^four or -OCH₃;

each R ³ is independently selected from H and fluorine;

R ⁴ is -P(O)(OH) ₂ ,

R ⁵ is -CF ₂ P(O)(OH) ₂ or -C(O)OH;

R ⁶ is -CF ₂ P(O)(OH) ₂ or -C(O)OH;

L₁ represents C₁-C₆alkylene, C₂-C₆alkenylene or -((CR^fourR^four)_pO)_q(CH₂)_p-, where C₁-C₆alkylene and C₂-C₆alkenylene in L₁ substituted with 0-4 fluoro groups;

each L ₂ is independently selected from C ₁ -C ₆ alkylene and -((CR ³ R ³ ) _p O) _q (CH ₂ ) _p - wherein the C ₁ -C ₆ alkylene in L ₂ is substituted with 0-4 fluoro groups;

L ₃ is arylene or 5-6 membered heteroarylene;

each p is independently selected from 1, 2, 3, 4, 5, and 6, and

q is 1, 2, 3, or 4.

Item 90. The lyophilisate according to item 89, wherein the compound is 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f ][1,7]naphthyridin-8-yl)propanoic acid.

Item 91. A lyophilisate prepared from a solution having a pH of 6.5-9.0 and containing a compound having the structure of formula (A) or a pharmaceutically acceptable salt thereof and a buffer,

formula (A),

where

R ¹ is -L ₁ R ⁴ , -L ₁ R ⁵ , -OL ₁ R ⁴ , -OL ₁ R ⁵ , CH ₃ , -C(=O)P(O)(OH) ₂ or -C(= O)CF ₂ P(O)(OH) ₂ ;

R² represents -L₂R^four, -L₂R⁶, -L₂L₃L₂R⁶, -L₂L₃R^four, -L₂L₃L₂R^four, -OL₂R^four, -OR^four, -OL₂R⁶, -OL₂L₃R⁶, -OL₂L₃L₂R⁶, -OL₂L_3R ^four -OL₂L₃L₂R^four or -OCH₃;

each R ³ is independently selected from H and fluorine;

R ⁴ is -P(O)(OH) ₂ ,

R ⁵ is -CF ₂ P(O)(OH) ₂ or -C(O)OH;

R ⁶ is -CF ₂ P(O)(OH) ₂ or -C(O)OH;

L₁ represents C₁-C₆alkylene, C₂-C₆alkenylene or -((CR^fourR^four)_pO)_q(CH₂)_p-, where C₁-C₆alkylene and C₂-C₆alkenylene in L₁ substituted with 0-4 fluoro groups;

each L ₂ is independently selected from C ₁ -C ₆ alkylene and -((CR ³ R ³ ) _p O) _q (CH ₂ ) _p - wherein the C ₁ -C ₆ alkylene in L ₂ is substituted with 0-4 fluoro groups;

L ₃ is arylene or 5-6 membered heteroarylene;

each p is independently selected from 1, 2, 3, 4, 5, and 6, and

q is 1, 2, 3, or 4.

Item 92. The lyophilisate according to item 91, wherein the compound is 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f ][1,7]naphthyridin-8-yl)propanoic acid.

Item 93 A pharmaceutical composition obtained by dissolving a lyophilizate according to any one of items 89-92 with water and mixing with a suspension of aluminum-containing particles.

Item 94. The pharmaceutical composition according to item 93, obtained by dissolving the lyophilisate according to any one of items 89-92 with water and mixing with a suspension of aluminum-containing particles, characterized by an aluminum content of 1-4 mg/ml.

Item 95. The pharmaceutical composition according to items 93-94, wherein the aluminum-containing particles are aluminum hydroxide particles.

BRIEF DESCRIPTION OF GRAPHICS

Figure 1. Compound 15 plasma concentration versus time curves in C57/BL6 mice harboring MC38 tumor cells after a single intratumoral (i.t.) or subcutaneous (sc) injection of 100 μg of a solution of free compound 15 or compound 15 adsorbed on aluminum hydroxide at a ratio of 1:1.5 w/w.

Figure 2. A) Plasma levels of TNFα in C57/BL6 mice harboring MC38 tumor cells after a single

intratumoral (i.t.) or subcutaneous (sc) injection of compound 15 adsorbed on aluminum hydroxide at a ratio of 1:1.5 w/w.

B) Plasma levels of IL-6 in C57/BL6 mice harboring MC38 tumor cells after a single intratumoral (i.t.) or subcutaneous (sc) injection of compound 15 adsorbed on aluminum hydroxide at a ratio of 1:1.5 w/w.

C) Plasma levels of IP-10 in C57/BL6 mice harboring MC38 tumor cells after a single intratumoral (i.t.) or subcutaneous (sc) injection of Compound 15 adsorbed on aluminum hydroxide at a ratio of 1:1.5 w/w.

Figure 3. A) Plasma levels of TNFα in C57/BL6 mice harboring MC38 tumor cells after a single

intratumoral (i.t.) or subcutaneous (sc) injection of compound 15 adsorbed on aluminum hydroxide at a ratio of 1:2 w/w.

B) Plasma levels of IL-6 in C57/BL6 mice harboring MC38 tumor cells after a single intratumoral (i.t.) or subcutaneous (sc) injection of compound 15 adsorbed on aluminum hydroxide at a ratio of 1:2 w/w.

C) Plasma levels of IP-10 in C57/BL6 mice harboring MC38 tumor cells after a single intratumoral (i.t.) or subcutaneous (sc) injection of compound 15 adsorbed on aluminum hydroxide at a ratio of 1:2 w/w.

Figure 4. Compound 15 plasma concentration versus time curves in male Wistar rats after a single subcutaneous injection of 600 mg of free compound 15 in 100 mM Tris buffer (pH 7.4), a single subcutaneous (sc) injection of 600 μg of free compound 15 adsorbed on aluminum hydroxide in 100 mM Tris buffer (pH 7.4) at a ratio of 1:2.5 w/w (97% binding), single subcutaneous (sc) injection of 200 µg of free compound 15 adsorbed on hydroxide aluminum, in 100 mM Tris buffer (pH 7.4) at a ratio of 1:2.5 w/w (94% binding) and a single subcutaneous (sc) injection of 50 μg of free compound 15 in 100 mM Tris buffer (pH 7 ,4) adsorbed on aluminum hydroxide at a ratio of 1:2.5 w/w (91% binding).

Figure 5. A) Compound 15 plasma concentration versus time curves in male Wistar rats after a single subcutaneous injection of 600 μg of compound 15 in 100 mM Tris (pH 7.4), a single subcutaneous injection of 600 μg of compound 15 adsorbed on aluminum hydroxide , in 100 mM Tris buffer (pH 7.4) at a ratio of 1:1.7 w/w (98% binding) and a single subcutaneous injection of 50 µg of compound 15 adsorbed on aluminum hydroxide in 100 mM Tris buffer (pH 7.4) at a ratio of 1:20 w/w (98% binding).

B) Plasma levels of IP-10 in male Wistar rats after a single subcutaneous injection of 600 μg of compound 15 in 100 mM Tris buffer (pH 7.4), a single subcutaneous injection of 600 μg of compound 15 adsorbed on aluminum hydroxide in 100 mM Tris buffer (pH 7.4) at a ratio of 1:1.7 w/w (98% binding) and a single subcutaneous injection of 50 µg of compound 15 adsorbed on aluminum hydroxide in 100 mM Tris buffer (pH 7.4 ) at a ratio of 1:20 w/w (98% binding).

Figure 6. Serum aluminum concentrations versus time after a dose of aluminum hydroxide alone (Group 2) or after a dose of Compound 15 with aluminum hydroxide (Group 5).

Figure 7. Serum aluminum concentration versus time curve after subcutaneous administration of compound 15 adsorbed on aluminum hydroxide and intravenous administration of AlCl ₃ ⋅6H ₂ O in saline.

Figure 8 Efficacy and dose response in an A20 mouse model of lymphoma following 2 weekly intratumoral (i.t.) injections of various doses of compound 15/aluminum hydroxide (at a constant ratio of 1:1.5 w/w and 97% binding).

Figure 9. Efficacy after a single i.t. injections of 100 μg compound 15/aluminum hydroxide at ratios of compound 15 and aluminum hydroxide of 1:1.5, 1:1, and 1:0.5 in an A20 mouse model of lymphoma.

Figure 10. A) Efficacy at the site of intratumoral injection after administration of compound 15/aluminum hydroxide, anti-PDL1 antibody or anti-CTLA4 antibody as single agents or after administration of combinations of compound 15/aluminum hydroxide and anti-PDL1 antibody and/or anti-CTLA4 antibody. Significant differences were calculated using a multiple comparison test with Tukey's post hoc test in a one-way ANOVA at day 22 post-implantation at N=9 per group, with significantly different levels of anti-PD-L1 antibody in the tumor alone at the treated site (* p <0.05 ). Levels of compound 15/aluminum hydroxide, compound 15/aluminum hydroxide with anti-PD-L1 antibody or anti-CTLA4 antibody, compound 15/aluminum hydroxide with anti-PD-L1 antibody and anti-CTLA4 antibody were significantly different ( **** p<0.0001 ).

B) Efficacy at a site remote from the injection site after administration of compound 15/aluminum hydroxide, anti-PDL1 antibody or anti-CTLA4 antibody as single agents or after administration of combinations of compound 15/aluminum hydroxide and anti-PDL1 antibody and/or anti-CTLA4 antibody. Significant differences were calculated using a multiple comparison test with Tukey's post hoc test in a one-way ANOVA at day 19 post-implantation at N=9 per group, with anti-CTLA4 antibody levels alone in the tumor at the resected site not significantly different from that of no treatment (* p <0.05). The level of anti-PD-L1 antibody was significantly different by itself (p<0.001). Compound 15/aluminum hydroxide levels alone were significantly different (** p <0.01). Compound 15/aluminum hydroxide levels with anti-PD-L1 antibody were significantly different (**** p <0.0001). Compound 15/aluminum hydroxide levels with anti-CTLA4 antibody were significantly different (* p <0.05). Compound 15/aluminum hydroxide levels were significantly different between PD-L1 antibody and CTLA4 antibody (**** p <0.0001).

C) Efficacy at the site of intratumoral injection after administration of Compound 15 or Compound 15/aluminum hydroxide alone, or after administration of a combination of an anti-PDL1 antibody and an anti-CTLA4 antibody, or after administration of triple combinations of Compound 15, an anti-PDL1 antibody, and an anti- CTLA4, or after the introduction of triple combinations of compound 15/aluminum hydroxide, and an antibody to PDL1, and an antibody to CTLA4.

D) Efficacy at a site distant from the injection site after administration of compound 15 or compound 15/aluminum hydroxide alone, or after administration of a combination of anti-PDL1 antibody and anti-CTLA4 antibody, or after administration of triple combinations of compound 15 and anti-PDL1 antibody , and antibodies to CTLA4 or after the introduction of triple combinations of compound 15/aluminum hydroxide and antibodies to PDL1 and antibodies to CTLA4.

DETAILED DESCRIPTION OF THE INVENTION

Definitions

The terms "alkenyl" or "alkene" as used herein refer to a partially unsaturated branched or straight chain hydrocarbon having at least one carbon-carbon double bond. Atoms oriented around the double bond are either in the cis (Z) or trans (E) conformation. In some embodiments, such an alkenyl or alkene group is optionally substituted. The terms "C ₂ -C ₃ alkenyl", "C ₂ -C ₄ alkenyl", "C ₂ -C ₅ alkenyl", "C ₂ -C ₆ alkenyl", "C ₂ -C ₇ alkenyl" and "C ₂ - C ₈ alkenyl" refers to an alkenyl group containing at least 2 and not more than 3, 4, 5, 6, 7 or 8 carbon atoms, respectively. In preferred embodiments, the alkenyl group is typically C ₂ -C ₆ alkenyl. Non-limiting examples of alkenyl groups include ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl, and the like.

The term "alkenylene" as used herein refers to a partially unsaturated branched or straight chain divalent hydrocarbon radical derived from an alkenyl group. In some embodiments, such an alkenylene group is optionally substituted. As used herein, the terms "C ₂ -C ₃ alkenylene", "C ₂ -C ₄ alkenylene", "C ₂ -C ₅ alkenylene", "C ₂ -C ₆ alkenylene", "C ₂ -C ₇ alkenylene", and "C ₂ -C ₈ alkenylene" refers to an alkenylene group containing at least 2 and not more than 3, 4, 5, 6, 7 or 8 carbon atoms, respectively. In preferred embodiments, the alkenylene group is typically C ₂ -C ₆ alkenylene. Non-limiting examples of alkenylene groups used herein include ethenylene, propenylene, butenylene, pentenylene, hexenylene, heptenylene, octenylene, nonenylene, decenylene, and the like.

The term "alkyl" as used herein refers to a branched or straight chain saturated hydrocarbon. The terms "C ₁ -C ₃ alkyl", "C ₁ -C ₄ alkyl", "C ₁ -C ₅ alkyl", "C ₁ -C ₆ alkyl", "C ₁ -C ₇ alkyl" and "C ₁ - C ₈ alkyl" refer to an alkyl group containing at least 1 and not more than 3, 4, 5, 6, 7 or 8 carbon atoms, respectively. In preferred embodiments, the alkyl group is typically C ₁ -C ₆ alkyl. Non-limiting examples of alkyl groups used herein include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, hexyl, heptyl, octyl, nonyl, decyl etc.

The term "alkylene" as used herein refers to a branched or straight chain saturated divalent hydrocarbon radical derived from an alkyl group. In some embodiments, such alkylene groups are optionally substituted. As used herein, the terms "C ₁ -C ₃ alkylene", "C ₁ -C ₄ alkylene", "C ₁ -C ₅ alkylene", "C ₁ -C ₆ alkylene", "C ₁ -C ₇ alkylene" and "C ₁ -C ₈ alkylene" refers to an alkylene group containing at least 1 and not more than 3, 4, 5, 6, 7 or 8 carbon atoms, respectively. In preferred embodiments, the alkylene group is typically C ₁ -C ₆ alkylene. Non-limiting examples of alkylene groups used herein include, methylene, ethylene, n-propylene, isopropylene, n-butylene, isobutylene, sec-butylene, t-butylene, n-pentylene, isopentylene, hexylene, and the like.

The term "aryl" as used herein refers to phenyl or naphthalene.

The term "arylene" as used herein means a divalent radical derived from an aryl group. In preferred embodiments, the arylene group is phenylene.

The term "5-6 membered heteroaryl" as used herein refers to a monocyclic aromatic ring structure having 5 or 6 ring members, where 1-3 ring members are independently selected from N, O, and S heteroatoms. Non-Limiting Examples 5-6 -membered heteroaryls include 2- or 3-furyl; 2- or 3-thienyl; 1-, 2- or 3-pyrrolyl; 2-, 4- or 5-oxazolyl; 2-, 4- or 5-thiazolyl; 1-, 2-, 4- or 5-imidazolyl; 1-, 3-, 4- or 5-pyrazolyl; 3-, 4- or 5-isoxazolyl; 3-, 4- or 5-isothiazolyl; 4- or 5-1,2,3-oxadiazolyl; 4- or 5-1,2,3-triazolyl; 2- or 5-1,3,4-thiadiazolyl; 2-, 3- or 4-pyridyl; 3-, 4-, 5- or 6-pyridazinyl; 2-, 4-, 5- or 6-pyrimidinyl and 2- or 3-pyrazinyl.

The term "heteroatoms" as used herein refers to nitrogen (N), oxygen (O), or sulfur (S) atoms.

The term "5-6 membered heteroarylene" as used herein means a divalent radical derived from a 5-6 membered heteroaryl group.

The term "hemoblastosis" as used herein refers to cancers that affect the bone marrow, blood cells, and lymphatic system. An example of hemoblastosis is leukemia.

The term "solid tumor" as used herein refers to an atypical mass in tissue that usually does not contain cysts or fluid areas. Generally, the term refers to cancerous (malignant) tumors, although a solid tumor may be a non-cancerous (benign) tumor. Examples of solid tumors are sarcoma types, carcinoma types, and lymphoma types, which include, without limitation, a tumor related to breast cancer, a tumor related to bladder cancer, a tumor related to head and neck cancer (e.g., squamous cell carcinoma of the head and neck (HNSCC)), tumor related to non-small cell lung cancer, tumor related to small cell lung cancer, tumor related to colorectal cancer, gastrointestinal stromal tumor, gastroesophageal carcinoma, tumor related to cancer of renal epithelial cells, tumor related to prostate cancer, a tumor related to liver cancer, a tumor related to colon cancer, a tumor related to pancreatic cancer, a tumor related to ovarian cancer, lymphoma, T-cell lymphoma of the skin, visceral tumors or melanoma.

The terms "combination" or "pharmaceutical combination" as used herein means a product that is obtained by mixing or combining more than one active ingredient and includes both fixed and non-fixed combinations of active ingredients. The term "fixed combination" means that the active ingredients, such as the compound disclosed herein, and one or more additional therapeutic agents, are administered to the subject simultaneously in the form of a single object or dose. The term "non-fixed combination" means that the active ingredients, such as the compound disclosed herein, and one or more additional therapeutic agents, are administered to a subject as separate entities simultaneously, in parallel, or sequentially without specific time limits, such administration provides therapeutically effective levels of the active ingredients in the body of the subject. The latter also applies to "cocktail" therapy, for example, the introduction of 3 or more active ingredients.

The terms "composition" or "pharmaceutical composition" as used herein refer to a mixture of a compound disclosed herein with at least one and optionally more pharmaceutically acceptable chemical components such as carriers, stabilizers, diluents, dispersants, suspending agents, thickeners and/or excipients.

The term "optical isomer" or "stereoisomer" as used herein refers to any of the various stereoisomeric configurations that may exist for a given compound of the present invention and includes geometric isomers. It is understood that a substituent may be attached at the chiral center of the carbon atom. The term "chiral" refers to molecules that are mismatched when superimposed with their mirror image partner, while the term "achiral" refers to molecules that are superimposed on their mirror image partner. Therefore, the present invention includes the enantiomers, diastereomers or racemates of the compound. "Enantiomers" are a pair of stereoisomers that are mismatched mirror images of each other. A 1:1 mixture of a pair of enantiomers is a "racemic" mixture. The term is used to refer to a racemic mixture, if appropriate. "Diastereoisomers" are stereoisomers that have at least two asymmetric atoms, but which are not mirror images of each other. Absolute stereochemistry is given according to the Cahn-Ingold-Prelog R-S system. If the compound is the pure enantiomer, the stereochemistry at each chiral carbon atom may be indicated as either R or S. Separated compounds whose absolute configuration is unknown may be indicated (+) or (-) depending on the direction (right- or levorotatory), in which they rotate plane-polarized light at the wavelength of the sodium D-line. Some of the compounds described herein contain one or more asymmetric centers or axes and may thus be the source of enantiomers, diastereomers, and other stereoisomeric forms that can be defined in terms of absolute stereochemistry as (R)- or (S)- .

The term "pharmaceutically acceptable salt" as used herein refers to a salt that does not abolish the biological activity and properties of the compounds disclosed herein and does not cause significant irritation to the subject to whom it is administered.

The term "subject" as used herein embraces mammals and non-mammals. Examples of mammals include, without limitation, humans, chimpanzees, great apes, non-human apes, cattle, horses, sheep, goats, pigs; rabbits, dogs, cats, rats, mice, guinea pigs, and the like. Examples of animals other than mammals include, without limitation, birds, fish, and the like. Often the subject is a person.

The term "subject in need of such treatment" refers to a subject who would benefit biologically, medically, or in terms of quality of life as a result of such treatment.

The term "therapeutically effective amount" as used herein refers to an amount that can increase an immune response, ameliorate at least one symptom or clinical sign of a tumor, and/or reduce the number and/or size of metastases. Reducing the intensity of at least one symptom or clinical sign of a tumor may include reducing the size of the tumor, stabilizing the size or growth of the tumor, reducing the rate of tumor growth, increasing the degree of tumor necrosis, changing the structure of the tumor, for example, decomposition, changing the biochemical marker associated with reduced development tumors, reducing tumor progression, or decreasing tumor survival. An increase in immune response refers to an increase in at least one cell-mediated immune response of a cell population that includes tumor cells, refers to an increase in at least one biochemical, histological or immunological marker associated with an improvement in the immunological profile of the tumor microenvironment. Markers for which an increase in the amount of the marker is associated with an improvement in the immunological profile of the tumor microenvironment include, without limitation, interferon-alpha; interferon-gamma; interferon-inducible proteins; interferon-gamma-induced protein 10 (IP-10); TNF-alpha; chemokines such as CCL2, CCL3, CCL4, CXCL2; activated T cells; activated B cells; activated NK cells; Tumor-specific T cells, tumor-associated activated macrophages; chemokine receptors such as CCR6; or lymphoid aggregates associated with the tumor. Markers associated with the tumor microenvironment can be determined, for example, by analyzing a biopsy (eg, obtained by needle biopsy) from the tumor, an area of a localized tumor, or a lymph node draining the tumor. Marker analysis can be performed using standard techniques such as histology (HNE staining), flow cytometry, gene expression assays (quantitative PCR), immunochemical techniques, as well as other techniques widely known to those skilled in the art.

The term "TLR7 agonist" as used herein refers to a compound that targets or activates the biological activity of the toll-like receptor 7 (TLR7). In particular, a "TLR7 agonist" may be a compound that activates TLR7 at an EC ₅₀ of less than 5 μM as measured by the reporter gene assay described herein, wherein human embryonic kidney 293 (HEK 293) cells were stably transfected using human TLR7. Preferably, a "TLR7 agonist" may be a compound that activates TLR7 at an EC ₅₀ of less than 1 μM as measured by the reporter gene assay described herein, wherein human embryonic kidney 293 (HEK 293) cells were stably transfected with human TLR7. A TLR7 agonist may be, for example, any compound described in WO 2011/049677 and the exemplary compounds described herein.

The terms "treat," "treat," "treatment," or "therapy" as used herein include treatment that alleviates, reduces, or alleviates at least one symptom in a subject, or has the effect of delaying the progression of a disease. For example, treatment may be the reduction of one or more symptoms of a disorder, or the complete elimination of a disorder such as cancer. In the context of the present invention, the term "treat" also means stopping, delaying the onset (ie, the period before the clinical manifestation of the disease) and/or reducing the risk of developing or exacerbating the disease. The term "protection" is used herein to mean preventing the delay or treatment, or, if necessary, the entire development, or continuation, or exacerbation of a disease in a subject, eg, a mammal or a human.

The terms "prevent", "exercise prevention" or "prevention" as used herein include prevention of at least one symptom caused by or associated with the condition, disease or disorder that is being prevented.

The names of the compounds presented in this document were obtained using ChemBioDraw Ultra 14.0 (CambridgeSoft®).

Unless otherwise indicated, the term "compounds of the present invention", "compounds of the invention" or "compounds disclosed herein" refers to compounds of formula (A) and their pharmaceutically acceptable salts, stereoisomers (including diastereoisomers and enantiomers), tautomers and isotopically labeled compounds (including deuterium substitutions).

As used herein, terms in the singular form and similar terms used in the context of the present invention (in particular, in the context of the claims) should be construed as covering both the singular form and the plural form, unless otherwise indicated in this document. or there is no clear contradiction with the context.

Description of the present invention and preferred embodiments

Pharmaceutical compositions

One aspect of the present invention is pharmaceutical compositions comprising a TLR7 agonist or a pharmaceutically acceptable salt thereof, one or more pharmaceutically acceptable excipients, and aluminum-containing particles. In some embodiments of this aspect, the pharmaceutical compositions are liquid compositions. In some embodiments, such liquid compositions are suspensions, while in other embodiments, such liquid compositions are solutions. In some embodiments of this aspect, these pharmaceutical compositions are solid compositions. In some embodiments, such solid compositions are lyophilizates, while in other embodiments, such solid compositions are spray-dried powders.

Another aspect of the present invention is a pharmaceutical composition comprising a TLR7 agonist or a pharmaceutically acceptable salt thereof, one or more pharmaceutically acceptable excipients, and a suspension of aluminum particles.

Another aspect of the present invention is pharmaceutical compositions containing a TLR7 agonist and one or more pharmaceutically acceptable excipients. In some embodiments of this aspect, these pharmaceutical compositions are solid compositions. In some embodiments, such solid compositions are lyophilizates, while in other embodiments, such solid compositions are spray-dried powders.

In particular, the pharmaceutical compositions of the present invention (liquid compositions or solid compositions) contain a compound having the structure of formula (A) or a pharmaceutically acceptable salt thereof,

formula (A),

where

R ¹ is -L ₁ R ⁴ , -L ₁ R ⁵ , -OL ₁ R ⁴ , -OL ₁ R ⁵ , CH ₃ , -C(=O)P(O)(OH) ₂ or -C(= O)CF ₂ P(O)(OH) ₂ ;

R² represents -L₂R^four, -L₂R⁶, -L₂L₃L₂R⁶, -L₂L₃R^four, -L₂L₃L₂R^four, -OL₂R^four, -OR^four, -OL₂R⁶, -OL₂L₃R⁶, -OL₂L₃L₂R⁶, -OL₂L_3R ^four -OL₂L₃L₂R^four or -OCH₃;

each R ³ is independently selected from H and fluorine;

R ⁴ is -P(O)(OH) ₂ ,

R ⁵ is -CF ₂ P(O)(OH) ₂ or -C(O)OH;

R ⁶ is -CF ₂ P(O)(OH) ₂ or -C(O)OH;

L₁ represents C₁-C₆alkylene, C₂-C₆alkenylene or -((CR^fourR^four)_pO)_q(CH₂)_p-, where C₁-C₆alkylene and C₂-C₆alkenylene in L₁ substituted with 0-4 fluoro groups;

each L ₂ is independently selected from C ₁ -C ₆ alkylene and -((CR ³ R ³ ) _p O) _q (CH ₂ ) _p - wherein the C ₁ -C ₆ alkylene in L ₂ is substituted with 0-4 fluoro groups;

L ₃ is arylene or 5-6 membered heteroarylene;

each p is independently selected from 1, 2, 3, 4, 5, and 6, and

q is 1, 2, 3 or 4,

and wherein the compound of formula (A) is a TLR7 agonist.

General procedures for the preparation of compounds of formula (A) are described in WO 2011/049677.

In some embodiments, the compounds of formula (A) are prepared as pharmaceutically acceptable base addition salts. Pharmaceutically acceptable base addition salts of the compounds of formula (A) include, without limitation, sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, copper, isopropylamine, benzathine, cholinate, diethanolamine, diethylamine, lysine, arginine, meglumine, piperazine salt forms. or tromethamine. Lists of additional suitable base addition salts can be found, for example, in "Remington's Pharmaceutical Sciences", 20th ed., Mack Publishing Company, Easton, Pa., (1985) and in "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002.

Pharmaceutical compositions according to the present invention are injectable compositions which contain a compound of formula (A) or a pharmaceutically acceptable salt thereof, aluminum particles and one or more pharmaceutically acceptable excipients. The compound of formula (A), or a pharmaceutically acceptable salt thereof, included in the pharmaceutical compositions of the present invention is present in a therapeutically effective amount. Pharmaceutically acceptable excipients included in the pharmaceutical compositions of the present invention include, without limitation, bulking agents, lyoprotectants, buffering agents, tonicity agents, isotonic agents, antioxidants, antimicrobial agents, antibacterial agents, antifungal agents, solubilizing agents, surfactants. substances and wetting agents. Such excipients for use in an injection formulation are known to those skilled in the art (see, for example, Remington's Pharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990 and Pharma Times, Vol. 45, No. 3, 2013 pp 65-77). Pharmaceutical compositions for parenteral use according to the present invention also contain water as a pharmaceutically and physiologically acceptable liquid carrier for injection.

Generally, to provide bulk and structure to the lyophilized powder, bulking agents are included in the lyophilized product to help dissolve the active agent. Lyoprotectors help to stabilize and prevent the decomposition of the active agent during freeze-drying and storage. Bulking agents and lyoprotectants that may be included in the pharmaceutical compositions of the present invention include, but are not limited to, sucrose, lactose, trehalose, mannitol, sorbitol, raffinose, glycine, histidine, polyethylene glycol, and low molecular weight polyvinyl pyrrolidones (i.e., povidone K12 and povidone K17).

Buffer agents are included in pharmaceutical compositions to adjust and stabilize pH and optimize the solubility and stability of active agents. Buffering agents are also used in the pharmaceutical compositions of the present invention to provide ionization of the phosphonic acid groups of the compounds of formula (A) (eg in the pH range of 7-9). Buffer agents that may be included in the pharmaceutical compositions of the present invention include, without limitation, tris, glycine, meglumine, histidine, and citrate/citric acid.

Tonicity agents and isotonic agents are included in pharmaceutical compositions to ensure that the composition is maintained isotonic in human plasma. Tonicity agents and isotonic agents that may be included in the pharmaceutical compositions of the present invention include, without limitation, dextrose, glycerin, sodium chloride, glycerin, and mannitol.

Antioxidants are used to prevent/minimize even the slightest oxidation of the active agent or excipients during storage, while antimicrobial agents are used to prevent the growth of microorganisms. Antioxidants that can be included in the pharmaceutical compositions of the present invention include, but are not limited to, ascorbic acid, acetylcysteine, sulfurous acid salts (bisulfite, metabisulfite), monothioglycerol, butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), and thiourea. Antimicrobial agents that can be included in the pharmaceutical compositions of the present invention include, without limitation, phenol, metacresol, benzyl alcohol, parabenmethyl, propyl, butyl, benzalkonium chloride, chlorobutanol, thimerosal, and phenylmercuric salts (acetate, borate, nitrate).

Solubilizing agents, which can be broadly classified as surfactants and co-solvents, help dissolve or increase the solubility of the active agent in the formulation. Surfactants that can be included in the pharmaceutical compositions of the present invention include, but are not limited to, polyoxyethylene sorbitan monooleate (Tween 80), sorbitan monooleate, polyoxyethylene sorbitan monolaurate (Tween 20), lecithin, polyoxyethylene-polyoxypropylene copolymers (Pluronics). Surfactants may also act as wetting agents, and surfactants/wetting agents that may be included in the pharmaceutical compositions of the present invention include, but are not limited to, lecithin, Polysorbate 20, Polysorbate 80, Pluronic F-68, and sorbitan trioleate (span 85 ).

Pharmaceutical compositions according to the present invention can be obtained using methods that involve mixing the compounds of formula (A) or its pharmaceutically acceptable salts with one or more pharmaceutically acceptable excipients and water. Alternatively, the pharmaceutical compositions of the present invention can be prepared by mixing a dissolved lyophilisate (dissolved with water) with a solution containing aluminum particles, the lyophilisate containing a compound of formula (A) or pharmaceutically acceptable salts thereof, a buffering agent (pH 7.0-8, 0), a bulking agent and a lyoprotectant.

In another aspect, pharmaceutical compositions according to the present invention can be obtained by mixing a dissolved lyophilisate (dissolved with water) with a solution containing aluminum particles, while the lyophilisate contains a compound of formula (A) or its pharmaceutically acceptable salts, a buffering agent (pH 7.0- 8.0), bulking agent, lyoprotectant, surfactant and wetting agent.

Particles that contain aluminum included in the pharmaceutical composition or lyophilisate of the present invention include, without limitation, aluminum hydroxide, aluminum oxyhydroxide, and aluminum hydroxyphosphate. The compounds of formula (A) can be associated with such particles, for example, by way of example only, aluminum hydroxide, aluminum oxyhydroxide and aluminum hydroxyphosphate. Aluminum particles have been used in vaccines for antigen binding. For a discussion of aluminum particles and their applications in vaccines, see Expert Rev. Vaccines , 46(5), 2007, 685-698 and Vaccines , 25, 2007, 6618-6624.

Some aspects and examples of pharmaceutical compositions according to the present invention are presented in the following list of numbered embodiments. It should be understood that the features indicated in each embodiment can be combined with other indicated features to obtain additional embodiments of the present invention.

Embodiment 1. A pharmaceutical composition comprising a TLR7 agonist having the structure of formula (A) or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients, wherein the compound of formula (A) is selected from any of the compounds in Table 1:

Table 1

Number
connections Structure Connection name 1

(3-(2-(2-(4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenoxy)ethoxy)ethoxy)-1 ,1-difluoropropyl)phosphonic acid 2

(3-(4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenoxy)propyl)phosphonic acid 3

4-(2-(5-Amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenyl dihydrogen phosphate four

((4-(2-(5-Amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenoxy)methyl)phosphonic acid five

5-(4-(2-(5-Amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenoxy)-1,1-difluoropentylphosphonic acid 6

(4-(4-(2-(5-Amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenoxy)-1,1-difluorobutyl)phosphonic acid 7

3-(2-(4-(2-(5-Amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenoxy)ethoxy)-1,1-difluoropropylphosphonic acid 8

2-(4-((4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenoxy)methyl)phenyl)-1,1- difluoroethylphosphonic acid nine

2-(5-Amino-2-(4-methoxy-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)-1,1-difluoro-2-oxoethylphosphonic acid 10

(E)-(2-(5-Amino-2-(4-methoxy-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)vinyl)phosphonic acid eleven

2-(5-Amino-2-(4-methoxy-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)ethylphosphonic acid 12

(E)-(2-(5-Amino-2-(4-methoxy-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)-1-fluorovinyl)phosphonic acid 13

(3-((4-(2-(5-Amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenoxy)methyl)phenyl)phosphonic acid fourteen

(5-Amino-2-(4-methoxy-2-methylphenethyl)benzo[f][1,7]naphthyridine-8-carbonyl)phosphonic acid 15

3-(5-Amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid sixteen

3-(5-Amino-2-(2-methyl-4-(3-phosphonopropoxy)phenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid 17

3-(5-Amino-2-(4-(4,4-difluoro-4-phosphonobutoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid eighteen

3-(5-amino-2-(4-(2-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridine-8 -yl) propanoic acid nineteen

3-(5-Amino-2-(2-methyl-4-(2-(2-(2-(2-phosphonoethoxy)ethoxy)ethoxy)ethoxy)phenethyl)benzo[f][1,7]naphthyridine-8 -yl) propanoic acid 20

3-(5-Amino-2-(2-methyl-4-(2-(2-(2-phosphonoethoxy)ethoxy)ethoxy)phenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid 21

3-(5-Amino-2-(2-methyl-4-(2-(2-phosphonoethoxy)ethoxy)phenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid 22

(2-(4-(2-(5-Amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenoxy)ethyl)phosphonic acid 23

(6-(4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenoxy)hexyl)phosphonic acid 24

(6-(4-(2-(5-Amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenoxy)-1,1-difluorohexyl)phosphonic acid 25

(4-((4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenoxy)methyl)benzyl)phosphonic acid 26

(2-(2-(2-(4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenoxy)ethoxy)ethoxy)ethyl) phosphonic acid 27

(5-(4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenoxy)pentyl)phosphonic acid 28

(4-(4-(2-(5-Amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenoxy)butyl)phosphonic acid

Embodiment 2. A pharmaceutical composition comprising a TLR7 agonist having the structure of formula (A) or a pharmaceutically acceptable salt thereof, aluminum particles and one or more pharmaceutically acceptable excipients, wherein the TLR7 agonist is a compound selected from any of the compounds in Table 1 .

Embodiment 3. A pharmaceutical composition comprising a TLR7 agonist having the structure of formula (A) or a pharmaceutically acceptable salt thereof, aluminum particles and one or more pharmaceutically acceptable excipients, wherein the TLR7 agonist is 3-(5-amino-2-( 4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid.

Embodiment 4. Pharmaceutical composition containing 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1.7] naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, aluminum particles and one or more pharmaceutically acceptable excipients.

Embodiment 5. A lyophilisate containing a TLR7 agonist having the structure of formula (A) or a pharmaceutically acceptable salt thereof, aluminum particles and one or more pharmaceutically acceptable excipients, wherein the TLR7 agonist is a compound selected from any of the compounds in Table 1.

Embodiment 6. A lyophilisate comprising a TLR7 agonist having the structure of formula (A) or a pharmaceutically acceptable salt thereof, aluminum particles and one or more pharmaceutically acceptable excipients, wherein the TLR7 agonist is 3-(5-amino-2-(4 -(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid.

Embodiment 7 Lyophilisate containing 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridine -8-yl) propanoic acid or a pharmaceutically acceptable salt thereof, aluminum particles and one or more pharmaceutically acceptable excipients.

Embodiment 8 A lyophilisate comprising a TLR7 agonist having the structure of formula (A) or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients, wherein the TLR7 agonist is 3-(5-amino-2-(4-(2 -(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid.

Embodiment 9 Lyophilisate containing 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridine -8-yl)propanoic acid or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.

Embodiment 10. A pharmaceutical composition comprising a compound having the structure of formula (A) or a pharmaceutically acceptable salt thereof, a suspension of aluminum particles, and one or more pharmaceutically acceptable excipients.

Embodiment 11. A pharmaceutical composition comprising a compound having the structure of formula (A) or a pharmaceutically acceptable salt thereof, a suspension of aluminum-containing particles, and a buffer agent.

Embodiment 12. A pharmaceutical composition comprising a compound having the structure of formula (A) or a pharmaceutically acceptable salt thereof, a suspension of aluminum particles, a buffer agent, and one or more pharmaceutically acceptable excipients.

Embodiment 13. A pharmaceutical composition comprising a compound of formula (A) or a pharmaceutically acceptable salt thereof, a suspension of aluminum particles and a buffer agent, wherein the composition has a pH in the range of 6.5-9.0.

Embodiment 14. A pharmaceutical composition comprising a compound of formula (A) or a pharmaceutically acceptable salt thereof, a suspension of aluminum particles, a buffer agent and one or more pharmaceutically acceptable excipients, wherein the composition has a pH in the range of 6.5-9.0.

Embodiment 15. A pharmaceutical composition comprising a compound of formula (A) or a pharmaceutically acceptable salt thereof, a suspension of aluminum particles and a buffering agent, wherein the composition has a pH in the range of 7.0-8.0.

Embodiment 16. A pharmaceutical composition comprising a compound of formula (A) or a pharmaceutically acceptable salt thereof, a suspension of aluminum particles, a buffer agent and one or more pharmaceutically acceptable excipients, wherein the composition has a pH in the range of 7.0-8.0.

Embodiment 17. A pharmaceutical composition comprising a compound of formula (A) or a pharmaceutically acceptable salt thereof, a suspension of aluminum particles, a buffer and sucrose, wherein the composition has a pH in the range of 7.0-8.0.

Embodiment 18. A pharmaceutical composition comprising a compound of formula (A) or a pharmaceutically acceptable salt thereof, a suspension of aluminum particles, a buffer agent and mannitol, wherein the composition has a pH in the range of 7.0-8.0.

Embodiment 19. A pharmaceutical composition comprising a compound of formula (A) or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles and a Tris buffer, wherein the composition has a pH in the range of 7.0-8.0.

Embodiment 20. A pharmaceutical composition comprising a compound of formula (A) or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles, Tris buffer and sucrose, wherein the composition has a pH in the range of 7.0-8.0.

Embodiment 21. Pharmaceutical composition containing 0.5-2 mg/ml of a compound of formula (A) or a pharmaceutically acceptable salt thereof, 5-100 mM Tris buffer, 5-10% (w/v) sucrose and a suspension of aluminum hydroxide particles , characterized by an aluminum content of 1-4 mg/ml, where the composition is characterized by a pH in the range of 7.0-8.0.

Embodiment 22. Pharmaceutical composition containing 0.5-2 mg/ml of a compound of formula (A) or a pharmaceutically acceptable salt thereof, 5-50 mM Tris buffer, 5-10% (w/v) sucrose and a suspension of aluminum hydroxide particles , characterized by an aluminum content of 1-4 mg/ml, where the composition is characterized by a pH in the range of 7.0-8.0.

Embodiment 23. Pharmaceutical composition containing 0.5-2 mg/ml of a compound of formula (A) or a pharmaceutically acceptable salt thereof, 5-20 mM Tris buffer, 5-10% (w/v) sucrose and a suspension of aluminum hydroxide particles , characterized by an aluminum content of 1-4 mg/ml, where the composition is characterized by a pH in the range of 7.0-8.0.

Embodiment 24. Pharmaceutical composition comprising 1 mg/mL of a compound of formula (A) or a pharmaceutically acceptable salt thereof, 5-20 mM Tris buffer, 5-10% (w/v) sucrose and a suspension of aluminum hydroxide particles characterized by an aluminum content 2 mg/ml, where the composition is characterized by a pH in the range of 7.0-8.0.

Embodiment 25. A pharmaceutical composition comprising 1 mg/mL of a compound of formula (A) or a pharmaceutically acceptable salt thereof, 16 mM Tris buffer, 7.5% (w/v) sucrose and a suspension of aluminum hydroxide particles having an aluminum content of 2 mg /ml, where the composition is characterized by a pH in the range of 7.0-8.0.

Embodiment 26. A pharmaceutical composition comprising 1 mg/mL of a compound of formula (A) or a pharmaceutically acceptable salt thereof, 5 mM Tris buffer, 8.25% (w/v) sucrose and a suspension of aluminum hydroxide particles having an aluminum content of 2 mg /ml, where the composition is characterized by a pH in the range of 7.0-8.0.

Embodiment 27 A pharmaceutical composition comprising 1 mg/mL of a compound of formula (A) or a pharmaceutically acceptable salt thereof, 16 mM Tris buffer, 7.5% (w/v) sucrose and a suspension of aluminum hydroxide particles having an aluminum content of 2 mg /ml, where the composition is characterized by a pH of 7.5 +/- 0.5.

Embodiment 28. A pharmaceutical composition comprising 1 mg/mL of a compound of formula (A) or a pharmaceutically acceptable salt thereof, 5 mM Tris buffer, 8.25% (w/v) sucrose, and a suspension of aluminum hydroxide particles having an aluminum content of 2 mg /ml, where the composition is characterized by a pH of 7.5 +/- 0.5.

Embodiment 29 A pharmaceutical composition comprising 1 mg/ml of a compound of formula (A) or a pharmaceutically acceptable salt thereof, 16 mM Tris buffer, 7.5% (w/v) sucrose and a suspension of aluminum hydroxide particles having an aluminum content of 2 mg /ml, where the composition is characterized by a pH of 7.5 +/- 0.3.

Embodiment 30. A pharmaceutical composition comprising 1 mg/mL of a compound of formula (A) or a pharmaceutically acceptable salt thereof, 5 mM Tris buffer, 8.25% (w/v) sucrose, and a suspension of aluminum hydroxide particles having an aluminum content of 2 mg /ml, where the composition is characterized by a pH of 7.5 +/- 0.3.

Embodiment 31. A pharmaceutical composition comprising a compound of formula (A) or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles, Tris buffer and mannitol, wherein the composition has a pH in the range of 7.0-8.0.

Embodiment 32. Pharmaceutical composition containing 0.5-2 mg/ml of a compound of formula (A) or a pharmaceutically acceptable salt thereof, 5-100 mM Tris buffer, 5-10% (w/v) mannitol, and a suspension of aluminum hydroxide particles , characterized by an aluminum content of 1-4 mg/ml, where the composition is characterized by a pH in the range of 7.0-8.0.

Embodiment 33. Pharmaceutical composition containing 0.5-2 mg/ml of a compound of formula (A) or a pharmaceutically acceptable salt thereof, 5-50 mM Tris buffer, 5-10% (w/v) mannitol, and a suspension of aluminum hydroxide particles , characterized by an aluminum content of 1-4 mg/ml, where the composition is characterized by a pH in the range of 7.0-8.0.

Embodiment 34. Pharmaceutical composition containing 0.5-2 mg/ml of a compound of formula (A) or a pharmaceutically acceptable salt thereof, 5-20 mM Tris buffer, 5-10% (w/v) mannitol, and a suspension of aluminum hydroxide particles , characterized by an aluminum content of 1-4 mg/ml, where the composition is characterized by a pH in the range of 7.0-8.0.

Embodiment 35. Pharmaceutical composition comprising 1 mg/mL of a compound of formula (A) or a pharmaceutically acceptable salt thereof, 5-20 mM Tris buffer, 5-10% (w/v) mannitol, and a suspension of aluminum hydroxide particles having an aluminum content 2 mg/ml, where the composition is characterized by a pH in the range of 7.0-8.0.

Embodiment 36. A pharmaceutical composition comprising 1 mg/mL of a compound of formula (A) or a pharmaceutically acceptable salt thereof, 16 mM Tris buffer, 7.5% (w/v) mannitol, and a suspension of aluminum hydroxide particles having an aluminum content of 2 mg /ml, where the composition is characterized by a pH in the range of 7.0-8.0.

Embodiment 37 A pharmaceutical composition comprising 1 mg/mL of a compound of formula (A) or a pharmaceutically acceptable salt thereof, 5 mM Tris buffer, 8.25% (w/v) mannitol, and a suspension of aluminum hydroxide particles having an aluminum content of 2 mg /ml, where the composition is characterized by a pH in the range of 7.0-8.0.

Embodiment 38. A pharmaceutical composition comprising 1 mg/mL of a compound of formula (A) or a pharmaceutically acceptable salt thereof, 16 mM Tris buffer, 7.5% (w/v) mannitol, and a suspension of aluminum hydroxide particles having an aluminum content of 2 mg /ml, where the composition is characterized by a pH of 7.5 +/- 0.5.

Embodiment 39. A pharmaceutical composition comprising 1 mg/mL of a compound of formula (A) or a pharmaceutically acceptable salt thereof, 5 mM Tris buffer, 8.25% (w/v) mannitol, and a suspension of aluminum hydroxide particles having an aluminum content of 2 mg /ml, where the composition is characterized by a pH of 7.5 +/- 0.5.

Embodiment 40. A pharmaceutical composition comprising 1 mg/mL of a compound of formula (A) or a pharmaceutically acceptable salt thereof, 16 mM Tris buffer, 7.5% (w/v) mannitol, and a suspension of aluminum hydroxide particles having an aluminum content of 2 mg /ml, where the composition is characterized by a pH of 7.5 +/- 0.3.

Embodiment 41 A pharmaceutical composition comprising 1 mg/mL of a compound of formula (A) or a pharmaceutically acceptable salt thereof, 5 mM Tris buffer, 8.25% (w/v) mannitol, and a suspension of aluminum hydroxide particles having an aluminum content of 2 mg /ml, where the composition is characterized by a pH of 7.5 +/- 0.3.

Embodiment 42. The pharmaceutical composition according to any one of Embodiments 10-41, wherein the compound of formula (A) is a compound selected from any of the compounds in Table 1, or a pharmaceutically acceptable salt thereof.

Embodiment 43. The pharmaceutical composition according to any one of Embodiments 10-42, wherein the compound of formula (A) is 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy )ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or 3-(5-amino-2-(2-methyl-4-(2-(2-(2 -phosphonoethoxy)ethoxy)ethoxy)phenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof.

Embodiment 44. The pharmaceutical composition according to any one of Embodiments 10-42, wherein the compound of formula (A) is 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy )ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof.

Embodiment 45. The pharmaceutical composition according to any one of Embodiments 10-42, wherein the compound of formula (A) is 3-(5-amino-2-(2-methyl-4-(2-(2-(2- phosphonoethoxy)ethoxy)ethoxy)phenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof.

Embodiment 46 A pharmaceutical composition according to any one of Embodiments 10-45, wherein the compound of formula (A) is present in a therapeutically effective amount.

Embodiment 47. A pharmaceutical composition according to any one of Embodiments 10-46, wherein the composition further comprises polyethylene glycol, polyoxyethylene sorbitan monooleate (Tween 80), or Pluronic F-68.

Embodiment 48 A pharmaceutical composition according to any one of Embodiments 10-46, wherein the composition further comprises 1-2% polyethylene glycol, polyoxyethylene sorbitan monooleate (Tween 80), or Pluronic F-68.

Embodiment 49 A pharmaceutical composition comprising 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7] naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, one or more pharmaceutically acceptable excipients, and a suspension of aluminum particles.

Embodiment 50 A pharmaceutical composition comprising 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7] naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a buffer agent and a suspension of aluminum particles.

Embodiment 51 A pharmaceutical composition comprising 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7] naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a buffering agent, one or more pharmaceutically acceptable excipients, and a suspension of aluminum particles.

Embodiment 52 A pharmaceutical composition comprising 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7] naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a buffer agent and a suspension of aluminum-containing particles, where the composition is characterized by a pH in the range of 6.5-9.0.

Embodiment 53 A pharmaceutical composition comprising 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7] naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a buffer agent, one or more pharmaceutically acceptable excipients and a suspension of aluminum-containing particles, where the composition is characterized by a pH in the range of 6.5-9.0.

Embodiment 54 A pharmaceutical composition comprising 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7] naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a buffer agent and a suspension of aluminum-containing particles, where the composition is characterized by a pH in the range of 7.0-8.0.

Embodiment 55 A pharmaceutical composition comprising 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7] naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a buffer agent, one or more pharmaceutically acceptable excipients and a suspension of aluminum-containing particles, where the composition is characterized by a pH in the range of 7.0-8.0.

Embodiment 56 A pharmaceutical composition comprising 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7] naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a buffer agent, sucrose and a suspension of aluminum-containing particles, where the composition is characterized by a pH in the range of 7.0-8.0.

Embodiment 57 A pharmaceutical composition comprising 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7] naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a buffer agent, mannitol and a suspension of aluminum-containing particles, where the composition is characterized by a pH in the range of 7.0-8.0.

Embodiment 58 A pharmaceutical composition comprising 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7] naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, Tris buffer and a suspension of aluminum hydroxide particles.

Embodiment 59 A pharmaceutical composition comprising 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7] naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, Tris buffer, sucrose and a suspension of aluminum hydroxide particles, where the composition is characterized by a pH in the range of 7.0-8.0.

Embodiment 60. Pharmaceutical composition containing 0.5-2 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo [f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, 5-100 mM Tris buffer, 5-10% (w/v) sucrose and a suspension of aluminum hydroxide particles, characterized by an aluminum content of 1 -4 mg/ml, where the composition is characterized by a pH in the range of 7.0-8.0.

Embodiment 61. Pharmaceutical composition containing 0.5-2 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo [f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, 5-50 mM Tris buffer, 5-10% (w/v) sucrose and a suspension of aluminum hydroxide particles, characterized by an aluminum content of 1 -4 mg/ml, where the composition is characterized by a pH in the range of 7.0-8.0.

Embodiment 62. Pharmaceutical composition containing 0.5-2 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo [f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, 5-20 mM Tris buffer, 5-10% (w/v) sucrose and a suspension of aluminum hydroxide particles characterized by an aluminum content of 1 -4 mg/ml, where the composition is characterized by a pH in the range of 7.0-8.0.

Embodiment 63 A pharmaceutical composition containing 1 mg/mL 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][ 1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, 5-20 mM Tris buffer, 5-10% (w/v) sucrose and a suspension of aluminum hydroxide particles, characterized by an aluminum content of 2 mg/ml, where the composition is characterized by a pH in the range of 7.0-8.0.

Embodiment 64. Pharmaceutical composition containing 1 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][ 1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, 16 mM Tris buffer, 7.5% (w/v) sucrose and a suspension of aluminum hydroxide particles characterized by an aluminum content of 2 mg/ml, wherein the composition characterized by pH in the range of 7.0-8.0.

Embodiment 65. Pharmaceutical composition containing 1 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][ 1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, 5 mM Tris buffer, 8.25% (w/v) sucrose and a suspension of aluminum hydroxide particles characterized by an aluminum content of 2 mg/ml, wherein the composition characterized by pH in the range of 7.0-8.0.

Embodiment 66. Pharmaceutical composition containing 1 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][ 1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, 16 mM Tris buffer, 7.5% (w/v) sucrose and a suspension of aluminum hydroxide particles characterized by an aluminum content of 2 mg/ml, wherein the composition characterized by a pH of 7.5 +/- 0.5.

Embodiment 67. Pharmaceutical composition containing 1 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][ 1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, 5 mM Tris buffer, 8.25% (w/v) sucrose and a suspension of aluminum hydroxide particles characterized by an aluminum content of 2 mg/ml, wherein the composition characterized by a pH of 7.5 +/- 0.5.

Embodiment 68. Pharmaceutical composition containing 1 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][ 1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, 16 mM Tris buffer, 7.5% (w/v) sucrose and a suspension of aluminum hydroxide particles characterized by an aluminum content of 2 mg/ml, wherein the composition characterized by a pH of 7.5 +/- 0.3.

Embodiment 69 A pharmaceutical composition containing 1 mg/mL 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][ 1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, 5 mM Tris buffer, 8.25% (w/v) sucrose and a suspension of aluminum hydroxide particles characterized by an aluminum content of 2 mg/ml, wherein the composition characterized by a pH of 7.5 +/- 0.3.

Embodiment 70 A pharmaceutical composition comprising 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7] naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, tris buffer, mannitol and a suspension of aluminum hydroxide particles, where the composition is characterized by a pH in the range of 7.0-8.0.

Embodiment 71. Pharmaceutical composition containing 0.5-2 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo [f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, 5-100 mM Tris buffer, 5-10% (w/v) mannitol, and an aluminum hydroxide particle suspension having an aluminum content of 1 -4 mg/ml, where the composition is characterized by a pH in the range of 7.0-8.0.

Embodiment 72. Pharmaceutical composition containing 0.5-2 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo [f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, 5-50 mM Tris buffer, 5-10% (w/v) mannitol, and an aluminum hydroxide particle suspension having an aluminum content of 1 -4 mg/ml, where the composition is characterized by a pH in the range of 7.0-8.0.

Embodiment 73. Pharmaceutical composition containing 0.5-2 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo [f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, 5-20 mM Tris buffer, 5-10% (w/v) mannitol, and an aluminum hydroxide particle suspension having an aluminum content of 1 -4 mg/ml, where the composition is characterized by a pH in the range of 7.0-8.0.

Embodiment 74. Pharmaceutical composition containing 1 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][ 1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, 5-20 mM Tris buffer, 5-10% (w/v) mannitol and a suspension of aluminum hydroxide particles characterized by an aluminum content of 2 mg/ml, where the composition is characterized by a pH in the range of 7.0-8.0.

Embodiment 75. Pharmaceutical composition containing 1 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][ 1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, 16 mM Tris buffer, 7.5% (w/v) mannitol and a suspension of aluminum hydroxide particles characterized by an aluminum content of 2 mg/mL, wherein the composition characterized by pH in the range of 7.0-8.0.

Embodiment 76. Pharmaceutical composition containing 1 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][ 1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, 5 mM Tris buffer, 8.25% (w/v) mannitol and a suspension of aluminum hydroxide particles characterized by an aluminum content of 2 mg/ml, wherein the composition characterized by pH in the range of 7.0-8.0.

Embodiment 77. Pharmaceutical composition containing 1 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][ 1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, 16 mM Tris buffer, 7.5% (w/v) mannitol and a suspension of aluminum hydroxide particles characterized by an aluminum content of 2 mg/mL, wherein the composition characterized by a pH of 7.5 +/- 0.5.

Embodiment 78. Pharmaceutical composition containing 1 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][ 1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, 5 mM Tris buffer, 8.25% (w/v) mannitol and a suspension of aluminum hydroxide particles characterized by an aluminum content of 2 mg/ml, wherein the composition characterized by a pH of 7.5 +/- 0.5.

Embodiment 79 A pharmaceutical composition containing 1 mg/mL 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][ 1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, 16 mM Tris buffer, 7.5% (w/v) mannitol and a suspension of aluminum hydroxide particles characterized by an aluminum content of 2 mg/mL, wherein the composition characterized by a pH of 7.5 +/- 0.3.

Embodiment 80. Pharmaceutical composition containing 1 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][ 1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, 5 mM Tris buffer, 8.25% (w/v) mannitol and a suspension of aluminum hydroxide particles characterized by an aluminum content of 2 mg/ml, wherein the composition characterized by a pH of 7.5 +/- 0.3.

Embodiment 81 A pharmaceutical composition according to any one of Embodiments 49-80 wherein 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl )benzo[f][1,7]naphthyridin-8-yl)propanoic acid is present in a therapeutically effective amount.

Embodiment 82. A pharmaceutical composition according to any one of Embodiments 49-81, wherein the composition further comprises polyethylene glycol, polyoxyethylene sorbitan monooleate (Tween 80), or Pluronic F-68.

Embodiment 83 A pharmaceutical composition according to any one of Embodiments 49-81, wherein the composition further comprises 1-2% polyethylene glycol, polyoxyethylene sorbitan monooleate (Tween 80), or Pluronic F-68.

Embodiment 84. A lyophilisate comprising a compound of formula (A) or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.

Embodiment 85. A lyophilisate containing a compound of formula (A) or a pharmaceutically acceptable salt thereof and a buffering agent.

Embodiment 86. A lyophilisate comprising a compound of formula (A) or a pharmaceutically acceptable salt thereof, a buffering agent, and one or more pharmaceutically acceptable excipients.

Embodiment 87 A lyophilisate comprising a compound of formula (A) or a pharmaceutically acceptable salt thereof and a Tris buffer.

Embodiment 88. A lyophilisate containing a compound of formula (A) or a pharmaceutically acceptable salt thereof, Tris buffer and sucrose.

Embodiment 89 A lyophilisate containing a compound of formula (A) or a pharmaceutically acceptable salt thereof, Tris buffer and mannitol.

Embodiment 90 A lyophilisate prepared from a solution having a pH of 6.5-9.0 and containing a compound of formula (A) or a pharmaceutically acceptable salt thereof and a buffer.

Embodiment 91 A lyophilisate prepared from a solution having a pH of 6.5-9.0 and containing a compound of formula (A) or a pharmaceutically acceptable salt thereof, a buffering agent and one or more pharmaceutically acceptable excipients.

Embodiment 92 A lyophilisate prepared from a solution having a pH of 7.0-8.0 and containing a compound of formula (A) or a pharmaceutically acceptable salt thereof and a buffer.

Embodiment 93 A lyophilisate prepared from a solution having a pH of 7.0-8.0 and containing a compound of formula (A) or a pharmaceutically acceptable salt thereof, a buffering agent and one or more pharmaceutically acceptable excipients.

Embodiment 94 A lyophilisate prepared from a solution having a pH of 7.0-8.0 and containing a compound of formula (A) or a pharmaceutically acceptable salt thereof, a buffer and sucrose.

Embodiment 95 A lyophilisate prepared from a solution having a pH of 7.0-8.0 and containing a compound of formula (A) or a pharmaceutically acceptable salt thereof, a buffer and mannitol.

Embodiment 96 A lyophilisate prepared from a solution having a pH of 7.0-8.0 and containing a compound of formula (A) or a pharmaceutically acceptable salt thereof and Tris buffer.

Embodiment 97 A lyophilisate prepared from a solution having a pH of 7.0-8.0 and containing a compound of formula (A) or a pharmaceutically acceptable salt thereof, Tris buffer and sucrose.

Embodiment 98 A lyophilisate prepared from a solution having a pH of 7.0-8.0 and containing 0.5-2 mg/mL of a compound of formula (A) or a pharmaceutically acceptable salt thereof, 5-100 mM Tris buffer and 5- 10% (w/v) sucrose.

Embodiment 99 A lyophilisate prepared from a solution having a pH of 7.0-8.0 and containing 0.5-2 mg/mL of a compound of formula (A) or a pharmaceutically acceptable salt thereof, 5-50 mM Tris buffer and 5- 10% (w/v) sucrose.

Embodiment 100. A lyophilisate prepared from a solution having a pH of 7.0-8.0 and containing 0.5-2 mg/ml of a compound of formula (A) or a pharmaceutically acceptable salt thereof, 5-20 mM Tris buffer and 5- 10% (w/v) sucrose.

Embodiment 101 A lyophilisate prepared from a solution having a pH of 7.0-8.0 and containing 1 mg/mL of a compound of formula (A) or a pharmaceutically acceptable salt thereof, 5-20 mM Tris buffer and 5-10% (wt.) /volume) sucrose.

Embodiment 102. A lyophilisate prepared from a solution having a pH of 7.0-8.0 and containing 1 mg/mL of a compound of formula (A) or a pharmaceutically acceptable salt thereof, 16 mM Tris buffer and 7.5% (w/v ) sucrose.

Embodiment 103 A lyophilisate prepared from a solution having a pH of 7.0-8.0 and containing 1 mg/mL of a compound of formula (A) or a pharmaceutically acceptable salt thereof, 5 mM Tris buffer and 8.25% (w/v ) sucrose.

Embodiment 104 A lyophilisate prepared from a solution having a pH of 7.5 +/- 0.5 and containing 1 mg/mL of a compound of formula (A) or a pharmaceutically acceptable salt thereof, 16 mM Tris buffer and 7.5% (wt.) /volume) sucrose.

Embodiment 105 A lyophilisate prepared from a solution having a pH of 7.5 +/- 0.5 and containing 1 mg/mL of a compound of formula (A) or a pharmaceutically acceptable salt thereof, 5 mM Tris buffer and 8.25% (wt.) /volume) sucrose.

Embodiment 106 A lyophilisate prepared from a solution having a pH of 7.5 +/- 0.3 and containing 1 mg/mL of a compound of formula (A) or a pharmaceutically acceptable salt thereof, 16 mM Tris buffer and 7.5% (wt.) /volume) sucrose.

Embodiment 107 A lyophilisate prepared from a solution having a pH of 7.5 +/- 0.3 and containing 1 mg/ml of a compound of formula (A) or a pharmaceutically acceptable salt thereof, 5 mM Tris buffer and 8.25% (wt.) /volume) sucrose.

Embodiment 108 A lyophilisate prepared from a solution having a pH of 7.0-8.0 and containing a compound of formula (A) or a pharmaceutically acceptable salt thereof, Tris buffer and mannitol.

Embodiment 109 A lyophilisate prepared from a solution having a pH of 7.0-8.0 and containing 0.5-2 mg/mL of a compound of formula (A) or a pharmaceutically acceptable salt thereof, 5-100 mM Tris buffer and 5- 10% (w/v) mannitol.

Embodiment 110 A lyophilisate prepared from a solution having a pH of 7.0-8.0 and containing 0.5-2 mg/mL of a compound of formula (A) or a pharmaceutically acceptable salt thereof, 5-50 mM Tris buffer and 5- 10% (w/v) mannitol.

Embodiment 111 A lyophilisate prepared from a solution having a pH of 7.0-8.0 and containing 0.5-2 mg/mL of a compound of formula (A) or a pharmaceutically acceptable salt thereof, 5-20 mM Tris buffer and 5- 10% (w/v) mannitol.

Embodiment 112 A lyophilisate prepared from a solution having a pH of 7.0-8.0 and containing 1 mg/mL of a compound of formula (A) or a pharmaceutically acceptable salt thereof, 5-20 mM Tris buffer and 5-10% (wt.) /volume) mannitol.

Embodiment 113 A lyophilisate prepared from a solution having a pH of 7.0-8.0 and containing 1 mg/mL of a compound of formula (A) or a pharmaceutically acceptable salt thereof, 16 mM Tris buffer and 7.5% (w/v ) mannitol.

Embodiment 114 A lyophilisate prepared from a solution having a pH of 7.0-8.0 and containing 1 mg/mL of a compound of formula (A) or a pharmaceutically acceptable salt thereof, 5 mM Tris buffer and 8.25% (w/v ) mannitol.

Embodiment 115 A lyophilisate prepared from a solution having a pH of 7.5 +/- 0.5 and containing 1 mg/mL of a compound of formula (A) or a pharmaceutically acceptable salt thereof, 16 mM Tris buffer and 7.5% (wt.) /volume) mannitol.

Embodiment 116 A lyophilisate prepared from a solution having a pH of 7.5 +/- 0.5 and containing 1 mg/mL of a compound of formula (A) or a pharmaceutically acceptable salt thereof, 5 mM Tris buffer and 8.25% (wt.) /volume) mannitol.

Embodiment 117 A lyophilisate prepared from a solution having a pH of 7.5 +/- 0.3 and containing 1 mg/mL of a compound of formula (A) or a pharmaceutically acceptable salt thereof, 16 mM Tris buffer and 7.5% (wt.) /volume) mannitol.

Embodiment 118 A lyophilisate prepared from a solution having a pH of 7.5 +/- 0.3 and containing 1 mg/mL of a compound of formula (A) or a pharmaceutically acceptable salt thereof, 5 mM Tris buffer and 8.25% (wt.) /volume) mannitol.

Embodiment 119. A lyophilisate according to any one of Embodiments 84-118, wherein the compound of formula (A) is a compound selected from any of the compounds in Table 1 or a pharmaceutically acceptable salt thereof.

Embodiment 120. A lyophilisate according to any one of Embodiments 84-118 wherein the compound of formula (A) is 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy) ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or 3-(5-amino-2-(2-methyl-4-(2-(2-(2- phosphonoethoxy)ethoxy)ethoxy)phenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof.

Embodiment 121. A lyophilisate according to any one of Embodiments 84-118 wherein the compound of formula (A) is 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy) ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof.

Embodiment 122 A lyophilisate according to any one of Embodiments 84-118 wherein the compound of formula (A) is 3-(5-amino-2-(2-methyl-4-(2-(2-(2-phosphonoethoxy )ethoxy)ethoxy)phenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof.

Embodiment 123 Lyophilisate containing 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridine -8-yl)propanoic acid or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.

Embodiment 124 Lyophilisate containing 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridine -8-yl)propanoic acid or a pharmaceutically acceptable salt thereof and a buffering agent.

Embodiment 125 Lyophilisate containing 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridine -8-yl) propanoic acid or a pharmaceutically acceptable salt thereof, a buffering agent and one or more pharmaceutically acceptable excipients.

Embodiment 126 Lyophilisate containing 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridine -8-yl) propanoic acid or a pharmaceutically acceptable salt thereof; and a Tris buffer.

Embodiment 127. Lyophilisate containing 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridine -8-yl) propanoic acid or a pharmaceutically acceptable salt thereof, Tris buffer and sucrose.

Embodiment 128. Lyophilisate containing 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridine -8-yl) propanoic acid or a pharmaceutically acceptable salt thereof, Tris buffer and mannitol.

Embodiment 129 A lyophilisate prepared from a solution having a pH of 6.5-9.0 and containing 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)- 2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof and a buffer agent.

Embodiment 130. A lyophilisate prepared from a solution having a pH of 6.5-9.0 and containing 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)- 2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a buffering agent and one or more pharmaceutically acceptable excipients.

Embodiment 131 A lyophilisate prepared from a solution having a pH of 7.0-8.0 and containing 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)- 2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof and a buffer agent.

Embodiment 132. A lyophilisate prepared from a solution having a pH of 7.0-8.0 and containing 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)- 2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a buffering agent and one or more pharmaceutically acceptable excipients.

Embodiment 133. A lyophilisate prepared from a solution having a pH of 7.0-8.0 and containing 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)- 2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a buffer and sucrose.

Embodiment 134. A lyophilisate prepared from a solution having a pH of 7.0-8.0 and containing 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)- 2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a buffer and mannitol.

Embodiment 135. A lyophilisate prepared from a solution having a pH of 7.0-8.0 and containing 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)- 2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof and Tris buffer.

Embodiment 136 A lyophilisate prepared from a solution having a pH of 7.0-8.0 and containing 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)- 2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, Tris buffer and sucrose.

Embodiment 137 A lyophilisate prepared from a solution having a pH of 7.0-8.0 and containing 0.5-2 mg/mL of 3-(5-amino-2-(4-(2-(3,3-difluoro -3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, 5-100 mM Tris buffer and 5-10% (wt/ volume) sucrose.

Embodiment 138. A lyophilisate prepared from a solution having a pH of 7.0-8.0 and containing 0.5-2 mg/mL of 3-(5-amino-2-(4-(2-(3,3-difluoro -3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, 5-50 mM Tris buffer and 5-10% (wt/ volume) sucrose.

Embodiment 139 A lyophilisate prepared from a solution having a pH of 7.0-8.0 and containing 0.5-2 mg/mL of 3-(5-amino-2-(4-(2-(3,3-difluoro -3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, 5-20 mM Tris buffer and 5-10% (wt/ volume) sucrose.

Embodiment 140 A lyophilisate prepared from a solution having a pH of 7.0-8.0 and containing 1 mg/mL of 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy )ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, 5-20 mM Tris buffer and 5-10% (w/v) sucrose.

Embodiment 141 A lyophilisate prepared from a solution having a pH of 7.0-8.0 and containing 1 mg/mL of 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy )ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, 16 mM Tris buffer and 7.5% (w/v) sucrose.

Embodiment 142 A lyophilisate prepared from a solution having a pH of 7.0-8.0 and containing 1 mg/mL of 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy )ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, 5 mM Tris buffer and 8.25% (w/v) sucrose.

Embodiment 143. A lyophilisate prepared from a solution having a pH of 7.5 +/- 0.5 and containing 1 mg/mL of 3-(5-amino-2-(4-(2-(3,3-difluoro-3 -phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, 16 mM Tris buffer and 7.5% (w/v) sucrose.

Embodiment 144. A lyophilisate prepared from a solution having a pH of 7.5 +/- 0.5 and containing 1 mg/mL of 3-(5-amino-2-(4-(2-(3,3-difluoro-3 -phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, 5 mM Tris buffer and 8.25% (w/v) sucrose.

Embodiment 145. A lyophilisate prepared from a solution having a pH of 7.5 +/- 0.3 and containing 1 mg/mL of 3-(5-amino-2-(4-(2-(3,3-difluoro-3 -phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, 16 mM Tris buffer and 7.5% (w/v) sucrose.

Embodiment 146. A lyophilisate prepared from a solution having a pH of 7.5 +/- 0.3 and containing 1 mg/mL of 3-(5-amino-2-(4-(2-(3,3-difluoro-3 -phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, 5 mM Tris buffer and 8.25% (w/v) sucrose.

Embodiment 147 A lyophilisate prepared from a solution having a pH of 7.0-8.0 and containing 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)- 2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, Tris buffer and mannitol.

Embodiment 148. A lyophilisate prepared from a solution having a pH of 7.0-8.0 and containing 0.5-2 mg/mL of 3-(5-amino-2-(4-(2-(3,3-difluoro -3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, 5-100 mM Tris buffer and 5-10% (wt/ volume) mannitol.

Embodiment 149 A lyophilisate prepared from a solution having a pH of 7.0-8.0 and containing 0.5-2 mg/mL of 3-(5-amino-2-(4-(2-(3,3-difluoro -3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, 5-50 mM Tris buffer and 5-10% (wt/ volume) mannitol.

Embodiment 150. A lyophilisate prepared from a solution having a pH of 7.0-8.0 and containing 0.5-2 mg/mL of 3-(5-amino-2-(4-(2-(3,3-difluoro -3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, 5-20 mM Tris buffer and 5-10% (wt/ volume) mannitol.

Embodiment 151 A lyophilisate prepared from a solution having a pH of 7.0-8.0 and containing 1 mg/mL of 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy )ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, 5-20 mM Tris buffer and 5-10% (w/v) mannitol.

Embodiment 152 A lyophilisate prepared from a solution having a pH of 7.0-8.0 and containing 1 mg/mL of 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy )ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, 16 mM Tris buffer and 7.5% (w/v) mannitol.

Embodiment 153 A lyophilisate prepared from a solution having a pH of 7.0-8.0 and containing 1 mg/mL of 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy )ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, 5 mM Tris buffer and 8.25% (w/v) mannitol.

Embodiment 154. A lyophilisate prepared from a solution having a pH of 7.5 +/- 0.5 and containing 1 mg/mL of 3-(5-amino-2-(4-(2-(3,3-difluoro-3 -phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, 16 mM Tris buffer and 7.5% (w/v) mannitol.

Embodiment 155. A lyophilisate prepared from a solution having a pH of 7.5 +/- 0.5 and containing 1 mg/mL of 3-(5-amino-2-(4-(2-(3,3-difluoro-3 -phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, 5 mM Tris buffer and 8.25% (w/v) mannitol.

Embodiment 156. A lyophilisate prepared from a solution having a pH of 7.5 +/- 0.3 and containing 1 mg/mL of 3-(5-amino-2-(4-(2-(3,3-difluoro-3 -phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, 16 mM Tris buffer and 7.5% (w/v) mannitol.

Embodiment 157. A lyophilisate prepared from a solution having a pH of 7.5 +/- 0.3 and containing 1 mg/mL of 3-(5-amino-2-(4-(2-(3,3-difluoro-3 -phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, 5 mM Tris buffer and 8.25% (w/v) mannitol.

Embodiment 158. A lyophilizate according to any one of Embodiments 84-157 further comprising aluminum-containing particles.

Embodiment 159. A lyophilisate according to any one of Embodiments 84-157 further comprising particles of aluminum hydroxide.

Embodiment 160. A lyophilisate according to any of Embodiments 84-159 further comprising polyethylene glycol, polyoxyethylene sorbitan monooleate (Tween 80), or Pluronic F-68.

Embodiment 161 A pharmaceutical composition obtained by dissolving a lyophilisate according to any of Embodiments 84-157 with water and mixing with a suspension of aluminum particles having an aluminum content of 1-4 mg/mL.

Embodiment 162. A pharmaceutical composition obtained by dissolving the lyophilisate of any one of Embodiments 84-157 with water and mixing with a suspension of aluminum hydroxide particles having an aluminum content of 1-4 mg/mL.

Embodiment 163 A pharmaceutical composition obtained by dissolving the lyophilisate of any one of Embodiments 84-157 with water and mixing with a suspension of aluminum particles having an aluminum content of 2 mg/mL.

Embodiment 164 A pharmaceutical composition obtained by dissolving a lyophilizate according to any of Embodiments 84-157 with water and mixing with a suspension of aluminum hydroxide particles having an aluminum content of 2 mg/mL.

The aluminum-containing particles in pharmaceutical compositions and certain lyophilisates according to the present invention may be present in the form of a suspension. As a rule, aluminum-containing particles are present in the form of a 0.1-5% suspension. In some embodiments, the implementation of the aluminum-containing particles may be present in the form of 0.1-2% suspension. The size distribution of aluminum-containing particles can be 0.1-20 micrometers. In some embodiments, the implementation of the distribution of aluminum-containing particles in size may be 1-20 micrometers. In some embodiments, the implementation of the distribution of aluminum-containing particles in size may be 2-10 micrometers. In other embodiments, the implementation of the aluminum-containing particles are 0.3-0.4% suspension with a size distribution of 2-10 micrometers. In another embodiment, a 0.4% suspension of aluminum-containing particles with a size distribution of 2-10 micrometers is provided.

By way of example, the aluminum-containing particles in the pharmaceutical compositions and certain lyophilisates of the present invention are aluminum hydroxide particles. Typically, the aluminum hydroxide particles are present as a 0.1-5% slurry, but preferably as a 0.1-2% slurry. The aluminum hydroxide particle size distribution is typically 1-20 micrometers, but preferably the aluminum hydroxide particle size distribution is 2-10 micrometers. In some embodiment, the aluminum hydroxide particles are present as a 0.3-0.4% suspension with a size distribution of 2-10 micrometers. In another embodiment, a 0.4% suspension of aluminum hydroxide particles with a size distribution of 2-10 micrometers is provided.

In some embodiments, the aluminum-containing particles are aluminum hydroxide particles and the compounds of formula (A) are bonded to/adsorbed on the aluminum hydroxide particles. In still other embodiments, the aluminum-containing particles are aluminum hydroxide particles and the compound is 3-(5 -amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid, where 3- (5-Amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid is linked to particles of aluminum hydroxide/adsorbed on particles of aluminum hydroxide.

The efficiency of binding compounds of formula (A) with aluminum-containing particles

The compounds of formula (A) in pharmaceutical compositions and lyophilisates according to the present invention can be associated with aluminum-containing particles, for example, by way of example only, aluminum hydroxide particles, aluminum oxyhydroxide particles and aluminum hydroxyphosphate particles. The compounds of formula (A) contain either a phosphate or a phosphonate (ionized phosphonic acid), with certain compounds of formula (A) having additional ionizable groups such as a carboxylic acid. Compounds of formula (A) can be bonded to/adsorbed onto aluminum hydroxide particles via ionic interactions between the aluminum ions of the aluminum-containing particle and the phosphate or phosphonate group of the compound of formula (A).

The binding efficiency of the compounds of formula (A) to the aluminum-containing particle, expressed as percentage (%) binding to the aluminum-containing particle, depends on the ratio (w/w) of the weight of the compound and the weight of aluminum in the aluminum-containing particles. In addition, depending on the ratio (weight/weight), the binding efficiency has an obvious dependence on pH. Binding to aluminum-containing particles/adsorption on aluminum-containing particles of compounds of formula (A) is mediated by ionic charge interactions between aluminum ions and the phosphate or phosphonate group of the compound of formula (A). Binding/adsorption is best achieved in the pH range from the point of zero charge (PZC) of the compound of formula (A) to the PZC of the aluminum-containing particles. The adsorption of compounds of formula (A) on aluminum-containing particles is demonstrated in Example 3 and Example 4. Example 4 illustrates the dependence of the binding efficiency on the ratio (w/w) of the weight of aluminum in the aluminum-containing particles and the weight of the compound, as well as the dependence on pH. In addition, at a constant aluminum to compound ratio, the binding efficiency may depend on the final concentration of the compound of formula (A) at values less than 0.5 mg/ml.

In some embodiments, the binding efficiency of the compound of formula (A) to the aluminum-containing particles is 75-100%. In other embodiments, the binding efficiency of the compound of formula (A) to the aluminum-containing particles is 80-100%. In additional embodiments, the binding efficiency of the compound of formula (A) to aluminum-containing particles is 95-100%. In additional embodiments, the binding efficiency of the compound of formula (A) to aluminum-containing particles is 97-100%. In additional embodiments, the binding efficiency of the compound of formula (A) to the aluminum-containing particles is 98-100%.

In some embodiments, the aluminum-containing particles are aluminum hydroxide particles and the binding efficiency of the compound of formula (A) to the aluminum hydroxide particles is 75-100%. In other embodiments, the aluminum-containing particles are aluminum hydroxide particles and the binding efficiency of the compound of formula (A) to the aluminum hydroxide particles is 80-100%. In further embodiments, the aluminum-containing particles are aluminum hydroxide particles and the binding efficiency of the compound of formula (A) to the aluminum hydroxide particles is 95-100%. In further embodiments, the aluminum-containing particles are aluminum hydroxide particles and the binding efficiency of the compound of formula (A) to the aluminum hydroxide particles is 97-100%. In further embodiments, the aluminum-containing particles are aluminum hydroxide particles and the binding efficiency of the compound of formula (A) to the aluminum hydroxide particles is 98-100%.

In another embodiment, the aluminum-containing particles are aluminum hydroxide particles and the compound is 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo [f][1,7]naphthyridin-8-yl)propanoic acid, where the binding efficiency of 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2 -methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid with particles of aluminum hydroxide is 95-100%. In a further embodiment, the aluminum-containing particles are aluminum hydroxide particles and the compound is 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo [f][1,7]naphthyridin-8-yl)propanoic acid, while the binding efficiency of 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)- 2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid with particles of aluminum hydroxide is 97-100%. In one embodiment, the aluminum-containing species is aluminum hydroxide and the compound is 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[ f][1,7]naphthyridin-8-yl)propanoic acid, while the binding efficiency of 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2 -methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid with particles of aluminum hydroxide is 98-100%.

Typically, a binding efficiency of approximately 75%-100% in the case of binding a compound of formula (A) to aluminum-containing particles can be achieved at a ratio (w/w) of the weight of aluminum in the aluminum-containing particles and the weight of the compound of formula (A) in range from about 0.8:1 to about 2.5:1. In some embodiments, binding efficiencies in the range of 80%-100% can be achieved with a ratio (w/w) of aluminum in the alumina-containing particles to a compound of formula (A) ranging from 1:1 to 2.5:1. In other embodiments, binding efficiencies in the range of 90%-100% can be achieved with a ratio (w/w) of aluminum in the alumina-containing particles to a compound of formula (A) ranging from 1.25:1 to 2.5:1. In other embodiments, binding efficiencies in the range of 97%-100% can be achieved with a ratio (w/w) of aluminum in the alumina-containing particles to a compound of formula (A) ranging from 1.5:1 to 2.5:1. In other embodiments, binding efficiencies in the range of 97%-100% can be achieved with a ratio (w/w) of aluminum in the alumina-containing particles to a compound of formula (A) ranging from 1.5:1 to 2:1. In other embodiments, binding efficiencies in the range of 98%-100% can be achieved with a ratio (w/w) of aluminum in the alumina-containing particles to the compound of formula (A) ranging from 1.5:1 to 2:1.

Typically, a binding efficiency of approximately 75% - 100% in the case of binding 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl) benzo[f][1,7]naphthyridin-8-yl)propane with alumina particles can be provided at a ratio (w/w) of the weight of aluminum in the alumina particles and the weight of 3-(5-amino-2-(4-(2- (3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1.7]naphthyridin-8-yl)propanoic ranging from about 0.8:1 to about 2.5 :1. In some embodiments, binding efficiencies in the range of 80%-100% can be achieved at a ratio (w/w) of the weight of aluminum in the aluminum-containing particles to the weight of 3-(5-amino-2-(4-(2-(3,3- difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic, ranging from 1:1 to 2.5:1. In other embodiments, binding efficiencies in the range of 90%-100% can be achieved at a ratio (w/w) of the weight of aluminum in the aluminum-containing particles to the weight of 3-(5-amino-2-(4-(2-(3,3- difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic, ranging from 1.25:1 to 2.5:1. In other embodiments, binding efficiencies in the range of 97%-100% can be achieved at a ratio (w/w) of the weight of aluminum in the aluminum-containing particles to the weight of 3-(5-amino-2-(4-(2-(3,3- difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic, ranging from 1.5:1 to 2.5:1. In other embodiments, binding efficiencies in the range of 97%-100% can be achieved at a ratio (w/w) of the weight of aluminum in the aluminum-containing particles to the weight of 3-(5-amino-2-(4-(2-(3,3- difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic, ranging from 1.5:1 to 2:1. In other embodiments, binding efficiencies in the range of 98%-100% can be achieved at a ratio (w/w) of the weight of aluminum in the aluminum-containing particles to the weight of 3-(5-amino-2-(4-(2-(3,3- difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic, ranging from 1.5:1 to 2:1.

Typically, a binding efficiency of approximately 75% - 100% in the case of binding 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl) benzo[f][1,7]naphthyridin-8-yl)propane with aluminum hydroxide particles can be provided at a ratio (w/w) of the weight of aluminum in the aluminum hydroxide particles and the weight of 3-(5-amino-2-(4-( 2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic ranging from about 0.8:1 to about 2 .5:1. In some embodiments, binding efficiencies in the range of 80%-100% can be achieved at a ratio (w/w) of the weight of aluminum in the aluminum hydroxide particles and the weight of 3-(5-amino-2-(4-(2-(3.3 -difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic, ranging from 1:1 to 2.5:1. In other embodiments, binding efficiencies in the range of 90%-100% can be achieved at a ratio (w/w) of the weight of aluminum in the aluminum hydroxide particles and the weight of 3-(5-amino-2-(4-(2-(3.3 -difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic, ranging from 1.25:1 to 2.5:1. In other embodiments, binding efficiencies in the range of 97%-100% can be achieved at a ratio (w/w) of the weight of aluminum in the aluminum hydroxide particles and the weight of 3-(5-amino-2-(4-(2-(3.3 -difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic, ranging from 1.5:1 to 2.5:1. In other embodiments, binding efficiencies in the range of 97%-100% can be achieved at a ratio (w/w) of the weight of aluminum in the aluminum hydroxide particles and the weight of 3-(5-amino-2-(4-(2-(3.3 -difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic, ranging from 1.5:1 to 2:1. In other embodiments, binding efficiencies in the range of 98%-100% can be achieved at a ratio (w/w) of the weight of aluminum in aluminum hydroxide particles and the weight of 3-(5-amino-2-(4-(2-(3.3 -difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic, ranging from 1.5:1 to 2:1.

The preferred ratio (w/w) of the weight of the aluminum in the alumina particles and the weight of the compound of formula (A) is 1.5:1, with the most preferred ratio (w/w) of the weight of the aluminum in the alumina particles and the weight of the compound of formula (A) being 2 :1.

The preferred ratio (w/w) of the weight of aluminum in the aluminum-containing particles and the weight of 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f ][1,7]naphthyridin-8-yl)propanoic acid is 1.5:1, with the most preferred ratio (w/w) of the weight of aluminum in aluminum-containing particles and the weight of 3-(5-amino-2-(4- (2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid is 2:1.

The preferred ratio (w/w) of the weight of aluminum in the aluminum hydroxide particles to the weight of the compound of formula (A) is 1.5:1, with the most preferred ratio (w/w) of the weight of aluminum in the aluminum hydroxide particles to the weight of the compound of formula (A) is 2:1.

The preferred ratio (w/w) of the weight of aluminum in aluminum hydroxide particles and the weight of 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[ f][1,7]naphthyridin-8-yl)propanoic acid is 1.5:1, with the most preferred ratio (w/w) of the weight of aluminum in aluminum hydroxide particles and the weight of 3-(5-amino-2-( 4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid is 2:1.

In some embodiments, the implementation of the pH used to ensure binding to aluminum-containing particles/adsorption on aluminum-containing particles of the compounds of formula (A), is in the range from pH 6.5 to pH 9.0. In some embodiments, the pH used to provide binding to/adsorption to the aluminum containing particles of compounds of formula (A) is in the range of pH 7 to pH 8. In preferred embodiments, the pH used to provide binding to the aluminum containing particles/ adsorption on aluminum-containing particles of aluminum hydroxide compounds of formula (A), is in the range from pH 7.2 to pH 7.8. In preferred embodiments, the pH used to ensure binding/adsorption to the aluminium-containing particles of the compounds of formula (A) is pH 7.5 +/- 0.5. In the most preferred embodiment, the pH used to ensure binding/adsorption to the aluminium-containing particles of the compounds of formula (A) is pH 7.5 +/- 0.3.

Accordingly, binding to aluminum-containing particles / adsorption on aluminum-containing particles 3- (5-amino-2- (4- (2- (3,3-difluoro-3-phosphonopropoxy) ethoxy) -2-methylphenethyl) benzo ,7]naphthyridin-8-yl)propanoic acid is mediated through ionic charge interactions between aluminum ions and the phosphonate group (ionized phosphonic acid) in 3-(5-amino-2-(4-(2-(3,3-difluoro- 3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid. Thus, the binding/adsorption of 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridine- 8-yl)propanoic acid is more effective in the pH range from zero charge point (PZC) 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2- methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid and PZC aluminum particles. In some embodiments, the pH used to provide binding/adsorption to the aluminum particles is 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2- methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid ranges from pH 6.5 to pH 9. In some embodiments, the pH used to provide binding/adsorption to the aluminum containing particles particles of 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid ranges from pH 7 to pH 8. In a more preferred embodiment, the pH used to ensure binding/adsorption to the aluminum particles is 3-(5-amino-2-(4-(2-(3, 3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid ranges from pH 7.2 to pH 7.8. In a preferred embodiment, the pH used to provide binding/adsorption to the aluminum particles is 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2- methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid is pH 7.5 +/- 0.5. In a preferred embodiment, the pH used to provide binding/adsorption to the aluminum particles is 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2- methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid is pH 7.5 +/- 0.3.

In preferred embodiments, the aluminum containing particles are aluminum hydroxide particles and, accordingly, binding to/adsorbing on aluminum hydroxide particles 3-(5-amino-2-(4-(2-(3,3-difluoro-3- phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid is mediated through ionic charge interactions between aluminum ions and the phosphonate group (ionized phosphonic acid) in 3-(5-amino- 2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid. Thus, binding/adsorption is more efficient in the pH range from the zero charge point (PZC) of 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2- methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid to PZC aluminum hydroxide particles. In some embodiments, the implementation of the pH used to provide binding to particles of aluminum hydroxide/adsorption on particles of aluminum hydroxide 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)- 2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid ranges from pH 6.5 to pH 9. In some embodiments, the pH used to provide binding/adsorption to the aluminum hydroxide particles on particles of aluminum hydroxide yl)propanoic acid ranges from pH 7 to pH 8. In a more preferred embodiment, the pH used to allow binding to/adsorbing onto the aluminum hydroxide particles is 3-(5-amino-2-(4-(2 -(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid, is in the range from pH 7.2 to pH 7, 8. In a preferred embodiment, the pH used to allow binding/adsorption of 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f] [1,7]naphthyridin-8-yl)propanoic acid is pH 7.5 +/- 0.5. In a preferred embodiment, the pH used to allow binding/adsorption of 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f] [1,7]naphthyridin-8-yl)propanoic acid is pH 7.5 +/- 0.3.

Retention at the site of administration-injection

Pharmaceutical compositions according to the present invention containing a compound of formula (A) or a pharmaceutically acceptable salt thereof can be administered by injection, in particular intratumorally (intratumoral injection), intramuscularly (intramuscularly injection), intradermally (intradermally injection) or subcutaneously (subcutaneously). In some embodiments, pharmaceutical compositions of the present invention containing a compound of formula (A) or a pharmaceutically acceptable salt thereof are administered intratumorally, while in other embodiments, pharmaceutical compositions of the present invention containing a compound of formula (A) or a pharmaceutically acceptable salt thereof are administered subcutaneously. In some embodiments of intratumoral administration, pharmaceutical compositions of the present invention comprising a compound of formula (A) or a pharmaceutically acceptable salt thereof may be administered/injected into the peritumoral region surrounding the tumor. The peritumoral area may contain antitumor immune cells.

Binding compounds of formula (A) to aluminum containing particles increases the retention of the compound of formula (A) at the injection site, which reduces the clearance of the compound and increases the half-life of the compound and thus reduces systemic exposure. In addition, retention at the tumor site may result in improved immune priming and reduced systemic inflammation compared to systemic administration of unbound (free) compounds of formula (A) or their pharmaceutically acceptable salts. Thus, the slow release of the compound of formula (A) is considered beneficial for both efficacy and safety as it minimizes potential systemic side effects from the TLR7 agonist and increases drug retention in the local tumor environment. Plasma concentration versus time profiles obtained after intratumoral injection of compound 15, free or bound with aluminum hydroxide, are shown in Example 5 to illustrate this depot effect.

Surprisingly, it was found that the systemic exposure to aluminum after administration of compound 15 associated with aluminum hydroxide was significantly lower than the systemic exposure after administration of aluminum hydroxide alone (see example 11).

Pharmacology and applicability

Pharmaceutical compositions according to the present invention can initiate an immune response to a tumor in a subject. Accordingly, the present invention provides methods for treating a solid tumor by initiating an immune response against a solid tumor in a subject. In addition, the present invention provides methods for treating hemoblastosis, carried out by initiating an immune response against a tumor in a subject.

One aspect of the present invention is a method of treating a solid tumor by administering to a subject in need thereof a pharmaceutical composition according to any one of embodiments 1-83 or 161-164.

One aspect of the present invention is a method of treating a solid tumor by intratumoral administration to a subject in need thereof of a pharmaceutical composition according to any one of embodiments 1-83 or 161-164.

One aspect of the present invention is a method of treating a solid tumor by administering to a subject in need thereof a pharmaceutical composition comprising a TLR7 agonist compound having the structure of formula (A) or a pharmaceutically acceptable salt thereof, aluminum-containing particles, and one or more pharmaceutically acceptable excipients.

One aspect of the present invention is a method of treating a solid tumor by administering to a subject in need thereof a pharmaceutical composition comprising a TLR7 agonist compound shown in Table 1 or a pharmaceutically acceptable salt thereof, aluminum particles and one or more pharmaceutically acceptable excipients. .

Another aspect of the present invention is the use of a pharmaceutical composition according to any of embodiments 1-83 or 161-164 for the treatment of a solid tumor.

Another aspect of the present invention is the use of a pharmaceutical composition comprising a TLR7 agonist compound having the structure of formula (A) or a pharmaceutically acceptable salt thereof, aluminum particles and one or more pharmaceutically acceptable adjuvants for the treatment of a solid tumor.

Another aspect of the present invention is the use of a pharmaceutical composition comprising a TLR7 agonist compound shown in Table 1 or a pharmaceutically acceptable salt thereof, aluminum particles and one or more pharmaceutically acceptable adjuvants for the treatment of a solid tumor.

Another aspect of the present invention is a pharmaceutical composition according to any one of embodiments 1-83 or 161-164 for use in the treatment of a solid tumor.

Another aspect of the present invention is a pharmaceutical composition comprising a TLR7 agonist compound having the structure of formula (A), or a pharmaceutically acceptable salt thereof, aluminum particles and one or more pharmaceutically acceptable excipients, for use in the treatment of a solid tumor.

Another aspect of the present invention is a pharmaceutical composition comprising a TLR7 agonist compound shown in Table 1 or a pharmaceutically acceptable salt thereof, aluminum particles and one or more pharmaceutically acceptable excipients for use in the treatment of a solid tumor.

The present invention provides methods for treating a solid tumor by administering intratumorally, intramuscularly, intradermally, or subcutaneously a pharmaceutical composition according to any of embodiments 1-83 or 161-164.

The present invention further provides methods for treating a solid tumor by administering intratumorally, intramuscularly, intradermally, or subcutaneously a pharmaceutical composition disclosed herein, comprising a compound of formula (A) or a pharmaceutically acceptable salt thereof, aluminum-containing particles, and one or more pharmaceutically acceptable excipients .

Another aspect of the present invention is a method for treating a solid tumor by intratumoral administration to a subject in need thereof of a pharmaceutical composition comprising a TLR7 agonist compound having the structure of formula (A), or a pharmaceutically acceptable salt thereof, aluminum-containing particles, and one or more pharmaceutically acceptable excipients.

Another aspect of the present invention is a method of treating a solid tumor by intratumoral administration to a subject in need thereof of a pharmaceutical composition comprising a TLR7 agonist compound shown in Table 1 or a pharmaceutically acceptable salt thereof, aluminum particles and one or more pharmaceutically acceptable excipients. substances.

Solid tumors that can be treated with such methods and uses include, but are not limited to, breast cancer tumor, bladder cancer tumor, head and neck cancer tumor, non-small cell lung cancer tumor, small cell lung cancer, tumor related to colorectal cancer, gastrointestinal stromal tumor, gastroesophageal carcinoma, tumor related to renal cell carcinoma, tumor related to prostate cancer, tumor related to liver cancer, tumor related to colon cancer, a tumor related to pancreatic cancer, a tumor related to ovarian cancer, lymphoma, skin T-cell lymphoma or melanoma.

Large solid tumors become infiltrated with a subpopulation of myeloid-derived suppressor cells (mMDSCs) that suppress antitumor immunity. In some embodiments, the present invention provides a method of treating a tumor having immunosuppressive properties. A tumor having immunosuppressive properties is a tumor that contains immunosuppressive-associated cells such as, for example, T Reg cells, myeloid-derived suppressor cells (MDSC), M2 macrophages, and the like, or immune-suppressive factors such as inducible synthase. nitric oxide (iNOS), PD-L1 and the like.

The amount of a compound of formula (A), or a pharmaceutically acceptable salt thereof, included in a pharmaceutical composition according to the present invention, which is used in the method or use according to the present invention, may vary in accordance with factors known in the art, such as, for example, physical and subject's clinical status, route of administration, composition content, planned dosing regimen or sequence. When considering such factors, the appropriate included amount can be easily determined by a person skilled in the art. By way of example, a pharmaceutical composition of the present invention may contain an amount of a compound of formula (A) or a pharmaceutically acceptable salt thereof to provide a dose of a compound of formula (A) or a pharmaceutically acceptable salt thereof to a subject, from about 0.05 mg to about 5 mg. Preferably, the pharmaceutical composition of the present invention contains an amount of a compound of formula (A) or a pharmaceutically acceptable salt thereof that provides a dose of the compound of formula (A) or a pharmaceutically acceptable salt thereof to a subject of from about 0.1 mg to about 1 mg.

With regard to the duration and frequency of use of a therapeutic agent, physicians of appropriate skill will usually monitor subjects to determine when treatment provides therapeutic benefit and to determine whether to increase or decrease the dose, increase or decrease the frequency of administration, stop treatment, restart treatment, or make other changes to the treatment regimen.

Examples of dosing regimens for administering a compound of formula (A) or a pharmaceutically acceptable salt thereof adsorbed on aluminum hydroxide, either alone or in combination with one or more additional therapeutic agents, are once a week, twice per week, three times a week or once a month during the cycle period, while such administration is carried out for 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 cycle periods.

The cycle period is the number and timing or recommended repetitions of the therapy, which is usually expressed as a number of days. Examples of the cycle period include every 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days or 31 days.

The dosing regimen may include a dose delay (pause) in which a compound of formula (A) or a pharmaceutically acceptable salt thereof adsorbed on aluminum hydroxide is administered during Cycle 1, with a compound of formula (A) or a pharmaceutically acceptable salt thereof adsorbed on aluminum hydroxide is not administered during one or more subsequent periods of the cycle.

As an example, during a nine cycle dosing regimen, a compound of formula (A) or a pharmaceutically acceptable salt thereof adsorbed on aluminum hydroxide is administered over cycles 1, 3, 5, 7 and 9 with a dose delay (pause) over cycles 2 , 4, 6 and 8, where the compound of formula (A) or its pharmaceutically acceptable salt adsorbed on aluminum hydroxide is not administered.

As another example, during an eight cycle dosing regimen, a compound of formula (A) or a pharmaceutically acceptable salt thereof adsorbed on aluminum hydroxide is administered over cycles 1, 2, 4, 5, 7 and 8 with a dose delay (pause) of during cycles 3 and 6, where the compound of formula (A) or its pharmaceutically acceptable salt adsorbed on aluminum hydroxide is not administered.

As a further example, during a six cycle dosing regimen, a compound of formula (A) or a pharmaceutically acceptable salt thereof adsorbed on aluminum hydroxide is administered during cycles 1, 2, 5 and 6 with a dose delay (pause) during cycles 3 and 4, where no compound of formula (A) or a pharmaceutically acceptable salt thereof adsorbed on aluminum hydroxide is administered. As an example of a six cycle dosing regimen designed to administer a compound of formula (A) or a pharmaceutically acceptable salt thereof adsorbed on aluminum hydroxide, either alone as a single agent or in combination with one or more additional therapeutic agents, a compound of formula (A ) or a pharmaceutically acceptable salt thereof adsorbed on aluminum hydroxide can be administered by intratumoral injection on days 1 and 15 (two-week regimen) or only on day 1 (monthly schedule) during a 28-day cycle. Intratumoral administration is given in cycles 1 and 2, followed by dosing delay for two cycles (cycles 3 and 4), and then repeated injections on days 1 and 15 (two-week regimen) or only on day 1 (monthly regimen) for cycles 5 and 6. The dose of a compound of formula (A), or a pharmaceutically acceptable salt thereof, administered over a six cycle regimen may be from about 0.1 mg to about 1 mg, or from about 0.1 mg to about 0.6 mg.

While the disclosed methods and uses for such compositions will generally be used to treat human subjects, they may also be used to treat similar or identical diseases in other vertebrates such as other primates, dogs, cats, horses, and cows.

Certain aspects and examples of pharmaceutical composition uses, pharmaceutical composition uses, and methods of the present invention are provided in the following list of further numbered embodiments. It should be understood that the features indicated in each embodiment can be combined with other indicated features to obtain additional embodiments of the present invention.

Embodiment 165. A method of treating a solid tumor by administering to a subject in need thereof a pharmaceutical composition according to any one of Embodiments 1-83 or 161-164.

Embodiment 166. A method of treating a solid tumor by intratumoral administration to a subject in need thereof of a pharmaceutical composition according to any one of Embodiments 1-83 or 161-164.

Embodiment 167. A method of treating a solid tumor by administering to a subject in need thereof a pharmaceutical composition comprising 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy) -2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, aluminum particles and one or more pharmaceutically acceptable excipients.

Embodiment 168. A method of treating a solid tumor by administering to a subject in need thereof a pharmaceutical composition comprising 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy) -2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles and one or more pharmaceutically acceptable excipients.

Embodiment 169. A method of treating a solid tumor by intratumoral administration to a subject in need thereof of a pharmaceutical composition comprising 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy )-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles and one or more pharmaceutically acceptable excipients.

Embodiment 170. A method of treating a solid tumor by intratumoral administration to a subject in need thereof of a pharmaceutical composition comprising 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy )-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, aluminum-containing particles and a buffer agent.

Embodiment 171. A method of treating a solid tumor by intratumoral administration to a subject in need thereof of a pharmaceutical composition comprising 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy )-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, aluminum particles, a buffering agent and one or more pharmaceutically acceptable excipients.

Embodiment 172. A method of treating a solid tumor by intratumoral administration to a subject in need thereof of a pharmaceutical composition having a pH of 7.0-8.0 and containing 3-(5-amino-2-(4-(2-(3 ,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, aluminum-containing particles and a buffer agent.

Embodiment 173. A method of treating a solid tumor by intratumorally administering to a subject in need thereof a pharmaceutical composition having a pH of 7.0-8.0 and containing 3-(5-amino-2-(4-(2-(3 ,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, aluminum-containing particles, a buffer agent and sucrose.

Embodiment 174. A method of treating a solid tumor by intratumorally administering to a subject in need thereof a pharmaceutical composition having a pH of 7.0-8.0 and containing 3-(5-amino-2-(4-(2-(3 ,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, aluminum-containing particles, a buffer agent and mannitol.

Embodiment 175. A method of treating a solid tumor by intratumoral administration to a subject in need thereof of a pharmaceutical composition having a pH of 7.0-8.0 containing 3-(5-amino-2-(4-(2-(3 ,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles and Tris buffer.

Embodiment 176. A method of treating a solid tumor by intratumoral administration to a subject in need thereof of a pharmaceutical composition having a pH of 7.0-8.0 and containing 3-(5-amino-2-(4-(2-(3 ,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, Tris buffer and sucrose.

Embodiment 177. A method of treating a solid tumor by intratumoral administration to a subject in need thereof of a pharmaceutical composition having a pH of 7.0-8.0 and containing 0.5-2 mg/mL of 3-(5-amino-2- (4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, hydroxide particle suspension aluminum, characterized by an aluminum content of 1-4 mg/ml, 5-100 mm Tris buffer and 5-10% (w/v) sucrose.

Embodiment 178. A method of treating a solid tumor by intratumoral administration to a subject in need thereof of a pharmaceutical composition having a pH of 7.0-8.0 and containing 0.5-2 mg/mL of 3-(5-amino-2- (4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, hydroxide particle suspension aluminum, characterized by an aluminum content of 1-4 mg/ml, 5-50 mm Tris buffer and 5-10% (w/v) sucrose.

Embodiment 179. A method of treating a solid tumor by intratumoral administration to a subject in need thereof of a pharmaceutical composition having a pH of 7.0-8.0 and containing 0.5-2 mg/mL of 3-(5-amino-2- (4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, hydroxide particle suspension aluminum, characterized by an aluminum content of 1-4 mg/ml, 5-20 mm Tris buffer and 5-10% (w/v) sucrose.

Embodiment 180. A method of treating a solid tumor by intratumorally administering to a subject in need thereof a pharmaceutical composition having a pH of 7.0-8.0 containing 1 mg/mL of 3-(5-amino-2-(4-( 2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles, characterized by the content aluminum 2 mg/ml, 5-20 mM Tris buffer and 5-10% (w/v) sucrose.

Embodiment 181. A method of treating a solid tumor by intratumoral administration to a subject in need thereof of a pharmaceutical composition having a pH of 7.0-8.0 containing 1 mg/mL of 3-(5-amino-2-(4-( 2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles, characterized by the content aluminum 2 mg/ml aluminum hydroxide, 16 mM Tris buffer and 7.5% (w/v) sucrose.

Embodiment 182. A method of treating a solid tumor by intratumoral administration to a subject in need thereof of a pharmaceutical composition having a pH of 7.0-8.0 containing 1 mg/mL of 3-(5-amino-2-(4-( 2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles, characterized by the content aluminum 2 mg/ml aluminum hydroxide, 5 mM Tris buffer and 8.25% (w/v) sucrose.

Embodiment 183. A method of treating a solid tumor by intratumoral administration to a subject in need thereof of a pharmaceutical composition having a pH of 7.0-8.0 and containing 3-(5-amino-2-(4-(2-(3 ,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, Tris buffer and mannitol.

Embodiment 184. A method of treating a solid tumor by intratumoral administration to a subject in need thereof of a pharmaceutical composition having a pH of 7.0-8.0 and containing 0.5-2 mg/mL of 3-(5-amino-2- (4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, hydroxide particle suspension aluminum, characterized by an aluminum content of 1-4 mg/ml, 5-100 mm Tris buffer and 5-10% (w/v) mannitol.

Embodiment 185. A method of treating a solid tumor by intratumoral administration to a subject in need thereof of a pharmaceutical composition having a pH of 7.0-8.0 and containing 0.5-2 mg/mL of 3-(5-amino-2- (4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, hydroxide particle suspension aluminum, characterized by an aluminum content of 1-4 mg/ml, 5-50 mm Tris buffer and 5-10% (w/v) mannitol.

Embodiment 186. A method of treating a solid tumor by intratumoral administration to a subject in need thereof of a pharmaceutical composition having a pH of 7.0-8.0 and containing 0.5-2 mg/mL of 3-(5-amino-2- (4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, hydroxide particle suspension aluminum, characterized by an aluminum content of 1-4 mg/ml, 5-20 mm Tris buffer and 5-10% (w/v) mannitol.

Embodiment 187. A method of treating a solid tumor by intratumoral administration to a subject in need thereof of a pharmaceutical composition having a pH of 7.0-8.0 and containing 1 mg/mL of 3-(5-amino-2-(4-( 2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles, characterized by the content aluminum 2 mg/ml, 5-20 mM Tris buffer and 5-10% (w/v) mannitol.

Embodiment 188. A method of treating a solid tumor by intratumoral administration to a subject in need thereof of a pharmaceutical composition having a pH of 7.0-8.0 and containing 1 mg/mL of 3-(5-amino-2-(4-( 2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles, characterized by the content aluminum 2 mg/ml aluminum hydroxide, 16 mm Tris buffer and 7.5% (w/v) mannitol.

Embodiment 189. A method of treating a solid tumor by intratumoral administration to a subject in need thereof of a pharmaceutical composition having a pH of 7.0-8.0 and containing 1 mg/mL of 3-(5-amino-2-(4-( 2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles, characterized by the content aluminum 2 mg/ml aluminum hydroxide, 5 mM Tris buffer and 8.25% (w/v) mannitol.

Embodiment 190. Use of a pharmaceutical composition for the treatment of a solid tumor, wherein the composition comprises 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[ f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, aluminum particles and one or more pharmaceutically acceptable excipients.

Embodiment 191 Use of a pharmaceutical composition for the treatment of a solid tumor, wherein the composition comprises 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[ f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles and one or more pharmaceutically acceptable excipients.

Embodiment 192. Use of a pharmaceutical composition for the treatment of a solid tumor, wherein the composition comprises 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[ f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, aluminum particles and a buffer agent.

Embodiment 193. Use of a pharmaceutical composition for the treatment of a solid tumor, wherein the composition comprises 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[ f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, aluminum particles, a buffering agent and one or more pharmaceutically acceptable excipients.

Embodiment 194. Use of a pharmaceutical composition for the treatment of a solid tumor, wherein the composition has a pH of 7.0-8.0 and contains 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy )ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, aluminum-containing particles and a buffer agent.

Embodiment 195. Use of a pharmaceutical composition for the treatment of a solid tumor, wherein the composition has a pH of 7.0-8.0 and contains 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy )ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, aluminum-containing particles, a buffer agent and sucrose.

Embodiment 196. The use of a pharmaceutical composition for the treatment of a solid tumor, wherein the composition has a pH of 7.0-8.0 and contains 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy )ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, aluminum-containing particles, a buffer agent and mannitol.

Embodiment 197. Use of a pharmaceutical composition for the treatment of a solid tumor, wherein the composition has a pH of 7.0-8.0 and contains 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy )ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles and Tris buffer.

Embodiment 198. Use of a pharmaceutical composition for the treatment of a solid tumor, wherein the composition has a pH of 7.0-8.0 and contains 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy )ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, Tris buffer and sucrose.

Embodiment 199. Use of a pharmaceutical composition for the treatment of a solid tumor, wherein the composition has a pH of 7.0-8.0 and contains 0.5-2 mg/mL of 3-(5-amino-2-(4-(2-(3 ,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles, characterized by an aluminum content of 1-4 mg/ml, 5-100 mM Tris buffer and 5-10% (w/v) sucrose.

Embodiment 200. Use of a pharmaceutical composition for the treatment of a solid tumor, wherein the composition has a pH of 7.0-8.0 and contains 0.5-2 mg/mL of 3-(5-amino-2-(4-(2-(3 ,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles, characterized by an aluminum content of 1-4 mg/ml, 5-50 mM Tris buffer and 5-10% (w/v) sucrose.

Embodiment 201 Use of a pharmaceutical composition for the treatment of a solid tumor, wherein the composition has a pH of 7.0-8.0 and contains 0.5-2 mg/mL of 3-(5-amino-2-(4-(2-(3 ,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles, characterized by an aluminum content of 1-4 mg/ml, 5-20 mM Tris buffer and 5-10% (w/v) sucrose.

Embodiment 202. Use of a pharmaceutical composition for the treatment of a solid tumor, wherein the composition has a pH of 7.0-8.0 and contains 1 mg/mL 3-(5-amino-2-(4-(2-(3,3-difluoro -3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles, characterized by an aluminum content of 2 mg/ml, 5- 20 mM Tris buffer and 5-10% (w/v) sucrose.

Embodiment 203. Use of a pharmaceutical composition for the treatment of a solid tumor, wherein the composition has a pH of 7.0-8.0 and contains 1 mg/mL 3-(5-amino-2-(4-(2-(3,3-difluoro -3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles, characterized by an aluminum content of 2 mg/ml, 16 mM tris buffer and 7.5% (w/v) sucrose.

Embodiment 204. Use of a pharmaceutical composition for the treatment of a solid tumor, wherein the composition has a pH of 7.0-8.0 and contains 1 mg/mL 3-(5-amino-2-(4-(2-(3,3-difluoro -3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles, characterized by an aluminum content of 2 mg/ml, 5 mM tris buffer and 8.25% (w/v) sucrose.

Embodiment 205. Use of a pharmaceutical composition for the treatment of a solid tumor, wherein the composition has a pH of 7.0-8.0 and contains 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy )ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, Tris buffer and mannitol.

Embodiment 206. Use of a pharmaceutical composition for the treatment of a solid tumor, wherein the composition has a pH of 7.0-8.0 and contains 0.5-2 mg/mL of 3-(5-amino-2-(4-(2-(3 ,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles, characterized by an aluminum content of 1-4 mg/ml, 5-100 mM Tris buffer and 5-10% (w/v) mannitol.

Embodiment 207. Use of a pharmaceutical composition for the treatment of a solid tumor, wherein the composition has a pH of 7.0-8.0 and contains 0.5-2 mg/mL of 3-(5-amino-2-(4-(2-(3 ,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles, characterized by an aluminum content of 1-4 mg/ml, 5-50 mM Tris buffer and 5-10% (w/v) mannitol.

Embodiment 208. Use of a pharmaceutical composition for the treatment of a solid tumor, wherein the composition has a pH of 7.0-8.0 and contains 0.5-2 mg/mL of 3-(5-amino-2-(4-(2-(3 ,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles, characterized by an aluminum content of 1-4 mg/ml, 5-20 mM Tris buffer and 5-10% (w/v) mannitol.

Embodiment 209. Use of a pharmaceutical composition for the treatment of a solid tumor, wherein the composition has a pH of 7.0-8.0 and contains 1 mg/mL 3-(5-amino-2-(4-(2-(3,3-difluoro -3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles, characterized by an aluminum content of 2 mg/ml, 5- 20 mM Tris buffer and 5-10% (w/v) mannitol.

Embodiment 210. Use of a pharmaceutical composition for the treatment of a solid tumor, wherein the composition has a pH of 7.0-8.0 and contains 1 mg/mL 3-(5-amino-2-(4-(2-(3,3-difluoro -3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles, characterized by an aluminum content of 2 mg/ml, 16 mM tris buffer and 7.5% (w/v) mannitol.

Embodiment 211. Use of a pharmaceutical composition for the treatment of a solid tumor, wherein the composition has a pH of 7.0-8.0 and contains 1 mg/mL 3-(5-amino-2-(4-(2-(3,3-difluoro -3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles, characterized by an aluminum content of 2 mg/ml, 5 mM tris buffer and 8.25% (w/v) mannitol.

Embodiment 212. A pharmaceutical composition for use in the treatment of a solid tumor, wherein the composition comprises 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl )benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, aluminum particles and one or more pharmaceutically acceptable excipients.

Embodiment 213. A pharmaceutical composition for use in the treatment of a solid tumor, wherein the composition comprises 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl )benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles and one or more pharmaceutically acceptable excipients.

Embodiment 214 A pharmaceutical composition for use in the treatment of a solid tumor, wherein the composition comprises 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl )benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, aluminum-containing particles and a buffer agent.

Embodiment 215. A pharmaceutical composition for use in the treatment of a solid tumor, wherein the composition comprises 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl )benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, aluminum particles, a buffering agent and one or more pharmaceutically acceptable excipients.

Embodiment 216. A pharmaceutical composition for use in the treatment of a solid tumor, wherein the composition has a pH of 7.0-8.0 and contains 3-(5-amino-2-(4-(2-(3,3-difluoro- 3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, aluminum-containing particles and a buffer agent.

Embodiment 217. A pharmaceutical composition for use in the treatment of a solid tumor, wherein the composition has a pH of 7.0-8.0 and contains 3-(5-amino-2-(4-(2-(3,3-difluoro- 3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, aluminum particles, a buffer agent and one or more pharmaceutically acceptable excipients.

Embodiment 218. A pharmaceutical composition for use in the treatment of a solid tumor, wherein the composition has a pH of 7.0-8.0 and contains 3-(5-amino-2-(4-(2-(3,3-difluoro- 3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, aluminum-containing particles and a buffer agent.

Embodiment 219. A pharmaceutical composition for use in the treatment of a solid tumor, wherein the composition has a pH of 7.0-8.0 and contains 3-(5-amino-2-(4-(2-(3,3-difluoro- 3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propane or a pharmaceutically acceptable salt thereof, aluminum-containing particles, buffer and sucrose.

Embodiment 220. A pharmaceutical composition for use in the treatment of a solid tumor, wherein the composition has a pH of 7.0-8.0 and contains 3-(5-amino-2-(4-(2-(3,3-difluoro- 3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, aluminum-containing particles, a buffer agent and mannitol.

Embodiment 221. A pharmaceutical composition for use in the treatment of a solid tumor, wherein the composition has a pH of 7.0-8.0 and contains 3-(5-amino-2-(4-(2-(3,3-difluoro- 3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles and Tris buffer.

Embodiment 222. A pharmaceutical composition for use in the treatment of a solid tumor, wherein the composition has a pH of 7.0-8.0 and contains 3-(5-amino-2-(4-(2-(3,3-difluoro- 3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, Tris buffer and sucrose.

Embodiment 223. A pharmaceutical composition for use in the treatment of a solid tumor, wherein the composition has a pH of 7.0-8.0 and contains 0.5-2 mg/ml 3-(5-amino-2-(4-(2 -(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles characterized by an aluminum content 1-4 mg/ml, 5-100 mM Tris buffer and 5-10% (w/v) sucrose.

Embodiment 224. A pharmaceutical composition for use in the treatment of a solid tumor, wherein the composition has a pH of 7.0-8.0 and contains 0.5-2 mg/ml 3-(5-amino-2-(4-(2 -(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles characterized by an aluminum content 1-4 mg/ml, 5-50 mM Tris buffer and 5-10% (w/v) sucrose.

Embodiment 225. A pharmaceutical composition for use in the treatment of a solid tumor, wherein the composition has a pH of 7.0-8.0 and contains 0.5-2 mg/ml 3-(5-amino-2-(4-(2 -(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles characterized by an aluminum content 1-4 mg/ml, 5-20 mM Tris buffer and 5-10% (w/v) sucrose.

Embodiment 226. A pharmaceutical composition for use in the treatment of a solid tumor, wherein the composition has a pH of 7.0-8.0 and contains 1.0 mg/mL 3-(5-amino-2-(4-(2-( 3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles, characterized by an aluminum content of 2 mg /ml, 5-20 mm Tris buffer and 5-10% (w/v) sucrose.

Embodiment 227. A pharmaceutical composition for use in the treatment of a solid tumor, wherein the composition has a pH of 7.0-8.0 and contains 1.0 mg/ml 3-(5-amino-2-(4-(2-( 3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles, characterized by an aluminum content of 2 mg /ml, 16 mm Tris buffer and 7.5% (w/v) sucrose.

Embodiment 228. A pharmaceutical composition for use in the treatment of a solid tumor, wherein the composition has a pH of 7.0-8.0 and contains 1.0 mg/mL 3-(5-amino-2-(4-(2-( 3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles, characterized by an aluminum content of 2 mg /ml, 5 mm Tris buffer and 8.25% (w/v) sucrose.

Embodiment 229. A pharmaceutical composition for use in the treatment of a solid tumor, wherein the composition has a pH of 7.0-8.0 and contains 0.5-2 mg/ml 3-(5-amino-2-(4-(2 -(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles characterized by an aluminum content 1-4 mg/ml, 5-100 mM Tris buffer and 5-10% (w/v) mannitol.

Embodiment 230. A pharmaceutical composition for use in the treatment of a solid tumor, wherein the composition has a pH of 7.0-8.0 and contains 0.5-2 mg/ml 3-(5-amino-2-(4-(2 -(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles characterized by an aluminum content 1-4 mg/ml, 5-50 mM Tris buffer and 5-10% (w/v) mannitol.

Embodiment 231. A pharmaceutical composition for use in the treatment of a solid tumor, wherein the composition has a pH of 7.0-8.0 and contains 0.5-2 mg/mL of 3-(5-amino-2-(4-(2 -(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles characterized by an aluminum content 1-4 mg/ml, 5-20 mM Tris buffer and 5-10% (w/v) mannitol.

Embodiment 232. A pharmaceutical composition for use in the treatment of a solid tumor, wherein the composition has a pH of 7.0-8.0 and contains 1.0 mg/mL 3-(5-amino-2-(4-(2-( 3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles, characterized by an aluminum content of 2 mg /ml, 5-20 mm Tris buffer and 5-10% (w/v) mannitol.

Embodiment 233. A pharmaceutical composition for use in the treatment of a solid tumor, wherein the composition has a pH of 7.0-8.0 and contains 1.0 mg/mL 3-(5-amino-2-(4-(2-( 3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles, characterized by an aluminum content of 2 mg /ml, 16 mm Tris buffer and 7.5% (w/v) mannitol.

Embodiment 234. A pharmaceutical composition for use in the treatment of a solid tumor, wherein the composition has a pH of 7.0-8.0 and contains 1.0 mg/ml 3-(5-amino-2-(4-(2-( 3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles, characterized by an aluminum content of 2 mg /ml, 5 mm Tris buffer and 8.25% (w/v) mannitol.

Example 7 illustrates the effect on tumor volume provided by the administration of a pharmaceutical composition containing a compound of formula (A) with or without aluminum containing particles. In particular, Example 7 illustrates the effect on tumor volume provided by the administration of a pharmaceutical composition containing 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2- methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid, with or without aluminum particles.

Combinations

The present invention also provides methods for treating a solid tumor by administering intratumorally, intramuscularly, intradermally, or subcutaneously a pharmaceutical composition according to any of embodiments 1-83 or 161-164 in combination with one or more pharmaceutical compositions containing another therapeutic agent. Such additional therapeutic agents may be a checkpoint inhibitor, a TLR9 agonist, a TLR8 agonist, a TLR7 agonist, a STING agonist, or a chemotherapeutic agent.

The present invention further provides methods for treating a solid tumor by administering intratumorally, intramuscularly, intradermally, or subcutaneously a pharmaceutical composition disclosed herein, comprising a compound of formula (A) or a pharmaceutically acceptable salt thereof, aluminum-containing particles, and one or more pharmaceutically acceptable excipients in combination with one or more pharmaceutical compositions containing another therapeutic agent. Such additional therapeutic agents may be a checkpoint inhibitor, a TLR9 agonist, a TLR8 agonist, a TLR7 agonist, a STING agonist, or a chemotherapeutic agent.

Major chemotherapy agents being considered for use in combination therapies include anastrozole (Arimidex®), bicalutamide (Casodex®), bleomycin sulfate (Blenoxane®), busulfan (Myleran®), busulfan injectable (Busulfex®), capecitabine (Xeloda® ), N4-pentoxycarbonyl-5-deoxy-5-fluorocytidine, carboplatin (Paraplatin®), carmustine (BiCNU®), chlorambucil (Leukeran®), cisplatin (Platinol®), cladribine (Leustatin®), cyclophosphamide (Cytoxan® or Neosar ®), cytarabine, cytosine arabinoside (Cytosar-U®), liposomal cytarabine injectable (DepoCyt®), dacarbazine (DTIC-Dome®), dactinomycin (Actinomycin D, Cosmegan), daunorubicin hydrochloride (Cerubidine®), liposomal daunorubicin citrate injectable (DaunoXome®), dexamethasone, docetaxel (Taxotere®), doxorubicin hydrochloride (Adriamycin®, Rubex®), etoposide (Vepesid®), fludarabine phosphate (Fludara®), 5-fluorouracil (Adrucil®, Efudex®), flutamide (Eulexin ®), tezacitibine, gemcitabine (difluorodeoxycytidine), hydroxyurea (Hyd rea®), idarubicin (Idamycin®), ifosfamide (IFEX®), irinotecan (Camptosar®), L-asparaginase (ELSPAR®), calcium leucovorin, melphalan (Alkeran®), 6-mercaptopurine (Purinethol®), methotrexate (Folex ®), mitoxantrone (Novantrone®), mylotarg, paclitaxel (Taxol®), phoenix (yttrium-90/MX-DTPA), pentostatin, polypheprosan 20 with carmustine for implantation (Gliadel®), tamoxifen citrate (Nolvadex®), teniposide ( Vumon®), 6-thioguanine, thiotepa, tirapazamine (Tirazone®), topotecan hydrochloride injection (Hycamptin®), vinblastine (Velban®), vincristine (Oncovin®), vinorelbine (Navelbine®), epirubicin (Ellence®), oxaliplatin (Eloxatin®), exemestane (Aromasin®), letrozole (Femara®), and fulvestrant (Faslodex®).

Combinations with checkpoint inhibitors

Toll-like receptors (TLRs) are a class of proteins that play an important role in pathogen recognition and activation of the innate immune system. To protect against autoimmunity, the immune system uses a family of receptors known as checkpoint receptors to suppress activated immune cells such as T cells. A number of tumors are able to express surface agonist proteins in checkpoint receptors and thus avoid antitumor immune response in the tumor environment. In order to provide an effective antitumor immune response in the tumor environment, this masking behavior can be overcome by blocking the checkpoint pathway by administering checkpoint pathway inhibitors and, in combination with this, activating the immune system by administering a Toll-like receptor 7 agonist.

The compounds of formula (A), or pharmaceutically acceptable salts thereof, are TLR7 agonists and thus activate multiple cell-mediated antitumor immune responses (such as, for example, T cell activation). Therefore, the combination of immune activation with a compound of formula (A) or a pharmaceutically acceptable salt thereof and blockade of immune checkpoint pathways with one or more checkpoint inhibitors can enhance and maintain an antitumor immune response initiated by a compound of formula (A) or its pharmaceutically acceptable salt. Thus, the present invention provides combinations of a pharmaceutical composition comprising a compound of formula (A), or a pharmaceutically acceptable salt thereof, in combination with one or more immune response checkpoint inhibitors. Accordingly, the present invention further provides methods and uses that can be used to treat solid tumors by administering such combinations.

In particular, the present invention provides combinations of a pharmaceutical composition according to any of embodiments 1-83 or 161-164 in combination with one or more pharmaceutical compositions containing one or more immune response checkpoint inhibitors. In some embodiments, the present invention provides a pharmaceutical composition according to any of embodiments 1-83 or 161-164, further comprising one or more immune response checkpoint inhibitors.

The present invention provides combinations of a pharmaceutical composition containing a compound of formula (A) or a pharmaceutically acceptable salt thereof, aluminum particles, one or more pharmaceutically acceptable excipients, in combination with one or more pharmaceutical compositions containing one or more immune response checkpoint inhibitors.

The immune checkpoint inhibitor can be a receptor inhibitor or a ligand inhibitor. The immune response checkpoint receptor that can be targeted by inhibitors includes, but is not limited to, cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), programmed death protein 1 (PD-1), lymphocyte activation gene 3 (LAG-3) , T-cell membrane protein 3 (TIM-3), B- and T-lymphocyte attenuator receptor (BTLA) and killer cell immunoglobulin-like receptor (KIR), and immune checkpoint receptor ligands that can be targeted by inhibitors, include, without limitation, programmed death protein ligand 1 (PD-L1) and programmed death protein ligand 2 (PD-L2).

The immune checkpoint inhibitor used in the combinations of the present invention may be a receptor inhibitor or a ligand inhibitor. As an example, an immune checkpoint inhibitor used in the combinations of the present invention is a CTLA-4 receptor inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor inhibitor, a TIM-3 receptor inhibitor, a BTLA receptor inhibitor, or a KIR receptor inhibitor. Further, by way of example, the immune checkpoint inhibitor used in the combinations of the present invention is an inhibitor of programmed death protein ligand 1 (PD-L1) and/or programmed death protein ligand 2 (PD-L2).

The immune checkpoint inhibitors used in the combinations of the present invention may be a small organic molecule (molecular weight less than 1000 daltons), a peptide, a polypeptide, a protein, an antibody, an antibody fragment, or an antibody derivative. In some embodiments, the immune checkpoint inhibitor used in the combinations of the present invention is an antibody. In some embodiments, the immune checkpoint inhibitor used in the combinations of the present invention, which is an antibody, is a monoclonal antibody. In some embodiments, the immune checkpoint inhibitor used in the combinations of the present invention, which is an antibody, is a human antibody or a humanized monoclonal antibody.

In some embodiments, the immune checkpoint inhibitor used in the combinations of the present invention is an anti-CTLA-4 receptor antibody, an anti-PD-1 receptor antibody, an anti-LAG-3 receptor antibody, an anti-TIM-3 receptor antibody, an BTLA, KIR receptor antibody, PD-L1 receptor antibody, or PD-L2 receptor antibody.

In some embodiments, the immune checkpoint inhibitor used in the combinations of the present invention is an inhibitor of the PD-L1/PD-1 pathway or the PD-L2/PD-1 pathway.

In one embodiment, the anti-PD-L1 antibody molecule for use in the combinations of the present invention is one of those disclosed in U.S. Patent Application No. 20160108123, filed October 13, 2015, titled "Antibody Molecules to PD-L1 and Uses Thereof" ("PD-L1 antibody molecules and uses"), incorporated by reference in its entirety.

In one embodiment, an anti-PD-L1 antibody comprises at least one or two heavy chain variable domains (optionally including a constant region), at least one or two light chain variable domains (optionally including a constant region), or both, containing the amino acid sequence of any of BAP058-hum01, BAP058-hum02, BAP058-hum03, BAP058-hum04, BAP058-hum05, BAP058-hum06, BAP058-hum07, BAP058-hum08, BAP058-hum09, BAP058-hum10, BAP058-hum11, BAP058 -hum12, BAP058-hum13, BAP058-hum14, BAP058-hum15, BAP058-hum16, BAP058-hum17, BAP058-Clone-K, BAP058-Clone-L, BAP058-Clone-M, BAP058-Clone-N or BAP058-Clone -O; or described in Table 1 of US Patent Application No. 20160108123, or encoded by the nucleotide sequence of Table 1 of US Patent Application No. 20160108123; or having a sequence substantially identical (eg, at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or more identical) to any of the aforementioned sequences.

In another embodiment, an anti-PD-L1 antibody molecule comprises at least one, two, or three complementarity determining regions (CDRs) from a heavy chain variable region and/or a light chain variable region of an antibody described herein, e.g., an antibody selected from any of BAP058-hum01, BAP058-hum02, BAP058-hum03, BAP058-hum04, BAP058-hum05, BAP058-hum06, BAP058-hum07, BAP058-hum08, BAP058-hum09, BAP058-hum10, BAP058-hum11, BAP058-hum12, BAP058-hum13, BAP058-hum14, BAP058-hum15, BAP058-hum16, BAP058-hum17, BAP058-Clone-K, BAP058-Clone-L, BAP058-Clone-M, BAP058-Clone-N or BAP058-Clone-O; or described in Table 1 of U.S. Patent Application No. 20160108123, or encoded by the nucleotide sequence of Table 1 of U.S. Patent Application No. 20160108123, or having a sequence that is substantially identical (e.g., at least 80%, 85%, 90% identical) , 92%, 95%, 97%, 98%, 99% or more) any of the above sequences.

In yet another embodiment, an anti-PD-L1 antibody molecule contains at least one, two, or three CDRs (or all CDRs in total) from a heavy chain variable region comprising the amino acid sequence shown in Table 1 of U.S. Patent Application No. 20160108123, or encoded by the nucleotide sequence shown in Table 1 of U.S. Patent Application No. 20160108123. In one embodiment, one or more CDRs (or collectively all CDRs) have one, two, three, four, five, six or more changes, such as amino acid substitutions or deletions compared to the amino acid sequence shown in Table 1 of US Patent Application No. 20160108123, or encoded by the nucleotide sequence shown in Table 1 of US Patent Application No. 20160108123.

In yet another embodiment, an anti-PD-L1 antibody molecule contains at least one, two, or three CDRs (or all CDRs in total) from a light chain variable region comprising the amino acid sequence shown in Table 1 of U.S. Patent Application No. 20160108123, or encoded by the nucleotide sequence shown in Table 1 of U.S. Patent Application No. 20160108123. In one embodiment, one or more CDRs (or collectively all CDRs) have one, two, three, four, five, six or more changes, such as amino acid substitutions or deletions compared to the amino acid sequence shown in Table 1 of US Patent Application No. 20160108123, or encoded by the nucleotide sequence shown in Table 1 of US Patent Application No. 20160108123. In certain embodiments, the PD-L1 antibody molecule provides for a substitution in the CDR of the light chain, for example one or more substitutions in the CDR1, CDR2 and/or CDR3 of the light chain.

In another embodiment, the PD-L1 antibody molecule contains at least one, two, three, four, five, or six CDRs (or all CDRs in total) from the heavy and light chain variable region, comprising the amino acid sequence shown in Table 1 of US Patent Application No. 20160108123, or encoded by the nucleotide sequence shown in Table 1 of US Patent Application No. 20160108123. In one embodiment, one or more CDRs (or collectively all CDRs) have one, two, three, four, five, six or more changes, such as amino acid substitutions or deletions, compared to the amino acid sequence shown in Table 1 of US Patent Application No. 20160108123, or encoded by the nucleotide sequence shown in Table 1 of US Patent Application No. 20160108123.

In one embodiment, an anti-PD-L1 antibody molecule contains at least one, two, or three CDRs or one, two, or three hypervariable loops from the heavy chain variable region of an antibody described herein, e.g., an antibody selected from any of BAP058-hum01 BAP058-hum02 BAP058-hum03 BAP058-hum04 BAP058-hum05 BAP058-hum06 BAP058-hum07 BAP058-hum08 BAP058-hum09 BAP058-hum10 BAP058-hum11 BAP058-hum12 BAP058-hum13 -hum14, BAP058-hum15, BAP058-hum16, BAP058-hum17, BAP058-Clone-K, BAP058-Clone-L, BAP058-Clone-M, BAP058-Clone-N or BAP058-Clone-O, as defined by Kabat and Chothia (eg, at least one, two, or three CDRs or hypervariable loops as defined by Kabat and Chothia as set out in Table 1 of US Patent Application No. 20160108123); or encoded by the nucleotide sequence from table 1 of US patent application No. 20160108123; or having a sequence substantially identical (eg, at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or more identical) to any of the above sequences; or which have at least one amino acid change but no more than two, three, or four changes (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions), compared to one, two, or three CDRs or hypervariable loops according to Kabat and/or Chothia shown in Table 1 of US Patent Application No. 20160108123.

In one embodiment, an anti-PD-L1 antibody molecule may comprise a VH CDR1 according to Kabat et al. ((1991), "Sequences of Proteins of Immunological Interest," 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD), or VH hypervariable loop 1 according to Chothia et al. (1992) J. Mol. Biol. 227:799-817, or a combination thereof, e.g. as shown in Table 1 of US Patent Application No. 20160108123. a sequence substantially identical to it (e.g., having at least one amino acid change, but no more than two, three, or four dimensions (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions)).An anti-PD-L1 antibody molecule may additionally contain, for example, CDR 2-3 VH according to Kabat et al., and CDR 1-3 VL according to Kabat et al., such as those shown in Table 1 of US Patent Application No. 20160108123.

In a preferred embodiment, an anti-PD-L1 antibody molecule for use in the combinations, methods and compositions of the present invention contains (see Table 2):

(a) a heavy chain variable region (VH) comprising the VHCDR1 amino acid sequence of SEQ ID NO: 5, the VHCDR2 amino acid sequence of SEQ ID NO: 6, and the VHCDR3 amino acid sequence of SEQ ID NO: 4; and a light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO: 14, the VLCDR2 amino acid sequence of SEQ ID NO: 15, and the VLCDR3 amino acid sequence of SEQ ID NO: 16;

(b) VH containing the VHCDR1 amino acid sequence of SEQ ID NO: 2, the VHCDR2 amino acid sequence of SEQ ID NO: 3, and the VHCDR3 amino acid sequence of SEQ ID NO: 4; and VL containing the amino acid sequence of VLCDR1 under SEQ ID NO: 11, the amino acid sequence of VLCDR2 under SEQ ID NO: 12 and the amino acid sequence of VLCDR3 under SEQ ID NO: 13;

(c) VH containing the VHCDR1 amino acid sequence of SEQ ID NO: 1, the VHCDR2 amino acid sequence of SEQ ID NO: 6, and the VHCDR3 amino acid sequence of SEQ ID NO: 4; and VL containing the amino acid sequence of VLCDR1 under SEQ ID NO: 14, the amino acid sequence of VLCDR2 under SEQ ID NO: 15 and the amino acid sequence of VLCDR3 under SEQ ID NO: 16; or

(d) a VH containing the VHCDR1 amino acid sequence of SEQ ID NO: 1, the VHCDR2 amino acid sequence of SEQ ID NO: 3, and the VHCDR3 amino acid sequence of SEQ ID NO: 4; and VL containing the VLCDR1 amino acid sequence of SEQ ID NO: 11, the VLCDR2 amino acid sequence of SEQ ID NO: 12, and the VLCDR3 amino acid sequence of SEQ ID NO: 13.

In one aspect, the anti-PD-L1 antibody molecule used in the combinations of the present invention comprises:

(a) a heavy chain variable domain containing the amino acid sequence of SEQ ID NO: 7 and a light chain variable domain containing the amino acid sequence of SEQ ID NO: 17.

table 2

Amino acid and nucleotide sequences of humanized mAb BAP058-hum013. Shown are the amino acid and nucleotide sequences of the heavy and light chain CDRs, the heavy and light chain variable regions, and the heavy and light chains.

BAP058-hum13-HC SEQ ID NO:2 (Kabat) HCDR1 SYWMY SEQ ID NO:3 (Kabat) HCDR2 RIDPNSGSTKYNEKFKN SEQ ID NO:4 (Kabat) HDDR3 DYRKGLYAMDY SEQ ID NO:5 (Chothia) HCDR1 GYTFTSY SEQ ID NO:6 (Chothia) HCDR2 DPNSGS SEQ ID NO:4 (Chothia) HDDR3 DYRKGLYAMDY SEQ ID NO:7 vh EVQLVQSGAEVKKPGATVKISCKVSGYTFTSYWMYWVRQARGQRLEWIGRIDPNSGSTKYNEKFKNRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDYRKGLYAMDYWGQGTTVTVSS SEQ ID NO:8 DNA encoding VH GAGGTCCAGCTGGTACAGTCTGGGGCTGAGGTGAAGAAGCCTGGGGCTACAGTGAAAATCTCCTGCAAGGTTTCTGGCTACACCTTCACCAGTTACTGGATGTACTGGGTGCGACAGGCTCGTGGACAACGCCTTGAGTGGATAGGTAGGATTGATCCTAATAGTGGGAGTACTAAGTACAATGAGAAGTTCAAGAACAGATTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTATCTTCAAATGAACAGCCTGAGAGCCGAGGACACGGCCGTGTATTACTGTGCAAGGGACTATAGAAAGGGGCTCTATGCTATGGACTACTGGGGCCAGGGCACCACCGTGACCGTGTCCTCC SEQ ID NO:9 heavy chain EVQLVQSGAEVKKPGATVKISCKVSGYTFTSYWMYWVRQARGQRLEWIGRIDPNSGSTKYNEKFKNRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDYRKGLYAMDYWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK SEQ ID NO:10 heavy chain DNA GAGGTCCAGCTGGTACAGTCTGGGGCTGAGGTGAAGAAGCCTGGGGCTACAGTGAAAATCTCCTGCAAGGTTTCTGGCTACACCTTCACCAGTTACTGGATGTACTGGGTGCGACAGGCTCGTGGACAACGCCTTGAGTGGATAGGTAGGATTGATCCTAATAGTGGGAGTACTAAGTACAATGAGAAGTTCAAGAACAGATTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTATCTTCAAATGAACAGCCTGAGAGCCGAGGACACGGCCGTGTATTACTGTGCAAGGGACTATAGAAAGGGGCTCTATGCTATGGACTACTGGGGCCAGGGCACCACCGTGACCGTGTCCTCCGCTTCCACCAAGGGCCCATCCGTCTTCCCCCTGGCGCCCTGCTCCAGGAGCACCTCCGAGAGCACAGCCGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACGAAGACCTACACCTGCAACGTAGATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGTCCAAATATGGTCCCCCATGCCCACCGTGCCCAGCACCTGAGTTCCTGGGGGGACCATCAGTCTTCCTGTTCCCCCCAAAACCCAAGGACACTCTCATGATCTCCCGGACCCCTGAGGTCACGTGCGTGGTGGTGGACGTGAGCCAGGAAGACCCCGAGGTCCAGTTCAACTGGTACGTGGATGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTTCAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAACGGCAAGGAGTACAAGTGCAAGGTGTCCAACAAAGGCCTCCCGTCCTCCATCGAGA AAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAGCCACAGGTGTACACCCTGCCCCCATCCCAGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTACCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAGGCTAACCGTGGACAAGAGCAGGTGGCAGGAGGGGAATGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACACAGAAGAGCCTCTCCCTGTCTCTGGGTAAA BAP058-hum13-LC SEQ ID NO:11 (Kabat) LCDR1 KASQDVGTAVA SEQ ID NO:12 (Kabat) LCDR2 WASTRHT SEQ ID NO:13 (Kabat) LCDR3 QQYNSYPLT SEQ ID NO:14 (Chothia) LCDR1 SQDVGTA SEQ ID NO:15 (Chothia) LCDR2 WAS SEQ ID NO:16 (Chothia) LCDR3 YNSYPL SEQ ID NO:17 VL AIQLTQSPSSLSASVGDRVTITCKASQDVGTAVAWYLQKPGQSPQLLIYWASTRHTGVPSRFSGSGSGTDFTFTISSLEAEDAATYYCQQYNSYPLTFGQGTKVEIK SEQ ID NO:18 DNA encoding VL GCCATCCAGTTGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCAAGGCCAGTCAGGATGTGGGTACTGCTGTAGCCTGGTACCTGCAGAAGCCAGGGCAGTCTCCACAGCTCCTGATCTATTGGGCATCCACCCGGCACACTGGGGTCCCCTCGAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACCTTTACCATCAGTAGCCTGGAAGCTGAAGATGCTGCAACATATTACTGTCAGCAGTATAACAGCTATCCTCTCACGTTCGGCCAAGGGACCAAGGTGGAAATCAAA SEQ ID NO:19 light chain AIQLTQSPSSLSASVGDRVTITCKASQDVGTAVAWYLQKPGQSPQLLIYWASTRHTGVPSRFSGSGSGTDFTFTISSLEAEDAATYYCQQYNSYPLTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTKTLSKPVNGSFTHQQ SEQ ID NO:20 light chain DNA GCCATCCAGTTGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCAAGGCCAGTCAGGATGTGGGTACTGCTGTAGCCTGGTACCTGCAGAAGCCAGGGCAGTCTCCACAGCTCCTGATCTATTGGGCATCCACCCGGCACACTGGGGTCCCCTCGAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACCTTTACCATCAGTAGCCTGGAAGCTGAAGATGCTGCAACATATTACTGTCAGCAGTATAACAGCTATCCTCTCACGTTCGGCCAAGGGACCAAGGTGGAAATCAAACGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT

In one embodiment, the PD-1 inhibitor partner of the combination of the present invention is an anti-PD-1 antibody molecule. In one embodiment, the PD-1 inhibitor is an anti-PD-1 antibody molecule described in US 2015/0210769 published July 30, 2015 under the title Antibody Molecules to PD-1 and Uses Thereof. 1 and their uses"), incorporated by reference in its entirety.

In one embodiment, an anti-PD-1 antibody molecule comprises at least one, two, three, four, five, or six complementarity determining regions (CDRs) (or all CDRs in total) from a heavy and light chain variable region comprising an amino acid sequence, shown in Table 3 (for example, from the BAP049-Clone-E or BAP049-Clone-B heavy and light chain variable region sequences disclosed in Table 3), or encoded by the nucleotide sequence shown in Table 3. In some embodiments, CDRs are defined according to the Kabat numbering scheme ( for example, as outlined in table 3). In some embodiments, CDRs are defined according to a Chothia numbering scheme (e.g., as outlined in table 3). In some embodiments, CDRs are defined according to a combined CDR numbering scheme from both Kabat and Chothia (e.g., as outlined in table 3). In one embodiment, VHCDR1 according to the combined Kabat and Chothia CDR numbering scheme contains the amino acid sequence GYTFTTYWMH (SEQ ID NO: 21). In one embodiment, one or more CDRs (or collectively all CDRs) have one, two, three, four, five, six or more changes, for example, amino acid substitutions (for example, conservative amino acid substitutions) or deletions compared to the amino acid sequence shown in Table 1 or encoded by the nucleotide sequence shown in Table 3.

In one embodiment, an anti-PD-1 antibody molecule comprises a heavy chain variable region (VH) comprising the VHCDR1 amino acid sequence of SEQ ID NO: 22, the VHCDR2 amino acid sequence of SEQ ID NO: 23, and the VHCDR3 amino acid sequence of SEQ ID NO: 24; and a light chain variable region (VL) containing the VLCDR1 amino acid sequence of SEQ ID NO: 31, the VLCDR2 amino acid sequence of SEQ ID NO: 32, and the VLCDR3 amino acid sequence of SEQ ID NO: 33, each of which is disclosed in Table 3.

In one embodiment, the antibody molecule contains a VH containing VHCDR1 encoded by the nucleotide sequence of SEQ ID NO: 45, VHCDR2 encoded by the nucleotide sequence of SEQ ID NO: 46, and VHCDR3 encoded by the nucleotide sequence of SEQ ID NO: 47; and VL containing VLCDR1 encoded by the nucleotide sequence of SEQ ID NO: 50, VLCDR2 encoded by the nucleotide sequence of SEQ ID NO: 51, and VLCDR3 encoded by the nucleotide sequence of SEQ ID NO: 52, each of which is disclosed in Table 3.

In one embodiment, the anti-PD-1 antibody molecule comprises a VH containing the amino acid sequence of SEQ ID NO: 27, or an amino acid sequence at least 85%, 90%, 95%, or 99% or greater identical to SEQ ID NO: 27. In one embodiment, an anti-PD-1 antibody molecule comprises a VL comprising an amino acid sequence under SEQ ID NO: 41 or an amino acid sequence at least 85%, 90%, 95%, or 99% or greater identical to SEQ ID NO: 41. In one embodiment, an anti-PD-1 antibody molecule comprises a VL comprising an amino acid sequence under SEQ ID NO: 37 or an amino acid sequence at least 85%, 90%, 95%, or 99% or greater identical to SEQ ID NO: 37. In one embodiment, the anti-PD-1 antibody molecule comprises a VH comprising the amino acid sequence of SEQ ID NO: 27 and a VL comprising the amino acid sequence of SEQ ID NO: 41. In one embodiment, the anti-PD-1 antibody molecule PD-1 contains a VH containing the amino acid sequence of SEQ ID NO: 27 and a VL containing the amino acid sequence of SEQ ID NO: 37.

In one embodiment, the antibody molecule contains a VH encoded by the nucleotide sequence of SEQ ID NO: 28 or by a nucleotide sequence at least 85%, 90%, 95%, or 99% or greater identical to SEQ ID NO: 28. In one embodiment, the antibody molecule contains a VL encoded by a nucleotide sequence of SEQ ID NO: 42 or 38 or a nucleotide sequence that is at least 85%, 90%, 95%, or 99% or more identical to SEQ ID NO: 42 or 38. In one embodiment, the antibody molecule contains a VH encoded by the nucleotide sequence of SEQ ID NO: 28 and a VL encoded by the nucleotide sequence of SEQ ID NO: 42 or 38.

In one embodiment, an anti-PD-1 antibody molecule comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 29 or an amino acid sequence at least 85%, 90%, 95%, or 99% or greater identical to SEQ ID NO: 29 In one embodiment, the anti-PD-1 antibody molecule comprises a light chain comprising the amino acid sequence of SEQ ID NO: 43 or an amino acid sequence at least 85%, 90%, 95%, or 99% or greater identical to SEQ ID NO: 43. In one embodiment, an anti-PD-1 antibody molecule comprises a light chain comprising the amino acid sequence of SEQ ID NO: 39 or an amino acid sequence at least 85%, 90%, 95%, or 99% or more identical to SEQ ID NO. : 39. In one embodiment, the anti-PD-1 antibody molecule comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 29 and a light chain comprising the amino acid sequence of SEQ ID NO: 43. In one embodiment, the anti-PD-1 antibody molecule comprises a heavy chain containing the amino acid sequence of SEQ ID NO: 29 and a light chain containing the amino acid sequence of SEQ ID NO: 39.

In one embodiment, the antibody molecule comprises a heavy chain encoded by the nucleotide sequence of SEQ ID NO: 30 or by a nucleotide sequence at least 85%, 90%, 95%, or 99% or greater identical to SEQ ID NO: 30. In one embodiment, implementation, the antibody molecule contains a light chain encoded by a nucleotide sequence under SEQ ID NO: 44 or 40 or a nucleotide sequence identical to at least 85%, 90%, 95% or 99% or more of SEQ ID NO: 44 or 40. In one in an embodiment, the antibody molecule contains a heavy chain encoded by the nucleotide sequence of SEQ ID NO: 30 and a light chain encoded by the nucleotide sequence of SEQ ID NO: 44 or 40.

The antibody molecules described herein can be generated using the vectors, host cells, and methods described in US 2015/0210769, incorporated by reference in its entirety.

The VH and VL regions can be subdivided into regions of hypervariability called "complementarity determining regions" (CDRs) that alternate with more conserved regions called "framework regions" (FR or FW).

The dimensions of the framework region and the CDR were accurately determined using a number of methods (see Fig. Kabat, E. A.,et al. (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, U.S. Department of Health and Human Services, NIH Publication No. 91-3242; Chothia, C.et al. (1987)J. Mol. biol. 196:901-917; and AbM detection used in Oxford Molecular's AbM antibody modeling software. Cm. in general, for exampleProtein Sequence and Structure Analysis of Antibody Variable Domains. In Antibody Engineering Lab Manual (Ed.: Duebel, S. and Kontermann, R., Springer-Verlag, Heidelberg).

The terms "complementarity determining region" and "CDR" as used herein refer to amino acid sequences in the variable regions of an antibody that confer antigen specificity and binding affinity. Typically, three CDRs are present in each heavy chain variable region (HCDR1, HCDR2, HCDR3), and three CDRs are present in each light chain variable region (LCDR1, LCDR2, LCDR3).

The precise boundaries of the amino acid sequence of a given CDR can be determined using any of a number of well known schemes, including those described in Kabat et al. (1991), "Sequences of Proteins of Immunological Interest," 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD (numbering scheme according to "Kabat"), Al-Lazikani et al. , (1997) JMB 273,927-948 (numbering scheme according to "Chothia"). As used herein, CDRs defined according to the "Chothia" numbering scheme are also sometimes referred to as "hypervariable loops".

For example, according to Kabat, the CDR amino acid residues in the heavy chain variable domain (VH) are numbered 31-35 (HCDR1), 50-65 (HCDR2), and 95-102 (HCDR3); and the CDR amino acid residues in the light chain variable domain (VL) are numbered 24-34 (LCDR1), 50-56 (LCDR2) and 89-97 (LCDR3). According to Chothia, the CDR amino acids in VH are numbered 26-32 (HCDR1), 52-56 (HCDR2), and 95-102 (HCDR3); and amino acid residues in VL are numbered 26-32 (LCDR1), 50-52 (LCDR2) and 91-96 (LCDR3). Combining the definitions of CDRs according to Kabat and according to Chothia, CDRs consist of amino acid residues 26-35 (HCDR1), 50-65 (HCDR2), and 95-102 (HCDR3) in human VH and amino acid residues 24-34 (LCDR1), 50-56 (LCDR2) and 89-97 (LCDR3) in human VL.

In general, unless specifically stated otherwise, anti-PD-1 antibody molecules may contain any combination of one or more Kabat CDRs and/or Chothia CDRs, for example, described in Table 3. In one embodiment, for the anti-PD-1 antibody molecules described in Table 3, the following definitions are used: HCDR1 according to the combined definitions of both Kabat and Chothia CDRs and HCCDR 2-3 and LCCDR 1 -3 according to the definition of CDR by Kabat. By all definitions, each of VH and VL typically contains three CDRs and four FRs, arranged from amino to carboxy in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4.

Calculations of homology or sequence identity between sequences (terms used interchangeably herein) are performed as follows.

To determine the percent identity of two amino acid sequences or two nucleic acid sequences, the sequences are aligned for optimal comparison (e.g., one or both of the first and second amino acid or nucleic acid sequences may be gapped for optimal alignment, and non-homologous sequences may be ignored for comparison purposes). In a preferred embodiment, the length of the reference sequence aligned for comparison purposes is at least 30%, preferably at least 40%, more preferably at least 50%, 60% and even more preferably at least 70%, 80%, 90%, 100% of the length of the reference sequence. The amino acid residues or nucleotides at the corresponding amino acid positions or nucleotide positions are then compared. When a position in the first sequence is occupied by the same amino acid residue or nucleotide as the corresponding position in the second sequence, then the molecules are identical at that position (as used herein, "identity" of an amino acid or nucleic acid is equivalent to "homology" of an amino acid or nucleic acid ).

The percentage identity of two sequences depends on the number of identical positions that the sequences share, taking into account the number of gaps and the length of each gap that must be entered for optimal alignment of the two sequences.

Comparing sequences and determining the percent identity of two sequences can be done using a mathematical algorithm. In a preferred embodiment, the percent identity of two amino acid sequences is determined using the Needleman-Wunsch algorithm ((1970) J. Mol. Biol. 48:444-453), which has been included in the GAP program as part of the GCG software package (available at www. gcg.com), using either the Blossom 62 matrix or the PAM250 matrix, and a gap opening penalty of 16, 14, 12, 10, 8, 6, or 4, and a gap extension penalty of 1, 2, 3 , 4, 5, or 6. In yet another preferred embodiment, percent identity between two nucleotide sequences is determined using the GAP program in the GCG software package (available at www.gcg.com) using the NWSgapdna.CMP matrix and gap opening penalty, of 40, 50, 60, 70, or 80, and a gap extension penalty of 1, 2, 3, 4, 5, or 6. An especially preferred set of parameters (and one that should be used unless otherwise noted) is ma A triage of Blossum weights of 62 with a gap opening penalty of 12, a gap extension penalty of 4, and a gap framing penalty of 5.

The percent identity of two amino acid or nucleotide sequences can be determined using the algorithm of E. Meyers and W. Miller ((1989) CABIOS , 4:11-17), which was included in the ALIGN program (version 2.0), using the PAM120 residue substitution weight table , a gap extension penalty of 12, and a gap opening penalty of 4.

The nucleic acid and protein sequences described herein can be used as a "query sequence" for searching public databases, for example, to identify other members of the family or related sequences. Such searches can be performed using the programs NBLAST and XBLAST (version 2.0) Altschul,et al. (1990)J. Mol. Biol. 215:403-10. BLAST nucleotide searches can be performed with the NBLAST program, score=100, wordlength=12, to obtain nucleotide sequences homologous to the nucleic acid molecules of the present invention. BLAST protein searches can be performed using the XBLAST program, score=50, wordlength=3, to obtain amino acid sequences homologous to the protein molecules of the present invention. Gapped BLAST can be used to obtain alignments with gaps for comparison purposes, as described in Altschulet al., (1997)Nucleic Acids Res. 25:3389-3402. When using the BLAST and Gapped BLAST programs, you can use the default settings from the respective programs (for example, XBLAST and NBLAST). Cm. www.ncbi.nlm.nih.gov.

A "conservative amino acid substitution" is one in which an amino acid residue is replaced with an amino acid residue having a similar side chain. Families of amino acid residues having similar side chains have been defined in the art. These families include amino acids with basic side chains (for example, lysine, arginine, histidine), acid side chains (for example, aspartic acid, glutamic acid), uncharged polar side chains (for example, glycine, asparagine, glutamine, serine, threonine, tyrosine, cysteine), nonpolar side chains (eg, alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, tryptophan), beta-branched side chains (eg, threonine, valine, isoleucine) and aromatic side chains (for example, tyrosine, phenylalanine, tryptophan, histidine).

Table 3 . Amino acid and nucleotide sequences of exemplary anti-PD-1 antibody molecules

HC BAP049-Clone-B SEQ ID NO: 22 (Kabat) HCDR1 TYWMH SEQ ID NO: 23 (Kabat) HCDR2 NIYPGTGGSNFDEKFKN SEQ ID NO: 24 (Kabat) HDDR3 WTTGTGAY SEQ ID NO: 25 (Chothia) HCDR1 GYTFTTY SEQ ID NO: 26 (Chothia) HCDR2 YPGTGG SEQ ID NO: 24 (Chothia) HDDR3 WTTGTGAY SEQ ID NO: 27 vh EVQLVQSGAEVKKPGESLRISCKGSGYTFTTYWMHWVRQATGQGLEWMGNIYPGTGGSNFDEKFKNRVTITADKSTSTAYMELSSLRSEDTAVYYCTRWTTGTGAYWGQGTTVTVSS SEQ ID NO: 28 DNA encoding VH Gaggtgcagctggtgcagtcaggcgccgaagtgaagaagcccggcgagtcactgagaattagctgtaaaggttcaggctacaccttcactacctactggatgcactgggtccgccaggctaccggtcaaggcctcgagtggatgggtaatatctaccccggcaccggcggctctaacttcgacgagaagtttaagaatagagtgactatcaccgccgataagtctactagcaccgcctatatggaactgtctagcctgagatcagaggacaccgccgtctactactgcactaggtggactaccggcacaggcgcctactggggtcaaggcactaccgtgaccgtgtctagc SEQ ID NO: 29 HC EVQLVQSGAEVKKPGESLRISCKGSGYTFTTYWMHWVRQATGQGLEWMGNIYPGTGGSNFDEKFKNRVTITADKSTSTAYMELSSLRSEDTAVYYCTRWTTGTGAYWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLG SEQ ID NO: 30 DNA encoding HC gaggtgcagctggtgcagtcaggcgccgaagtgaagaagcccggcgagtcactgagaattagctgtaaaggttcaggctacaccttcactacctactggatgcactgggtccgccaggctaccggtcaaggcctcgagtggatgggtaatatctaccccggcaccggcggctctaacttcgacgagaagtttaagaatagagtgactatcaccgccgataagtctactagcaccgcctatatggaactgtctagcctgagatcagaggacaccgccgtctactactgcactaggtggactaccggcacaggcgcctactggggtcaaggcactaccgtgaccgtgtctagcgctagcactaagggcccgtccgtgttccccctggcaccttgtagccggagcactagcgaatccaccgctgccctcggctgcctggtcaaggattacttcccggagcccgtgaccgtgtcctggaacagcggagccctgacctccggagtgcacaccttccccgctgtgctgcagagctccgggctgtactcgctgtcgtcggtggtcacggtgccttcatctagcctgggtaccaagacctacacttgcaacgtggaccacaagccttccaacactaaggtggacaagcgcgtcgaatcgaagtacggcccaccgtgcccgccttgtcccgcgccggagttcctcggcggtccctcggtctttctgttcccaccgaagcccaaggacactttgatgatttcccgcacccctgaagtgacatgcgtggtcgtggacgtgtcacaggaagatccggaggtgcagttcaattggtacgtggatggcgtcgaggtgcacaacgccaaaaccaagccgagggaggagcagttcaactccacttaccgcgtcgtgtccgtgctgacggtgctgcatcaggactggctgaacgggaaggagtacaagtgcaaagtgtccaacaagggacttcctagctcaatcgaaaagaccatct cgaaagccaagggacagccccgggaaccccaagtgtataccctgccaccgagccaggaagaaatgactaagaaccaagtctcattgacttgccttgtgaagggcttctacccatcggatatcgccgtggaatgggagtccaacggccagccggaaaacaactacaagaccacccctccggtgctggactcagacggatccttcttcctctactcgcggctgaccgtggataagagcagatggcaggagggaaatgtgttcagctgttctgtgatgcatgaagccctgcacaaccactacactcagaagtccctgtccctctccctggga LC BAP049-Clone-B SEQ ID NO: 31 (Kabat) LCDR1 KSSQSLLDSGNQKNFLT SEQ ID NO: 32 (Kabat) LCDR2 WASTRES SEQ ID NO: 33 (Kabat) LCDR3 QNDYSYPYT SEQ ID NO: 34 (Chothia) LCDR1 SQSLLDSGNQKNF SEQ ID NO: 35 (Chothia) LCDR2 WAS SEQ ID NO: 36 (Chothia) LCDR3 DYSYPY SEQ ID NO: 37 VL EIVLTQSPATLSLSPGERATLSCKSSQSLLDSGNQKNFLTWYQQKPGKAPKLLIYWASTRESGVPSRFSGSGSGTDFTFTISSLQPEDIATYYCQNDYSYPYTFGQGTKVEIK SEQ ID NO: 38 DNA encoding VL Gagatcgtcctgactcagtcacccgctaccctgagcctgagccctggcgagcgggctacactgagctgtaaatctagtcagtcactgctggatagcggtaatcagaagaacttcctgacctggtatcagcagaagcccggtaaagcccctaagctgctgatctactgggcctctactagagaatcaggcgtgccctctaggtttagcggtagcggtagtggcaccgacttcaccttcactatctctagcctgcagcccgaggatatcgctacctactactgtcagaacgactatagctacccctacaccttcggtcaaggcactaaggtcgagattaag SEQ ID NO: 39 LC EIVLTQSPATLSPGERATLSCKSSQSLLDSGNQKNFLTWYQQKPGKAPKLLIYWASTRESGVPSRFSGSGSGTDFTFTISSLQPEDIATYYCQNDYSYPYTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYTKHKNSFACE SEQ ID NO: 40 DNA encoding LC Gagatcgtcctgactcagtcacccgctaccctgagcctgagccctggcgagcgggctacactgagctgtaaatctagtcagtcactgctggatagcggtaatcagaagaacttcctgacctggtatcagcagaagcccggtaaagcccctaagctgctgatctactgggcctctactagagaatcaggcgtgccctctaggtttagcggtagcggtagtggcaccgacttcaccttcactatctctagcctgcagcccgaggatatcgctacctactactgtcagaacgactatagctacccctacaccttcggtcaaggcactaaggtcgagattaagcgtacggtggccgctcccagcgtgttcatcttcccccccagcgacgagcagctgaagagcggcaccgccagcgtggtgtgcctgctgaacaacttctacccccgggaggccaaggtgcagtggaaggtggacaacgccctgcagagcggcaacagccaggagagcgtcaccgagcaggacagcaaggactccacctacagcctgagcagcaccctgaccctgagcaaggccgactacgagaagcataaggtgtacgcctgcgaggtgacccaccagggcctgtccagccccgtgaccaagagcttcaacaggggcgagtgc HC BAP049-Clone-E SEQ ID NO: 22 (Kabat) HCDR1 TYWMH SEQ ID NO: 23 (Kabat) HCDR2 NIYPGTGGSNFDEKFKN SEQ ID NO: 24 (Kabat) HDDR3 WTTGTGAY SEQ ID NO: 25 (Chothia) HCDR1 GYTFTTY SEQ ID NO: 26 (Chothia) HCDR2 YPGTGG SEQ ID NO: 24 (Chothia) HDDR3 WTTGTGAY SEQ ID NO: 27 vh EVQLVQSGAEVKKPGESLRISCKGSGYTFTTYWMHWVRQATGQGLEWMGNIYPGTGGSNFDEKFKNRVTITADKSTSTAYMELSSLRSEDTAVYYCTRWTTGTGAYWGQGTTVTVSS SEQ ID NO: 28 DNA encoding VH Gaggtgcagctggtgcagtcaggcgccgaagtgaagaagcccggcgagtcactgagaattagctgtaaaggttcaggctacaccttcactacctactggatgcactgggtccgccaggctaccggtcaaggcctcgagtggatgggtaatatctaccccggcaccggcggctctaacttcgacgagaagtttaagaatagagtgactatcaccgccgataagtctactagcaccgcctatatggaactgtctagcctgagatcagaggacaccgccgtctactactgcactaggtggactaccggcacaggcgcctactggggtcaaggcactaccgtgaccgtgtctagc SEQ ID NO: 29 HC EVQLVQSGAEVKKPGESLRISCKGSGYTFTTYWMHWVRQATGQGLEWMGNIYPGTGGSNFDEKFKNRVTITADKSTSTAYMELSSLRSEDTAVYYCTRWTTGTGAYWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLG SEQ ID NO: 30 DNA encoding HC gaggtgcagctggtgcagtcaggcgccgaagtgaagaagcccggcgagtcactgagaattagctgtaaaggttcaggctacaccttcactacctactggatgcactgggtccgccaggctaccggtcaaggcctcgagtggatgggtaatatctaccccggcaccggcggctctaacttcgacgagaagtttaagaatagagtgactatcaccgccgataagtctactagcaccgcctatatggaactgtctagcctgagatcagaggacaccgccgtctactactgcactaggtggactaccggcacaggcgcctactggggtcaaggcactaccgtgaccgtgtctagcgctagcactaagggcccgtccgtgttccccctggcaccttgtagccggagcactagcgaatccaccgctgccctcggctgcctggtcaaggattacttcccggagcccgtgaccgtgtcctggaacagcggagccctgacctccggagtgcacaccttccccgctgtgctgcagagctccgggctgtactcgctgtcgtcggtggtcacggtgccttcatctagcctgggtaccaagacctacacttgcaacgtggaccacaagccttccaacactaaggtggacaagcgcgtcgaatcgaagtacggcccaccgtgcccgccttgtcccgcgccggagttcctcggcggtccctcggtctttctgttcccaccgaagcccaaggacactttgatgatttcccgcacccctgaagtgacatgcgtggtcgtggacgtgtcacaggaagatccggaggtgcagttcaattggtacgtggatggcgtcgaggtgcacaacgccaaaaccaagccgagggaggagcagttcaactccacttaccgcgtcgtgtccgtgctgacggtgctgcatcaggactggctgaacgggaaggagtacaagtgcaaagtgtccaacaagggacttcctagctcaatcgaaaagaccatct cgaaagccaagggacagccccgggaaccccaagtgtataccctgccaccgagccaggaagaaatgactaagaaccaagtctcattgacttgccttgtgaagggcttctacccatcggatatcgccgtggaatgggagtccaacggccagccggaaaacaactacaagaccacccctccggtgctggactcagacggatccttcttcctctactcgcggctgaccgtggataagagcagatggcaggagggaaatgtgttcagctgttctgtgatgcatgaagccctgcacaaccactacactcagaagtccctgtccctctccctggga LC BAP049-Clone-E SEQ ID NO: 31 (Kabat) LCDR1 KSSQSLLDSGNQKNFLT SEQ ID NO: 32 (Kabat) LCDR2 WASTRES SEQ ID NO: 33 (Kabat) LCDR3 QNDYSYPYT SEQ ID NO: 34 (Chothia) LCDR1 SQSLLDSGNQKNF SEQ ID NO: 35 (Chothia) LCDR2 WAS SEQ ID NO: 36 (Chothia) LCDR3 DYSYPY SEQ ID NO: 41 VL EIVLTQSPATLSLSPGERATLSCKSSQSLLDSGNQKNFLTWYQQKPGQAPRLLIYWASTRESGVPSRFSGSGSGTDFTFTISSLEAEDAATYYCQNDYSYPYTFGQGTKVEIK SEQ ID NO: 42 DNA encoding VL Gagatcgtcctgactcagtcacccgctaccctgagcctgagccctggcgagcgggctacactgagctgtaaatctagtcagtcactgctggatagcggtaatcagaagaacttcctgacctggtatcagcagaagcccggtcaagcccctagactgctgatctactgggcctctactagagaatcaggcgtgccctctaggtttagcggtagcggtagtggcaccgacttcaccttcactatctctagcctggaagccgaggacgccgctacctactactgtcagaacgactatagctacccctacaccttcggtcaaggcactaaggtcgagattaag SEQ ID NO: 43 LC EIVLTQSPATLSLSPGERATLSCKSSQSLLDSGNQKNFLTWYQQKPGQAPRLLIYWASTRESGVPSRFSGSGSGTDFTFTISSLEAEDAATYYCQNDYSYPYTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTKTLSKADYEKTHNKSSVY SEQ ID NO: 44 DNA encoding LC Gagatcgtcctgactcagtcacccgctaccctgagcctgagccctggcgagcgggctacactgagctgtaaatctagtcagtcactgctggatagcggtaatcagaagaacttcctgacctggtatcagcagaagcccggtcaagcccctagactgctgatctactgggcctctactagagaatcaggcgtgccctctaggtttagcggtagcggtagtggcaccgacttcaccttcactatctctagcctggaagccgaggacgccgctacctactactgtcagaacgactatagctacccctacaccttcggtcaaggcactaaggtcgagattaagcgtacggtggccgctcccagcgtgttcatcttcccccccagcgacgagcagctgaagagcggcaccgccagcgtggtgtgcctgctgaacaacttctacccccgggaggccaaggtgcagtggaaggtggacaacgccctgcagagcggcaacagccaggagagcgtcaccgagcaggacagcaaggactccacctacagcctgagcagcaccctgaccctgagcaaggccgactacgagaagcataaggtgtacgcctgcgaggtgacccaccagggcctgtccagccccgtgaccaagagcttcaacaggggcgagtgc HC BAP049-Clone-B SEQ ID NO: 45 (Kabat) HCDR1 ACCTACTGGATGAC SEQ ID NO: 46 (Kabat) HCDR2 AATATCTACCCCGGCACCGGCGGCTCTAACTTCGACGAGAAGTTTAAGAAT SEQ ID NO: 47 (Kabat) HDDR3 TGGACTACCGGCACAGGCGCCTAC SEQ ID NO: 48 (Chothia) HCDR1 GGCTACACCTTCACTACCTAC SEQ ID NO: 49 (Chothia) HCDR2 TACCCCGGCACCGGCGGC SEQ ID NO: 47 (Chothia) HDDR3 TGGACTACCGGCACAGGCGCCTAC LC BAP049-Clone-B SEQ ID NO: 50 (Kabat) LCDR1 AAATCTAGTCAGTCACTGCTGGATAGCGGTAATCAGAAGAACTTCCTGACC SEQ ID NO: 51 (Kabat) LCDR2 TGGGCCTCTACTAGAGAATCA SEQ ID NO: 52 (Kabat) LCDR3 CAGAACGACTATAGCTACCCCTACACC SEQ ID NO: 53 (Chothia) LCDR1 AGTCAGTCACTGCTGGATAGCGGTAATCAGAAGAACTTC SEQ ID NO: 54 (Chothia) LCDR2 TGGGCCTCT SEQ ID NO: 55 (Chothia) LCDR3 GACTATAGCTACCCCTAC HC BAP049-Clone-E SEQ ID NO: 45 (Kabat) HCDR1 ACCTACTGGATGAC SEQ ID NO: 46 (Kabat) HCDR2 AATATCTACCCCGGCACCGGCGGCTCTAACTTCGACGAGAAGTTTAAGAAT SEQ ID NO: 47 (Kabat) HDDR3 TGGACTACCGGCACAGGCGCCTAC SEQ ID NO: 48 (Chothia) HCDR1 GGCTACACCTTCACTACCTAC SEQ ID NO: 49 (Chothia) HCDR2 TACCCCGGCACCGGCGGC SEQ ID NO: 47 (Chothia) HDDR3 TGGACTACCGGCACAGGCGCCTAC LC BAP049-Clone-E SEQ ID NO: 50 (Kabat) LCDR1 AAATCTAGTCAGTCACTGCTGGATAGCGGTAATCAGAAGAACTTCCTGACC SEQ ID NO: 51 (Kabat) LCDR2 TGGGCCTCTACTAGAGAATCA SEQ ID NO: 52 (Kabat) LCDR3 CAGAACGACTATAGCTACCCCTACACC SEQ ID NO: 53 (Chothia) LCDR1 AGTCAGTCACTGCTGGATAGCGGTAATCAGAAGAACTTC SEQ ID NO: 54 (Chothia) LCDR2 TGGGCCTCT SEQ ID NO: 55 (Chothia) LCDR3 GACTATAGCTACCCCTAC

In a preferred embodiment, an anti-PD-1 antibody for use in the combinations, methods and compositions of the present invention comprises:

(a) a heavy chain variable region (VH) comprising the VHCDR1 amino acid sequence of SEQ ID NO: 25, the VHCDR2 amino acid sequence of SEQ ID NO: 26, and the VHCDR3 amino acid sequence of SEQ ID NO: 24; and a light chain variable region (VL) containing the VLCDR1 amino acid sequence of SEQ ID NO: 34, the VLCDR2 amino acid sequence of SEQ ID NO: 35, and the VLCDR3 amino acid sequence of SEQ ID NO: 36;

(b) a heavy chain variable region (VH) comprising the VHCDR1 amino acid sequence of SEQ ID NO: 22, the VHCDR2 amino acid sequence of SEQ ID NO: 23, and the VHCDR3 amino acid sequence of SEQ ID NO: 24; and a light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO: 31, the VLCDR2 amino acid sequence of SEQ ID NO: 32, and the VLCDR3 amino acid sequence of SEQ ID NO: 33;

(c) a heavy chain variable region (VH) comprising the VHCDR1 amino acid sequence of SEQ ID NO: 21, the VHCDR2 amino acid sequence of SEQ ID NO: 26, and the VHCDR3 amino acid sequence of SEQ ID NO: 24; and a light chain variable region (VL) containing the VLCDR1 amino acid sequence of SEQ ID NO: 34, the VLCDR2 amino acid sequence of SEQ ID NO: 35, and the VLCDR3 amino acid sequence of SEQ ID NO: 36; or

(d) a heavy chain variable region (VH) comprising the VHCDR1 amino acid sequence of SEQ ID NO: 21, the VHCDR2 amino acid sequence of SEQ ID NO: 23, and the VHCDR3 amino acid sequence of SEQ ID NO: 24; and a light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO: 31, the VLCDR2 amino acid sequence of SEQ ID NO: 32, and the VLCDR3 amino acid sequence of SEQ ID NO: 33.

In another preferred embodiment, an anti-PD-1 antibody for use in the combinations, methods and compositions of the present invention comprises a VH comprising the amino acid sequence of SEQ ID NO: 27 and a VL comprising the amino acid sequence of SEQ ID NO: 41.

In another preferred embodiment, an anti-PD-1 antibody for use in the combinations, methods and compositions of the present invention comprises a VH comprising the amino acid sequence of SEQ ID NO: 27 and a VL comprising the amino acid sequence of SEQ ID NO: 37.

In another preferred embodiment, an anti-PD-1 antibody for use in the combinations, methods and compositions of the present invention comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 29 and a light chain comprising the amino acid sequence of SEQ ID NO: 43.

In another preferred embodiment, an anti-PD-1 antibody for use in the combinations, methods and compositions of the present invention comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 29 and a light chain comprising the amino acid sequence of SEQ ID NO: 39.

Other exemplary PD-1 inhibitors for use in the combinations described herein

In one embodiment, the anti-PD-1 antibody molecule is nivolumab (Bristol-Myers Squibb), also known as MDX-1106, MDX-1106-04, ONO-4538, BMS-936558, or OPDIVO®. Nivolumab (clone 5C4) and other anti-PD-1 antibodies are disclosed in US 8008449 and WO 2006/121168, incorporated by reference in their entirety. In one embodiment, an anti-PD-1 antibody molecule comprises one or more CDR sequences (or all CDR sequences in aggregate), a heavy chain or light chain variable region sequence, or a nivolumab heavy chain or light chain sequence, e.g., disclosed in table 4.

In one embodiment, the PD-1 antibody molecule is pembrolizumab (Merck & Co), also known as lambrolizumab, MK-3475, MK03475, SCH-900475, or KEYTRUDA®. Pembrolizumab and other anti-PD-1 antibodies are disclosed in Hamid, O.et al. (2013)New England Journal of Medicine 369 (2): 134-44, US 8354509 and WO 2009/114335, incorporated by reference in their entirety. In one embodiment, an anti-PD-1 antibody molecule comprises one or more CDR sequences (or collectively all CDR sequences), a pembrolizumab heavy chain or light chain variable region sequence, or a pembrolizumab heavy chain or light chain sequence, e.g., disclosed in table 4.

In one embodiment, the anti-PD-1 antibody molecule is pidilizumab (CureTech), also known as CT-011. Pidilizumab and other anti-PD-1 antibodies are disclosed in Rosenblatt, J.et al. (2011)J Immunotherapy34(5): 409-18, US 7695715, US 7332582 and US 8686119, incorporated by reference in their entirety. In one embodiment, an anti-PD-1 antibody molecule comprises one or more CDR sequences (or all CDR sequences in aggregate), a heavy chain or light chain variable region sequence, or a pidilizumab heavy chain or light chain sequence, e.g., disclosed in table 4.

In one embodiment, the anti-PD-1 antibody molecule is MEDI0680 (Medimmune), also known as AMP-514. MEDI0680 and other anti-PD-1 antibodies are disclosed in US 9205148 and WO 2012/145493, incorporated by reference in their entirety. In one embodiment, an anti-PD-1 antibody molecule comprises one or more CDR sequences (or all CDR sequences in aggregate), a heavy chain or light chain variable region sequence, or a MEDI0680 heavy chain or light chain sequence.

In one embodiment, the anti-PD-1 antibody molecule is REGN2810 (Regeneron). In one embodiment, an anti-PD-1 antibody molecule comprises one or more CDR sequences (or all CDR sequences in combination), a heavy chain or light chain variable region sequence, or a REGN2810 heavy chain or light chain sequence.

In one embodiment, the anti-PD-1 antibody molecule is PF-06801591 (Pfizer). In one embodiment, an anti-PD-1 antibody molecule comprises one or more CDR sequences (or all CDR sequences in total), a heavy chain or light chain variable region sequence, or a PF-06801591 heavy chain or light chain sequence.

In one embodiment, the anti-PD-1 antibody molecule is BGB-A317 or BGB-108 (Beigene). In one embodiment, an anti-PD-1 antibody molecule comprises one or more CDR sequences (or all CDR sequences in combination), a heavy chain or light chain variable region sequence, or a BGB-A317 or BGB-108 heavy chain or light chain sequence.

In one embodiment, the anti-PD-1 antibody molecule is INCSHR1210 (Incyte), also known as INCSHR01210 or SHR-1210. In one embodiment, an anti-PD-1 antibody molecule comprises one or more CDR sequences (or all CDR sequences in combination), a heavy chain or light chain variable region sequence, or an INCSHR1210 heavy chain or light chain sequence.

In one embodiment, the anti-PD-1 antibody molecule is TSR-042 (Tesaro), also known as ANB011. In one embodiment, an anti-PD-1 antibody molecule comprises one or more CDR sequences (or all CDR sequences in combination), a heavy chain or light chain variable region sequence, or a TSR-042 heavy chain or light chain sequence.

Additional known anti-PD-1 antibodies include those described, for example, in Wo 2015/112800, Wo 2016/092419, Wo 2015/085847, Wo 2014/179664, Wo 2014/194302, Wo 2014/209804, Wo 2015/200119, US 8735553, US 7488802, US 8927697, US 8993731 and US and US incorporated by reference in its entirety.

In one embodiment, an anti-PD-1 antibody is an antibody that competes for binding to and/or binds to the same epitope on PD-1 as one of the anti-PD-1 antibodies described herein.

In one embodiment, a PD-1 inhibitor is a peptide that inhibits a signaling pathway involving PD-1, e.g., as described in US 8907053, incorporated by reference in its entirety. In one embodiment, the PD-1 inhibitor is an immunoadhesin (e.g., an immunoadhesin containing an extracellular or PD-1 binding portion of PD-L1 or PD-L2 fused to a constant region (e.g., Fc region of the immunoglobulin sequence)). In one embodiment, the PD-1 inhibitor is AMP-224 (B7-DCIg (Amplimmune), e.g., disclosed in WO 2010/027827 and WO 2011/066342, incorporated by reference in its entirety).

Table 4 . Amino acid sequences of other exemplary anti-PD-1 antibody molecules

Nivolumab SEQ ID NO: 56 HC QVQLVESGGGVVQPGRSLRLDCKASGITFSNSGMHWVRQAPGKGLEWVAVIWYDGSKRYYADSVKGRFTISRDNSKNTLFLQMNSLRAEDTAVYYCATNDDYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK SEQ ID NO: 57 LC EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQSSNWPRTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSS pembrolizumab SEQ ID NO: 58 HC QVQLVQSGVEVKKPGASVKVSCKASGYTFTNYYMYWVRQAPGQGLEWMGGINPSNGGTNFNEKFKNRVTLTTDSSTTTAYMELKSLQFDDTAVYYCARRDYRFDMGFDYWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK SEQ ID NO: 59 LC EIVLTQSPATLSPGERATLSCRASKGVSTSGYSYLHWYQQKPGQAPRLLIYLASYLESGVPARFSGSGSGTDFTLTISSLEPEDFAVYYCQHSRDLPLTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLECPVNSFTHQACEVQ Pidilizumab SEQ ID NO: 60 HC QVQLVQSGSELKKPGASVKISCKASGYTFTNYGMNWVRQAPGQGLQWMGWINTDSGESTYAEEFKGRFVFSLDTSVNTAYLQITSLTAEDTGMYFCVRVGYDALDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO: 61 LC EIVLTQSPSSLSASVGDRVTITCSARSSVSYMHWFQQKPGKAPKLWIYRTSNLASGVPSRFSGSGSGTSYCLTINSLQPEDFATYYCQQRSSFPLTFGGGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTKTLSKPVRGSFTHNACEVQ

Certain aspects and examples of combinations according to the present invention are presented in the following list of numbered embodiments. It should be understood that the features indicated in each embodiment can be combined with other indicated features to obtain additional embodiments of the present invention.

Embodiment 235. A pharmaceutical combination comprising:

a) a first pharmaceutical composition selected from any of embodiments 1-83 or 161-164, and

b) a second pharmaceutical composition comprising an immune checkpoint inhibitor and one or more pharmaceutically acceptable excipients.

Embodiment 236. A pharmaceutical combination comprising:

a) a first pharmaceutical composition comprising a compound of formula (A) or a pharmaceutically acceptable salt thereof, aluminum particles, a buffering agent and one or more pharmaceutically acceptable excipients, and

b) a second pharmaceutical composition comprising an immune checkpoint inhibitor and one or more pharmaceutically acceptable excipients.

Embodiment 237. A pharmaceutical combination comprising:

a) a first pharmaceutical composition comprising a compound of formula (A) or a pharmaceutically acceptable salt thereof, aluminum particles, a buffering agent and one or more pharmaceutically acceptable excipients, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is selected from a CTLA-4 receptor inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor inhibitor, a TIM-3 receptor inhibitor , a BTLA receptor inhibitor, a KIR receptor inhibitor, a PD-L1 inhibitor, or a PD-L2 inhibitor.

Embodiment 238. A pharmaceutical combination comprising:

a) a first pharmaceutical composition comprising a compound of formula (A) or a pharmaceutically acceptable salt thereof, aluminum particles, a buffering agent and one or more pharmaceutically acceptable excipients, and

b) a second pharmaceutical composition comprising an anti-PD-1 antibody and one or more pharmaceutically acceptable excipients.

Embodiment 239. A pharmaceutical combination comprising:

a) a first pharmaceutical composition comprising a compound of formula (A) or a pharmaceutically acceptable salt thereof, aluminum particles, a buffering agent and one or more pharmaceutically acceptable excipients, and

b) a second pharmaceutical composition comprising an anti-PD-L1 antibody and one or more pharmaceutically acceptable excipients.

Embodiment 240. A pharmaceutical combination comprising:

a) a first pharmaceutical composition comprising a compound of formula (A) or a pharmaceutically acceptable salt thereof, aluminum particles, a buffering agent and one or more pharmaceutically acceptable excipients, and

b) a second pharmaceutical composition comprising an anti-PD-L1 antibody selected from Table 2 and one or more pharmaceutically acceptable excipients.

Embodiment 241. A pharmaceutical combination comprising:

a) a first pharmaceutical composition comprising a compound of formula (A) or a pharmaceutically acceptable salt thereof, aluminum particles, a buffering agent and one or more pharmaceutically acceptable excipients, and

b) a second pharmaceutical composition comprising an anti-PD-L1 antibody comprising a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 7 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 17, and one or several pharmaceutically acceptable excipients.

Embodiment 242. A pharmaceutical combination comprising:

a) a first pharmaceutical composition comprising a compound of formula (A) or a pharmaceutically acceptable salt thereof, aluminum particles, a buffering agent and one or more pharmaceutically acceptable excipients, and

b) a second pharmaceutical composition comprising an anti-PD-1 antibody selected from Table 3 and one or more pharmaceutically acceptable excipients.

Embodiment 243 A pharmaceutical combination comprising:

a) a first pharmaceutical composition comprising a compound of formula (A) or a pharmaceutically acceptable salt thereof, aluminum particles, a buffering agent and one or more pharmaceutically acceptable excipients, and

b) a second pharmaceutical composition comprising an anti-PD-1 antibody comprising a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 27 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 37, and one or several pharmaceutically acceptable excipients.

Embodiment 244. A pharmaceutical combination comprising:

a) a first pharmaceutical composition containing 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridine -8-yl) propanoic acid or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffering agent and one or more pharmaceutically acceptable excipients, and

b) a second pharmaceutical composition comprising an immune checkpoint inhibitor and one or more pharmaceutically acceptable excipients.

Embodiment 245. A pharmaceutical combination comprising:

a) a first pharmaceutical composition containing 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridine -8-yl) propanoic acid or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffering agent and one or more pharmaceutically acceptable excipients, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is selected from a CTLA-4 receptor inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor inhibitor, a TIM-3 receptor inhibitor , a BTLA receptor inhibitor, a KIR receptor inhibitor, a PD-L1 inhibitor, or a PD-L2 inhibitor.

Embodiment 246. A pharmaceutical combination comprising:

a) a first pharmaceutical composition containing 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridine -8-yl) propanoic acid or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffering agent and one or more pharmaceutically acceptable excipients, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-PD-1 antibody.

Embodiment 247. A pharmaceutical combination comprising:

a) a first pharmaceutical composition containing 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridine -8-yl) propanoic acid or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffering agent and one or more pharmaceutically acceptable excipients, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-PD-1 antibody from Table 3.

Embodiment 248. A pharmaceutical combination comprising:

a) a first pharmaceutical composition containing 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridine -8-yl) propanoic acid or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffering agent and one or more pharmaceutically acceptable excipients, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-PD-L1 antibody containing a heavy chain variable domain that contains the amino acid sequence of SEQ ID NO: 27, and a light chain variable domain which contains the amino acid sequence of SEQ ID NO: 37.

Embodiment 249. A pharmaceutical combination comprising:

a) a first pharmaceutical composition containing 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridine -8-yl) propanoic acid or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffering agent and one or more pharmaceutically acceptable excipients, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-PD-L1 antibody.

Embodiment 250. A pharmaceutical combination comprising:

a) a first pharmaceutical composition containing 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridine -8-yl) propanoic acid or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffering agent and one or more pharmaceutically acceptable excipients, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-PD-L1 antibody from Table 2.

Embodiment 251. A pharmaceutical combination comprising:

a) a first pharmaceutical composition containing 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridine -8-yl) propanoic acid or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffering agent and one or more pharmaceutically acceptable excipients, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-PD-L1 antibody containing a heavy chain variable domain that contains the amino acid sequence of SEQ ID NO: 7, and a light chain variable domain which contains the amino acid sequence of SEQ ID NO: 17.

Embodiment 252. A pharmaceutical combination comprising:

a) a first pharmaceutical composition characterized by a pH of 7.0-8.0 containing 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl) benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, Tris buffer and mannitol, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is selected from a CTLA-4 receptor inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor inhibitor, a TIM-3 receptor inhibitor , a BTLA receptor inhibitor, a KIR receptor inhibitor, a PD-L1 inhibitor, or a PD-L2 inhibitor.

Embodiment 253. A pharmaceutical combination comprising:

a) a first pharmaceutical composition characterized by a pH of 7.0-8.0 containing 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl) benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, Tris buffer and sucrose, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is selected from a CTLA-4 receptor inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor inhibitor, a TIM-3 receptor inhibitor , a BTLA receptor inhibitor, a KIR receptor inhibitor, a PD-L1 inhibitor, or a PD-L2 inhibitor.

Embodiment 254. A pharmaceutical combination comprising:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 0.5-2 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy )ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles, characterized by an aluminum content of 1-4 mg/ml, 5-100 mM tris buffer and 5-10% (w/v) mannitol, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is selected from a CTLA-4 receptor inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor inhibitor, a TIM-3 receptor inhibitor , a BTLA receptor inhibitor, a KIR receptor inhibitor, a PD-L1 inhibitor, or a PD-L2 inhibitor.

Embodiment 255. A pharmaceutical combination comprising:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 0.5-2 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy )ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles, characterized by an aluminum content of 1-4 mg/ml, 5-100 mM Tris buffer and 5-10% (w/v) sucrose, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is selected from a CTLA-4 receptor inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor inhibitor, a TIM-3 receptor inhibitor , a BTLA receptor inhibitor, a KIR receptor inhibitor, a PD-L1 inhibitor, or a PD-L2 inhibitor.

Embodiment 256. A pharmaceutical combination comprising:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 0.5-2 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy )ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles, characterized by an aluminum content of 1-4 mg/ml, 5-50 mM tris buffer and 5-10% (w/v) mannitol, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is selected from a CTLA-4 receptor inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor inhibitor, a TIM-3 receptor inhibitor , a BTLA receptor inhibitor, a KIR receptor inhibitor, a PD-L1 inhibitor, or a PD-L2 inhibitor.

Embodiment 257. A pharmaceutical combination comprising:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 0.5-2 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy )ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles, characterized by an aluminum content of 1-4 mg/ml, 5-50 mM Tris buffer and 5-10% (w/v) sucrose, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is selected from a CTLA-4 receptor inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor inhibitor, a TIM-3 receptor inhibitor , a BTLA receptor inhibitor, a KIR receptor inhibitor, a PD-L1 inhibitor, or a PD-L2 inhibitor.

Embodiment 258. A pharmaceutical combination comprising:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 0.5-2 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy )ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles characterized by an aluminum content of 1-4 mg/ml, 5-20 mM tris buffer and 5-10% (w/v) mannitol, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is selected from a CTLA-4 receptor inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor inhibitor, a TIM-3 receptor inhibitor , a BTLA receptor inhibitor, a KIR receptor inhibitor, a PD-L1 inhibitor, or a PD-L2 inhibitor.

Embodiment 259. A pharmaceutical combination comprising:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 0.5-2 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy )ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles characterized by an aluminum content of 1-4 mg/ml, 5-20 mM Tris buffer and 5-10% (w/v) sucrose, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is selected from a CTLA-4 receptor inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor inhibitor, a TIM-3 receptor inhibitor , a BTLA receptor inhibitor, a KIR receptor inhibitor, a PD-L1 inhibitor, or a PD-L2 inhibitor.

Embodiment 260. A pharmaceutical combination comprising:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 1 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)- 2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles characterized by an aluminum content of 2 mg/ml, 16 mM Tris buffer and 7.5% (weight/volume) mannitol, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is selected from a CTLA-4 receptor inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor inhibitor, a TIM-3 receptor inhibitor , a BTLA receptor inhibitor, a KIR receptor inhibitor, a PD-L1 inhibitor, or a PD-L2 inhibitor.

Embodiment 261. A pharmaceutical combination comprising:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 1 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)- 2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles characterized by an aluminum content of 2 mg/ml, 16 mM Tris buffer and 7.5% (weight/volume) sucrose, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is selected from a CTLA-4 receptor inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor inhibitor, a TIM-3 receptor inhibitor , a BTLA receptor inhibitor, a KIR receptor inhibitor, a PD-L1 inhibitor, or a PD-L2 inhibitor.

Embodiment 262. A pharmaceutical combination comprising:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 1 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)- 2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles characterized by an aluminum content of 2 mg/ml, 5 mM Tris buffer and 8.25% (weight/volume) mannitol, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is selected from a CTLA-4 receptor inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor inhibitor, a TIM-3 receptor inhibitor , a BTLA receptor inhibitor, a KIR receptor inhibitor, a PD-L1 inhibitor, or a PD-L2 inhibitor.

Embodiment 263. A pharmaceutical combination comprising:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 1 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)- 2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles characterized by an aluminum content of 2 mg/ml, 5 mM Tris buffer and 8.25% (weight/volume) sucrose, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is selected from a CTLA-4 receptor inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor inhibitor, a TIM-3 receptor inhibitor , a BTLA receptor inhibitor, a KIR receptor inhibitor, a PD-L1 inhibitor, or a PD-L2 inhibitor.

Embodiment 264. A pharmaceutical combination comprising:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 0.5-2 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy )ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles, characterized by an aluminum content of 1-4 mg/ml, 5-100 mM tris buffer and 5-10% (w/v) mannitol, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-PD-L1 antibody.

Embodiment 265. A pharmaceutical combination comprising:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 0.5-2 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy )ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles, characterized by an aluminum content of 1-4 mg/ml, 5-100 mM Tris buffer and 5-10% (w/v) sucrose, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-PD-L1 antibody.

Embodiment 266. A pharmaceutical combination comprising:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 0.5-2 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy )ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles, characterized by an aluminum content of 1-4 mg/ml, 5-50 mM tris buffer and 5-10% (w/v) mannitol, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-PD-L1 antibody.

Embodiment 267. A pharmaceutical combination comprising:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 0.5-2 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy )ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles, characterized by an aluminum content of 1-4 mg/ml, 5-50 mM Tris buffer and 5-10% (w/v) sucrose, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-PD-L1 antibody.

Embodiment 268. A pharmaceutical combination comprising:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 0.5-2 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy )ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles characterized by an aluminum content of 1-4 mg/ml, 5-20 mM tris buffer and 5-10% (w/v) mannitol, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-PD-L1 antibody.

Embodiment 269. A pharmaceutical combination comprising:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 0.5-2 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy )ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles characterized by an aluminum content of 1-4 mg/ml, 5-20 mM Tris buffer and 5-10% (w/v) sucrose, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-PD-L1 antibody.

Embodiment 270. A pharmaceutical combination comprising:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 1 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)- 2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles characterized by an aluminum content of 2 mg/ml, 16 mM Tris buffer and 7.5% (weight/volume) mannitol, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-PD-L1 antibody.

Embodiment 271. A pharmaceutical combination comprising:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 1 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)- 2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles characterized by an aluminum content of 2 mg/ml, 16 mM Tris buffer and 7.5% (weight/volume) sucrose, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-PD-L1 antibody.

Embodiment 272. A pharmaceutical combination comprising:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 1 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)- 2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles characterized by an aluminum content of 2 mg/ml, 5 mM Tris buffer and 8.25% (weight/volume) mannitol, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-PD-L1 antibody.

Embodiment 273. A pharmaceutical combination comprising:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 1 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)- 2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles characterized by an aluminum content of 2 mg/ml, 5 mM Tris buffer and 8.25% (weight/volume) sucrose, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-PD-L1 antibody.

Embodiment 274 A pharmaceutical combination according to any one of Embodiments 264-273, wherein the anti-PD-L1 antibody is an anti-PD-L1 antibody from Table 2.

Embodiment 275. The pharmaceutical combination according to any of embodiments 264-274, wherein the anti-PD-L1 antibody is an anti-PD-L1 antibody comprising a heavy chain variable domain that comprises the amino acid sequence of SEQ ID NO: 7, and the variable a light chain domain that contains the amino acid sequence of SEQ ID NO: 17.

Embodiment 276. A pharmaceutical combination comprising:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 0.5-2 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy )ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles, characterized by an aluminum content of 1-4 mg/ml, 5-100 mM tris buffer and 5-10% (w/v) mannitol, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-PD-1 antibody.

Embodiment 277. A pharmaceutical combination comprising:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 0.5-2 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy )ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles, characterized by an aluminum content of 1-4 mg/ml, 5-100 mM Tris buffer and 5-10% (w/v) sucrose, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-PD-1 antibody.

Embodiment 278. A pharmaceutical combination comprising:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 0.5-2 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy )ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles, characterized by an aluminum content of 1-4 mg/ml, 5-50 mM tris buffer and 5-10% (w/v) mannitol, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-PD-1 antibody.

Embodiment 279. A pharmaceutical combination comprising:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 0.5-2 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy )ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles, characterized by an aluminum content of 1-4 mg/ml, 5-50 mM Tris buffer and 5-10% (w/v) sucrose, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-PD-1 antibody.

Embodiment 280. A pharmaceutical combination comprising:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 0.5-2 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy )ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles characterized by an aluminum content of 1-4 mg/ml, 5-20 mM tris buffer and 5-10% (w/v) mannitol, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-PD-1 antibody.

Embodiment 281. A pharmaceutical combination comprising:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 0.5-2 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy )ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles characterized by an aluminum content of 1-4 mg/ml, 5-20 mM Tris buffer and 5-10% (w/v) sucrose, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-PD-1 antibody.

Embodiment 282. A pharmaceutical combination comprising:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 1 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)- 2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles characterized by an aluminum content of 2 mg/ml, 16 mM Tris buffer and 7.5% (weight/volume) mannitol, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-PD-1 antibody.

Embodiment 283. A pharmaceutical combination comprising:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 1 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)- 2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles characterized by an aluminum content of 2 mg/ml, 16 mM Tris buffer and 7.5% (weight/volume) sucrose, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-PD-1 antibody.

Embodiment 284. A pharmaceutical combination comprising:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 1 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)- 2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles characterized by an aluminum content of 2 mg/ml, 5 mM Tris buffer and 8.25% (weight/volume) mannitol, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-PD-1 antibody.

Embodiment 285. A pharmaceutical combination comprising:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 1 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)- 2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles characterized by an aluminum content of 2 mg/ml, 5 mM Tris buffer and 8.25% (weight/volume) sucrose, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-PD-1 antibody.

Embodiment 286. The pharmaceutical combination according to any one of Embodiments 276-285, wherein the anti-PD-1 antibody is an anti-PD-1 antibody from Table 3.

Embodiment 287. The pharmaceutical combination according to any one of embodiments 276-286, wherein the anti-PD1 antibody is an anti-PD-1 antibody comprising a heavy chain variable domain that comprises the amino acid sequence of SEQ ID NO: 27 and a light variable domain. chain which contains the amino acid sequence under SEQ ID NO: 37.

Embodiment 288. The pharmaceutical combination according to any of embodiments 236-287, wherein the first pharmaceutical composition comprises a therapeutically effective amount of a compound of Formula A and the second pharmaceutical composition comprises a therapeutically effective amount of an immune response checkpoint inhibitor, an anti-PD-L1 antibody, or an antibody to PD-1.

Embodiment 289. The pharmaceutical combination according to any one of Embodiments 244-287, wherein the first pharmaceutical composition comprises a therapeutically effective amount of 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy )ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, and the second pharmaceutical composition contains a therapeutically effective amount of an immune response checkpoint inhibitor, anti-PD-L1 antibody or antibodies to PD-1.

Embodiment 290. A pharmaceutical combination comprising:

a) a first pharmaceutical composition containing 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridine -8-yl) propanoic acid or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffering agent and one or more pharmaceutically acceptable excipients, and

b) a second pharmaceutical composition containing tremelimumab and one or more pharmaceutically acceptable excipients.

Embodiment 291. A pharmaceutical combination comprising:

a) a first pharmaceutical composition containing 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridine -8-yl) propanoic acid or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffering agent and one or more pharmaceutically acceptable excipients, and

b) a second pharmaceutical composition containing lambrolizumab and one or more pharmaceutically acceptable excipients.

Embodiment 292. A pharmaceutical combination comprising:

a) a first pharmaceutical composition containing 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridine -8-yl) propanoic acid or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffering agent and one or more pharmaceutically acceptable excipients, and

b) a second pharmaceutical composition containing pidilizumab and one or more pharmaceutically acceptable excipients.

Embodiment 293. A pharmaceutical combination comprising:

a) a first pharmaceutical composition containing 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridine -8-yl) propanoic acid or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffering agent and one or more pharmaceutically acceptable excipients, and

b) a second pharmaceutical composition containing nivolumab and one or more pharmaceutically acceptable excipients.

Embodiment 294 A pharmaceutical composition combination comprising:

a) a first pharmaceutical composition containing 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridine -8-yl) propanoic acid or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffering agent and one or more pharmaceutically acceptable excipients, and

b) a second pharmaceutical composition containing lirilumab and one or more pharmaceutically acceptable excipients.

Embodiment 295. A pharmaceutical combination comprising:

a) a first pharmaceutical composition containing a compound of formula (A) or a pharmaceutically acceptable salt thereof, aluminum particles, a buffering agent and one or more pharmaceutically acceptable excipients,

b) a second pharmaceutical composition comprising an immune checkpoint inhibitor and one or more pharmaceutically acceptable excipients, and

c) a third pharmaceutical composition comprising an immune checkpoint inhibitor that is different from the immune checkpoint inhibitor of the second pharmaceutical composition and one or more pharmaceutically acceptable excipients.

Embodiment 296. A pharmaceutical combination comprising:

a) a first pharmaceutical composition containing a compound of formula (A) or a pharmaceutically acceptable salt thereof, aluminum particles, a buffering agent and one or more pharmaceutically acceptable excipients,

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is selected from a CTLA-4 receptor inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor inhibitor, a TIM-3 receptor inhibitor , a BTLA receptor inhibitor, a KIR receptor inhibitor, a PD-L1 inhibitor, or a PD-L2 inhibitor, and

c) a third pharmaceutical composition comprising an immune response checkpoint inhibitor that is different from the immune response checkpoint inhibitor of the second pharmaceutical composition, and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is selected from a CTLA-4 receptor inhibitor, a receptor inhibitor PD-1, LAG-3 receptor inhibitor, TIM-3 receptor inhibitor, BTLA receptor inhibitor, KIR receptor inhibitor, PD-L1 inhibitor, or PD-L2 inhibitor.

Embodiment 297. A pharmaceutical combination comprising:

a) a first pharmaceutical composition containing a compound of formula (A) or a pharmaceutically acceptable salt thereof, aluminum particles, a buffering agent and one or more pharmaceutically acceptable excipients,

b) a second pharmaceutical composition comprising an anti-PD-L1 antibody and one or more pharmaceutically acceptable excipients, and

c) a third pharmaceutical composition comprising an immune response checkpoint inhibitor that is different from the immune response checkpoint inhibitor of the second pharmaceutical composition, and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is selected from a CTLA-4 receptor inhibitor, a receptor inhibitor PD-1, LAG-3 receptor inhibitor, TIM-3 receptor inhibitor, BTLA receptor inhibitor, KIR receptor inhibitor, PD-L1 inhibitor, or PD-L2 inhibitor.

Embodiment 298. A pharmaceutical combination comprising:

a) a first pharmaceutical composition containing a compound of formula (A) or a pharmaceutically acceptable salt thereof, aluminum particles, a buffering agent and one or more pharmaceutically acceptable excipients,

b) a second pharmaceutical composition comprising an anti-PD-L1 antibody and one or more pharmaceutically acceptable excipients, and

c) a third pharmaceutical composition comprising an anti-CTLA-4 antibody and one or more pharmaceutically acceptable excipients.

Embodiment 299. A pharmaceutical combination comprising:

a) a first pharmaceutical composition containing a compound of formula (A) or a pharmaceutically acceptable salt thereof, aluminum particles, a buffering agent and one or more pharmaceutically acceptable excipients,

b) a second pharmaceutical composition comprising an anti-PD-L1 antibody from Table 2 and one or more pharmaceutically acceptable excipients, and

c) a third pharmaceutical composition comprising an anti-CTLA-4 antibody and one or more pharmaceutically acceptable excipients.

Embodiment 300. A pharmaceutical combination comprising:

a) a first pharmaceutical composition containing a compound of formula (A) or a pharmaceutically acceptable salt thereof, aluminum particles, a buffering agent and one or more pharmaceutically acceptable excipients,

b) a second pharmaceutical composition comprising an anti-PD-L1 antibody comprising a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 7 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 17, and one or several pharmaceutically acceptable excipients, and

c) a third pharmaceutical composition comprising an anti-CTLA-4 antibody and one or more pharmaceutically acceptable excipients.

Embodiment 301. A pharmaceutical combination comprising:

a) a first pharmaceutical composition containing a compound of formula (A) or a pharmaceutically acceptable salt thereof, aluminum particles, a buffering agent and one or more pharmaceutically acceptable excipients,

b) a second pharmaceutical composition comprising an anti-PD-1 antibody and one or more pharmaceutically acceptable excipients, and

c) a third pharmaceutical composition comprising an immune response checkpoint inhibitor that is different from the immune response checkpoint inhibitor of the second pharmaceutical composition, and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is selected from a CTLA-4 receptor inhibitor, a receptor inhibitor PD-1, LAG-3 receptor inhibitor, TIM-3 receptor inhibitor, BTLA receptor inhibitor, KIR receptor inhibitor, PD-L1 inhibitor, or PD-L2 inhibitor.

Embodiment 302. A pharmaceutical combination comprising:

a) a first pharmaceutical composition containing a compound of formula (A) or a pharmaceutically acceptable salt thereof, aluminum particles, a buffering agent and one or more pharmaceutically acceptable excipients,

b) a second pharmaceutical composition comprising an anti-PD-1 antibody and one or more pharmaceutically acceptable excipients, and

c) a third pharmaceutical composition comprising an anti-CTLA-4 antibody and one or more pharmaceutically acceptable excipients.

Embodiment 303. A pharmaceutical combination comprising:

a) a first pharmaceutical composition containing a compound of formula (A) or a pharmaceutically acceptable salt thereof, aluminum particles, a buffering agent and one or more pharmaceutically acceptable excipients,

b) a second pharmaceutical composition comprising an anti-PD-1 antibody from Table 3 and one or more pharmaceutically acceptable excipients, and

c) a third pharmaceutical composition comprising an anti-CTLA-4 antibody and one or more pharmaceutically acceptable excipients.

Embodiment 304. A pharmaceutical combination comprising:

a) a first pharmaceutical composition containing a compound of formula (A) or a pharmaceutically acceptable salt thereof, aluminum particles, a buffering agent and one or more pharmaceutically acceptable excipients,

b) a second pharmaceutical composition comprising an anti-PD-1 antibody comprising a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 27 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 37, and one or several pharmaceutically acceptable excipients, and

c) a third pharmaceutical composition comprising an anti-CTLA-4 antibody and one or more pharmaceutically acceptable excipients.

Embodiment 305. A pharmaceutical combination comprising:

a) a first pharmaceutical composition containing 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridine -8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffering agent and one or more pharmaceutically acceptable excipients,

b) a second pharmaceutical composition comprising an immune checkpoint inhibitor and one or more pharmaceutically acceptable excipients, and

c) a third pharmaceutical composition comprising an immune checkpoint inhibitor that is different from the immune checkpoint inhibitor of the second pharmaceutical composition and one or more pharmaceutically acceptable excipients.

Embodiment 306. A pharmaceutical combination comprising:

a) a first pharmaceutical composition containing 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridine -8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffering agent and one or more pharmaceutically acceptable excipients,

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is selected from a CTLA-4 receptor inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor inhibitor, a TIM-3 receptor inhibitor , a BTLA receptor inhibitor, a KIR receptor inhibitor, a PD-L1 inhibitor, or a PD-L2 inhibitor, and

c) a third pharmaceutical composition comprising an immune response checkpoint inhibitor that is different from the immune response checkpoint inhibitor of the second pharmaceutical composition and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is selected from a CTLA-4 receptor inhibitor, a receptor inhibitor PD-1, LAG-3 receptor inhibitor, TIM-3 receptor inhibitor, BTLA receptor inhibitor, KIR receptor inhibitor, PD-L1 inhibitor, or PD-L2 inhibitor.

Embodiment 307. A pharmaceutical combination comprising:

a) a first pharmaceutical composition containing 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridine -8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffering agent and one or more pharmaceutically acceptable excipients,

b) a second pharmaceutical composition comprising an anti-PD-L1 antibody and one or more pharmaceutically acceptable excipients, and

c) a third pharmaceutical composition comprising an immune response checkpoint inhibitor that is different from the immune response checkpoint inhibitor of the second pharmaceutical composition, and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is selected from a CTLA-4 receptor inhibitor, a receptor inhibitor PD-1, LAG-3 receptor inhibitor, TIM-3 receptor inhibitor, BTLA receptor inhibitor, KIR receptor inhibitor, PD-L1 inhibitor, or PD-L2 inhibitor.

Embodiment 308. A pharmaceutical combination comprising:

a) a first pharmaceutical composition containing 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridine -8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffering agent and one or more pharmaceutically acceptable excipients,

b) a second pharmaceutical composition comprising an anti-PD-L1 antibody from Table 2 and one or more pharmaceutically acceptable excipients, and

c) a third pharmaceutical composition comprising an anti-CTLA-4 antibody and one or more pharmaceutically acceptable excipients.

Embodiment 309. A pharmaceutical combination comprising:

a) a first pharmaceutical composition containing 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridine -8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffering agent and one or more pharmaceutically acceptable excipients,

b) a second pharmaceutical composition comprising an anti-PD-L1 antibody comprising a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 7 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 17, and one or several pharmaceutically acceptable excipients, and

c) a third pharmaceutical composition comprising an anti-CTLA-4 antibody and one or more pharmaceutically acceptable excipients.

Embodiment 310. A pharmaceutical combination comprising:

a) a first pharmaceutical composition containing 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridine -8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffering agent and one or more pharmaceutically acceptable excipients,

b) a second pharmaceutical composition comprising an anti-PD-1 antibody and one or more pharmaceutically acceptable excipients, and

c) a third pharmaceutical composition comprising an immune response checkpoint inhibitor that is different from the immune response checkpoint inhibitor of the second pharmaceutical composition, and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is selected from a CTLA-4 receptor inhibitor, a receptor inhibitor PD-1, LAG-3 receptor inhibitor, TIM-3 receptor inhibitor, BTLA receptor inhibitor, KIR receptor inhibitor, PD-L1 inhibitor, or PD-L2 inhibitor.

Embodiment 311. A pharmaceutical combination comprising:

a) a first pharmaceutical composition containing 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridine -8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffering agent and one or more pharmaceutically acceptable excipients,

b) a second pharmaceutical composition comprising an anti-PD-1 antibody from Table 3 and one or more pharmaceutically acceptable excipients, and

c) a third pharmaceutical composition comprising an anti-CTLA-4 antibody and one or more pharmaceutically acceptable excipients.

Embodiment 312. A pharmaceutical combination comprising:

a) a first pharmaceutical composition containing 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridine -8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffering agent and one or more pharmaceutically acceptable excipients,

b) a second pharmaceutical composition comprising an anti-PD-1 antibody comprising a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 27 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 37, and one or several pharmaceutically acceptable excipients, and

c) a third pharmaceutical composition comprising an anti-CTLA-4 antibody and one or more pharmaceutically acceptable excipients.

Embodiment 313. A pharmaceutical combination comprising:

a) a first pharmaceutical composition containing 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridine -8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffering agent and one or more pharmaceutically acceptable excipients,

b) a second pharmaceutical composition containing ipilimumab and one or more pharmaceutically acceptable excipients,

c) and a third pharmaceutical composition containing nivolumab and one or more pharmaceutically acceptable excipients.

Embodiment 314. A pharmaceutical combination comprising:

a) a first pharmaceutical composition containing 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridine -8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffering agent and one or more pharmaceutically acceptable excipients,

b) a second pharmaceutical composition comprising ipilimumab and one or more pharmaceutically acceptable excipients, and

c) a third pharmaceutical composition containing lambrolizumab and one or more pharmaceutically acceptable excipients.

Embodiment 315. A pharmaceutical combination comprising:

a) a first pharmaceutical composition characterized by a pH of 7.0-8.0 containing 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl) benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, Tris buffer and mannitol, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is selected from a CTLA-4 receptor inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor inhibitor, a TIM-3 receptor inhibitor , a BTLA receptor inhibitor, a KIR receptor inhibitor, a PD-L1 inhibitor, or a PD-L2 inhibitor, and

c) a third pharmaceutical composition comprising an immune response checkpoint inhibitor that is different from the immune response checkpoint inhibitor of the second pharmaceutical composition, and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is selected from a CTLA-4 receptor inhibitor, a receptor inhibitor PD-1, LAG-3 receptor inhibitor, TIM-3 receptor inhibitor, BTLA receptor inhibitor, KIR receptor inhibitor, PD-L1 inhibitor, or PD-L2 inhibitor.

Embodiment 316. A pharmaceutical combination comprising:

a) a first pharmaceutical composition characterized by a pH of 7.0-8.0 containing 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl) benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, Tris buffer and sucrose, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is selected from a CTLA-4 receptor inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor inhibitor, a TIM-3 receptor inhibitor , a BTLA receptor inhibitor, a KIR receptor inhibitor, a PD-L1 inhibitor, or a PD-L2 inhibitor, and

c) a third pharmaceutical composition comprising an immune response checkpoint inhibitor that is different from the immune response checkpoint inhibitor of the second pharmaceutical composition, and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is selected from a CTLA-4 receptor inhibitor, a receptor inhibitor PD-1, LAG-3 receptor inhibitor, TIM-3 receptor inhibitor, BTLA receptor inhibitor, KIR receptor inhibitor, PD-L1 inhibitor, or PD-L2 inhibitor.

Embodiment 317. A pharmaceutical combination comprising:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 0.5-2 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy )ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles, characterized by an aluminum content of 1-4 mg/ml, 5-100 mM tris buffer and 5-10% (w/v) mannitol, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is selected from a CTLA-4 receptor inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor inhibitor, a TIM-3 receptor inhibitor , a BTLA receptor inhibitor, a KIR receptor inhibitor, a PD-L1 inhibitor, or a PD-L2 inhibitor, and

c) a third pharmaceutical composition comprising an immune response checkpoint inhibitor that is different from the immune response checkpoint inhibitor of the second pharmaceutical composition, and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is selected from a CTLA-4 receptor inhibitor, a receptor inhibitor PD-1, LAG-3 receptor inhibitor, TIM-3 receptor inhibitor, BTLA receptor inhibitor, KIR receptor inhibitor, PD-L1 inhibitor, or PD-L2 inhibitor.

Embodiment 318. A pharmaceutical combination comprising:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 0.5-2 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy )ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles, characterized by an aluminum content of 1-4 mg/ml, 5-100 mM Tris buffer and 5-10% (w/v) sucrose, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is selected from a CTLA-4 receptor inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor inhibitor, a TIM-3 receptor inhibitor , a BTLA receptor inhibitor, a KIR receptor inhibitor, a PD-L1 inhibitor, or a PD-L2 inhibitor, and

c) a third pharmaceutical composition comprising an immune response checkpoint inhibitor that is different from the immune response checkpoint inhibitor of the second pharmaceutical composition, and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is selected from a CTLA-4 receptor inhibitor, a receptor inhibitor PD-1, LAG-3 receptor inhibitor, TIM-3 receptor inhibitor, BTLA receptor inhibitor, KIR receptor inhibitor, PD-L1 inhibitor, or PD-L2 inhibitor.

Embodiment 319. A pharmaceutical combination comprising:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 0.5-2 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy )ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles, characterized by an aluminum content of 1-4 mg/ml, 5-50 mM tris buffer and 5-10% (w/v) mannitol, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is selected from a CTLA-4 receptor inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor inhibitor, a TIM-3 receptor inhibitor , a BTLA receptor inhibitor, a KIR receptor inhibitor, a PD-L1 inhibitor, or a PD-L2 inhibitor, and

c) a third pharmaceutical composition comprising an immune response checkpoint inhibitor that is different from the immune response checkpoint inhibitor of the second pharmaceutical composition, and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is selected from a CTLA-4 receptor inhibitor, a receptor inhibitor PD-1, LAG-3 receptor inhibitor, TIM-3 receptor inhibitor, BTLA receptor inhibitor, KIR receptor inhibitor, PD-L1 inhibitor, or PD-L2 inhibitor.

Embodiment 320. A pharmaceutical combination comprising:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 0.5-2 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy )ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles, characterized by an aluminum content of 1-4 mg/ml, 5-50 mM Tris buffer and 5-10% (w/v) sucrose, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is selected from a CTLA-4 receptor inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor inhibitor, a TIM-3 receptor inhibitor , a BTLA receptor inhibitor, a KIR receptor inhibitor, a PD-L1 inhibitor, or a PD-L2 inhibitor, and

c) a third pharmaceutical composition comprising an immune response checkpoint inhibitor that is different from the immune response checkpoint inhibitor of the second pharmaceutical composition, and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is selected from a CTLA-4 receptor inhibitor, a receptor inhibitor PD-1, LAG-3 receptor inhibitor, TIM-3 receptor inhibitor, BTLA receptor inhibitor, KIR receptor inhibitor, PD-L1 inhibitor, or PD-L2 inhibitor.

Embodiment 321. A pharmaceutical combination comprising:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 0.5-2 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy )ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles characterized by an aluminum content of 1-4 mg/ml, 5-20 mM tris buffer and 5-10% (w/v) mannitol, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is selected from a CTLA-4 receptor inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor inhibitor, a TIM-3 receptor inhibitor , a BTLA receptor inhibitor, a KIR receptor inhibitor, a PD-L1 inhibitor, or a PD-L2 inhibitor, and

c) a third pharmaceutical composition comprising an immune response checkpoint inhibitor that is different from the immune response checkpoint inhibitor of the second pharmaceutical composition, and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is selected from a CTLA-4 receptor inhibitor, a receptor inhibitor PD-1, LAG-3 receptor inhibitor, TIM-3 receptor inhibitor, BTLA receptor inhibitor, KIR receptor inhibitor, PD-L1 inhibitor, or PD-L2 inhibitor.

Embodiment 322. A pharmaceutical combination comprising:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 0.5-2 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy )ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles characterized by an aluminum content of 1-4 mg/ml, 5-20 mM Tris buffer and 5-10% (w/v) sucrose, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is selected from a CTLA-4 receptor inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor inhibitor, a TIM-3 receptor inhibitor , a BTLA receptor inhibitor, a KIR receptor inhibitor, a PD-L1 inhibitor, or a PD-L2 inhibitor, and

c) a third pharmaceutical composition comprising an immune response checkpoint inhibitor that is different from the immune response checkpoint inhibitor of the second pharmaceutical composition, and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is selected from a CTLA-4 receptor inhibitor, a receptor inhibitor PD-1, LAG-3 receptor inhibitor, TIM-3 receptor inhibitor, BTLA receptor inhibitor, KIR receptor inhibitor, PD-L1 inhibitor, or PD-L2 inhibitor.

Embodiment 323. A pharmaceutical combination comprising:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 1 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)- 2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles characterized by an aluminum content of 2 mg/ml, 16 mM Tris buffer and 7.5% (weight/volume) mannitol, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is selected from a CTLA-4 receptor inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor inhibitor, a TIM-3 receptor inhibitor , a BTLA receptor inhibitor, a KIR receptor inhibitor, a PD-L1 inhibitor, or a PD-L2 inhibitor, and

c) a third pharmaceutical composition comprising an immune response checkpoint inhibitor that is different from the immune response checkpoint inhibitor of the second pharmaceutical composition, and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is selected from a CTLA-4 receptor inhibitor, a receptor inhibitor PD-1, LAG-3 receptor inhibitor, TIM-3 receptor inhibitor, BTLA receptor inhibitor, KIR receptor inhibitor, PD-L1 inhibitor, or PD-L2 inhibitor.

Embodiment 324. A pharmaceutical combination comprising:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 1 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)- 2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles characterized by an aluminum content of 2 mg/ml, 16 mM Tris buffer and 7.5% (weight/volume) sucrose, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is selected from a CTLA-4 receptor inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor inhibitor, a TIM-3 receptor inhibitor , a BTLA receptor inhibitor, a KIR receptor inhibitor, a PD-L1 inhibitor, or a PD-L2 inhibitor, and

c) a third pharmaceutical composition comprising an immune response checkpoint inhibitor that is different from the immune response checkpoint inhibitor of the second pharmaceutical composition, and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is selected from a CTLA-4 receptor inhibitor, a receptor inhibitor PD-1, LAG-3 receptor inhibitor, TIM-3 receptor inhibitor, BTLA receptor inhibitor, KIR receptor inhibitor, PD-L1 inhibitor, or PD-L2 inhibitor.

Embodiment 325. A pharmaceutical combination comprising:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 1 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)- 2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles characterized by an aluminum content of 2 mg/ml, 5 mM Tris buffer and 8.25% (weight/volume) mannitol, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is selected from a CTLA-4 receptor inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor inhibitor, a TIM-3 receptor inhibitor , a BTLA receptor inhibitor, a KIR receptor inhibitor, a PD-L1 inhibitor, or a PD-L2 inhibitor, and

c) a third pharmaceutical composition comprising an immune response checkpoint inhibitor that is different from the immune response checkpoint inhibitor of the second pharmaceutical composition, and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is selected from a CTLA-4 receptor inhibitor, a receptor inhibitor PD-1, LAG-3 receptor inhibitor, TIM-3 receptor inhibitor, BTLA receptor inhibitor, KIR receptor inhibitor, PD-L1 inhibitor, or PD-L2 inhibitor.

Embodiment 326. A pharmaceutical combination comprising:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 1 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)- 2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles characterized by an aluminum content of 2 mg/ml, 5 mM Tris buffer and 8.25% (weight/volume) sucrose, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is selected from a CTLA-4 receptor inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor inhibitor, a TIM-3 receptor inhibitor , a BTLA receptor inhibitor, a KIR receptor inhibitor, a PD-L1 inhibitor, or a PD-L2 inhibitor, and

c) a third pharmaceutical composition comprising an immune response checkpoint inhibitor that is different from the immune response checkpoint inhibitor of the second pharmaceutical composition, and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is selected from a CTLA-4 receptor inhibitor, a receptor inhibitor PD-1, LAG-3 receptor inhibitor, TIM-3 receptor inhibitor, BTLA receptor inhibitor, KIR receptor inhibitor, PD-L1 inhibitor, or PD-L2 inhibitor.

Embodiment 327. A pharmaceutical combination comprising:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 0.5-2 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy )ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles, characterized by an aluminum content of 1-4 mg/ml, 5-100 mM tris buffer and 5-10% (w/v) mannitol, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-PD-L1 antibody, and

c) a third pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is selected from a CTLA-4 receptor inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor inhibitor, a TIM-3 receptor inhibitor , a BTLA receptor inhibitor, a KIR receptor inhibitor, a PD-L1 inhibitor, or a PD-L2 inhibitor.

Embodiment 328. A pharmaceutical combination comprising:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 0.5-2 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy )ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles, characterized by an aluminum content of 1-4 mg/ml, 5-100 mM Tris buffer and 5-10% (w/v) sucrose, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-PD-L1 antibody, and

c) a third pharmaceutical composition comprising an immune response checkpoint inhibitor that is different from the immune response checkpoint inhibitor of the second pharmaceutical composition, and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is selected from a CTLA-4 receptor inhibitor, a receptor inhibitor PD-1, LAG-3 receptor inhibitor, TIM-3 receptor inhibitor, BTLA receptor inhibitor, KIR receptor inhibitor, PD-L1 inhibitor, or PD-L2 inhibitor.

Embodiment 329. A pharmaceutical combination comprising:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 0.5-2 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy )ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles, characterized by an aluminum content of 1-4 mg/ml, 5-50 mM tris buffer and 5-10% (w/v) mannitol, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-PD-L1 antibody, and

c) a third pharmaceutical composition comprising an immune response checkpoint inhibitor that is different from the immune response checkpoint inhibitor of the second pharmaceutical composition, and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is selected from a CTLA-4 receptor inhibitor, a receptor inhibitor PD-1, LAG-3 receptor inhibitor, TIM-3 receptor inhibitor, BTLA receptor inhibitor, KIR receptor inhibitor, PD-L1 inhibitor, or PD-L2 inhibitor.

Embodiment 330. A pharmaceutical combination comprising:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 0.5-2 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy )ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles, characterized by an aluminum content of 1-4 mg/ml, 5-50 mM Tris buffer and 5-10% (w/v) sucrose, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-PD-L1 antibody, and

c) a third pharmaceutical composition comprising an immune response checkpoint inhibitor that is different from the immune response checkpoint inhibitor of the second pharmaceutical composition, and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is selected from a CTLA-4 receptor inhibitor, a receptor inhibitor PD-1, LAG-3 receptor inhibitor, TIM-3 receptor inhibitor, BTLA receptor inhibitor, KIR receptor inhibitor, PD-L1 inhibitor, or PD-L2 inhibitor.

Embodiment 331. A pharmaceutical combination comprising:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 0.5-2 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy )ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles characterized by an aluminum content of 1-4 mg/ml, 5-20 mM tris buffer and 5-10% (w/v) mannitol, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-PD-L1 antibody, and

c) a third pharmaceutical composition comprising an immune response checkpoint inhibitor that is different from the immune response checkpoint inhibitor of the second pharmaceutical composition, and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is selected from a CTLA-4 receptor inhibitor, a receptor inhibitor PD-1, LAG-3 receptor inhibitor, TIM-3 receptor inhibitor, BTLA receptor inhibitor, KIR receptor inhibitor, PD-L1 inhibitor, or PD-L2 inhibitor.

Embodiment 332. A pharmaceutical combination comprising:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 0.5-2 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy )ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles characterized by an aluminum content of 1-4 mg/ml, 5-20 mM Tris buffer and 5-10% (w/v) sucrose, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-PD-L1 antibody, and

c) a third pharmaceutical composition comprising an immune response checkpoint inhibitor that is different from the immune response checkpoint inhibitor of the second pharmaceutical composition, and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is selected from a CTLA-4 receptor inhibitor, a receptor inhibitor PD-1, LAG-3 receptor inhibitor, TIM-3 receptor inhibitor, BTLA receptor inhibitor, KIR receptor inhibitor, PD-L1 inhibitor, or PD-L2 inhibitor.

Embodiment 333. A pharmaceutical combination comprising:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 1 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)- 2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles characterized by an aluminum content of 2 mg/ml, 16 mM Tris buffer and 7.5% (weight/volume) mannitol, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-PD-L1 antibody, and

c) a third pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-CTLA-4 antibody.

Embodiment 334. A pharmaceutical combination comprising:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 1 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)- 2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles characterized by an aluminum content of 2 mg/ml, 16 mM Tris buffer and 7.5% (weight/volume) sucrose, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-PD-L1 antibody, and

c) a third pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-CTLA-4 antibody.

Embodiment 335. A pharmaceutical combination comprising:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 1 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)- 2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles characterized by an aluminum content of 2 mg/ml, 5 mM Tris buffer and 8.25% (weight/volume) mannitol, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-PD-L1 antibody, and

c) a third pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-CTLA-4 antibody.

Embodiment 336. A pharmaceutical combination comprising:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 1 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)- 2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles characterized by an aluminum content of 2 mg/ml, 5 mM Tris buffer and 8.25% (weight/volume) sucrose, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-PD-L1 antibody, and

c) a third pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-CTLA-4 antibody.

Embodiment 337. A pharmaceutical combination according to any one of Embodiments 355-364, wherein the anti-PD-L1 antibody is an anti-PD-L1 antibody from Table 2.

Embodiment 338. The pharmaceutical combination according to any one of embodiments 355-364, wherein the anti-PD-L1 antibody is an anti-PD-L1 antibody containing a heavy chain variable domain that contains the amino acid sequence of SEQ ID NO: 7, and the variable a light chain domain that contains the amino acid sequence of SEQ ID NO: 17.

Embodiment 339. A pharmaceutical combination comprising:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 0.5-2 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy )ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles, characterized by an aluminum content of 1-4 mg/ml, 5-100 mM tris buffer and 5-10% (w/v) mannitol, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-PD-1 antibody, and

c) a third pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is selected from a CTLA-4 receptor inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor inhibitor, a TIM-3 receptor inhibitor , a BTLA receptor inhibitor, a KIR receptor inhibitor, a PD-L1 inhibitor, or a PD-L2 inhibitor.

Embodiment 340. A pharmaceutical combination comprising:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 0.5-2 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy )ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles, characterized by an aluminum content of 1-4 mg/ml, 5-100 mM Tris buffer and 5-10% (w/v) sucrose, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-PD-1 antibody, and

c) a third pharmaceutical composition comprising an immune response checkpoint inhibitor that is different from the immune response checkpoint inhibitor of the second pharmaceutical composition, and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is selected from a CTLA-4 receptor inhibitor, a receptor inhibitor PD-1, LAG-3 receptor inhibitor, TIM-3 receptor inhibitor, BTLA receptor inhibitor, KIR receptor inhibitor, PD-L1 inhibitor, or PD-L2 inhibitor.

Embodiment 341. A pharmaceutical combination comprising:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 0.5-2 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy )ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles, characterized by an aluminum content of 1-4 mg/ml, 5-50 mM tris buffer and 5-10% (w/v) mannitol, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-PD-1 antibody, and

c) a third pharmaceutical composition comprising an immune response checkpoint inhibitor that is different from the immune response checkpoint inhibitor of the second pharmaceutical composition, and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is selected from a CTLA-4 receptor inhibitor, a receptor inhibitor PD-1, LAG-3 receptor inhibitor, TIM-3 receptor inhibitor, BTLA receptor inhibitor, KIR receptor inhibitor, PD-L1 inhibitor, or PD-L2 inhibitor.

Embodiment 342. A pharmaceutical combination comprising:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 0.5-2 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy )ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles, characterized by an aluminum content of 1-4 mg/ml, 5-50 mM Tris buffer and 5-10% (w/v) sucrose, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-PD-1 antibody, and

c) a third pharmaceutical composition comprising an immune response checkpoint inhibitor that is different from the immune response checkpoint inhibitor of the second pharmaceutical composition, and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is selected from a CTLA-4 receptor inhibitor, a receptor inhibitor PD-1, LAG-3 receptor inhibitor, TIM-3 receptor inhibitor, BTLA receptor inhibitor, KIR receptor inhibitor, PD-L1 inhibitor, or PD-L2 inhibitor.

Embodiment 343. A pharmaceutical combination comprising:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 0.5-2 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy )ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles characterized by an aluminum content of 1-4 mg/ml, 5-20 mM tris buffer and 5-10% (w/v) mannitol, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-PD-1 antibody, and

c) a third pharmaceutical composition comprising an immune response checkpoint inhibitor that is different from the immune response checkpoint inhibitor of the second pharmaceutical composition, and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is selected from a CTLA-4 receptor inhibitor, a receptor inhibitor PD-1, LAG-3 receptor inhibitor, TIM-3 receptor inhibitor, BTLA receptor inhibitor, KIR receptor inhibitor, PD-L1 inhibitor, or PD-L2 inhibitor.

Embodiment 344. A pharmaceutical combination comprising:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 0.5-2 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy )ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles characterized by an aluminum content of 1-4 mg/ml, 5-20 mM Tris buffer and 5-10% (w/v) sucrose, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-PD-1 antibody, and

c) a third pharmaceutical composition comprising an immune response checkpoint inhibitor that is different from the immune response checkpoint inhibitor of the second pharmaceutical composition, and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is selected from a CTLA-4 receptor inhibitor, a receptor inhibitor PD-1, LAG-3 receptor inhibitor, TIM-3 receptor inhibitor, BTLA receptor inhibitor, KIR receptor inhibitor, PD-L1 inhibitor, or PD-L2 inhibitor.

Embodiment 345. A pharmaceutical combination comprising:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 1 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)- 2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles characterized by an aluminum content of 2 mg/ml, 16 mM Tris buffer and 7.5% (weight/volume) mannitol, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-PD-1 antibody, and

c) a third pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-CTLA-4 antibody.

Embodiment 346. A pharmaceutical combination comprising:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 1 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)- 2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles characterized by an aluminum content of 2 mg/ml, 16 mM Tris buffer and 7.5% (weight/volume) sucrose, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-PD-1 antibody, and

c) a third pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-CTLA-4 antibody.

Embodiment 347. A pharmaceutical combination comprising:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 1 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)- 2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles characterized by an aluminum content of 2 mg/ml, 5 mM Tris buffer and 8.25% (weight/volume) mannitol, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-PD-1 antibody, and

c) a third pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-CTLA-4 antibody.

Embodiment 348. A pharmaceutical combination comprising:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 1 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)- 2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles characterized by an aluminum content of 2 mg/ml, 5 mM Tris buffer and 8.25% (weight/volume) sucrose, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-PD-1 antibody, and

c) a third pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-CTLA-4 antibody.

Embodiment 349 A pharmaceutical combination according to any one of Embodiments 367-376 wherein the anti-PD-1 antibody is an anti-PD-1 antibody from Table 3.

Embodiment 350. The pharmaceutical combination according to any one of Embodiments 367-376, wherein the anti-PD1 antibody is an anti-PD-1 antibody comprising a heavy chain variable domain that comprises the amino acid sequence of SEQ ID NO: 27 and a light variable domain. chain which contains the amino acid sequence under SEQ ID NO: 37.

Embodiment 351. The pharmaceutical combination according to any of embodiments 295-304, wherein the first pharmaceutical composition comprises a therapeutically effective amount of a compound of Formula A, the second pharmaceutical composition comprises a therapeutically effective amount of an immune response checkpoint inhibitor, an anti-PD-L1 antibody, an anti- CTLA-4 or anti-PD-1 antibodies, and the third pharmaceutical composition comprises a therapeutically effective amount of an immune checkpoint inhibitor, an anti-PD-L1 antibody, an anti-CTLA-4 antibody, or an anti-PD-1 antibody.

Embodiment 352. A pharmaceutical combination according to any one of Embodiments 305-350, wherein the first pharmaceutical composition comprises a therapeutically effective amount of 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy )ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, the second pharmaceutical composition contains a therapeutically effective amount of an immune response checkpoint inhibitor, anti-PD-L1 antibody, an anti-CTLA-4 antibody or an anti-PD-1 antibody, and the third pharmaceutical composition comprises a therapeutically effective amount of an immune checkpoint inhibitor, an anti-PD-L1 antibody, an anti-CTLA-4 antibody, or an anti-PD-1 antibody.

The present invention further provides a method for treating a solid tumor by administering to a subject a pharmaceutical composition that comprises a compound of formula (A) or a pharmaceutically acceptable salt thereof, aluminum particles, one or more pharmaceutically acceptable excipients, and an immune response checkpoint inhibitor.

The present invention further provides a method for treating a solid tumor by administering to a subject, intratumorally, intramuscularly, intradermally, or subcutaneously, a pharmaceutical composition that contains a compound of formula (A) or a pharmaceutically acceptable salt thereof, aluminum-containing particles, one or more pharmaceutically acceptable excipients, and an inhibitor of control immune response points.

The present invention further provides a method for treating a solid tumor by intratumoral administration to a subject of a pharmaceutical composition that comprises a compound of formula (A) or a pharmaceutically acceptable salt thereof, aluminum particles, one or more pharmaceutically acceptable excipients, and an immune response checkpoint inhibitor.

The present invention further provides a method for treating a solid tumor by administering a pharmaceutical combination comprising:

a) a pharmaceutical composition comprising a compound of formula (A) or a pharmaceutically acceptable salt thereof, aluminum particles and one or more pharmaceutically acceptable excipients, and

b) a pharmaceutical composition containing immune response checkpoint inhibitors and one or more pharmaceutically acceptable excipients,

wherein the pharmaceutical compositions are administered separately via the same or different routes of administration, either simultaneously or at different times. A pharmaceutical composition containing a compound of formula (A) or a pharmaceutically acceptable salt thereof, aluminum-containing particles and one or more pharmaceutically acceptable excipients can be administered intratumorally, intramuscularly, intradermally or subcutaneously, while the pharmaceutical composition containing immune response checkpoint inhibitors and one or more several pharmaceutically acceptable excipients may be administered intratumorally, intramuscularly, intradermally, subcutaneously, intravenously, or by intraperitoneal injection, by lavage, or by infusion.

In one embodiment, a method for treating a solid tumor is provided by intratumoral administration of a pharmaceutical combination comprising:

a) a first pharmaceutical composition comprising a compound of formula (A) or a pharmaceutically acceptable salt thereof, aluminum particles and one or more pharmaceutically acceptable excipients, and

b) a second pharmaceutical composition containing one or more immune response checkpoint inhibitors and one or more pharmaceutically acceptable excipients,

where both pharmaceutical compositions are administered intratumorally to the same tumor or to the area immediately surrounding the outer edge of the same tumor. In some embodiments, these pharmaceutical compositions are administered at different times, while in other embodiments, these pharmaceutical compositions are administered simultaneously.

The present invention further provides a method for treating a solid tumor by administering a pharmaceutical combination comprising:

a) a first pharmaceutical composition containing a compound of formula (A) or a pharmaceutically acceptable salt thereof, aluminum particles and one or more pharmaceutically acceptable excipients,

b) a second pharmaceutical composition comprising an immune checkpoint inhibitor and one or more pharmaceutically acceptable excipients, and

c) a third pharmaceutical composition comprising an immune checkpoint inhibitor that is different from the immune checkpoint inhibitor of the second pharmaceutical composition and one or more pharmaceutically acceptable excipients,

wherein the pharmaceutical compositions are administered separately via the same or different routes of administration, either simultaneously or at different times. A pharmaceutical composition comprising a compound of formula (A) or a pharmaceutically acceptable salt thereof, aluminum particles and one or more pharmaceutically acceptable excipients may be administered intratumorally, intramuscularly, intradermally or subcutaneously, wherein the pharmaceutical compositions comprising an immune response checkpoint inhibitor and one or more several pharmaceutically acceptable excipients may be administered intratumorally, intramuscularly, intradermally, subcutaneously, intravenously, by intraperitoneal injection, by lavage, or by infusion.

In one embodiment, a method for treating a solid tumor is provided by administering a pharmaceutical combination comprising:

a) a first pharmaceutical composition containing a compound of formula (A) or a pharmaceutically acceptable salt thereof, aluminum particles and one or more pharmaceutically acceptable excipients,

b) a second pharmaceutical composition comprising an immune checkpoint inhibitor and one or more pharmaceutically acceptable excipients, and

c) a third pharmaceutical composition comprising an immune checkpoint inhibitor that is different from the immune checkpoint inhibitor of the second pharmaceutical composition and one or more pharmaceutically acceptable excipients,

wherein the pharmaceutical compositions are administered intratumorally to the same tumor or to the area immediately surrounding the outer edge of the same tumor. In some embodiments, these three pharmaceutical compositions are administered at different times, while in other embodiments, these three pharmaceutical compositions are administered simultaneously.

The present invention further provides the use of a pharmaceutical composition for the treatment of a solid tumor, wherein the pharmaceutical composition comprises a compound of formula (A) or a pharmaceutically acceptable salt thereof, aluminum-containing particles, one or more pharmaceutically acceptable excipients, and an immune response checkpoint inhibitor.

The present invention further provides the use of a pharmaceutical combination for the treatment of a solid tumor, wherein the pharmaceutical combination comprises:

a) a first pharmaceutical composition comprising a compound of formula (A) or a pharmaceutically acceptable salt thereof, aluminum particles and one or more pharmaceutically acceptable excipients, and

b) a second pharmaceutical composition containing immune response checkpoint inhibitors and one or more pharmaceutically acceptable excipients.

The present invention further provides the use of a pharmaceutical combination for the treatment of a solid tumor, wherein the pharmaceutical combination comprises:

a) a first pharmaceutical composition containing a compound of formula (A) or a pharmaceutically acceptable salt thereof, aluminum particles and one or more pharmaceutically acceptable excipients,

b) a second pharmaceutical composition comprising an immune checkpoint inhibitor and one or more pharmaceutically acceptable excipients, and

c) a third pharmaceutical composition comprising an immune checkpoint inhibitor that is different from the immune checkpoint inhibitor of the second pharmaceutical composition and one or more pharmaceutically acceptable excipients,

The present invention further provides a pharmaceutical composition for use in the treatment of a solid tumor, wherein the pharmaceutical composition comprises a compound of formula (A) or a pharmaceutically acceptable salt thereof, aluminum-containing particles, one or more pharmaceutically acceptable excipients, and an immune response checkpoint inhibitor.

The present invention further provides a pharmaceutical combination for use in the treatment of a solid tumor, wherein the pharmaceutical combination comprises:

a) a first pharmaceutical composition comprising a compound of formula (A) or a pharmaceutically acceptable salt thereof, aluminum particles and one or more pharmaceutically acceptable excipients, and

b) a second pharmaceutical composition containing immune response checkpoint inhibitors and one or more pharmaceutically acceptable excipients.

The present invention further provides a pharmaceutical combination for use in the treatment of a solid tumor, wherein the pharmaceutical combination comprises:

a) a first pharmaceutical composition containing a compound of formula (A) or a pharmaceutically acceptable salt thereof, aluminum particles and one or more pharmaceutically acceptable excipients,

b) a second pharmaceutical composition comprising an immune checkpoint inhibitor and one or more pharmaceutically acceptable excipients, and

c) a third pharmaceutical composition comprising an immune checkpoint inhibitor that is different from the immune checkpoint inhibitor of the second pharmaceutical composition and one or more pharmaceutically acceptable excipients,

Solid tumors that can be treated with such methods and uses include, but are not limited to, breast cancer tumor, bladder cancer tumor, head and neck cancer tumor, non-small cell lung cancer tumor, small cell lung cancer, tumor related to colorectal cancer, gastrointestinal stromal tumor, gastroesophageal carcinoma, tumor related to renal cell carcinoma, tumor related to prostate cancer, tumor related to liver cancer, tumor related to colon cancer, a tumor related to pancreatic cancer, a tumor related to ovarian cancer, lymphoma, skin T-cell lymphoma or melanoma.

Large solid tumors become infiltrated with a subpopulation of myeloid-derived suppressor cells (mMDSCs) that suppress antitumor immunity. In some embodiments, the present invention provides a method of treating a tumor having immunosuppressive properties. A tumor having immunosuppressive properties is a tumor that contains immunosuppressive-associated cells such as, for example, T Reg cells, myeloid-derived suppressor cells (MDSC), M2 macrophages, and the like, or immune-suppressive factors such as inducible synthase. nitric oxide (iNOS), PD-L1 and the like.

The amount of a compound of formula (A), or a pharmaceutically acceptable salt thereof, included in a pharmaceutical composition according to the present invention, which is used in the method or use according to the present invention, may vary in accordance with factors known in the art, such as, for example, physical and subject's clinical status, route of administration, composition content, planned dosing regimen or sequence. When considering such factors, the appropriate included amount can be easily determined by a person skilled in the art. By way of example, a pharmaceutical composition of the present invention may contain an amount of a compound of formula (A) or a pharmaceutically acceptable salt thereof to provide a dose of a compound of formula (A) or a pharmaceutically acceptable salt thereof to a subject, from about 0.05 mg to about 5 mg. Preferably, the pharmaceutical composition of the present invention contains an amount of a compound of formula (A) or a pharmaceutically acceptable salt thereof that provides a dose of the compound of formula (A) or a pharmaceutically acceptable salt thereof to a subject of from about 0.1 mg to about 1 mg.

While the disclosed methods and uses for such compositions and combinations will generally be used to treat human subjects, they may also be used to treat similar or identical diseases in other vertebrates such as other primates, dogs, cats, horses, and cows.

Certain aspects and examples of methods according to the present invention are presented in the following list of additional numbered embodiments. It should be understood that the features indicated in each embodiment can be combined with other indicated features to obtain additional embodiments of the present invention.

Embodiment 353. A method of treating a solid tumor by administering to a subject in need thereof a pharmaceutical composition comprising 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy) -2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, aluminum particles, a buffer agent, one or more pharmaceutically acceptable excipients, and an immune response checkpoint inhibitor.

Embodiment 354. A method of treating a solid tumor by administering to a subject in need thereof a pharmaceutical composition comprising 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy) -2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffer agent, one or more pharmaceutically acceptable excipients, and an immune response checkpoint inhibitor.

Embodiment 355. A method of treating a solid tumor by intratumoral administration to a subject in need thereof of a pharmaceutical composition comprising 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy )-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffer agent, one or more pharmaceutically acceptable excipients, and an immune response checkpoint inhibitor.

Embodiment 356. A method of treating a solid tumor by intratumoral administration to a subject in need thereof of a pharmaceutical composition comprising 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy )-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffer agent, one or more pharmaceutically acceptable excipients, and an immune response checkpoint inhibitor, selected from a CTLA-4 receptor inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor inhibitor, a TIM-3 receptor inhibitor, a BTLA receptor inhibitor, a KIR receptor inhibitor, a PD-L1 inhibitor, or a PD-L2 inhibitor.

Embodiment 357. A method of treating a solid tumor by intratumoral administration to a subject in need thereof of a pharmaceutical composition comprising 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy )-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffering agent, one or more pharmaceutically acceptable excipients, and a PD-L1 inhibitor.

Embodiment 358. A method of treating a solid tumor by intratumoral administration to a subject in need thereof of a pharmaceutical composition comprising 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy )-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffering agent, one or more pharmaceutically acceptable excipients, and a PD-1 receptor inhibitor.

Embodiment 359. A method of treating a solid tumor by intratumoral administration to a subject in need thereof of a pharmaceutical composition comprising 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy )-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffer, one or more pharmaceutically acceptable excipients, and an anti-PD-L1 antibody.

Embodiment 360. A method of treating a solid tumor by intratumoral administration to a subject in need thereof of a pharmaceutical composition comprising 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy )-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffering agent, one or more pharmaceutically acceptable excipients, and an anti-PD-L1 antibody from table 2.

Embodiment 361. A method of treating a solid tumor by intratumoral administration to a subject in need thereof of a pharmaceutical composition comprising 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy )-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffer agent, one or more pharmaceutically acceptable excipients, and an anti-PD-L1 antibody, containing a heavy chain variable domain, which contains the amino acid sequence under SEQ ID NO: 7, and a light chain variable domain, which contains the amino acid sequence under SEQ ID NO: 17.

Embodiment 362. A method of treating a solid tumor by intratumoral administration to a subject in need thereof of a pharmaceutical composition comprising 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy )-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffering agent, one or more pharmaceutically acceptable excipients, and an anti-PD-1 antibody from table 3.

Embodiment 363. A method of treating a solid tumor by intratumorally administering to a subject in need thereof a pharmaceutical composition comprising 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy )-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffer agent, one or more pharmaceutically acceptable excipients, and an anti-PD-1 antibody, containing a heavy chain variable domain, which contains the amino acid sequence under SEQ ID NO: 27, and a light chain variable domain, which contains the amino acid sequence under SEQ ID NO: 37.

Embodiment 364 Use of a pharmaceutical composition comprising 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7 ]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, aluminum particles, a buffer agent, one or more pharmaceutically acceptable excipients, and an immune response checkpoint inhibitor, for the treatment of a solid tumor.

Embodiment 365 Use of a pharmaceutical composition comprising 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7 ]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffer agent, one or more pharmaceutically acceptable excipients, and an immune response checkpoint inhibitor, for the treatment of a solid tumor.

Embodiment 366 Use of a pharmaceutical composition comprising 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7 ]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffer agent, one or more pharmaceutically acceptable excipients, and an immune response checkpoint inhibitor, for the treatment of a solid tumor, wherein the checkpoint inhibitor is selected from a CTLA receptor inhibitor -4, a PD-1 receptor inhibitor, a LAG-3 receptor inhibitor, a TIM-3 receptor inhibitor, a BTLA receptor inhibitor, a KIR receptor inhibitor, a PD-L1 inhibitor, or a PD-L2 inhibitor.

Embodiment 367 Use of a pharmaceutical composition comprising 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7 ]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffer agent, one or more pharmaceutically acceptable excipients, and a PD-1 receptor inhibitor, for the treatment of a solid tumor.

Embodiment 368 Use of a pharmaceutical composition comprising 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7 ]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffer agent, one or more pharmaceutically acceptable excipients, and a PD-L1 inhibitor, for the treatment of a solid tumor.

Embodiment 369 Use of a pharmaceutical composition comprising 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7 ]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffer agent, one or more pharmaceutically acceptable excipients, and an anti-PD-L1 antibody, for the treatment of a solid tumor.

Embodiment 370 Use of a pharmaceutical composition comprising 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7 ]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffer agent, one or more pharmaceutically acceptable excipients, and an anti-PD-L1 antibody from Table 2, for the treatment of a solid tumor.

Embodiment 371 Use of a pharmaceutical composition comprising 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1.7 ]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffer agent, one or more pharmaceutically acceptable excipients, and an anti-PD-L1 antibody containing a heavy chain variable domain that contains the amino acid sequence of SEQ ID NO : 7, and a light chain variable domain that contains the amino acid sequence of SEQ ID NO: 17, for the treatment of a solid tumor.

Embodiment 372 A pharmaceutical composition comprising 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7] naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, aluminum particles, a buffer agent, one or more pharmaceutically acceptable excipients, and an immune response checkpoint inhibitor, for use in the treatment of a solid tumor.

Embodiment 373 A pharmaceutical composition comprising 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7] naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffering agent, one or more pharmaceutically acceptable excipients, and an immune response checkpoint inhibitor for use in the treatment of a solid tumor.

Embodiment 374 A pharmaceutical composition comprising 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7] naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffering agent, one or more pharmaceutically acceptable excipients, and an immune response checkpoint inhibitor for use in the treatment of a solid tumor, wherein the checkpoint inhibitor is selected from inhibitor CTLA-4 receptor inhibitor, PD-1 receptor inhibitor, LAG-3 receptor inhibitor, TIM-3 receptor inhibitor, BTLA receptor inhibitor, KIR receptor inhibitor, PD-L1 inhibitor, or PD-L2 inhibitor.

Embodiment 375 A pharmaceutical composition comprising 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7] naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffering agent, one or more pharmaceutically acceptable excipients, and a PD-1 receptor inhibitor for use in the treatment of a solid tumor.

Embodiment 376 A pharmaceutical composition comprising 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7] naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffering agent, one or more pharmaceutically acceptable excipients, and a PD-L1 inhibitor for use in the treatment of a solid tumor.

Embodiment 377 A pharmaceutical composition comprising 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7] naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffering agent, one or more pharmaceutically acceptable excipients, and an anti-PD-L1 antibody for use in the treatment of a solid tumor.

Embodiment 378 A pharmaceutical composition comprising 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7] naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffer, one or more pharmaceutically acceptable excipients, and an anti-PD-L1 antibody of Table 2 for use in the treatment of a solid tumor.

Embodiment 379 A pharmaceutical composition comprising 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7] naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffer agent, one or more pharmaceutically acceptable excipients, and an anti-PD-L1 antibody containing a heavy chain variable domain that contains the amino acid sequence of SEQ ID NO: 7 and a light chain variable domain which contains the amino acid sequence of SEQ ID NO: 17 for use in the treatment of a solid tumor.

Embodiment 380. A pharmaceutical composition comprising 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7] naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffering agent, one or more pharmaceutically acceptable excipients, and an anti-PD-1 antibody of Table 3 for use in the treatment of a solid tumor.

Embodiment 381 A pharmaceutical composition comprising 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7] naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffer agent, one or more pharmaceutically acceptable excipients, and an anti-PD-L1 antibody containing a heavy chain variable domain that contains the amino acid sequence of SEQ ID NO: 27 and a light chain variable domain which contains the amino acid sequence of SEQ ID NO: 37 for use in the treatment of a solid tumor.

Embodiment 382. A method of treating a solid tumor in a subject by administering a pharmaceutical combination according to any one of Embodiments 235-294.

Embodiment 383. A method of treating a solid tumor in a subject, carried out by administering the pharmaceutical combination according to any one of embodiments 235-294, wherein the first pharmaceutical composition is administered intratumorally and the second pharmaceutical composition is administered intratumorally, intramuscularly, intradermally, subcutaneously, intravenously, via intraperitoneal injection, by lavage or by infusion.

Embodiment 384. A method of treating a solid tumor in a subject by administering a pharmaceutical combination, wherein the pharmaceutical combination comprises:

a) a first pharmaceutical composition containing 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridine -8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, aluminum particles, a buffering agent and one or more pharmaceutically acceptable excipients, and

b) a second pharmaceutical composition containing immune response checkpoint inhibitors and one or more pharmaceutically acceptable excipients.

Embodiment 385. A method of treating a solid tumor in a subject by administering a pharmaceutical combination, wherein the pharmaceutical combination comprises:

a) a first pharmaceutical composition containing 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridine -8-yl) propanoic acid or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffering agent and one or more pharmaceutically acceptable excipients, and

b) a second pharmaceutical composition containing immune response checkpoint inhibitors and one or more pharmaceutically acceptable excipients.

Embodiment 386. A method of treating a solid tumor in a subject by administering a pharmaceutical combination, wherein the pharmaceutical combination comprises:

a) a first pharmaceutical composition containing 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridine -8-yl) propanoic acid or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffering agent and one or more pharmaceutically acceptable excipients, and

b) a second pharmaceutical composition containing immune response checkpoint inhibitors and one or more pharmaceutically acceptable excipients,

and wherein the first pharmaceutical composition is administered intratumorally and the second pharmaceutical composition is administered intratumorally, intramuscularly, intradermally, subcutaneously, intravenously, by intraperitoneal injection, by lavage, or by infusion.

Embodiment 387. A method of treating a solid tumor in a subject by administering a pharmaceutical combination, wherein the pharmaceutical combination comprises:

a) a first pharmaceutical composition containing 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridine -8-yl) propanoic acid or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffering agent and one or more pharmaceutically acceptable excipients, and

b) a second pharmaceutical composition containing immune response checkpoint inhibitors and one or more pharmaceutically acceptable excipients,

and wherein the first pharmaceutical composition is administered intratumorally and the second pharmaceutical composition is administered via intraperitoneal injection.

Embodiment 388. A method of treating a solid tumor in a subject by administering a pharmaceutical combination, wherein the pharmaceutical combination comprises:

a) a first pharmaceutical composition containing 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridine -8-yl) propanoic acid or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffering agent and one or more pharmaceutically acceptable excipients, and

b) a second pharmaceutical composition containing immune response checkpoint inhibitors and one or more pharmaceutically acceptable excipients,

wherein the checkpoint inhibitor is selected from a CTLA-4 receptor inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor inhibitor, a TIM-3 receptor inhibitor, a BTLA receptor inhibitor, a KIR receptor inhibitor, a PD-L1 inhibitor, or a PD-L2 inhibitor.

Embodiment 389. A method of treating a solid tumor in a subject by administering a pharmaceutical combination, wherein the pharmaceutical combination comprises:

a) a first pharmaceutical composition containing 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridine -8-yl) propanoic acid or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffering agent and one or more pharmaceutically acceptable excipients, and

b) a second pharmaceutical composition comprising a PD-1 receptor inhibitor and one or more pharmaceutically acceptable excipients.

Embodiment 390. A method of treating a solid tumor in a subject by administering a pharmaceutical combination, wherein the pharmaceutical combination comprises:

a) a first pharmaceutical composition containing 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridine -8-yl) propanoic acid or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffering agent and one or more pharmaceutically acceptable excipients, and

b) a second pharmaceutical composition containing a PD-L1 inhibitor and one or more pharmaceutically acceptable excipients.

Embodiment 391. A method of treating a solid tumor in a subject by administering a pharmaceutical combination, wherein the pharmaceutical combination comprises:

a) a first pharmaceutical composition containing 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridine -8-yl) propanoic acid or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffering agent and one or more pharmaceutically acceptable excipients, and

b) a second pharmaceutical composition comprising immune response checkpoint inhibitors and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is selected from a CTLA-4 receptor inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor inhibitor, a TIM-3 receptor inhibitor , a BTLA receptor inhibitor, a KIR receptor inhibitor, a PD-L1 inhibitor, or a PD-L2 inhibitor,

and wherein the first pharmaceutical composition is administered intratumorally and the second pharmaceutical composition is administered intratumorally, intramuscularly, intradermally, subcutaneously, intravenously, by intraperitoneal injection, by lavage, or by infusion.

Embodiment 392. A method of treating a solid tumor in a subject by administering a pharmaceutical combination, wherein the pharmaceutical combination comprises:

a) a first pharmaceutical composition containing 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridine -8-yl) propanoic acid or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffering agent and one or more pharmaceutically acceptable excipients, and

b) a second pharmaceutical composition comprising immune response checkpoint inhibitors and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is selected from a CTLA-4 receptor inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor inhibitor, a TIM-3 receptor inhibitor , a BTLA receptor inhibitor, a KIR receptor inhibitor, a PD-L1 inhibitor, or a PD-L2 inhibitor,

and wherein the first pharmaceutical composition is administered intratumorally and the second pharmaceutical composition is administered via intraperitoneal injection.

Embodiment 393. A method of treating a solid tumor in a subject by administering a pharmaceutical combination, wherein the pharmaceutical combination comprises:

a) a first pharmaceutical composition containing 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridine -8-yl) propanoic acid or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffering agent and one or more pharmaceutically acceptable excipients, and

b) a second pharmaceutical composition comprising a PD-1 receptor inhibitor and one or more pharmaceutically acceptable excipients,

and wherein the first pharmaceutical composition is administered intratumorally and the second pharmaceutical composition is administered intratumorally, intramuscularly, intradermally, subcutaneously, intravenously, by intraperitoneal injection, by lavage, or by infusion.

Embodiment 394. A method of treating a solid tumor in a subject by administering a pharmaceutical combination, wherein the pharmaceutical combination comprises:

a) a first pharmaceutical composition containing 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridine -8-yl) propanoic acid or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffering agent and one or more pharmaceutically acceptable excipients, and

b) a second pharmaceutical composition comprising a PD-1 receptor inhibitor and one or more pharmaceutically acceptable excipients,

and wherein the first pharmaceutical composition is administered intratumorally and the second pharmaceutical composition is administered via intraperitoneal injection.

Embodiment 395. A method of treating a solid tumor in a subject by administering a pharmaceutical combination, wherein the pharmaceutical combination comprises:

a) a first pharmaceutical composition containing 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridine -8-yl) propanoic acid or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffering agent and one or more pharmaceutically acceptable excipients, and

b) a second pharmaceutical composition containing a PD-L1 inhibitor and one or more pharmaceutically acceptable excipients,

and wherein the first pharmaceutical composition is administered intratumorally and the second pharmaceutical composition is administered intratumorally, intramuscularly, intradermally, subcutaneously, intravenously, by intraperitoneal injection, by lavage, or by infusion.

Embodiment 396. A method of treating a solid tumor in a subject by administering a pharmaceutical combination, wherein the pharmaceutical combination comprises:

a) a first pharmaceutical composition containing 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridine -8-yl) propanoic acid or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffering agent and one or more pharmaceutically acceptable excipients, and

b) a second pharmaceutical composition containing a PD-L1 inhibitor and one or more pharmaceutically acceptable excipients,

and wherein the first pharmaceutical composition is administered intratumorally and the second pharmaceutical composition is administered via intraperitoneal injection.

Embodiment 397. A method of treating a solid tumor in a subject by administering a pharmaceutical combination, wherein the pharmaceutical combination comprises:

a) a first pharmaceutical composition containing 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridine -8-yl) propanoic acid or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffering agent and one or more pharmaceutically acceptable excipients, and

b) a second pharmaceutical composition comprising an anti-PD-L1 antibody and one or more pharmaceutically acceptable excipients,

and wherein the first pharmaceutical composition is administered intratumorally and the second pharmaceutical composition is administered via intraperitoneal injection.

Embodiment 398. A method of treating a solid tumor in a subject by administering a pharmaceutical combination, wherein the pharmaceutical combination comprises:

a) a first pharmaceutical composition containing 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridine -8-yl) propanoic acid or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffering agent and one or more pharmaceutically acceptable excipients, and

b) a second pharmaceutical composition comprising an anti-PD-L1 antibody from Table 2 and one or more pharmaceutically acceptable excipients,

and wherein the first pharmaceutical composition is administered intratumorally and the second pharmaceutical composition is administered via intraperitoneal injection.

Embodiment 399. A method of treating a solid tumor in a subject by administering a pharmaceutical combination, wherein the pharmaceutical combination comprises:

a) a first pharmaceutical composition containing 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridine -8-yl) propanoic acid or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffering agent and one or more pharmaceutically acceptable excipients, and

b) a second pharmaceutical composition comprising an anti-PD-L1 antibody comprising a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 7 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 17, and one or several pharmaceutically acceptable excipients,

and wherein the first pharmaceutical composition is administered intratumorally and the second pharmaceutical composition is administered via intraperitoneal injection.

Embodiment 400. A method of treating a solid tumor in a subject by administering a pharmaceutical combination, wherein the pharmaceutical combination comprises:

a) a first pharmaceutical composition containing 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridine -8-yl) propanoic acid or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffering agent and one or more pharmaceutically acceptable excipients, and

b) a second pharmaceutical composition comprising an anti-PD-1 antibody and one or more pharmaceutically acceptable excipients,

and wherein the first pharmaceutical composition is administered intratumorally and the second pharmaceutical composition is administered via intraperitoneal injection.

Embodiment 401. A method of treating a solid tumor in a subject by administering a pharmaceutical combination, wherein the pharmaceutical combination comprises:

a) a first pharmaceutical composition containing 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridine -8-yl) propanoic acid or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffering agent and one or more pharmaceutically acceptable excipients, and

b) a second pharmaceutical composition comprising an anti-PD-1 antibody from Table 3 and one or more pharmaceutically acceptable excipients,

and wherein the first pharmaceutical composition is administered intratumorally and the second pharmaceutical composition is administered via intraperitoneal injection.

Embodiment 402. A method of treating a solid tumor in a subject by administering a pharmaceutical combination, wherein the pharmaceutical combination comprises:

a) a first pharmaceutical composition containing 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridine -8-yl) propanoic acid or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffering agent and one or more pharmaceutically acceptable excipients, and

b) a second pharmaceutical composition comprising an anti-PD-1 antibody comprising a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 27 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 37, and one or several pharmaceutically acceptable excipients,

and wherein the first pharmaceutical composition is administered intratumorally and the second pharmaceutical composition is administered via intraperitoneal injection.

Embodiment 403. A method of treating a solid tumor in a subject by administering a pharmaceutical combination, wherein the pharmaceutical combination comprises:

a) a first pharmaceutical composition containing 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridine -8-yl) propanoic acid or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffering agent and one or more pharmaceutically acceptable excipients, and

b) a second pharmaceutical composition containing ipilimumab and one or more pharmaceutically acceptable excipients,

and wherein the first pharmaceutical composition is administered intratumorally and the second pharmaceutical composition is administered intratumorally, intramuscularly, intradermally, subcutaneously, intravenously, by intraperitoneal injection, by lavage, or by infusion.

Embodiment 404. A method of treating a solid tumor in a subject by administering a pharmaceutical combination, wherein the pharmaceutical combination comprises:

a) a first pharmaceutical composition containing 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridine -8-yl) propanoic acid or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffering agent and one or more pharmaceutically acceptable excipients, and

b) a second pharmaceutical composition containing tremelimumab and one or more pharmaceutically acceptable excipients,

and wherein the first pharmaceutical composition is administered intratumorally and the second pharmaceutical composition is administered intratumorally, intramuscularly, intradermally, subcutaneously, intravenously, by intraperitoneal injection, by lavage, or by infusion.

Embodiment 405. A method of treating a solid tumor in a subject by administering a pharmaceutical combination, wherein the pharmaceutical combination comprises:

a) a first pharmaceutical composition containing 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridine -8-yl) propanoic acid or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffering agent and one or more pharmaceutically acceptable excipients, and

b) a second pharmaceutical composition containing lambrolizumab and one or more pharmaceutically acceptable excipients,

and wherein the first pharmaceutical composition is administered intratumorally and the second pharmaceutical composition is administered intratumorally, intramuscularly, intradermally, subcutaneously, intravenously, by intraperitoneal injection, by lavage, or by infusion.

Embodiment 406. A method of treating a solid tumor in a subject by administering a pharmaceutical combination, wherein the pharmaceutical combination comprises:

a) a first pharmaceutical composition containing 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridine -8-yl) propanoic acid or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffering agent and one or more pharmaceutically acceptable excipients, and

b) a second pharmaceutical composition containing pidilizumab and one or more pharmaceutically acceptable excipients,

and wherein the first pharmaceutical composition is administered intratumorally and the second pharmaceutical composition is administered intratumorally, intramuscularly, intradermally, subcutaneously, intravenously, by intraperitoneal injection, by lavage, or by infusion.

Embodiment 407. A method of treating a solid tumor in a subject by administering a pharmaceutical combination, wherein the pharmaceutical combination comprises:

a) a first pharmaceutical composition containing 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridine -8-yl) propanoic acid or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffering agent and one or more pharmaceutically acceptable excipients, and

b) a second pharmaceutical composition containing nivolumab and one or more pharmaceutically acceptable excipients,

and wherein the first pharmaceutical composition is administered intratumorally and the second pharmaceutical composition is administered intratumorally, intramuscularly, intradermally, subcutaneously, intravenously, by intraperitoneal injection, by lavage, or by infusion.

Embodiment 408. A method of treating a solid tumor in a subject by administering a pharmaceutical combination, wherein the pharmaceutical combination comprises:

a) a first pharmaceutical composition containing 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridine -8-yl) propanoic acid or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffering agent and one or more pharmaceutically acceptable excipients, and

b) a second pharmaceutical composition containing lirilumab and one or more pharmaceutically acceptable excipients,

and wherein the first pharmaceutical composition is administered intratumorally and the second pharmaceutical composition is administered intratumorally, intramuscularly, intradermally, subcutaneously, intravenously, by intraperitoneal injection, by lavage, or by infusion.

Embodiment 409. A method of treating a solid tumor in a subject by administering a pharmaceutical combination, wherein the pharmaceutical combination comprises:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 0.5-2 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy )ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles, characterized by an aluminum content of 1-4 mg/ml, 5-100 mM tris buffer and 5-10% (w/v) mannitol, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-PD-L1 antibody.

Embodiment 410. A method of treating a solid tumor in a subject by administering a pharmaceutical combination, wherein the pharmaceutical combination comprises:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 0.5-2 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy )ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles, characterized by an aluminum content of 1-4 mg/ml, 5-100 mM Tris buffer and 5-10% (w/v) sucrose, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-PD-L1 antibody.

Embodiment 411. A method of treating a solid tumor in a subject by administering a pharmaceutical combination, wherein the pharmaceutical combination comprises:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 0.5-2 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy )ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles, characterized by an aluminum content of 1-4 mg/ml, 5-50 mM tris buffer and 5-10% (w/v) mannitol, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-PD-L1 antibody.

Embodiment 412. A method of treating a solid tumor in a subject by administering a pharmaceutical combination, wherein the pharmaceutical combination comprises:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 0.5-2 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy )ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles, characterized by an aluminum content of 1-4 mg/ml, 5-50 mM Tris buffer and 5-10% (w/v) sucrose, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-PD-L1 antibody.

Embodiment 413. A method of treating a solid tumor in a subject by administering a pharmaceutical combination, wherein the pharmaceutical combination comprises:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 0.5-2 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy )ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles characterized by an aluminum content of 1-4 mg/ml, 5-20 mM tris buffer and 5-10% (w/v) mannitol, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-PD-L1 antibody.

Embodiment 414. A method of treating a solid tumor in a subject by administering a pharmaceutical combination, wherein the pharmaceutical combination comprises:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 0.5-2 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy )ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles characterized by an aluminum content of 1-4 mg/ml, 5-20 mM Tris buffer and 5-10% (w/v) sucrose, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-PD-L1 antibody.

Embodiment 415. A method of treating a solid tumor in a subject by administering a pharmaceutical combination, wherein the pharmaceutical combination comprises:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 1 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)- 2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles characterized by an aluminum content of 2 mg/ml, 16 mM Tris buffer and 7.5% (weight/volume) mannitol, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-PD-L1 antibody.

Embodiment 416. A method of treating a solid tumor in a subject by administering a pharmaceutical combination, wherein the pharmaceutical combination comprises:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 1 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)- 2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles characterized by an aluminum content of 2 mg/ml, 16 mM Tris buffer and 7.5% (weight/volume) sucrose, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-PD-L1 antibody.

Embodiment 417. A method of treating a solid tumor in a subject by administering a pharmaceutical combination, wherein the pharmaceutical combination comprises:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 1 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)- 2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles characterized by an aluminum content of 2 mg/ml, 5 mM Tris buffer and 8.25% (weight/volume) mannitol, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-PD-L1 antibody.

Embodiment 418. A method of treating a solid tumor in a subject by administering a pharmaceutical combination, wherein the pharmaceutical combination comprises:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 1 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)- 2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles characterized by an aluminum content of 2 mg/ml, 5 mM Tris buffer and 8.25% (weight/volume) sucrose, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-PD-L1 antibody.

Embodiment 419. The method according to any one of embodiments 409-418, wherein the anti-PD-L1 antibody is an anti-PD-L1 antibody from Table 2.

Embodiment 420. The method according to any of embodiments 409-418, wherein the anti-PD-L1 antibody is an anti-PD-L1 antibody comprising a heavy chain variable domain that comprises the amino acid sequence of SEQ ID NO: 7 and the variable domain light chain which contains the amino acid sequence of SEQ ID NO: 17.

Embodiment 421. A method of treating a solid tumor in a subject by administering a pharmaceutical combination, wherein the pharmaceutical combination comprises:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 0.5-2 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy )ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles, characterized by an aluminum content of 1-4 mg/ml, 5-100 mM tris buffer and 5-10% (w/v) mannitol, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-PD-1 antibody.

Embodiment 422. A method of treating a solid tumor in a subject by administering a pharmaceutical combination, wherein the pharmaceutical combination comprises:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 0.5-2 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy )ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles, characterized by an aluminum content of 1-4 mg/ml, 5-100 mM Tris buffer and 5-10% (w/v) sucrose, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-PD-1 antibody.

Embodiment 423. A method of treating a solid tumor in a subject by administering a pharmaceutical combination, wherein the pharmaceutical combination comprises:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 0.5-2 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy )ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles, characterized by an aluminum content of 1-4 mg/ml, 5-50 mM tris buffer and 5-10% (w/v) mannitol, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-PD-1 antibody.

Embodiment 424. A method of treating a solid tumor in a subject by administering a pharmaceutical combination, wherein the pharmaceutical combination comprises:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 0.5-2 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy )ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles, characterized by an aluminum content of 1-4 mg/ml, 5-50 mM Tris buffer and 5-10% (w/v) sucrose, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-PD-1 antibody.

Embodiment 425. A method of treating a solid tumor in a subject by administering a pharmaceutical combination, wherein the pharmaceutical combination comprises:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 0.5-2 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy )ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles characterized by an aluminum content of 1-4 mg/ml, 5-20 mM tris buffer and 5-10% (w/v) mannitol, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-PD-1 antibody.

Embodiment 426. A method of treating a solid tumor in a subject by administering a pharmaceutical combination, wherein the pharmaceutical combination comprises:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 0.5-2 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy )ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles characterized by an aluminum content of 1-4 mg/ml, 5-20 mM Tris buffer and 5-10% (w/v) sucrose, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-PD-1 antibody.

Embodiment 427. A method of treating a solid tumor in a subject by administering a pharmaceutical combination, wherein the pharmaceutical combination comprises:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 1 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)- 2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles characterized by an aluminum content of 2 mg/ml, 16 mM Tris buffer and 7.5% (weight/volume) mannitol, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-PD-1 antibody.

Embodiment 428. A method of treating a solid tumor in a subject by administering a pharmaceutical combination, wherein the pharmaceutical combination comprises:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 1 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)- 2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles characterized by an aluminum content of 2 mg/ml, 16 mM Tris buffer and 7.5% (weight/volume) sucrose, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-PD-1 antibody.

Embodiment 429. A method of treating a solid tumor in a subject by administering a pharmaceutical combination, wherein the pharmaceutical combination comprises:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 1 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)- 2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles characterized by an aluminum content of 2 mg/ml, 5 mM Tris buffer and 8.25% (weight/volume) mannitol, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-PD-1 antibody.

Embodiment 430. A method of treating a solid tumor in a subject by administering a pharmaceutical combination, wherein the pharmaceutical combination comprises:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 1 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)- 2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles characterized by an aluminum content of 2 mg/ml, 5 mM Tris buffer and 8.25% (weight/volume) sucrose, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-PD-1 antibody.

Embodiment 431. The method according to any one of embodiments 421-430, wherein the anti-PD-1 antibody is an anti-PD-1 antibody from Table 3.

Embodiment 432. The method according to any one of embodiments 421-430, wherein the anti-PD1 antibody is an anti-PD-1 antibody comprising a heavy chain variable domain that comprises the amino acid sequence of SEQ ID NO: 27 and a light chain variable domain , which contains the amino acid sequence under SEQ ID NO: 37.

Embodiment 433. The method according to any one of embodiments 409-432, wherein the first pharmaceutical composition is administered intratumorally and the second pharmaceutical composition is administered intratumorally, intramuscularly, intradermally, subcutaneously, intravenously, by intraperitoneal injection, by lavage, or by infusion.

Embodiment 434. The method according to any one of embodiments 409-433, wherein the first pharmaceutical composition is administered intratumorally and the second pharmaceutical composition is administered via intraperitoneal injection.

Embodiment 435. Use of a pharmaceutical combination according to any of Embodiments 235-294 for the treatment of a solid tumor.

Embodiment 436. Use of a pharmaceutical combination for the treatment of a solid tumor, wherein the pharmaceutical combination contains:

a) a first pharmaceutical composition containing 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridine -8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, aluminum particles, a buffering agent and one or more pharmaceutically acceptable excipients, and

b) a second pharmaceutical composition containing immune response checkpoint inhibitors and one or more pharmaceutically acceptable excipients.

Embodiment 437. Use of a pharmaceutical combination for the treatment of a solid tumor, wherein the pharmaceutical combination contains:

a) a first pharmaceutical composition containing 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridine -8-yl) propanoic acid or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffering agent and one or more pharmaceutically acceptable excipients, and

b) a second pharmaceutical composition containing immune response checkpoint inhibitors and one or more pharmaceutically acceptable excipients.

Embodiment 438. Use of a pharmaceutical combination for the treatment of a solid tumor, wherein the pharmaceutical combination contains:

a) a first pharmaceutical composition containing 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridine -8-yl) propanoic acid or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffering agent and one or more pharmaceutically acceptable excipients, and

b) a second pharmaceutical composition containing immune response checkpoint inhibitors and one or more pharmaceutically acceptable excipients,

wherein the checkpoint inhibitor is selected from a CTLA-4 receptor inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor inhibitor, a TIM-3 receptor inhibitor, a BTLA receptor inhibitor, a KIR receptor inhibitor, a PD-L1 inhibitor, or a PD-L2 inhibitor.

Embodiment 439. Use of a pharmaceutical combination for the treatment of a solid tumor, wherein the pharmaceutical combination contains:

a) a first pharmaceutical composition containing 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridine -8-yl) propanoic acid or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffering agent and one or more pharmaceutically acceptable excipients, and

b) a second pharmaceutical composition comprising a PD-1 receptor inhibitor and one or more pharmaceutically acceptable excipients.

Embodiment 440. Use of a pharmaceutical combination for the treatment of a solid tumor, wherein the pharmaceutical combination contains:

a) a first pharmaceutical composition containing 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridine -8-yl) propanoic acid or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffering agent and one or more pharmaceutically acceptable excipients, and

b) a second pharmaceutical composition containing a PD-L1 inhibitor and one or more pharmaceutically acceptable excipients.

Embodiment 441. Use of a pharmaceutical combination for the treatment of a solid tumor, wherein the pharmaceutical combination contains:

a) a first pharmaceutical composition containing 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridine -8-yl) propanoic acid or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffering agent and one or more pharmaceutically acceptable excipients, and

b) a second pharmaceutical composition comprising an anti-PD-L1 antibody and one or more pharmaceutically acceptable excipients.

Embodiment 442. Use of a pharmaceutical combination for the treatment of a solid tumor, wherein the pharmaceutical combination contains:

a) a first pharmaceutical composition containing 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridine -8-yl) propanoic acid or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffering agent and one or more pharmaceutically acceptable excipients, and

b) a second pharmaceutical composition comprising an anti-PD-L1 antibody from Table 2 and one or more pharmaceutically acceptable excipients.

Embodiment 443. Use of a pharmaceutical combination for the treatment of a solid tumor, wherein the pharmaceutical combination contains:

a) a first pharmaceutical composition containing 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridine -8-yl) propanoic acid or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffering agent and one or more pharmaceutically acceptable excipients, and

b) a second pharmaceutical composition comprising an anti-PD-L1 antibody comprising a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 7 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 17.

Embodiment 444 Use of a pharmaceutical combination for the treatment of a solid tumor, wherein the pharmaceutical combination contains:

a) a first pharmaceutical composition containing 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridine -8-yl) propanoic acid or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffering agent and one or more pharmaceutically acceptable excipients, and

b) a second pharmaceutical composition comprising an anti-PD-1 antibody and one or more pharmaceutically acceptable excipients.

Embodiment 445. Use of a pharmaceutical combination for the treatment of a solid tumor, wherein the pharmaceutical combination contains:

a) a first pharmaceutical composition containing 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridine -8-yl) propanoic acid or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffering agent and one or more pharmaceutically acceptable excipients, and

b) a second pharmaceutical composition comprising an anti-PD-1 antibody from Table 3 and one or more pharmaceutically acceptable excipients.

Embodiment 446. Use of a pharmaceutical combination for the treatment of a solid tumor, wherein the pharmaceutical combination contains:

a) a first pharmaceutical composition containing 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridine -8-yl) propanoic acid or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffering agent and one or more pharmaceutically acceptable excipients, and

b) a second pharmaceutical composition comprising an anti-PD-1 antibody comprising a heavy chain variable domain which comprises the amino acid sequence of SEQ ID NO: 27 and a light chain variable domain which comprises the amino acid sequence of SEQ ID NO: 37.

Embodiment 447. Use of a pharmaceutical combination for the treatment of a solid tumor, wherein the pharmaceutical combination contains:

a) a first pharmaceutical composition containing 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridine -8-yl) propanoic acid or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffering agent and one or more pharmaceutically acceptable excipients, and

b) a second pharmaceutical composition containing ipilimumab and one or more pharmaceutically acceptable excipients.

Embodiment 448. Use of a pharmaceutical combination for the treatment of a solid tumor, wherein the pharmaceutical combination contains:

a) a first pharmaceutical composition containing 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridine -8-yl) propanoic acid or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffering agent and one or more pharmaceutically acceptable excipients, and

b) a second pharmaceutical composition containing tremelimumab and one or more pharmaceutically acceptable excipients.

Embodiment 449. Use of a pharmaceutical combination for the treatment of a solid tumor, wherein the pharmaceutical combination contains:

a) a first pharmaceutical composition containing 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridine -8-yl) propanoic acid or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffering agent and one or more pharmaceutically acceptable excipients, and

b) a second pharmaceutical composition containing lambrolizumab and one or more pharmaceutically acceptable excipients.

Embodiment 450. Use of a pharmaceutical combination for the treatment of a solid tumor, wherein the pharmaceutical combination contains:

a) a first pharmaceutical composition containing 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridine -8-yl) propanoic acid or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffering agent and one or more pharmaceutically acceptable excipients, and

b) a second pharmaceutical composition containing pidilizumab and one or more pharmaceutically acceptable excipients.

Embodiment 451. Use of a pharmaceutical combination for the treatment of a solid tumor, wherein the pharmaceutical combination contains:

a) a first pharmaceutical composition containing 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridine -8-yl) propanoic acid or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffering agent and one or more pharmaceutically acceptable excipients, and

b) a second pharmaceutical composition containing nivolumab and one or more pharmaceutically acceptable excipients.

Embodiment 452. Use of a pharmaceutical combination for the treatment of a solid tumor, wherein the pharmaceutical combination contains:

a) a first pharmaceutical composition containing 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridine -8-yl) propanoic acid or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffering agent and one or more pharmaceutically acceptable excipients, and

b) a second pharmaceutical composition containing lirilumab and one or more pharmaceutically acceptable excipients.

Embodiment 453. Use of a pharmaceutical combination for the treatment of a solid tumor, wherein the pharmaceutical combination contains:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 0.5-2 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy )ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles, characterized by an aluminum content of 1-4 mg/ml, 5-100 mM tris buffer and 5-10% (w/v) mannitol, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-PD-L1 antibody.

Embodiment 454. Use of a pharmaceutical combination for the treatment of a solid tumor, wherein the pharmaceutical combination contains:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 0.5-2 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy )ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles, characterized by an aluminum content of 1-4 mg/ml, 5-100 mM Tris buffer and 5-10% (w/v) sucrose, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-PD-L1 antibody.

Embodiment 455. Use of a pharmaceutical combination for the treatment of a solid tumor, wherein the pharmaceutical combination contains:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 0.5-2 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy )ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles, characterized by an aluminum content of 1-4 mg/ml, 5-50 mM tris buffer and 5-10% (w/v) mannitol, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-PD-L1 antibody.

Embodiment 456. Use of a pharmaceutical combination for the treatment of a solid tumor, wherein the pharmaceutical combination contains:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 0.5-2 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy )ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles, characterized by an aluminum content of 1-4 mg/ml, 5-50 mM Tris buffer and 5-10% (w/v) sucrose, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-PD-L1 antibody.

Embodiment 457. Use of a pharmaceutical combination for the treatment of a solid tumor, wherein the pharmaceutical combination contains:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 0.5-2 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy )ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles characterized by an aluminum content of 1-4 mg/ml, 5-20 mM tris buffer and 5-10% (w/v) mannitol, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-PD-L1 antibody.

Embodiment 458. Use of a pharmaceutical combination for the treatment of a solid tumor, wherein the pharmaceutical combination contains:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 0.5-2 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy )ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles characterized by an aluminum content of 1-4 mg/ml, 5-20 mM Tris buffer and 5-10% (w/v) sucrose, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-PD-L1 antibody.

Embodiment 459. Use of a pharmaceutical combination for the treatment of a solid tumor, wherein the pharmaceutical combination contains:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 1 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)- 2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles characterized by an aluminum content of 2 mg/ml, 16 mM Tris buffer and 7.5% (weight/volume) mannitol, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-PD-L1 antibody.

Embodiment 460. Use of a pharmaceutical combination for the treatment of a solid tumor, wherein the pharmaceutical combination comprises:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 1 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)- 2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles characterized by an aluminum content of 2 mg/ml, 16 mM Tris buffer and 7.5% (weight/volume) sucrose, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-PD-L1 antibody.

Embodiment 461. Use of a pharmaceutical combination for the treatment of a solid tumor, wherein the pharmaceutical combination contains:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 1 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)- 2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles characterized by an aluminum content of 2 mg/ml, 5 mM Tris buffer and 8.25% (weight/volume) mannitol, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-PD-L1 antibody.

Embodiment 462. Use of a pharmaceutical combination for the treatment of a solid tumor, wherein the pharmaceutical combination contains:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 1 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)- 2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles characterized by an aluminum content of 2 mg/ml, 5 mM Tris buffer and 8.25% (weight/volume) sucrose, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-PD-L1 antibody.

Embodiment 463 Use according to any one of Embodiments 453-462 wherein the anti-PD-L1 antibody is an anti-PD-L1 antibody from Table 2.

Embodiment 464. Use according to any one of embodiments 453-462, wherein the anti-PD-L1 antibody is an anti-PD-L1 antibody comprising a heavy chain variable domain that comprises the amino acid sequence of SEQ ID NO: 7 and the variable domain light chain which contains the amino acid sequence of SEQ ID NO: 17.

Embodiment 465. Use of a pharmaceutical combination for the treatment of a solid tumor, wherein the pharmaceutical combination contains:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 0.5-2 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy )ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles, characterized by an aluminum content of 1-4 mg/ml, 5-100 mM tris buffer and 5-10% (w/v) mannitol, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-PD-1 antibody.

Embodiment 466. Use of a pharmaceutical combination for the treatment of a solid tumor, wherein the pharmaceutical combination contains:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 0.5-2 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy )ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles, characterized by an aluminum content of 1-4 mg/ml, 5-100 mM Tris buffer and 5-10% (w/v) sucrose, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-PD-1 antibody.

Embodiment 467. Use of a pharmaceutical combination for the treatment of a solid tumor, wherein the pharmaceutical combination contains:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 0.5-2 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy )ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles, characterized by an aluminum content of 1-4 mg/ml, 5-50 mM tris buffer and 5-10% (w/v) mannitol, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-PD-1 antibody.

Embodiment 468. Use of a pharmaceutical combination for the treatment of a solid tumor, wherein the pharmaceutical combination contains:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 0.5-2 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy )ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles, characterized by an aluminum content of 1-4 mg/ml, 5-50 mM Tris buffer and 5-10% (w/v) sucrose, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-PD-1 antibody.

Embodiment 469 Use of a pharmaceutical combination for the treatment of a solid tumor, wherein the pharmaceutical combination comprises:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 0.5-2 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy )ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles characterized by an aluminum content of 1-4 mg/ml, 5-20 mM tris buffer and 5-10% (w/v) mannitol, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-PD-1 antibody.

Embodiment 470. Use of a pharmaceutical combination for the treatment of a solid tumor, wherein the pharmaceutical combination contains:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 0.5-2 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy )ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles characterized by an aluminum content of 1-4 mg/ml, 5-20 mM Tris buffer and 5-10% (w/v) sucrose, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-PD-1 antibody.

Embodiment 471. Use of a pharmaceutical combination for the treatment of a solid tumor, wherein the pharmaceutical combination contains:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 1 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)- 2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles characterized by an aluminum content of 2 mg/ml, 16 mM Tris buffer and 7.5% (weight/volume) mannitol, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-PD-1 antibody.

Embodiment 472. Use of a pharmaceutical combination for the treatment of a solid tumor, wherein the pharmaceutical combination contains:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 1 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)- 2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles characterized by an aluminum content of 2 mg/ml, 16 mM Tris buffer and 7.5% (weight/volume) sucrose, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-PD-1 antibody.

Embodiment 473 Use of a pharmaceutical combination for the treatment of a solid tumor, wherein the pharmaceutical combination contains:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 1 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)- 2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles characterized by an aluminum content of 2 mg/ml, 5 mM Tris buffer and 8.25% (weight/volume) mannitol, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-PD-1 antibody.

Embodiment 474. Use of a pharmaceutical combination for the treatment of a solid tumor, wherein the pharmaceutical combination contains:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 1 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)- 2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles characterized by an aluminum content of 2 mg/ml, 5 mM Tris buffer and 8.25% (weight/volume) sucrose, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-PD-1 antibody.

Embodiment 475 Use according to any one of Embodiments 464-476 wherein the anti-PD-1 antibody is an anti-PD-1 antibody from Table 3.

Embodiment 476. Use according to any one of embodiments 464-476, wherein the anti-PD1 antibody is an anti-PD-1 antibody comprising a heavy chain variable domain that comprises the amino acid sequence of SEQ ID NO: 27 and a light chain variable domain , which contains the amino acid sequence under SEQ ID NO: 37.

Embodiment 477 A pharmaceutical combination according to any one of Embodiments 235-294 for use in the treatment of a solid tumor.

Embodiment 478 A pharmaceutical combination for use in the treatment of a solid tumor, wherein the pharmaceutical combination comprises:

a) a first pharmaceutical composition containing 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridine -8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, aluminum particles, a buffering agent and one or more pharmaceutically acceptable excipients, and

b) a second pharmaceutical composition containing immune response checkpoint inhibitors and one or more pharmaceutically acceptable excipients.

Embodiment 479 A pharmaceutical combination for use in the treatment of a solid tumor, wherein the pharmaceutical combination comprises:

a) a first pharmaceutical composition containing 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridine -8-yl) propanoic acid or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffering agent and one or more pharmaceutically acceptable excipients, and

b) a second pharmaceutical composition containing immune response checkpoint inhibitors and one or more pharmaceutically acceptable excipients.

Embodiment 480 A pharmaceutical combination for use in the treatment of a solid tumor, wherein the pharmaceutical combination comprises:

a) a first pharmaceutical composition containing 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridine -8-yl) propanoic acid or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffering agent and one or more pharmaceutically acceptable excipients, and

b) a second pharmaceutical composition containing immune response checkpoint inhibitors and one or more pharmaceutically acceptable excipients,

wherein the checkpoint inhibitor is selected from a CTLA-4 receptor inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor inhibitor, a TIM-3 receptor inhibitor, a BTLA receptor inhibitor, a KIR receptor inhibitor, a PD-L1 inhibitor, or a PD-L2 inhibitor.

Embodiment 481 A pharmaceutical combination for use in the treatment of a solid tumor, wherein the pharmaceutical combination comprises:

a) a first pharmaceutical composition containing 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridine -8-yl) propanoic acid or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffering agent and one or more pharmaceutically acceptable excipients, and

b) a second pharmaceutical composition comprising a PD-1 receptor inhibitor and one or more pharmaceutically acceptable excipients.

Embodiment 482 A pharmaceutical combination for use in the treatment of a solid tumor, wherein the pharmaceutical combination comprises:

a) a first pharmaceutical composition containing 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridine -8-yl) propanoic acid or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffering agent and one or more pharmaceutically acceptable excipients, and

b) a second pharmaceutical composition containing a PD-L1 inhibitor and one or more pharmaceutically acceptable excipients.

Embodiment 483 A pharmaceutical combination for use in the treatment of a solid tumor, wherein the pharmaceutical combination comprises:

a) a first pharmaceutical composition containing 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridine -8-yl) propanoic acid or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffering agent and one or more pharmaceutically acceptable excipients, and

b) a second pharmaceutical composition comprising an anti-PD-L1 antibody and one or more pharmaceutically acceptable excipients.

Embodiment 484 A pharmaceutical combination for use in the treatment of a solid tumor, wherein the pharmaceutical combination comprises:

a) a first pharmaceutical composition containing 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridine -8-yl) propanoic acid or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffering agent and one or more pharmaceutically acceptable excipients, and

b) a second pharmaceutical composition comprising an anti-PD-L1 antibody from Table 2 and one or more pharmaceutically acceptable excipients.

Embodiment 485 A pharmaceutical combination for use in the treatment of a solid tumor, wherein the pharmaceutical combination comprises:

a) a first pharmaceutical composition containing 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridine -8-yl) propanoic acid or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffering agent and one or more pharmaceutically acceptable excipients, and

b) a second pharmaceutical composition comprising an anti-PD-L1 antibody comprising a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 7 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 17.

Embodiment 486 A pharmaceutical combination for use in the treatment of a solid tumor, wherein the pharmaceutical combination comprises:

a) a first pharmaceutical composition containing 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridine -8-yl) propanoic acid or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffering agent and one or more pharmaceutically acceptable excipients, and

b) a second pharmaceutical composition comprising an anti-PD-1 antibody and one or more pharmaceutically acceptable excipients.

Embodiment 487 A pharmaceutical combination for use in the treatment of a solid tumor, wherein the pharmaceutical combination comprises:

a) a first pharmaceutical composition containing 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridine -8-yl) propanoic acid or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffering agent and one or more pharmaceutically acceptable excipients, and

b) a second pharmaceutical composition comprising an anti-PD-1 antibody from Table 3 and one or more pharmaceutically acceptable excipients.

Embodiment 488 A pharmaceutical combination for use in the treatment of a solid tumor, wherein the pharmaceutical combination comprises:

a) a first pharmaceutical composition containing 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridine -8-yl) propanoic acid or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffering agent and one or more pharmaceutically acceptable excipients, and

b) a second pharmaceutical composition comprising an anti-PD-1 antibody comprising a heavy chain variable domain which comprises the amino acid sequence of SEQ ID NO: 27 and a light chain variable domain which comprises the amino acid sequence of SEQ ID NO: 37.

Embodiment 489 A pharmaceutical combination for use in the treatment of a solid tumor, wherein the pharmaceutical combination comprises:

a) a first pharmaceutical composition containing 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridine -8-yl) propanoic acid or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffering agent and one or more pharmaceutically acceptable excipients, and

b) a second pharmaceutical composition containing ipilimumab and one or more pharmaceutically acceptable excipients.

Embodiment 490 A pharmaceutical combination for use in the treatment of a solid tumor, wherein the pharmaceutical combination comprises:

a) a first pharmaceutical composition containing 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridine -8-yl) propanoic acid or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffering agent and one or more pharmaceutically acceptable excipients, and

b) a second pharmaceutical composition containing tremelimumab and one or more pharmaceutically acceptable excipients.

Embodiment 491 A pharmaceutical combination for use in the treatment of a solid tumor, wherein the pharmaceutical combination comprises:

a) a first pharmaceutical composition containing 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridine -8-yl) propanoic acid or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffering agent and one or more pharmaceutically acceptable excipients, and

b) a second pharmaceutical composition containing lambrolizumab and one or more pharmaceutically acceptable excipients.

Embodiment 492 A pharmaceutical combination for use in the treatment of a solid tumor, wherein the pharmaceutical combination comprises:

a) a first pharmaceutical composition containing 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridine -8-yl) propanoic acid or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffering agent and one or more pharmaceutically acceptable excipients, and

b) a second pharmaceutical composition containing pidilizumab and one or more pharmaceutically acceptable excipients.

Embodiment 493 A pharmaceutical combination for use in the treatment of a solid tumor, wherein the pharmaceutical combination comprises:

a) a first pharmaceutical composition containing 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridine -8-yl) propanoic acid or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffering agent and one or more pharmaceutically acceptable excipients, and

b) a second pharmaceutical composition containing nivolumab and one or more pharmaceutically acceptable excipients.

Embodiment 494. A method of treating a solid tumor in a subject by administering a pharmaceutical combination, wherein the pharmaceutical combination comprises:

a) a first pharmaceutical composition containing 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridine -8-yl) propanoic acid or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffering agent and one or more pharmaceutically acceptable excipients, and

b) a second pharmaceutical composition containing lirilumab and one or more pharmaceutically acceptable excipients.

Embodiment 495 A pharmaceutical combination for use in the treatment of a solid tumor, wherein the pharmaceutical combination comprises:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 0.5-2 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy )ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles, characterized by an aluminum content of 1-4 mg/ml, 5-100 mM tris buffer and 5-10% (w/v) mannitol, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-PD-L1 antibody.

Embodiment 496 A pharmaceutical combination for use in the treatment of a solid tumor, wherein the pharmaceutical combination comprises:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 0.5-2 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy )ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles, characterized by an aluminum content of 1-4 mg/ml, 5-100 mM Tris buffer and 5-10% (w/v) sucrose, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-PD-L1 antibody.

Embodiment 497. A pharmaceutical combination for use in the treatment of a solid tumor, wherein the pharmaceutical combination comprises:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 0.5-2 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy )ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles, characterized by an aluminum content of 1-4 mg/ml, 5-50 mM tris buffer and 5-10% (w/v) mannitol, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-PD-L1 antibody.

Embodiment 498 A pharmaceutical combination for use in the treatment of a solid tumor, wherein the pharmaceutical combination comprises:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 0.5-2 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy )ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles, characterized by an aluminum content of 1-4 mg/ml, 5-50 mM Tris buffer and 5-10% (w/v) sucrose, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-PD-L1 antibody.

Embodiment 499. A pharmaceutical combination for use in the treatment of a solid tumor, wherein the pharmaceutical combination comprises:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 0.5-2 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy )ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles characterized by an aluminum content of 1-4 mg/ml, 5-20 mM tris buffer and 5-10% (w/v) mannitol, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-PD-L1 antibody.

Embodiment 500 A pharmaceutical combination for use in the treatment of a solid tumor, wherein the pharmaceutical combination comprises:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 0.5-2 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy )ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles characterized by an aluminum content of 1-4 mg/ml, 5-20 mM Tris buffer and 5-10% (w/v) sucrose, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-PD-L1 antibody.

Embodiment 501 A pharmaceutical combination for use in the treatment of a solid tumor, wherein the pharmaceutical combination comprises:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 1 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)- 2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles characterized by an aluminum content of 2 mg/ml, 16 mM Tris buffer and 7.5% (weight/volume) mannitol, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-PD-L1 antibody.

Embodiment 502 A pharmaceutical combination for use in the treatment of a solid tumor, wherein the pharmaceutical combination comprises:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 1 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)- 2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles characterized by an aluminum content of 2 mg/ml, 16 mM Tris buffer and 7.5% (weight/volume) sucrose, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-PD-L1 antibody.

Embodiment 503 A pharmaceutical combination for use in the treatment of a solid tumor, wherein the pharmaceutical combination contains:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 1 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)- 2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles characterized by an aluminum content of 2 mg/ml, 5 mM Tris buffer and 8.25% (weight/volume) mannitol, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-PD-L1 antibody.

Embodiment 504 A pharmaceutical combination for use in the treatment of a solid tumor, wherein the pharmaceutical combination contains:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 1 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)- 2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles characterized by an aluminum content of 2 mg/ml, 5 mM Tris buffer and 8.25% (weight/volume) sucrose, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-PD-L1 antibody.

Embodiment 505. A pharmaceutical combination according to any one of Embodiments 495-504, wherein the anti-PD-L1 antibody is an anti-PD-L1 antibody from Table 2.

Embodiment 506. The pharmaceutical combination according to any one of embodiments 495-504, wherein the anti-PD-L1 antibody is an anti-PD-L1 antibody containing a heavy chain variable domain that contains the amino acid sequence of SEQ ID NO: 7, and the variable a light chain domain that contains the amino acid sequence of SEQ ID NO: 17.

Embodiment 507 A pharmaceutical combination for use in the treatment of a solid tumor, wherein the pharmaceutical combination comprises:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 0.5-2 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy )ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles, characterized by an aluminum content of 1-4 mg/ml, 5-100 mM tris buffer and 5-10% (w/v) mannitol, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-PD-1 antibody.

Embodiment 508 A pharmaceutical combination for use in the treatment of a solid tumor, wherein the pharmaceutical combination comprises:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 0.5-2 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy )ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles, characterized by an aluminum content of 1-4 mg/ml, 5-100 mM Tris buffer and 5-10% (w/v) sucrose, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-PD-1 antibody.

Embodiment 509 A pharmaceutical combination for use in the treatment of a solid tumor, wherein the pharmaceutical combination comprises:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 0.5-2 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy )ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles, characterized by an aluminum content of 1-4 mg/ml, 5-50 mM tris buffer and 5-10% (w/v) mannitol, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-PD-1 antibody.

Embodiment 510 A pharmaceutical combination for use in the treatment of a solid tumor, wherein the pharmaceutical combination comprises:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 0.5-2 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy )ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles, characterized by an aluminum content of 1-4 mg/ml, 5-50 mM Tris buffer and 5-10% (w/v) sucrose, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-PD-1 antibody.

Embodiment 511 A pharmaceutical combination for use in the treatment of a solid tumor, wherein the pharmaceutical combination contains:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 0.5-2 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy )ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles characterized by an aluminum content of 1-4 mg/ml, 5-20 mM tris buffer and 5-10% (w/v) mannitol, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-PD-1 antibody.

Embodiment 512 A pharmaceutical combination for use in the treatment of a solid tumor, wherein the pharmaceutical combination comprises:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 0.5-2 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy )ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles characterized by an aluminum content of 1-4 mg/ml, 5-20 mM Tris buffer and 5-10% (w/v) sucrose, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-PD-1 antibody.

Embodiment 513 A pharmaceutical combination for use in the treatment of a solid tumor, wherein the pharmaceutical combination comprises:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 1 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)- 2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles characterized by an aluminum content of 2 mg/ml, 16 mM Tris buffer and 7.5% (weight/volume) mannitol, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-PD-1 antibody.

Embodiment 514 A pharmaceutical combination for use in the treatment of a solid tumor, wherein the pharmaceutical combination comprises:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 1 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)- 2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles characterized by an aluminum content of 2 mg/ml, 16 mM Tris buffer and 7.5% (weight/volume) sucrose, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-PD-1 antibody.

Embodiment 515 A pharmaceutical combination for use in the treatment of a solid tumor, wherein the pharmaceutical combination comprises:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 1 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)- 2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles characterized by an aluminum content of 2 mg/ml, 5 mM Tris buffer and 8.25% (weight/volume) mannitol, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-PD-1 antibody.

Embodiment 516 A pharmaceutical combination for use in the treatment of a solid tumor, wherein the pharmaceutical combination comprises:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 1 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)- 2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles characterized by an aluminum content of 2 mg/ml, 5 mM Tris buffer and 8.25% (weight/volume) sucrose, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-PD-1 antibody.

Embodiment 517. A pharmaceutical combination according to any of embodiments 506-518, wherein the anti-PD-1 antibody is an anti-PD-1 antibody from Table 3.

Embodiment 518. The pharmaceutical combination according to any one of embodiments 506-518, wherein the anti-PD1 antibody is an anti-PD-1 antibody comprising a heavy chain variable domain that comprises the amino acid sequence of SEQ ID NO: 27 and a light variable domain. chain that contains the amino acid sequence under SEQ ID NO: 37.

Embodiment 519. A method of treating a solid tumor in a subject by administering a pharmaceutical combination according to any one of Embodiments 295-352.

Embodiment 520. A method of treating a solid tumor in a subject by administering a pharmaceutical combination according to any one of Embodiments 295-352, wherein the first pharmaceutical composition is administered intratumorally and the second and third pharmaceutical compositions are administered intratumorally, intramuscularly, intradermally, subcutaneously, intravenously , by intraperitoneal injection, by lavage, or by infusion.

Embodiment 521. A method of treating a solid tumor in a subject by administering a pharmaceutical combination, wherein the pharmaceutical combination comprises:

a) a first pharmaceutical composition containing a compound of formula (A) or a pharmaceutically acceptable salt thereof, aluminum particles, a buffering agent and one or more pharmaceutically acceptable excipients,

b) a second pharmaceutical composition comprising an immune checkpoint inhibitor and one or more pharmaceutically acceptable excipients, and

c) a third pharmaceutical composition comprising an immune checkpoint inhibitor that is different from the immune checkpoint inhibitor of the second pharmaceutical composition and one or more pharmaceutically acceptable excipients,

and wherein the first pharmaceutical composition, the second pharmaceutical composition, and the third pharmaceutical composition are administered separately and sequentially in any order.

Embodiment 522. A method of treating a solid tumor in a subject by administering a pharmaceutical combination, wherein the pharmaceutical combination comprises:

a) a first pharmaceutical composition containing a compound of formula (A) or a pharmaceutically acceptable salt thereof, aluminum particles, a buffering agent and one or more pharmaceutically acceptable excipients,

b) a second pharmaceutical composition comprising an immune checkpoint inhibitor and one or more pharmaceutically acceptable excipients, and

c) a third pharmaceutical composition comprising an immune checkpoint inhibitor that is different from the immune checkpoint inhibitor of the second pharmaceutical composition and one or more pharmaceutically acceptable excipients,

and where the first pharmaceutical composition is administered first and the second pharmaceutical composition, the third pharmaceutical composition is then administered separately and sequentially in any order.

Embodiment 523. A method of treating a solid tumor in a subject by administering a pharmaceutical combination, wherein the pharmaceutical combination comprises:

a) a first pharmaceutical composition containing a compound of formula (A) or a pharmaceutically acceptable salt thereof, aluminum particles, a buffering agent and one or more pharmaceutically acceptable excipients,

b) a second pharmaceutical composition comprising an immune checkpoint inhibitor and one or more pharmaceutically acceptable excipients, and

c) a third pharmaceutical composition comprising an immune checkpoint inhibitor that is different from the immune checkpoint inhibitor of the second pharmaceutical composition and one or more pharmaceutically acceptable excipients,

and where the first pharmaceutical composition, the second pharmaceutical composition and the third pharmaceutical composition containing the above are administered simultaneously.

Embodiment 524. A method of treating a solid tumor in a subject by administering a pharmaceutical combination, wherein the pharmaceutical combination comprises:

a) a first pharmaceutical composition comprising a compound of formula (A) or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffering agent and one or more pharmaceutically acceptable excipients,

b) a second pharmaceutical composition comprising an immune checkpoint inhibitor and one or more pharmaceutically acceptable excipients, and

c) a third pharmaceutical composition comprising an immune checkpoint inhibitor that is different from the immune checkpoint inhibitor of the second pharmaceutical composition and one or more pharmaceutically acceptable excipients,

and wherein the first pharmaceutical composition, the second pharmaceutical composition, and the third pharmaceutical composition are administered separately and sequentially in any order.

Embodiment 525. A method of treating a solid tumor in a subject by administering a pharmaceutical combination, wherein the pharmaceutical combination comprises:

a) a first pharmaceutical composition comprising a compound of formula (A) or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffering agent and one or more pharmaceutically acceptable excipients,

b) a second pharmaceutical composition comprising an immune checkpoint inhibitor and one or more pharmaceutically acceptable excipients, and

c) a third pharmaceutical composition comprising an immune checkpoint inhibitor that is different from the immune checkpoint inhibitor of the second pharmaceutical composition and one or more pharmaceutically acceptable excipients,

and wherein the first pharmaceutical composition is administered first, and the second pharmaceutical composition and the third pharmaceutical composition are then administered separately and sequentially in any order.

Embodiment 526. A method of treating a solid tumor in a subject by administering a pharmaceutical combination, wherein the pharmaceutical combination comprises:

d) a first pharmaceutical composition containing a compound of formula (A) or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffering agent and one or more pharmaceutically acceptable excipients,

e) a second pharmaceutical composition comprising an immune checkpoint inhibitor and one or more pharmaceutically acceptable excipients, and

f) a third pharmaceutical composition comprising an immune checkpoint inhibitor that is different from the immune checkpoint inhibitor of the second pharmaceutical composition and one or more pharmaceutically acceptable excipients,

and where the first pharmaceutical composition, the second pharmaceutical composition and the third pharmaceutical composition are administered simultaneously.

Embodiment 527. A method of treating a solid tumor in a subject by administering a pharmaceutical combination, wherein the pharmaceutical combination comprises:

a) a first pharmaceutical composition comprising a compound of formula (A) or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffering agent and one or more pharmaceutically acceptable excipients,

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is selected from a CTLA-4 receptor inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor inhibitor, a TIM-3 receptor inhibitor , a BTLA receptor inhibitor, a KIR receptor inhibitor, a PD-L1 inhibitor, or a PD-L2 inhibitor, and

c) a third pharmaceutical composition comprising an immune response checkpoint inhibitor that is different from the immune response checkpoint inhibitor of the second pharmaceutical composition, and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is selected from a CTLA-4 receptor inhibitor, a receptor inhibitor PD-1, LAG-3 receptor inhibitor, TIM-3 receptor inhibitor, BTLA receptor inhibitor, KIR receptor inhibitor, PD-L1 inhibitor or PD-L2 inhibitor,

and wherein the first pharmaceutical composition, the second pharmaceutical composition, and the third pharmaceutical composition are administered separately and sequentially in any order.

Embodiment 528. A method of treating a solid tumor in a subject by administering a pharmaceutical combination, wherein the pharmaceutical combination comprises:

a) a first pharmaceutical composition comprising a compound of formula (A) or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffering agent and one or more pharmaceutically acceptable excipients,

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is selected from a CTLA-4 receptor inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor inhibitor, a TIM-3 receptor inhibitor , a BTLA receptor inhibitor, a KIR receptor inhibitor, a PD-L1 inhibitor, or a PD-L2 inhibitor, and

c) a third pharmaceutical composition comprising an immune response checkpoint inhibitor that is different from the immune response checkpoint inhibitor of the second pharmaceutical composition, and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is selected from a CTLA-4 receptor inhibitor, a receptor inhibitor PD-1, LAG-3 receptor inhibitor, TIM-3 receptor inhibitor, BTLA receptor inhibitor, KIR receptor inhibitor, PD-L1 inhibitor or PD-L2 inhibitor,

and wherein the first pharmaceutical composition is administered first, and the second pharmaceutical composition and the third pharmaceutical composition are then administered separately and sequentially in any order.

Embodiment 529. A method of treating a solid tumor in a subject by administering a pharmaceutical combination, wherein the pharmaceutical combination comprises:

a) a first pharmaceutical composition comprising a compound of formula (A) or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffering agent and one or more pharmaceutically acceptable excipients,

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is selected from a CTLA-4 receptor inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor inhibitor, a TIM-3 receptor inhibitor , a BTLA receptor inhibitor, a KIR receptor inhibitor, a PD-L1 inhibitor, or a PD-L2 inhibitor, and

c) a third pharmaceutical composition comprising an immune response checkpoint inhibitor that is different from the immune response checkpoint inhibitor of the second pharmaceutical composition, and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is selected from a CTLA-4 receptor inhibitor, a receptor inhibitor PD-1, LAG-3 receptor inhibitor, TIM-3 receptor inhibitor, BTLA receptor inhibitor, KIR receptor inhibitor, PD-L1 inhibitor or PD-L2 inhibitor,

and wherein the first pharmaceutical composition, the second pharmaceutical composition and the third pharmaceutical composition containing the other checkpoint inhibitor are administered simultaneously.

Embodiment 530. A method of treating a solid tumor in a subject by administering a pharmaceutical combination, wherein the pharmaceutical combination comprises:

a) a first pharmaceutical composition comprising a compound of formula (A) or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffering agent and one or more pharmaceutically acceptable excipients,

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is selected from a CTLA-4 receptor inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor inhibitor, a TIM-3 receptor inhibitor , a BTLA receptor inhibitor, a KIR receptor inhibitor, a PD-L1 inhibitor, or a PD-L2 inhibitor, and

c) a third pharmaceutical composition comprising an immune response checkpoint inhibitor that is different from the immune response checkpoint inhibitor of the second pharmaceutical composition, and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is selected from a CTLA-4 receptor inhibitor, a receptor inhibitor PD-1, LAG-3 receptor inhibitor, TIM-3 receptor inhibitor, BTLA receptor inhibitor, KIR receptor inhibitor, PD-L1 inhibitor or PD-L2 inhibitor,

and where the first pharmaceutical composition is administered intratumorally, and the second pharmaceutical composition and the third pharmaceutical composition are administered intratumorally, intramuscularly, intradermally, subcutaneously, intravenously, by intraperitoneal injection, by lavage or by infusion, and where the first pharmaceutical composition, the second pharmaceutical composition and the third pharmaceutical composition administered individually and sequentially in any order.

Embodiment 531. A method of treating a solid tumor in a subject by administering a pharmaceutical combination, wherein the pharmaceutical combination comprises:

a) a first pharmaceutical composition comprising a compound of formula (A) or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffering agent and one or more pharmaceutically acceptable excipients,

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is selected from a CTLA-4 receptor inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor inhibitor, a TIM-3 receptor inhibitor , a BTLA receptor inhibitor, a KIR receptor inhibitor, a PD-L1 inhibitor, or a PD-L2 inhibitor, and

c) a third pharmaceutical composition comprising an immune response checkpoint inhibitor that is different from the immune response checkpoint inhibitor of the second pharmaceutical composition, and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is selected from a CTLA-4 receptor inhibitor, a receptor inhibitor PD-1, LAG-3 receptor inhibitor, TIM-3 receptor inhibitor, BTLA receptor inhibitor, KIR receptor inhibitor, PD-L1 inhibitor or PD-L2 inhibitor,

and wherein the first pharmaceutical composition is administered intratumorally first, and the second pharmaceutical composition and the third pharmaceutical composition are then administered via intraperitoneal injection separately and sequentially in any order.

Embodiment 532. A method of treating a solid tumor in a subject by administering a pharmaceutical combination, wherein the pharmaceutical combination comprises:

a) a first pharmaceutical composition comprising a compound of formula (A) or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffering agent and one or more pharmaceutically acceptable excipients,

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is selected from a CTLA-4 receptor inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor inhibitor, a TIM-3 receptor inhibitor , a BTLA receptor inhibitor, a KIR receptor inhibitor, a PD-L1 inhibitor, or a PD-L2 inhibitor, and

c) a third pharmaceutical composition comprising an immune response checkpoint inhibitor that is different from the immune response checkpoint inhibitor of the second pharmaceutical composition, and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is selected from a CTLA-4 receptor inhibitor, a receptor inhibitor PD-1, LAG-3 receptor inhibitor, TIM-3 receptor inhibitor, BTLA receptor inhibitor, KIR receptor inhibitor, PD-L1 inhibitor or PD-L2 inhibitor,

and wherein the first pharmaceutical composition is administered intratumorally, and the second pharmaceutical composition and the third pharmaceutical composition are administered via intraperitoneal injection, and the first pharmaceutical composition, the second pharmaceutical composition, and the third pharmaceutical composition are administered simultaneously.

Embodiment 533. A method of treating a solid tumor in a subject by administering a pharmaceutical combination, wherein the pharmaceutical combination comprises:

a) a first pharmaceutical composition comprising a compound of formula (A) or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffering agent and one or more pharmaceutically acceptable excipients,

b) a second pharmaceutical composition comprising a CTLA-4 receptor inhibitor and one or more pharmaceutically acceptable excipients, and

c) a third pharmaceutical composition containing a PD-L1 inhibitor and one or more pharmaceutically acceptable excipients,

and where the first pharmaceutical composition is administered intratumorally, and the second pharmaceutical composition and the third pharmaceutical composition are administered intratumorally, intramuscularly, intradermally, subcutaneously, intravenously, by intraperitoneal injection, by lavage or by infusion, and where the first pharmaceutical composition, the second pharmaceutical composition and the third pharmaceutical composition administered individually and sequentially in any order.

Embodiment 534. A method of treating a solid tumor in a subject by administering a pharmaceutical combination, wherein the pharmaceutical combination comprises:

a) a first pharmaceutical composition comprising a compound of formula (A) or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffering agent and one or more pharmaceutically acceptable excipients,

b) a second pharmaceutical composition comprising a CTLA-4 receptor inhibitor and one or more pharmaceutically acceptable excipients, and

c) a third pharmaceutical composition containing a PD-L1 inhibitor and one or more pharmaceutically acceptable excipients,

and wherein the first pharmaceutical composition is administered intratumorally first, and the second pharmaceutical composition and the third pharmaceutical composition are then administered via intraperitoneal injection separately and sequentially in any order.

Embodiment 535. A method of treating a solid tumor in a subject by administering a pharmaceutical combination, wherein the pharmaceutical combination comprises:

a) a first pharmaceutical composition comprising a compound of formula (A) or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffering agent and one or more pharmaceutically acceptable excipients,

b) a second pharmaceutical composition comprising a CTLA-4 receptor inhibitor and one or more pharmaceutically acceptable excipients, and

c) a third pharmaceutical composition containing a PD-L1 inhibitor and one or more pharmaceutically acceptable excipients,

and where the first pharmaceutical composition is administered intratumorally, and the second pharmaceutical composition and the third pharmaceutical composition are administered by intraperitoneal injection, and where the first pharmaceutical composition, the second pharmaceutical composition and the third pharmaceutical composition are administered simultaneously.

Embodiment 536. A method of treating a solid tumor in a subject by administering a pharmaceutical combination, wherein the pharmaceutical combination comprises:

a) a first pharmaceutical composition comprising a compound of formula (A) or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffering agent and one or more pharmaceutically acceptable excipients,

b) a second pharmaceutical composition comprising an anti-CTLA-4 antibody and one or more pharmaceutically acceptable excipients, and

c) a third pharmaceutical composition comprising an anti-PD-L1 antibody and one or more pharmaceutically acceptable excipients,

and where the first pharmaceutical composition is administered intratumorally, and the second pharmaceutical composition and the third pharmaceutical composition are administered intratumorally, intramuscularly, intradermally, subcutaneously, intravenously, by intraperitoneal injection, by lavage or by infusion, and where the first pharmaceutical composition, the second pharmaceutical composition and the third pharmaceutical composition administered individually and sequentially in any order.

Embodiment 537. A method of treating a solid tumor in a subject by administering a pharmaceutical combination, wherein the pharmaceutical combination comprises:

a) a first pharmaceutical composition comprising a compound of formula (A) or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffering agent and one or more pharmaceutically acceptable excipients,

b) a second pharmaceutical composition comprising an anti-CTLA-4 antibody and one or more pharmaceutically acceptable excipients, and

c) a third pharmaceutical composition comprising an anti-PD-L1 antibody and one or more pharmaceutically acceptable excipients,

and wherein the first pharmaceutical composition is administered intratumorally first, and the second pharmaceutical composition and the third pharmaceutical composition are then administered via intraperitoneal injection separately and sequentially in any order.

Embodiment 538. A method of treating a solid tumor in a subject by administering a pharmaceutical combination, wherein the pharmaceutical combination comprises:

a) a first pharmaceutical composition comprising a compound of formula (A) or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffering agent and one or more pharmaceutically acceptable excipients,

b) a second pharmaceutical composition comprising an anti-CTLA-4 antibody and one or more pharmaceutically acceptable excipients, and

c) a third pharmaceutical composition comprising an anti-PD-L1 antibody and one or more pharmaceutically acceptable excipients,

and where the first pharmaceutical composition is administered intratumorally, and the second pharmaceutical composition and the third pharmaceutical composition are administered by intraperitoneal injection, and where the first pharmaceutical composition, the second pharmaceutical composition and the third pharmaceutical composition are administered simultaneously.

Embodiment 539. A method of treating a solid tumor in a subject by administering a pharmaceutical combination, wherein the pharmaceutical combination comprises:

a) a first pharmaceutical composition comprising a compound of formula (A) or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffering agent and one or more pharmaceutically acceptable excipients,

b) a second pharmaceutical composition comprising an anti-CTLA-4 antibody and one or more pharmaceutically acceptable excipients, and

c) a third pharmaceutical composition comprising an anti-PD-L1 antibody from Table 2 and one or more pharmaceutically acceptable excipients,

and where the first pharmaceutical composition is administered intratumorally, and the second pharmaceutical composition and the third pharmaceutical composition are administered intratumorally, intramuscularly, intradermally, subcutaneously, intravenously, by intraperitoneal injection, by lavage or by infusion, and where the first pharmaceutical composition, the second pharmaceutical composition and the third pharmaceutical composition administered individually and sequentially in any order.

Embodiment 540. A method of treating a solid tumor in a subject by administering a pharmaceutical combination, wherein the pharmaceutical combination comprises:

a) a first pharmaceutical composition comprising a compound of formula (A) or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffering agent and one or more pharmaceutically acceptable excipients,

b) a second pharmaceutical composition comprising an anti-CTLA-4 antibody and one or more pharmaceutically acceptable excipients, and

c) a third pharmaceutical composition comprising an anti-PD-L1 antibody from Table 2 and one or more pharmaceutically acceptable excipients,

and wherein the first pharmaceutical composition is administered intratumorally first, and the second pharmaceutical composition and the third pharmaceutical composition are then administered via intraperitoneal injection separately and sequentially in any order.

Embodiment 541. A method of treating a solid tumor in a subject by administering a pharmaceutical combination, wherein the pharmaceutical combination comprises:

a) a first pharmaceutical composition comprising a compound of formula (A) or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffering agent and one or more pharmaceutically acceptable excipients,

b) a second pharmaceutical composition comprising an anti-CTLA-4 antibody and one or more pharmaceutically acceptable excipients, and

c) a third pharmaceutical composition comprising an anti-PD-L1 antibody from Table 2 and one or more pharmaceutically acceptable excipients,

and where the first pharmaceutical composition is administered intratumorally, and the second pharmaceutical composition and the third pharmaceutical composition are administered by intraperitoneal injection, and where the first pharmaceutical composition, the second pharmaceutical composition and the third pharmaceutical composition are administered simultaneously.

Embodiment 542. A method of treating a solid tumor in a subject by administering a pharmaceutical combination, wherein the pharmaceutical combination comprises:

a) a first pharmaceutical composition comprising a compound of formula (A) or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffering agent and one or more pharmaceutically acceptable excipients,

b) a second pharmaceutical composition comprising an anti-CTLA-4 antibody and one or more pharmaceutically acceptable excipients, and

c) a third pharmaceutical composition comprising an anti-PD-L1 antibody comprising a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 7 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 17, and one or several pharmaceutically acceptable excipients,

and where the first pharmaceutical composition is administered intratumorally, and the second pharmaceutical composition and the third pharmaceutical composition are administered intratumorally, intramuscularly, intradermally, subcutaneously, intravenously, by intraperitoneal injection, by lavage or by infusion, and where the first pharmaceutical composition, the second pharmaceutical composition and the third pharmaceutical composition administered individually and sequentially in any order.

Embodiment 543. A method of treating a solid tumor in a subject by administering a pharmaceutical combination, wherein the pharmaceutical combination comprises:

a) a first pharmaceutical composition comprising a compound of formula (A) or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffering agent and one or more pharmaceutically acceptable excipients,

b) a second pharmaceutical composition comprising an anti-CTLA-4 antibody and one or more pharmaceutically acceptable excipients, and

c) a third pharmaceutical composition comprising an anti-PD-L1 antibody comprising a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 7 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 17, and one or several pharmaceutically acceptable excipients,

and wherein the first pharmaceutical composition is administered intratumorally first, and the second pharmaceutical composition and the third pharmaceutical composition are then administered via intraperitoneal injection separately and sequentially in any order.

Embodiment 544. A method of treating a solid tumor in a subject by administering a pharmaceutical combination, wherein the pharmaceutical combination comprises:

a) a first pharmaceutical composition comprising a compound of formula (A) or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffering agent and one or more pharmaceutically acceptable excipients,

b) a second pharmaceutical composition comprising an anti-CTLA-4 antibody and one or more pharmaceutically acceptable excipients, and

c) a third pharmaceutical composition comprising an anti-PD-L1 antibody comprising a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 7 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 17, and one or several pharmaceutically acceptable excipients,

and where the first pharmaceutical composition is administered intratumorally, and the second pharmaceutical composition and the third pharmaceutical composition are administered by intraperitoneal injection, and where the first pharmaceutical composition, the second pharmaceutical composition and the third pharmaceutical composition are administered simultaneously.

Embodiment 545. A method of treating a solid tumor in a subject by administering a pharmaceutical combination, wherein the pharmaceutical combination comprises:

a) a first pharmaceutical composition containing 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridine -8-yl) propanoic acid or a pharmaceutically acceptable salt thereof, aluminum particles, a buffering agent and one or more pharmaceutically acceptable excipients,

b) a second pharmaceutical composition comprising an immune checkpoint inhibitor and one or more pharmaceutically acceptable excipients, and

c) a third pharmaceutical composition comprising an immune checkpoint inhibitor that is different from the immune checkpoint inhibitor of the second pharmaceutical composition and one or more pharmaceutically acceptable excipients,

and wherein the first pharmaceutical composition, the second pharmaceutical composition, and the third pharmaceutical composition are administered separately and sequentially in any order.

Embodiment 546. A method of treating a solid tumor in a subject by administering a pharmaceutical combination, wherein the pharmaceutical combination comprises:

a) a first pharmaceutical composition containing 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridine -8-yl) propanoic acid or a pharmaceutically acceptable salt thereof, aluminum particles, a buffering agent and one or more pharmaceutically acceptable excipients,

b) a second pharmaceutical composition comprising an immune checkpoint inhibitor and one or more pharmaceutically acceptable excipients, and

c) a third pharmaceutical composition comprising an immune checkpoint inhibitor that is different from the immune checkpoint inhibitor of the second pharmaceutical composition and one or more pharmaceutically acceptable excipients,

and where the first pharmaceutical composition is administered first and the second pharmaceutical composition, the third pharmaceutical composition is then administered separately and sequentially in any order.

Embodiment 547. A method of treating a solid tumor in a subject by administering a pharmaceutical combination, wherein the pharmaceutical combination comprises:

a) a first pharmaceutical composition containing 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridine -8-yl) propanoic acid or a pharmaceutically acceptable salt thereof, aluminum particles, a buffering agent and one or more pharmaceutically acceptable excipients,

b) a second pharmaceutical composition comprising an immune checkpoint inhibitor and one or more pharmaceutically acceptable excipients, and

c) a third pharmaceutical composition comprising an immune checkpoint inhibitor that is different from the immune checkpoint inhibitor of the second pharmaceutical composition and one or more pharmaceutically acceptable excipients,

and where the first pharmaceutical composition, the second pharmaceutical composition and the third pharmaceutical composition containing the above are administered simultaneously.

Embodiment 548. A method of treating a solid tumor in a subject by administering a pharmaceutical combination, wherein the pharmaceutical combination comprises:

a) a first pharmaceutical composition containing 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridine -8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffering agent and one or more pharmaceutically acceptable excipients,

b) a second pharmaceutical composition comprising an immune checkpoint inhibitor and one or more pharmaceutically acceptable excipients, and

c) a third pharmaceutical composition comprising an immune checkpoint inhibitor that is different from the immune checkpoint inhibitor of the second pharmaceutical composition and one or more pharmaceutically acceptable excipients,

and wherein the first pharmaceutical composition, the second pharmaceutical composition, and the third pharmaceutical composition are administered separately and sequentially in any order.

Embodiment 549. A method of treating a solid tumor in a subject by administering a pharmaceutical combination, wherein the pharmaceutical combination comprises:

a) a first pharmaceutical composition containing 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridine -8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffering agent and one or more pharmaceutically acceptable excipients,

b) a second pharmaceutical composition comprising an immune checkpoint inhibitor and one or more pharmaceutically acceptable excipients, and

c) a third pharmaceutical composition comprising an immune checkpoint inhibitor that is different from the immune checkpoint inhibitor of the second pharmaceutical composition and one or more pharmaceutically acceptable excipients,

and wherein the first pharmaceutical composition is administered first, and the second pharmaceutical composition and the third pharmaceutical composition are then administered separately and sequentially in any order.

Embodiment 550. A method of treating a solid tumor in a subject by administering a pharmaceutical combination, wherein the pharmaceutical combination comprises:

a) a first pharmaceutical composition containing 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridine -8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffering agent and one or more pharmaceutically acceptable excipients,

b) a second pharmaceutical composition comprising an immune checkpoint inhibitor and one or more pharmaceutically acceptable excipients, and

c) a third pharmaceutical composition comprising an immune checkpoint inhibitor that is different from the immune checkpoint inhibitor of the second pharmaceutical composition and one or more pharmaceutically acceptable excipients,

and where the first pharmaceutical composition, the second pharmaceutical composition and the third pharmaceutical composition are administered simultaneously.

Embodiment 551. A method of treating a solid tumor in a subject by administering a pharmaceutical combination, wherein the pharmaceutical combination comprises:

a) a first pharmaceutical composition containing 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridine -8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffering agent and one or more pharmaceutically acceptable excipients,

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is selected from a CTLA-4 receptor inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor inhibitor, a TIM-3 receptor inhibitor , a BTLA receptor inhibitor, a KIR receptor inhibitor, a PD-L1 inhibitor, or a PD-L2 inhibitor, and

c) a third pharmaceutical composition comprising an immune response checkpoint inhibitor that is different from the immune response checkpoint inhibitor of the second pharmaceutical composition, and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is selected from a CTLA-4 receptor inhibitor, a receptor inhibitor PD-1, LAG-3 receptor inhibitor, TIM-3 receptor inhibitor, BTLA receptor inhibitor, KIR receptor inhibitor, PD-L1 inhibitor or PD-L2 inhibitor,

and wherein the first pharmaceutical composition, the second pharmaceutical composition, and the third pharmaceutical composition are administered separately and sequentially in any order.

Embodiment 552. A method of treating a solid tumor in a subject by administering a pharmaceutical combination, wherein the pharmaceutical combination comprises:

a) a first pharmaceutical composition containing 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridine -8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffering agent and one or more pharmaceutically acceptable excipients,

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is selected from a CTLA-4 receptor inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor inhibitor, a TIM-3 receptor inhibitor , a BTLA receptor inhibitor, a KIR receptor inhibitor, a PD-L1 inhibitor, or a PD-L2 inhibitor, and

c) a third pharmaceutical composition comprising an immune response checkpoint inhibitor that is different from the immune response checkpoint inhibitor of the second pharmaceutical composition, and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is selected from a CTLA-4 receptor inhibitor, a receptor inhibitor PD-1, LAG-3 receptor inhibitor, TIM-3 receptor inhibitor, BTLA receptor inhibitor, KIR receptor inhibitor, PD-L1 inhibitor or PD-L2 inhibitor,

and wherein the first pharmaceutical composition is administered first, and the second pharmaceutical composition and the third pharmaceutical composition are then administered separately and sequentially in any order.

Embodiment 553. A method of treating a solid tumor in a subject by administering a pharmaceutical combination, wherein the pharmaceutical combination comprises:

a) a first pharmaceutical composition containing 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridine -8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffering agent and one or more pharmaceutically acceptable excipients,

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is selected from a CTLA-4 receptor inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor inhibitor, a TIM-3 receptor inhibitor , a BTLA receptor inhibitor, a KIR receptor inhibitor, a PD-L1 inhibitor, or a PD-L2 inhibitor, and

c) a third pharmaceutical composition comprising an immune response checkpoint inhibitor that is different from the immune response checkpoint inhibitor of the second pharmaceutical composition, and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is selected from a CTLA-4 receptor inhibitor, a receptor inhibitor PD-1, LAG-3 receptor inhibitor, TIM-3 receptor inhibitor, BTLA receptor inhibitor, KIR receptor inhibitor, PD-L1 inhibitor or PD-L2 inhibitor,

and wherein the first pharmaceutical composition, the second pharmaceutical composition and the third pharmaceutical composition containing the other checkpoint inhibitor are administered simultaneously.

Embodiment 554. A method of treating a solid tumor in a subject by administering a pharmaceutical combination, wherein the pharmaceutical combination comprises:

a) a first pharmaceutical composition containing 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridine -8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffering agent and one or more pharmaceutically acceptable excipients,

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is selected from a CTLA-4 receptor inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor inhibitor, a TIM-3 receptor inhibitor , a BTLA receptor inhibitor, a KIR receptor inhibitor, a PD-L1 inhibitor, or a PD-L2 inhibitor, and

c) a third pharmaceutical composition comprising an immune response checkpoint inhibitor that is different from the immune response checkpoint inhibitor of the second pharmaceutical composition, and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is selected from a CTLA-4 receptor inhibitor, a receptor inhibitor PD-1, LAG-3 receptor inhibitor, TIM-3 receptor inhibitor, BTLA receptor inhibitor, KIR receptor inhibitor, PD-L1 inhibitor or PD-L2 inhibitor,

and where the first pharmaceutical composition is administered intratumorally, and the second pharmaceutical composition and the third pharmaceutical composition are administered intratumorally, intramuscularly, intradermally, subcutaneously, intravenously, by intraperitoneal injection, by lavage or by infusion, and where the first pharmaceutical composition, the second pharmaceutical composition and the third pharmaceutical composition administered individually and sequentially in any order.

Embodiment 555. A method of treating a solid tumor in a subject by administering a pharmaceutical combination, wherein the pharmaceutical combination comprises:

a) a first pharmaceutical composition containing 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridine -8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffering agent and one or more pharmaceutically acceptable excipients,

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is selected from a CTLA-4 receptor inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor inhibitor, a TIM-3 receptor inhibitor , a BTLA receptor inhibitor, a KIR receptor inhibitor, a PD-L1 inhibitor, or a PD-L2 inhibitor, and

c) a third pharmaceutical composition comprising an immune response checkpoint inhibitor that is different from the immune response checkpoint inhibitor of the second pharmaceutical composition, and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is selected from a CTLA-4 receptor inhibitor, a receptor inhibitor PD-1, LAG-3 receptor inhibitor, TIM-3 receptor inhibitor, BTLA receptor inhibitor, KIR receptor inhibitor, PD-L1 inhibitor or PD-L2 inhibitor,

and wherein the first pharmaceutical composition is administered intratumorally first, and the second pharmaceutical composition and the third pharmaceutical composition are then administered via intraperitoneal injection separately and sequentially in any order.

Embodiment 556. A method of treating a solid tumor in a subject by administering a pharmaceutical combination, wherein the pharmaceutical combination comprises:

a) a first pharmaceutical composition containing 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridine -8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffering agent and one or more pharmaceutically acceptable excipients,

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is selected from a CTLA-4 receptor inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor inhibitor, a TIM-3 receptor inhibitor , a BTLA receptor inhibitor, a KIR receptor inhibitor, a PD-L1 inhibitor, or a PD-L2 inhibitor, and

c) a third pharmaceutical composition comprising an immune response checkpoint inhibitor that is different from the immune response checkpoint inhibitor of the second pharmaceutical composition, and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is selected from a CTLA-4 receptor inhibitor, a receptor inhibitor PD-1, LAG-3 receptor inhibitor, TIM-3 receptor inhibitor, BTLA receptor inhibitor, KIR receptor inhibitor, PD-L1 inhibitor or PD-L2 inhibitor,

and wherein the first pharmaceutical composition is administered intratumorally, and the second pharmaceutical composition and the third pharmaceutical composition are administered via intraperitoneal injection, and the first pharmaceutical composition, the second pharmaceutical composition, and the third pharmaceutical composition are administered simultaneously.

Embodiment 557. A method of treating a solid tumor in a subject by administering a pharmaceutical combination, wherein the pharmaceutical combination comprises:

a) a first pharmaceutical composition containing 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridine -8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffering agent and one or more pharmaceutically acceptable excipients,

b) a second pharmaceutical composition comprising a CTLA-4 receptor inhibitor and one or more pharmaceutically acceptable excipients, and

c) a third pharmaceutical composition containing a PD-L1 inhibitor and one or more pharmaceutically acceptable excipients,

and where the first pharmaceutical composition is administered intratumorally, and the second pharmaceutical composition and the third pharmaceutical composition are administered intratumorally, intramuscularly, intradermally, subcutaneously, intravenously, by intraperitoneal injection, by lavage or by infusion, and where the first pharmaceutical composition, the second pharmaceutical composition and the third pharmaceutical composition administered individually and sequentially in any order.

Embodiment 558. A method of treating a solid tumor in a subject by administering a pharmaceutical combination, wherein the pharmaceutical combination comprises:

a) a first pharmaceutical composition containing 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridine -8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffering agent and one or more pharmaceutically acceptable excipients,

b) a second pharmaceutical composition comprising a CTLA-4 receptor inhibitor and one or more pharmaceutically acceptable excipients, and

c) a third pharmaceutical composition containing a PD-L1 inhibitor and one or more pharmaceutically acceptable excipients,

and wherein the first pharmaceutical composition is administered intratumorally first, and the second pharmaceutical composition and the third pharmaceutical composition are then administered via intraperitoneal injection separately and sequentially in any order.

Embodiment 559. A method of treating a solid tumor in a subject by administering a pharmaceutical combination, wherein the pharmaceutical combination comprises:

a) a first pharmaceutical composition containing 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridine -8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffering agent and one or more pharmaceutically acceptable excipients,

b) a second pharmaceutical composition comprising a CTLA-4 receptor inhibitor and one or more pharmaceutically acceptable excipients, and

c) a third pharmaceutical composition containing a PD-L1 inhibitor and one or more pharmaceutically acceptable excipients,

and where the first pharmaceutical composition is administered intratumorally, and the second pharmaceutical composition and the third pharmaceutical composition are administered by intraperitoneal injection, and where the first pharmaceutical composition, the second pharmaceutical composition and the third pharmaceutical composition are administered simultaneously.

Embodiment 560. A method of treating a solid tumor in a subject by administering a pharmaceutical combination, wherein the pharmaceutical combination comprises:

a) a first pharmaceutical composition containing 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridine -8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffering agent and one or more pharmaceutically acceptable excipients,

b) a second pharmaceutical composition comprising an anti-CTLA-4 antibody and one or more pharmaceutically acceptable excipients, and

c) a third pharmaceutical composition comprising an anti-PD-L1 antibody and one or more pharmaceutically acceptable excipients,

and where the first pharmaceutical composition is administered intratumorally, and the second pharmaceutical composition and the third pharmaceutical composition are administered intratumorally, intramuscularly, intradermally, subcutaneously, intravenously, by intraperitoneal injection, by lavage or by infusion, and where the first pharmaceutical composition, the second pharmaceutical composition and the third pharmaceutical composition administered individually and sequentially in any order.

Embodiment 561. A method of treating a solid tumor in a subject by administering a pharmaceutical combination, wherein the pharmaceutical combination comprises:

a) a first pharmaceutical composition containing 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridine -8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffering agent and one or more pharmaceutically acceptable excipients,

b) a second pharmaceutical composition comprising an anti-CTLA-4 antibody and one or more pharmaceutically acceptable excipients, and

c) a third pharmaceutical composition comprising an anti-PD-L1 antibody and one or more pharmaceutically acceptable excipients,

and wherein the first pharmaceutical composition is administered intratumorally first, and the second pharmaceutical composition and the third pharmaceutical composition are then administered via intraperitoneal injection separately and sequentially in any order.

Embodiment 562. A method of treating a solid tumor in a subject by administering a pharmaceutical combination, wherein the pharmaceutical combination comprises:

a) a first pharmaceutical composition containing 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridine -8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffering agent and one or more pharmaceutically acceptable excipients,

b) a second pharmaceutical composition comprising an anti-CTLA-4 antibody and one or more pharmaceutically acceptable excipients, and

c) a third pharmaceutical composition comprising an anti-PD-L1 antibody and one or more pharmaceutically acceptable excipients,

and where the first pharmaceutical composition is administered intratumorally, and the second pharmaceutical composition and the third pharmaceutical composition are administered by intraperitoneal injection, and where the first pharmaceutical composition, the second pharmaceutical composition and the third pharmaceutical composition are administered simultaneously.

Embodiment 563. A method of treating a solid tumor in a subject by administering a pharmaceutical combination, wherein the pharmaceutical combination comprises:

a) a first pharmaceutical composition containing 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridine -8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffering agent and one or more pharmaceutically acceptable excipients,

b) a second pharmaceutical composition comprising an anti-CTLA-4 antibody and one or more pharmaceutically acceptable excipients, and

c) a third pharmaceutical composition comprising an anti-PD-L1 antibody from Table 2 and one or more pharmaceutically acceptable excipients,

and where the first pharmaceutical composition is administered intratumorally, and the second pharmaceutical composition and the third pharmaceutical composition are administered intratumorally, intramuscularly, intradermally, subcutaneously, intravenously, by intraperitoneal injection, by lavage or by infusion, and where the first pharmaceutical composition, the second pharmaceutical composition and the third pharmaceutical composition administered individually and sequentially in any order.

Embodiment 564. A method of treating a solid tumor in a subject by administering a pharmaceutical combination, wherein the pharmaceutical combination comprises:

a) a first pharmaceutical composition containing 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridine -8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffering agent and one or more pharmaceutically acceptable excipients,

b) a second pharmaceutical composition comprising an anti-CTLA-4 antibody and one or more pharmaceutically acceptable excipients, and

c) a third pharmaceutical composition comprising an anti-PD-L1 antibody from Table 2 and one or more pharmaceutically acceptable excipients,

and wherein the first pharmaceutical composition is administered intratumorally first, and the second pharmaceutical composition and the third pharmaceutical composition are then administered via intraperitoneal injection separately and sequentially in any order.

Embodiment 565. A method of treating a solid tumor in a subject by administering a pharmaceutical combination, wherein the pharmaceutical combination comprises:

a) a first pharmaceutical composition containing 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridine -8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffering agent and one or more pharmaceutically acceptable excipients,

b) a second pharmaceutical composition comprising an anti-CTLA-4 antibody and one or more pharmaceutically acceptable excipients, and

c) a third pharmaceutical composition comprising an anti-PD-L1 antibody from Table 2 and one or more pharmaceutically acceptable excipients,

and where the first pharmaceutical composition is administered intratumorally, and the second pharmaceutical composition and the third pharmaceutical composition are administered by intraperitoneal injection, and where the first pharmaceutical composition, the second pharmaceutical composition and the third pharmaceutical composition are administered simultaneously.

Embodiment 566. A method of treating a solid tumor in a subject by administering a pharmaceutical combination, wherein the pharmaceutical combination comprises:

a) a first pharmaceutical composition containing 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridine -8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffering agent and one or more pharmaceutically acceptable excipients,

b) a second pharmaceutical composition comprising an anti-CTLA-4 antibody and one or more pharmaceutically acceptable excipients, and

c) a third pharmaceutical composition comprising an anti-PD-L1 antibody comprising a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 7 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 17, and one or several pharmaceutically acceptable excipients,

and where the first pharmaceutical composition is administered intratumorally, and the second pharmaceutical composition and the third pharmaceutical composition are administered intratumorally, intramuscularly, intradermally, subcutaneously, intravenously, by intraperitoneal injection, by lavage or by infusion, and where the first pharmaceutical composition, the second pharmaceutical composition and the third pharmaceutical composition administered individually and sequentially in any order.

Embodiment 567. A method of treating a solid tumor in a subject by administering a pharmaceutical combination, wherein the pharmaceutical combination comprises:

a) a first pharmaceutical composition containing 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridine -8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffering agent and one or more pharmaceutically acceptable excipients,

b) a second pharmaceutical composition comprising an anti-CTLA-4 antibody and one or more pharmaceutically acceptable excipients, and

c) a third pharmaceutical composition comprising an anti-PD-L1 antibody comprising a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 7 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 17, and one or several pharmaceutically acceptable excipients,

and wherein the first pharmaceutical composition is administered intratumorally first, and the second pharmaceutical composition and the third pharmaceutical composition are then administered via intraperitoneal injection separately and sequentially in any order.

Embodiment 568. A method of treating a solid tumor in a subject by administering a pharmaceutical combination, wherein the pharmaceutical combination comprises:

a) a first pharmaceutical composition containing 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridine -8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffering agent and one or more pharmaceutically acceptable excipients,

b) a second pharmaceutical composition comprising an anti-CTLA-4 antibody and one or more pharmaceutically acceptable excipients, and

c) a third pharmaceutical composition comprising an anti-PD-L1 antibody which comprises a heavy chain variable domain which comprises the amino acid sequence of SEQ ID NO: 7 and a light chain variable domain which comprises the amino acid sequence of SEQ ID NO: 17,

and where the first pharmaceutical composition is administered intratumorally, and the second pharmaceutical composition and the third pharmaceutical composition are administered by intraperitoneal injection, and where the first pharmaceutical composition, the second pharmaceutical composition and the third pharmaceutical composition are administered simultaneously.

Embodiment 569. A method of treating a solid tumor in a subject by administering a pharmaceutical combination, wherein the pharmaceutical combination comprises:

a) a first pharmaceutical composition containing 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridine -8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffering agent and one or more pharmaceutically acceptable excipients,

b) a second pharmaceutical composition comprising a CTLA-4 receptor inhibitor and one or more pharmaceutically acceptable excipients, and

c) a third pharmaceutical composition containing a PD-1 inhibitor and one or more pharmaceutically acceptable excipients,

and where the first pharmaceutical composition is administered intratumorally, and the second pharmaceutical composition and the third pharmaceutical composition are administered intratumorally, intramuscularly, intradermally, subcutaneously, intravenously, by intraperitoneal injection, by lavage or by infusion, and where the first pharmaceutical composition, the second pharmaceutical composition and the third pharmaceutical composition administered individually and sequentially in any order.

Embodiment 570. A method of treating a solid tumor in a subject by administering a pharmaceutical combination, wherein the pharmaceutical combination comprises:

a) a first pharmaceutical composition containing 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridine -8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffering agent and one or more pharmaceutically acceptable excipients,

b) a second pharmaceutical composition comprising a CTLA-4 receptor inhibitor and one or more pharmaceutically acceptable excipients, and

c) a third pharmaceutical composition containing a PD-1 inhibitor and one or more pharmaceutically acceptable excipients,

and wherein the first pharmaceutical composition is administered intratumorally first, and the second pharmaceutical composition and the third pharmaceutical composition are then administered via intraperitoneal injection separately and sequentially in any order.

Embodiment 571. A method of treating a solid tumor in a subject by administering a pharmaceutical combination, wherein the pharmaceutical combination comprises:

a) a first pharmaceutical composition containing 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridine -8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffering agent and one or more pharmaceutically acceptable excipients,

b) a second pharmaceutical composition comprising a CTLA-4 receptor inhibitor and one or more pharmaceutically acceptable excipients, and

c) a third pharmaceutical composition containing a PD-1 inhibitor and one or more pharmaceutically acceptable excipients,

and where the first pharmaceutical composition is administered intratumorally, and the second pharmaceutical composition and the third pharmaceutical composition are administered by intraperitoneal injection, and where the first pharmaceutical composition, the second pharmaceutical composition and the third pharmaceutical composition are administered simultaneously.

Embodiment 572. A method of treating a solid tumor in a subject by administering a pharmaceutical combination, wherein the pharmaceutical combination comprises:

a) a first pharmaceutical composition containing 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridine -8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffering agent and one or more pharmaceutically acceptable excipients,

b) a second pharmaceutical composition comprising an anti-CTLA-4 antibody and one or more pharmaceutically acceptable excipients, and

c) a third pharmaceutical composition containing an anti-PD-1 antibody and one or more pharmaceutically acceptable excipients,

and where the first pharmaceutical composition is administered intratumorally, and the second pharmaceutical composition and the third pharmaceutical composition are administered intratumorally, intramuscularly, intradermally, subcutaneously, intravenously, by intraperitoneal injection, by lavage or by infusion, and where the first pharmaceutical composition, the second pharmaceutical composition and the third pharmaceutical composition administered individually and sequentially in any order.

Embodiment 573. A method of treating a solid tumor in a subject by administering a pharmaceutical combination, wherein the pharmaceutical combination comprises:

a) a first pharmaceutical composition containing 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridine -8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffering agent and one or more pharmaceutically acceptable excipients,

b) a second pharmaceutical composition comprising an anti-CTLA-4 antibody and one or more pharmaceutically acceptable excipients, and

c) a third pharmaceutical composition containing an anti-PD-1 antibody and one or more pharmaceutically acceptable excipients,

and wherein the first pharmaceutical composition is administered intratumorally first, and the second pharmaceutical composition and the third pharmaceutical composition are then administered via intraperitoneal injection separately and sequentially in any order.

Embodiment 574. A method of treating a solid tumor in a subject by administering a pharmaceutical combination, wherein the pharmaceutical combination comprises:

a) a first pharmaceutical composition containing 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridine -8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffering agent and one or more pharmaceutically acceptable excipients,

b) a second pharmaceutical composition comprising an anti-CTLA-4 antibody and one or more pharmaceutically acceptable excipients, and

c) a third pharmaceutical composition containing an anti-PD-1 antibody and one or more pharmaceutically acceptable excipients,

and where the first pharmaceutical composition is administered intratumorally, and the second pharmaceutical composition and the third pharmaceutical composition are administered by intraperitoneal injection, and where the first pharmaceutical composition, the second pharmaceutical composition and the third pharmaceutical composition are administered simultaneously.

Embodiment 575. A method of treating a solid tumor in a subject by administering a pharmaceutical combination, wherein the pharmaceutical combination comprises:

a) a first pharmaceutical composition containing 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridine -8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffering agent and one or more pharmaceutically acceptable excipients,

b) a second pharmaceutical composition comprising an anti-CTLA-4 antibody and one or more pharmaceutically acceptable excipients, and

c) a third pharmaceutical composition comprising an anti-PD-1 antibody from Table 3 and one or more pharmaceutically acceptable excipients,

and where the first pharmaceutical composition is administered intratumorally, and the second pharmaceutical composition and the third pharmaceutical composition are administered intratumorally, intramuscularly, intradermally, subcutaneously, intravenously, by intraperitoneal injection, by lavage or by infusion, and where the first pharmaceutical composition, the second pharmaceutical composition and the third pharmaceutical composition administered individually and sequentially in any order.

Embodiment 576. A method of treating a solid tumor in a subject by administering a pharmaceutical combination, wherein the pharmaceutical combination comprises:

a) a first pharmaceutical composition containing 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridine -8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffering agent and one or more pharmaceutically acceptable excipients,

b) a second pharmaceutical composition comprising an anti-CTLA-4 antibody and one or more pharmaceutically acceptable excipients, and

c) a third pharmaceutical composition comprising an anti-PD-1 antibody from Table 3 and one or more pharmaceutically acceptable excipients,

and wherein the first pharmaceutical composition is administered intratumorally first, and the second pharmaceutical composition and the third pharmaceutical composition are then administered via intraperitoneal injection separately and sequentially in any order.

Embodiment 577. A method of treating a solid tumor in a subject by administering a pharmaceutical combination, wherein the pharmaceutical combination comprises:

a) a first pharmaceutical composition containing 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridine -8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffering agent and one or more pharmaceutically acceptable excipients,

b) a second pharmaceutical composition comprising an anti-CTLA-4 antibody and one or more pharmaceutically acceptable excipients, and

c) a third pharmaceutical composition comprising an anti-PD-1 antibody from Table 3 and one or more pharmaceutically acceptable excipients,

and where the first pharmaceutical composition is administered intratumorally, and the second pharmaceutical composition and the third pharmaceutical composition are administered by intraperitoneal injection, and where the first pharmaceutical composition, the second pharmaceutical composition and the third pharmaceutical composition are administered simultaneously.

Embodiment 578. A method of treating a solid tumor in a subject by administering a pharmaceutical combination, wherein the pharmaceutical combination comprises:

a) a first pharmaceutical composition containing 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridine -8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffering agent and one or more pharmaceutically acceptable excipients,

b) a second pharmaceutical composition comprising an anti-CTLA-4 antibody and one or more pharmaceutically acceptable excipients, and

c) a third pharmaceutical composition comprising an anti-PD-1 antibody comprising a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 27 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 37, and one or several pharmaceutically acceptable excipients,

and where the first pharmaceutical composition is administered intratumorally, and the second pharmaceutical composition and the third pharmaceutical composition are administered intratumorally, intramuscularly, intradermally, subcutaneously, intravenously, by intraperitoneal injection, by lavage or by infusion, and where the first pharmaceutical composition, the second pharmaceutical composition and the third pharmaceutical composition administered individually and sequentially in any order.

Embodiment 579. A method of treating a solid tumor in a subject by administering a pharmaceutical combination, wherein the pharmaceutical combination comprises:

a) a first pharmaceutical composition containing 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridine -8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffering agent and one or more pharmaceutically acceptable excipients,

b) a second pharmaceutical composition comprising an anti-CTLA-4 antibody and one or more pharmaceutically acceptable excipients, and

c) a third pharmaceutical composition comprising an anti-PD-1 antibody comprising a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 27 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 37, and one or several pharmaceutically acceptable excipients,

and wherein the first pharmaceutical composition is administered intratumorally first, and the second pharmaceutical composition and the third pharmaceutical composition are then administered via intraperitoneal injection separately and sequentially in any order.

Embodiment 580. A method of treating a solid tumor in a subject by administering a pharmaceutical combination, wherein the pharmaceutical combination comprises:

a) a first pharmaceutical composition containing 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridine -8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffering agent and one or more pharmaceutically acceptable excipients,

b) a second pharmaceutical composition comprising an anti-CTLA-4 antibody and one or more pharmaceutically acceptable excipients, and

c) a third pharmaceutical composition comprising an anti-PD-1 antibody which comprises a heavy chain variable domain which comprises the amino acid sequence of SEQ ID NO:27 and a light chain variable domain which comprises the amino acid sequence of SEQ ID NO:37,

and where the first pharmaceutical composition is administered intratumorally, and the second pharmaceutical composition and the third pharmaceutical composition are administered by intraperitoneal injection, and where the first pharmaceutical composition, the second pharmaceutical composition and the third pharmaceutical composition are administered simultaneously.

Embodiment 581. A method of treating a solid tumor in a subject by administering a pharmaceutical combination, wherein the pharmaceutical combination comprises:

a) a first pharmaceutical composition comprising a compound of formula (A) or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffering agent and one or more pharmaceutically acceptable excipients,

b) a second pharmaceutical composition comprising ipilimumab and one or more pharmaceutically acceptable excipients, and

c) a third pharmaceutical composition comprising an anti-PD-L1 antibody and one or more pharmaceutically acceptable excipients,

and where the first pharmaceutical composition is administered intratumorally, and the second pharmaceutical composition and the third pharmaceutical composition are administered intratumorally, intramuscularly, intradermally, subcutaneously, intravenously, by intraperitoneal injection, by lavage or by infusion, and where the first pharmaceutical composition, the second pharmaceutical composition and the third pharmaceutical composition administered individually and sequentially in any order.

Embodiment 582. A method of treating a solid tumor in a subject by administering a pharmaceutical combination, wherein the pharmaceutical combination comprises:

a) a first pharmaceutical composition comprising a compound of formula (A) or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffering agent and one or more pharmaceutically acceptable excipients,

b) a second pharmaceutical composition comprising ipilimumab and one or more pharmaceutically acceptable excipients, and

c) a third pharmaceutical composition comprising an anti-PD-L1 antibody and one or more pharmaceutically acceptable excipients,

and wherein the first pharmaceutical composition is administered intratumorally first, and the second pharmaceutical composition and the third pharmaceutical composition are then administered via intraperitoneal injection separately and sequentially in any order.

Embodiment 583. A method of treating a solid tumor in a subject by administering a pharmaceutical combination, wherein the pharmaceutical combination comprises:

a) a first pharmaceutical composition comprising a compound of formula (A) or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffering agent and one or more pharmaceutically acceptable excipients,

b) a second pharmaceutical composition comprising ipilimumab and one or more pharmaceutically acceptable excipients, and

c) a third pharmaceutical composition comprising an anti-PD-L1 antibody and one or more pharmaceutically acceptable excipients,

and where the first pharmaceutical composition is administered intratumorally, and the second pharmaceutical composition and the third pharmaceutical composition are administered by intraperitoneal injection, and where the first pharmaceutical composition, the second pharmaceutical composition and the third pharmaceutical composition are administered simultaneously.

Embodiment 584. A method of treating a solid tumor in a subject by administering a pharmaceutical combination, wherein the pharmaceutical combination comprises:

a) a first pharmaceutical composition containing 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridine -8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffering agent and one or more pharmaceutically acceptable excipients,

b) a second pharmaceutical composition comprising ipilimumab and one or more pharmaceutically acceptable excipients, and

c) a third pharmaceutical composition comprising an anti-PD-L1 antibody and one or more pharmaceutically acceptable excipients,

and where the first pharmaceutical composition is administered intratumorally, and the second pharmaceutical composition and the third pharmaceutical composition are administered intratumorally, intramuscularly, intradermally, subcutaneously, intravenously, by intraperitoneal injection, by lavage or by infusion, and where the first pharmaceutical composition, the second pharmaceutical composition and the third pharmaceutical composition administered individually and sequentially in any order.

Embodiment 585. A method of treating a solid tumor in a subject by administering a pharmaceutical combination, wherein the pharmaceutical combination comprises:

a) a first pharmaceutical composition containing 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridine -8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffering agent and one or more pharmaceutically acceptable excipients,

b) a second pharmaceutical composition comprising ipilimumab and one or more pharmaceutically acceptable excipients, and

c) a third pharmaceutical composition comprising an anti-PD-L1 antibody and one or more pharmaceutically acceptable excipients,

and wherein the first pharmaceutical composition is administered intratumorally first, and the second pharmaceutical composition and the third pharmaceutical composition are then administered via intraperitoneal injection separately and sequentially in any order.

Embodiment 586. A method of treating a solid tumor in a subject by administering a pharmaceutical combination, wherein the pharmaceutical combination comprises:

a) a first pharmaceutical composition containing 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridine -8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffering agent and one or more pharmaceutically acceptable excipients,

b) a second pharmaceutical composition comprising ipilimumab and one or more pharmaceutically acceptable excipients, and

c) a third pharmaceutical composition comprising an anti-PD-L1 antibody and one or more pharmaceutically acceptable excipients,

and where the first pharmaceutical composition is administered intratumorally, and the second pharmaceutical composition and the third pharmaceutical composition are administered by intraperitoneal injection, and where the first pharmaceutical composition, the second pharmaceutical composition and the third pharmaceutical composition are administered simultaneously.

Embodiment 587. A method of treating a solid tumor in a subject by administering a pharmaceutical combination, wherein the pharmaceutical combination comprises:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 0.5-2 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy )ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles, characterized by an aluminum content of 1-4 mg/ml, 5-100 mM tris buffer and 5-10% (w/v) mannitol, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is selected from a CTLA-4 receptor inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor inhibitor, a TIM-3 receptor inhibitor , a BTLA receptor inhibitor, a KIR receptor inhibitor, a PD-L1 inhibitor, or a PD-L2 inhibitor, and

c) a third pharmaceutical composition comprising an immune response checkpoint inhibitor that is different from the immune response checkpoint inhibitor of the second pharmaceutical composition, and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is selected from a CTLA-4 receptor inhibitor, a receptor inhibitor PD-1, LAG-3 receptor inhibitor, TIM-3 receptor inhibitor, BTLA receptor inhibitor, KIR receptor inhibitor, PD-L1 inhibitor, or PD-L2 inhibitor.

Embodiment 588. A method of treating a solid tumor in a subject by administering a pharmaceutical combination, wherein the pharmaceutical combination comprises:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 0.5-2 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy )ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles, characterized by an aluminum content of 1-4 mg/ml, 5-100 mM Tris buffer and 5-10% (w/v) sucrose, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is selected from a CTLA-4 receptor inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor inhibitor, a TIM-3 receptor inhibitor , a BTLA receptor inhibitor, a KIR receptor inhibitor, a PD-L1 inhibitor, or a PD-L2 inhibitor, and

c) a third pharmaceutical composition comprising an immune response checkpoint inhibitor that is different from the immune response checkpoint inhibitor of the second pharmaceutical composition, and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is selected from a CTLA-4 receptor inhibitor, a receptor inhibitor PD-1, LAG-3 receptor inhibitor, TIM-3 receptor inhibitor, BTLA receptor inhibitor, KIR receptor inhibitor, PD-L1 inhibitor, or PD-L2 inhibitor.

Embodiment 589. A method of treating a solid tumor in a subject by administering a pharmaceutical combination, wherein the pharmaceutical combination comprises:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 0.5-2 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy )ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles, characterized by an aluminum content of 1-4 mg/ml, 5-50 mM tris buffer and 5-10% (w/v) mannitol, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is selected from a CTLA-4 receptor inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor inhibitor, a TIM-3 receptor inhibitor , a BTLA receptor inhibitor, a KIR receptor inhibitor, a PD-L1 inhibitor, or a PD-L2 inhibitor, and

c) a third pharmaceutical composition comprising an immune response checkpoint inhibitor that is different from the immune response checkpoint inhibitor of the second pharmaceutical composition, and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is selected from a CTLA-4 receptor inhibitor, a receptor inhibitor PD-1, LAG-3 receptor inhibitor, TIM-3 receptor inhibitor, BTLA receptor inhibitor, KIR receptor inhibitor, PD-L1 inhibitor, or PD-L2 inhibitor.

Embodiment 590. A method of treating a solid tumor in a subject by administering a pharmaceutical combination, wherein the pharmaceutical combination comprises:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 0.5-2 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy )ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles, characterized by an aluminum content of 1-4 mg/ml, 5-50 mM Tris buffer and 5-10% (w/v) sucrose, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is selected from a CTLA-4 receptor inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor inhibitor, a TIM-3 receptor inhibitor , a BTLA receptor inhibitor, a KIR receptor inhibitor, a PD-L1 inhibitor, or a PD-L2 inhibitor, and

c) a third pharmaceutical composition comprising an immune response checkpoint inhibitor that is different from the immune response checkpoint inhibitor of the second pharmaceutical composition, and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is selected from a CTLA-4 receptor inhibitor, a receptor inhibitor PD-1, LAG-3 receptor inhibitor, TIM-3 receptor inhibitor, BTLA receptor inhibitor, KIR receptor inhibitor, PD-L1 inhibitor, or PD-L2 inhibitor.

Embodiment 591. A method of treating a solid tumor in a subject by administering a pharmaceutical combination, wherein the pharmaceutical combination comprises:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 0.5-2 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy )ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles characterized by an aluminum content of 1-4 mg/ml, 5-20 mM tris buffer and 5-10% (w/v) mannitol, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is selected from a CTLA-4 receptor inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor inhibitor, a TIM-3 receptor inhibitor , a BTLA receptor inhibitor, a KIR receptor inhibitor, a PD-L1 inhibitor, or a PD-L2 inhibitor, and

c) a third pharmaceutical composition comprising an immune response checkpoint inhibitor that is different from the immune response checkpoint inhibitor of the second pharmaceutical composition and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is selected from a CTLA-4 receptor inhibitor, a receptor inhibitor PD-1, LAG-3 receptor inhibitor, TIM-3 receptor inhibitor, BTLA receptor inhibitor, KIR receptor inhibitor, PD-L1 inhibitor, or PD-L2 inhibitor.

Embodiment 592. A method of treating a solid tumor in a subject by administering a pharmaceutical combination, wherein the pharmaceutical combination comprises:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 0.5-2 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy )ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles characterized by an aluminum content of 1-4 mg/ml, 5-20 mM Tris buffer and 5-10% (w/v) sucrose, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is selected from a CTLA-4 receptor inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor inhibitor, a TIM-3 receptor inhibitor , a BTLA receptor inhibitor, a KIR receptor inhibitor, a PD-L1 inhibitor, or a PD-L2 inhibitor, and

c) a third pharmaceutical composition comprising an immune response checkpoint inhibitor that is different from the immune response checkpoint inhibitor of the second pharmaceutical composition, and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is selected from a CTLA-4 receptor inhibitor, a receptor inhibitor PD-1, LAG-3 receptor inhibitor, TIM-3 receptor inhibitor, BTLA receptor inhibitor, KIR receptor inhibitor, PD-L1 inhibitor, or PD-L2 inhibitor.

Embodiment 593. A method of treating a solid tumor in a subject by administering a pharmaceutical combination, wherein the pharmaceutical combination comprises:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 1 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)- 2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles characterized by an aluminum content of 2 mg/ml, 16 mM Tris buffer and 7.5% (weight/volume) mannitol, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is selected from a CTLA-4 receptor inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor inhibitor, a TIM-3 receptor inhibitor , a BTLA receptor inhibitor, a KIR receptor inhibitor, a PD-L1 inhibitor, or a PD-L2 inhibitor, and

c) a third pharmaceutical composition comprising an immune response checkpoint inhibitor that is different from the immune response checkpoint inhibitor of the second pharmaceutical composition, and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is selected from a CTLA-4 receptor inhibitor, a receptor inhibitor PD-1, LAG-3 receptor inhibitor, TIM-3 receptor inhibitor, BTLA receptor inhibitor, KIR receptor inhibitor, PD-L1 inhibitor, or PD-L2 inhibitor.

Embodiment 594. A method of treating a solid tumor in a subject by administering a pharmaceutical combination, wherein the pharmaceutical combination comprises:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 1 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)- 2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles characterized by an aluminum content of 2 mg/ml, 16 mM Tris buffer and 7.5% (weight/volume) sucrose, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is selected from a CTLA-4 receptor inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor inhibitor, a TIM-3 receptor inhibitor , a BTLA receptor inhibitor, a KIR receptor inhibitor, a PD-L1 inhibitor, or a PD-L2 inhibitor, and

c) a third pharmaceutical composition comprising an immune response checkpoint inhibitor that is different from the immune response checkpoint inhibitor of the second pharmaceutical composition, and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is selected from a CTLA-4 receptor inhibitor, a receptor inhibitor PD-1, LAG-3 receptor inhibitor, TIM-3 receptor inhibitor, BTLA receptor inhibitor, KIR receptor inhibitor, PD-L1 inhibitor, or PD-L2 inhibitor.

Embodiment 595. A method of treating a solid tumor in a subject by administering a pharmaceutical combination, wherein the pharmaceutical combination comprises:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 1 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)- 2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles characterized by an aluminum content of 2 mg/ml, 5 mM Tris buffer and 8.25% (weight/volume) mannitol, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is selected from a CTLA-4 receptor inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor inhibitor, a TIM-3 receptor inhibitor , a BTLA receptor inhibitor, a KIR receptor inhibitor, a PD-L1 inhibitor, or a PD-L2 inhibitor, and

c) a third pharmaceutical composition comprising an immune response checkpoint inhibitor that is different from the immune response checkpoint inhibitor of the second pharmaceutical composition, and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is selected from a CTLA-4 receptor inhibitor, a receptor inhibitor PD-1, LAG-3 receptor inhibitor, TIM-3 receptor inhibitor, BTLA receptor inhibitor, KIR receptor inhibitor, PD-L1 inhibitor, or PD-L2 inhibitor.

Embodiment 596. A method of treating a solid tumor in a subject by administering a pharmaceutical combination, wherein the pharmaceutical combination comprises:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 1 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)- 2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles characterized by an aluminum content of 2 mg/ml, 5 mM Tris buffer and 8.25% (weight/volume) sucrose, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is selected from a CTLA-4 receptor inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor inhibitor, a TIM-3 receptor inhibitor , a BTLA receptor inhibitor, a KIR receptor inhibitor, a PD-L1 inhibitor, or a PD-L2 inhibitor, and

c) a third pharmaceutical composition comprising an immune response checkpoint inhibitor that is different from the immune response checkpoint inhibitor of the second pharmaceutical composition, and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is selected from a CTLA-4 receptor inhibitor, a receptor inhibitor PD-1, LAG-3 receptor inhibitor, TIM-3 receptor inhibitor, BTLA receptor inhibitor, KIR receptor inhibitor, PD-L1 inhibitor, or PD-L2 inhibitor.

Embodiment 597. A method of treating a solid tumor in a subject by administering a pharmaceutical combination, wherein the pharmaceutical combination comprises:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 0.5-2 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy )ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles, characterized by an aluminum content of 1-4 mg/ml, 5-100 mM tris buffer and 5-10% (w/v) mannitol, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-PD-L1 antibody, and

c) a third pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is selected from a CTLA-4 receptor inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor inhibitor, a TIM-3 receptor inhibitor , a BTLA receptor inhibitor, a KIR receptor inhibitor, a PD-L1 inhibitor, or a PD-L2 inhibitor.

Embodiment 598. A method of treating a solid tumor in a subject by administering a pharmaceutical combination, wherein the pharmaceutical combination comprises:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 0.5-2 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy )ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles, characterized by an aluminum content of 1-4 mg/ml, 5-100 mM Tris buffer and 5-10% (w/v) sucrose, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-PD-L1 antibody, and

c) a third pharmaceutical composition comprising an immune response checkpoint inhibitor that is different from the immune response checkpoint inhibitor of the second pharmaceutical composition, and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is selected from a CTLA-4 receptor inhibitor, a receptor inhibitor PD-1, LAG-3 receptor inhibitor, TIM-3 receptor inhibitor, BTLA receptor inhibitor, KIR receptor inhibitor, PD-L1 inhibitor, or PD-L2 inhibitor.

Embodiment 599. A method of treating a solid tumor in a subject by administering a pharmaceutical combination, wherein the pharmaceutical combination comprises:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 0.5-2 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy )ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles, characterized by an aluminum content of 1-4 mg/ml, 5-50 mM tris buffer and 5-10% (w/v) mannitol, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-PD-L1 antibody, and

c) a third pharmaceutical composition comprising an immune response checkpoint inhibitor that is different from the immune response checkpoint inhibitor of the second pharmaceutical composition, and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is selected from a CTLA-4 receptor inhibitor, a receptor inhibitor PD-1, LAG-3 receptor inhibitor, TIM-3 receptor inhibitor, BTLA receptor inhibitor, KIR receptor inhibitor, PD-L1 inhibitor, or PD-L2 inhibitor.

Embodiment 600. A method of treating a solid tumor in a subject by administering a pharmaceutical combination, wherein the pharmaceutical combination comprises:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 0.5-2 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy )ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles, characterized by an aluminum content of 1-4 mg/ml, 5-50 mM Tris buffer and 5-10% (w/v) sucrose, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-PD-L1 antibody, and

c) a third pharmaceutical composition comprising an immune response checkpoint inhibitor that is different from the immune response checkpoint inhibitor of the second pharmaceutical composition, and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is selected from a CTLA-4 receptor inhibitor, a receptor inhibitor PD-1, LAG-3 receptor inhibitor, TIM-3 receptor inhibitor, BTLA receptor inhibitor, KIR receptor inhibitor, PD-L1 inhibitor, or PD-L2 inhibitor.

Embodiment 601. A method of treating a solid tumor in a subject by administering a pharmaceutical combination, wherein the pharmaceutical combination comprises:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 0.5-2 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy )ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles characterized by an aluminum content of 1-4 mg/ml, 5-20 mM tris buffer and 5-10% (w/v) mannitol, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-PD-L1 antibody, and

c) a third pharmaceutical composition comprising an immune response checkpoint inhibitor that is different from the immune response checkpoint inhibitor of the second pharmaceutical composition, and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is selected from a CTLA-4 receptor inhibitor, a receptor inhibitor PD-1, LAG-3 receptor inhibitor, TIM-3 receptor inhibitor, BTLA receptor inhibitor, KIR receptor inhibitor, PD-L1 inhibitor, or PD-L2 inhibitor.

Embodiment 602. A method of treating a solid tumor in a subject by administering a pharmaceutical combination, wherein the pharmaceutical combination comprises:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 0.5-2 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy )ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles characterized by an aluminum content of 1-4 mg/ml, 5-20 mM Tris buffer and 5-10% (w/v) sucrose, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-PD-L1 antibody, and

c) a third pharmaceutical composition comprising an immune response checkpoint inhibitor that is different from the immune response checkpoint inhibitor of the second pharmaceutical composition, and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is selected from a CTLA-4 receptor inhibitor, a receptor inhibitor PD-1, LAG-3 receptor inhibitor, TIM-3 receptor inhibitor, BTLA receptor inhibitor, KIR receptor inhibitor, PD-L1 inhibitor, or PD-L2 inhibitor.

Embodiment 603. A method of treating a solid tumor in a subject by administering a pharmaceutical combination, wherein the pharmaceutical combination comprises:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 1 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)- 2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles characterized by an aluminum content of 2 mg/ml, 16 mM Tris buffer and 7.5% (weight/volume) mannitol, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-PD-L1 antibody, and

c) a third pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-CTLA-4 antibody.

Embodiment 604. A method of treating a solid tumor in a subject by administering a pharmaceutical combination, wherein the pharmaceutical combination comprises:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 1 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)- 2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles characterized by an aluminum content of 2 mg/ml, 16 mM Tris buffer and 7.5% (weight/volume) sucrose, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-PD-L1 antibody, and

c) a third pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-CTLA-4 antibody.

Embodiment 605. A method of treating a solid tumor in a subject by administering a pharmaceutical combination, wherein the pharmaceutical combination comprises:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 1 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)- 2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles characterized by an aluminum content of 2 mg/ml, 5 mM Tris buffer and 8.25% (weight/volume) mannitol, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-PD-L1 antibody, and

c) a third pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-CTLA-4 antibody.

Embodiment 606. A method of treating a solid tumor in a subject by administering a pharmaceutical combination, wherein the pharmaceutical combination comprises:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 1 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)- 2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles characterized by an aluminum content of 2 mg/ml, 5 mM Tris buffer and 8.25% (weight/volume) sucrose, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-PD-L1 antibody, and

c) a third pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-CTLA-4 antibody.

Embodiment 607. The method according to any of embodiments 587-606, wherein the anti-PD-L1 antibody is an anti-PD-L1 antibody from Table 2.

Embodiment 608. The method according to any one of embodiments 587-606, wherein the anti-PD-L1 antibody is an anti-PD-L1 antibody comprising a heavy chain variable domain that comprises the amino acid sequence of SEQ ID NO: 7 and the variable domain light chain which contains the amino acid sequence of SEQ ID NO: 17.

Embodiment 609. A method of treating a solid tumor in a subject by administering a pharmaceutical combination, wherein the pharmaceutical combination comprises:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 0.5-2 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy )ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles, characterized by an aluminum content of 1-4 mg/ml, 5-100 mM tris buffer and 5-10% (w/v) mannitol, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-PD-1 antibody, and

c) a third pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is selected from a CTLA-4 receptor inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor inhibitor, a TIM-3 receptor inhibitor , a BTLA receptor inhibitor, a KIR receptor inhibitor, a PD-L1 inhibitor, or a PD-L2 inhibitor.

Embodiment 610. A method of treating a solid tumor in a subject by administering a pharmaceutical combination, wherein the pharmaceutical combination comprises:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 0.5-2 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy )ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles, characterized by an aluminum content of 1-4 mg/ml, 5-100 mM Tris buffer and 5-10% (w/v) sucrose, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-PD-1 antibody, and

c) a third pharmaceutical composition comprising an immune response checkpoint inhibitor that is different from the immune response checkpoint inhibitor of the second pharmaceutical composition, and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is selected from a CTLA-4 receptor inhibitor, a receptor inhibitor PD-1, LAG-3 receptor inhibitor, TIM-3 receptor inhibitor, BTLA receptor inhibitor, KIR receptor inhibitor, PD-L1 inhibitor, or PD-L2 inhibitor.

Embodiment 611. A method of treating a solid tumor in a subject by administering a pharmaceutical combination, wherein the pharmaceutical combination comprises:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 0.5-2 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy )ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles, characterized by an aluminum content of 1-4 mg/ml, 5-50 mM tris buffer and 5-10% (w/v) mannitol, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-PD-1 antibody, and

c) a third pharmaceutical composition comprising an immune response checkpoint inhibitor that is different from the immune response checkpoint inhibitor of the second pharmaceutical composition, and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is selected from a CTLA-4 receptor inhibitor, a receptor inhibitor PD-1, LAG-3 receptor inhibitor, TIM-3 receptor inhibitor, BTLA receptor inhibitor, KIR receptor inhibitor, PD-L1 inhibitor, or PD-L2 inhibitor.

Embodiment 612. A method of treating a solid tumor in a subject by administering a pharmaceutical combination, wherein the pharmaceutical combination comprises:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 0.5-2 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy )ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles, characterized by an aluminum content of 1-4 mg/ml, 5-50 mM Tris buffer and 5-10% (w/v) sucrose, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-PD-1 antibody, and

c) a third pharmaceutical composition comprising an immune response checkpoint inhibitor that is different from the immune response checkpoint inhibitor of the second pharmaceutical composition, and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is selected from a CTLA-4 receptor inhibitor, a receptor inhibitor PD-1, LAG-3 receptor inhibitor, TIM-3 receptor inhibitor, BTLA receptor inhibitor, KIR receptor inhibitor, PD-L1 inhibitor, or PD-L2 inhibitor.

Embodiment 613. A method of treating a solid tumor in a subject by administering a pharmaceutical combination, wherein the pharmaceutical combination comprises:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 0.5-2 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy )ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles characterized by an aluminum content of 1-4 mg/ml, 5-20 mM tris buffer and 5-10% (w/v) mannitol, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-PD-1 antibody, and

c) a third pharmaceutical composition comprising an immune response checkpoint inhibitor that is different from the immune response checkpoint inhibitor of the second pharmaceutical composition, and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is selected from a CTLA-4 receptor inhibitor, a receptor inhibitor PD-1, LAG-3 receptor inhibitor, TIM-3 receptor inhibitor, BTLA receptor inhibitor, KIR receptor inhibitor, PD-L1 inhibitor, or PD-L2 inhibitor.

Embodiment 614. A method of treating a solid tumor in a subject by administering a pharmaceutical combination, wherein the pharmaceutical combination comprises:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 0.5-2 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy )ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles characterized by an aluminum content of 1-4 mg/ml, 5-20 mM Tris buffer and 5-10% (w/v) sucrose, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-PD-1 antibody, and

c) a third pharmaceutical composition comprising an immune response checkpoint inhibitor that is different from the immune response checkpoint inhibitor of the second pharmaceutical composition, and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is selected from a CTLA-4 receptor inhibitor, a receptor inhibitor PD-1, LAG-3 receptor inhibitor, TIM-3 receptor inhibitor, BTLA receptor inhibitor, KIR receptor inhibitor, PD-L1 inhibitor, or PD-L2 inhibitor.

Embodiment 615. A method of treating a solid tumor in a subject by administering a pharmaceutical combination, wherein the pharmaceutical combination comprises:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 1 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)- 2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles characterized by an aluminum content of 2 mg/ml, 16 mM Tris buffer and 7.5% (weight/volume) mannitol, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-PD-1 antibody, and

c) a third pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-CTLA-4 antibody.

Embodiment 616. A method of treating a solid tumor in a subject by administering a pharmaceutical combination, wherein the pharmaceutical combination comprises:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 1 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)- 2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles characterized by an aluminum content of 2 mg/ml, 16 mM Tris buffer and 7.5% (weight/volume) sucrose, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-PD-1 antibody, and

c) a third pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-CTLA-4 antibody.

Embodiment 617. A method of treating a solid tumor in a subject by administering a pharmaceutical combination, wherein the pharmaceutical combination comprises:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 1 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)- 2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles characterized by an aluminum content of 2 mg/ml, 5 mM Tris buffer and 8.25% (weight/volume) mannitol, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-PD-1 antibody, and

c) a third pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-CTLA-4 antibody.

Embodiment 618. A method of treating a solid tumor in a subject by administering a pharmaceutical combination, wherein the pharmaceutical combination comprises:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 1 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)- 2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles characterized by an aluminum content of 2 mg/ml, 5 mM Tris buffer and 8.25% (weight/volume) sucrose, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-PD-1 antibody, and

c) a third pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-CTLA-4 antibody.

Embodiment 619. The method according to any of embodiments 609-618, wherein the anti-PD-1 antibody is an anti-PD-1 antibody from Table 3.

Embodiment 620. The method according to any one of embodiments 609-618, wherein the anti-PD1 antibody is an anti-PD-1 antibody comprising a heavy chain variable domain that comprises the amino acid sequence of SEQ ID NO: 27 and a light chain variable domain , which contains the amino acid sequence under SEQ ID NO: 37.

Embodiment 621. The method according to any one of embodiments 587-620, wherein the first pharmaceutical composition is administered intratumorally, and the second pharmaceutical composition and the third pharmaceutical composition are administered intratumorally, intramuscularly, intradermally, subcutaneously, intravenously, via intraperitoneal injection, via lavage, or via infusion.

Embodiment 622. The method according to any one of embodiments 587-620, wherein the first pharmaceutical composition is administered intratumorally and the second pharmaceutical composition and the third pharmaceutical composition are administered via intraperitoneal injection.

Embodiment 623. Use of a pharmaceutical combination according to any of Embodiments 295-352 for the treatment of a solid tumor.

Embodiment 624 Use of a pharmaceutical combination for the treatment of a solid tumor, wherein the pharmaceutical combination comprises:

a) a first pharmaceutical composition containing a compound of formula (A) or a pharmaceutically acceptable salt thereof, aluminum particles, a buffering agent and one or more pharmaceutically acceptable excipients,

b) a second pharmaceutical composition comprising an immune checkpoint inhibitor and one or more pharmaceutically acceptable excipients, and

c) a third pharmaceutical composition comprising an immune checkpoint inhibitor that is different from the immune checkpoint inhibitor of the second pharmaceutical composition and one or more pharmaceutically acceptable excipients.

Embodiment 625 Use of a pharmaceutical combination for the treatment of a solid tumor, wherein the pharmaceutical combination contains:

a) a first pharmaceutical composition comprising a compound of formula (A) or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffering agent and one or more pharmaceutically acceptable excipients,

b) a second pharmaceutical composition comprising an immune checkpoint inhibitor and one or more pharmaceutically acceptable excipients, and

c) a third pharmaceutical composition comprising an immune checkpoint inhibitor that is different from the immune checkpoint inhibitor of the second pharmaceutical composition and one or more pharmaceutically acceptable excipients.

Embodiment 626 Use of a pharmaceutical combination for the treatment of a solid tumor, wherein the pharmaceutical combination comprises:

a) a first pharmaceutical composition comprising a compound of formula (A) or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffering agent and one or more pharmaceutically acceptable excipients,

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is selected from a CTLA-4 receptor inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor inhibitor, a TIM-3 receptor inhibitor , a BTLA receptor inhibitor, a KIR receptor inhibitor, a PD-L1 inhibitor, or a PD-L2 inhibitor, and

c) a third pharmaceutical composition comprising an immune response checkpoint inhibitor that is different from the immune response checkpoint inhibitor of the second pharmaceutical composition, and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is selected from a CTLA-4 receptor inhibitor, a receptor inhibitor PD-1, LAG-3 receptor inhibitor, TIM-3 receptor inhibitor, BTLA receptor inhibitor, KIR receptor inhibitor, PD-L1 inhibitor, or PD-L2 inhibitor.

Embodiment 627. Use of a pharmaceutical combination for the treatment of a solid tumor, wherein the pharmaceutical combination contains:

a) a first pharmaceutical composition comprising a compound of formula (A) or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffering agent and one or more pharmaceutically acceptable excipients,

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is selected from a CTLA-4 receptor inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor inhibitor, a TIM-3 receptor inhibitor , a BTLA receptor inhibitor, a KIR receptor inhibitor, a PD-L1 inhibitor, or a PD-L2 inhibitor, and

c) a third pharmaceutical composition comprising an immune response checkpoint inhibitor that is different from the immune response checkpoint inhibitor of the second pharmaceutical composition, and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is selected from a CTLA-4 receptor inhibitor, a receptor inhibitor PD-1, LAG-3 receptor inhibitor, TIM-3 receptor inhibitor, BTLA receptor inhibitor, KIR receptor inhibitor, PD-L1 inhibitor, or PD-L2 inhibitor.

Embodiment 628. Use of a pharmaceutical combination for the treatment of a solid tumor, wherein the pharmaceutical combination contains:

a) a first pharmaceutical composition comprising a compound of formula (A) or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffering agent and one or more pharmaceutically acceptable excipients,

b) a second pharmaceutical composition comprising a CTLA-4 receptor inhibitor and one or more pharmaceutically acceptable excipients, and

c) a third pharmaceutical composition containing a PD-L1 inhibitor and one or more pharmaceutically acceptable excipients.

Embodiment 629 Use of a pharmaceutical combination for the treatment of a solid tumor, wherein the pharmaceutical combination contains:

a) a first pharmaceutical composition comprising a compound of formula (A) or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffering agent and one or more pharmaceutically acceptable excipients,

b) a second pharmaceutical composition comprising an anti-CTLA-4 antibody and one or more pharmaceutically acceptable excipients, and

c) a third pharmaceutical composition comprising an anti-PD-L1 antibody and one or more pharmaceutically acceptable excipients.

Embodiment 630. Use of a pharmaceutical combination for the treatment of a solid tumor, wherein the pharmaceutical combination contains:

a) a first pharmaceutical composition comprising a compound of formula (A) or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffering agent and one or more pharmaceutically acceptable excipients,

b) a second pharmaceutical composition comprising an anti-CTLA-4 antibody and one or more pharmaceutically acceptable excipients, and

c) a third pharmaceutical composition comprising an anti-PD-L1 antibody from Table 2 and one or more pharmaceutically acceptable excipients.

Embodiment 631. Use of a pharmaceutical combination for the treatment of a solid tumor, wherein the pharmaceutical combination contains:

a) a first pharmaceutical composition comprising a compound of formula (A) or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffering agent and one or more pharmaceutically acceptable excipients,

b) a second pharmaceutical composition comprising an anti-CTLA-4 antibody and one or more pharmaceutically acceptable excipients, and

c) a third pharmaceutical composition comprising an anti-PD-L1 antibody comprising a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 7 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 17, and one or several pharmaceutically acceptable excipients.

Embodiment 632. Use of a pharmaceutical combination for the treatment of a solid tumor, wherein the pharmaceutical combination contains:

a) a first pharmaceutical composition comprising a compound of formula (A) or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffering agent and one or more pharmaceutically acceptable excipients,

b) a second pharmaceutical composition comprising a CTLA-4 receptor inhibitor and one or more pharmaceutically acceptable excipients, and

c) a third pharmaceutical composition containing a PD-1 inhibitor and one or more pharmaceutically acceptable excipients.

Embodiment 633. Use of a pharmaceutical combination for the treatment of a solid tumor, wherein the pharmaceutical combination contains:

a) a first pharmaceutical composition comprising a compound of formula (A) or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffering agent and one or more pharmaceutically acceptable excipients,

b) a second pharmaceutical composition comprising an anti-CTLA-4 antibody and one or more pharmaceutically acceptable excipients, and

c) a third pharmaceutical composition comprising an anti-PD-1 antibody and one or more pharmaceutically acceptable excipients.

Embodiment 634. Use of a pharmaceutical combination for the treatment of a solid tumor, wherein the pharmaceutical combination contains:

a) a first pharmaceutical composition comprising a compound of formula (A) or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffering agent and one or more pharmaceutically acceptable excipients,

b) a second pharmaceutical composition comprising an anti-CTLA-4 antibody and one or more pharmaceutically acceptable excipients, and

c) a third pharmaceutical composition comprising an anti-PD-1 antibody from Table 3 and one or more pharmaceutically acceptable excipients.

Embodiment 635. Use of a pharmaceutical combination for the treatment of a solid tumor, wherein the pharmaceutical combination contains:

a) a first pharmaceutical composition comprising a compound of formula (A) or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffering agent and one or more pharmaceutically acceptable excipients,

b) a second pharmaceutical composition comprising an anti-CTLA-4 antibody and one or more pharmaceutically acceptable excipients, and

c) a third pharmaceutical composition comprising an anti-PD-1 antibody comprising a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 27 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 37, and one or several pharmaceutically acceptable excipients.

Embodiment 636 Use of a pharmaceutical combination for the treatment of a solid tumor, wherein the pharmaceutical combination contains:

a) a first pharmaceutical composition containing 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridine -8-yl) propanoic acid or a pharmaceutically acceptable salt thereof, aluminum particles, a buffering agent and one or more pharmaceutically acceptable excipients,

b) a second pharmaceutical composition comprising an immune checkpoint inhibitor and one or more pharmaceutically acceptable excipients, and

c) a third pharmaceutical composition comprising an immune checkpoint inhibitor that is different from the immune checkpoint inhibitor of the second pharmaceutical composition and one or more pharmaceutically acceptable excipients.

Embodiment 637. Use of a pharmaceutical combination for the treatment of a solid tumor, wherein the pharmaceutical combination contains:

a) a first pharmaceutical composition containing 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridine -8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffering agent and one or more pharmaceutically acceptable excipients,

b) a second pharmaceutical composition comprising an immune checkpoint inhibitor and one or more pharmaceutically acceptable excipients, and

c) a third pharmaceutical composition comprising an immune checkpoint inhibitor that is different from the immune checkpoint inhibitor of the second pharmaceutical composition and one or more pharmaceutically acceptable excipients.

Embodiment 638. Use of a pharmaceutical combination for the treatment of a solid tumor, wherein the pharmaceutical combination contains:

a) a first pharmaceutical composition containing 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridine -8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffering agent and one or more pharmaceutically acceptable excipients,

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is selected from a CTLA-4 receptor inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor inhibitor, a TIM-3 receptor inhibitor , a BTLA receptor inhibitor, a KIR receptor inhibitor, a PD-L1 inhibitor, or a PD-L2 inhibitor, and

c) a third pharmaceutical composition comprising an immune response checkpoint inhibitor that is different from the immune response checkpoint inhibitor of the second pharmaceutical composition and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is selected from a CTLA-4 receptor inhibitor, a receptor inhibitor PD-1, LAG-3 receptor inhibitor, TIM-3 receptor inhibitor, BTLA receptor inhibitor, KIR receptor inhibitor, PD-L1 inhibitor, or PD-L2 inhibitor.

Embodiment 639. Use of a pharmaceutical combination for the treatment of a solid tumor, wherein the pharmaceutical combination contains:

a) a first pharmaceutical composition containing 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridine -8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffering agent and one or more pharmaceutically acceptable excipients,

b) a second pharmaceutical composition comprising a CTLA-4 receptor inhibitor and one or more pharmaceutically acceptable excipients, and

c) a third pharmaceutical composition containing a PD-L1 inhibitor and one or more pharmaceutically acceptable excipients.

Embodiment 640. Use of a pharmaceutical combination for the treatment of a solid tumor, wherein the pharmaceutical combination contains:

a) a first pharmaceutical composition containing 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridine -8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffering agent and one or more pharmaceutically acceptable excipients,

b) a second pharmaceutical composition comprising an anti-CTLA-4 antibody and one or more pharmaceutically acceptable excipients, and

c) a third pharmaceutical composition comprising an anti-PD-L1 antibody and one or more pharmaceutically acceptable excipients.

Embodiment 641 Use of a pharmaceutical combination for the treatment of a solid tumor, wherein the pharmaceutical combination contains:

a) a first pharmaceutical composition containing 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridine -8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffering agent and one or more pharmaceutically acceptable excipients,

b) a second pharmaceutical composition comprising an anti-CTLA-4 antibody and one or more pharmaceutically acceptable excipients, and

c) a third pharmaceutical composition comprising an anti-PD-L1 antibody from Table 2 and one or more pharmaceutically acceptable excipients.

Embodiment 642. Use of a pharmaceutical combination for the treatment of a solid tumor, wherein the pharmaceutical combination contains:

a) a first pharmaceutical composition containing 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridine -8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffering agent and one or more pharmaceutically acceptable excipients,

b) a second pharmaceutical composition comprising an anti-CTLA-4 antibody and one or more pharmaceutically acceptable excipients, and

c) a third pharmaceutical composition comprising an anti-PD-L1 antibody comprising a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 7 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 17, and one or several pharmaceutically acceptable excipients.

Embodiment 643 Use of a pharmaceutical combination for the treatment of a solid tumor, wherein the pharmaceutical combination contains:

a) a first pharmaceutical composition containing 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridine -8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffering agent and one or more pharmaceutically acceptable excipients,

b) a second pharmaceutical composition comprising a CTLA-4 receptor inhibitor and one or more pharmaceutically acceptable excipients, and

c) a third pharmaceutical composition containing a PD-1 inhibitor and one or more pharmaceutically acceptable excipients.

Embodiment 644 Use of a pharmaceutical combination for the treatment of a solid tumor, wherein the pharmaceutical combination comprises:

a) a first pharmaceutical composition containing 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridine -8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffering agent and one or more pharmaceutically acceptable excipients,

b) a second pharmaceutical composition comprising an anti-CTLA-4 antibody and one or more pharmaceutically acceptable excipients, and

c) a third pharmaceutical composition comprising an anti-PD-1 antibody and one or more pharmaceutically acceptable excipients.

Embodiment 645 Use of a pharmaceutical combination for the treatment of a solid tumor, wherein the pharmaceutical combination contains:

a) a first pharmaceutical composition containing 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridine -8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffering agent and one or more pharmaceutically acceptable excipients,

b) a second pharmaceutical composition comprising an anti-CTLA-4 antibody and one or more pharmaceutically acceptable excipients, and

c) a third pharmaceutical composition comprising an anti-PD-1 antibody from Table 3 and one or more pharmaceutically acceptable excipients.

Embodiment 646 Use of a pharmaceutical combination for the treatment of a solid tumor, wherein the pharmaceutical combination comprises:

a) a first pharmaceutical composition containing 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridine -8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffering agent and one or more pharmaceutically acceptable excipients,

b) a second pharmaceutical composition comprising an anti-CTLA-4 antibody and one or more pharmaceutically acceptable excipients, and

c) a third pharmaceutical composition comprising an anti-PD-1 antibody comprising a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 27 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 37, and one or several pharmaceutically acceptable excipients.

Embodiment 647 Use of a pharmaceutical combination for the treatment of a solid tumor, wherein the pharmaceutical combination contains:

a) a first pharmaceutical composition comprising a compound of formula (A) or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffering agent and one or more pharmaceutically acceptable excipients,

b) a second pharmaceutical composition comprising ipilimumab and one or more pharmaceutically acceptable excipients, and

c) a third pharmaceutical composition comprising an anti-PD-L1 antibody and one or more pharmaceutically acceptable excipients.

Embodiment 648. Use of a pharmaceutical combination for the treatment of a solid tumor, wherein the pharmaceutical combination contains:

a) a first pharmaceutical composition containing 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridine -8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffering agent and one or more pharmaceutically acceptable excipients,

b) a second pharmaceutical composition comprising ipilimumab and one or more pharmaceutically acceptable excipients, and

c) a third pharmaceutical composition comprising an anti-PD-L1 antibody and one or more pharmaceutically acceptable excipients.

Embodiment 649. Use of a pharmaceutical combination for the treatment of a solid tumor, wherein the pharmaceutical combination contains:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 0.5-2 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy )ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles, characterized by an aluminum content of 1-4 mg/ml, 5-100 mM tris buffer and 5-10% (w/v) mannitol, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is selected from a CTLA-4 receptor inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor inhibitor, a TIM-3 receptor inhibitor , a BTLA receptor inhibitor, a KIR receptor inhibitor, a PD-L1 inhibitor, or a PD-L2 inhibitor, and

c) a third pharmaceutical composition comprising an immune response checkpoint inhibitor that is different from the immune response checkpoint inhibitor of the second pharmaceutical composition, and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is selected from a CTLA-4 receptor inhibitor, a receptor inhibitor PD-1, LAG-3 receptor inhibitor, TIM-3 receptor inhibitor, BTLA receptor inhibitor, KIR receptor inhibitor, PD-L1 inhibitor, or PD-L2 inhibitor.

Embodiment 650 Use of a pharmaceutical combination for the treatment of a solid tumor, wherein the pharmaceutical combination comprises:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 0.5-2 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy )ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles, characterized by an aluminum content of 1-4 mg/ml, 5-100 mM Tris buffer and 5-10% (w/v) sucrose, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is selected from a CTLA-4 receptor inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor inhibitor, a TIM-3 receptor inhibitor , a BTLA receptor inhibitor, a KIR receptor inhibitor, a PD-L1 inhibitor, or a PD-L2 inhibitor, and

c) a third pharmaceutical composition comprising an immune response checkpoint inhibitor that is different from the immune response checkpoint inhibitor of the second pharmaceutical composition, and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is selected from a CTLA-4 receptor inhibitor, a receptor inhibitor PD-1, LAG-3 receptor inhibitor, TIM-3 receptor inhibitor, BTLA receptor inhibitor, KIR receptor inhibitor, PD-L1 inhibitor, or PD-L2 inhibitor.

Embodiment 651. Use of a pharmaceutical combination for the treatment of a solid tumor, wherein the pharmaceutical combination contains:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 0.5-2 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy )ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles, characterized by an aluminum content of 1-4 mg/ml, 5-50 mM tris buffer and 5-10% (w/v) mannitol, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is selected from a CTLA-4 receptor inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor inhibitor, a TIM-3 receptor inhibitor , a BTLA receptor inhibitor, a KIR receptor inhibitor, a PD-L1 inhibitor, or a PD-L2 inhibitor, and

c) a third pharmaceutical composition comprising an immune response checkpoint inhibitor that is different from the immune response checkpoint inhibitor of the second pharmaceutical composition, and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is selected from a CTLA-4 receptor inhibitor, a receptor inhibitor PD-1, LAG-3 receptor inhibitor, TIM-3 receptor inhibitor, BTLA receptor inhibitor, KIR receptor inhibitor, PD-L1 inhibitor, or PD-L2 inhibitor.

Embodiment 652. Use of a pharmaceutical combination for the treatment of a solid tumor, wherein the pharmaceutical combination contains:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 0.5-2 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy )ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles, characterized by an aluminum content of 1-4 mg/ml, 5-50 mM Tris buffer and 5-10% (w/v) sucrose, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is selected from a CTLA-4 receptor inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor inhibitor, a TIM-3 receptor inhibitor , a BTLA receptor inhibitor, a KIR receptor inhibitor, a PD-L1 inhibitor, or a PD-L2 inhibitor, and

c) a third pharmaceutical composition comprising an immune response checkpoint inhibitor that is different from the immune response checkpoint inhibitor of the second pharmaceutical composition, and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is selected from a CTLA-4 receptor inhibitor, a receptor inhibitor PD-1, LAG-3 receptor inhibitor, TIM-3 receptor inhibitor, BTLA receptor inhibitor, KIR receptor inhibitor, PD-L1 inhibitor, or PD-L2 inhibitor.

Embodiment 653. Use of a pharmaceutical combination for the treatment of a solid tumor, wherein the pharmaceutical combination contains:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 0.5-2 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy )ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles characterized by an aluminum content of 1-4 mg/ml, 5-20 mM tris buffer and 5-10% (w/v) mannitol, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is selected from a CTLA-4 receptor inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor inhibitor, a TIM-3 receptor inhibitor , a BTLA receptor inhibitor, a KIR receptor inhibitor, a PD-L1 inhibitor, or a PD-L2 inhibitor, and

c) a third pharmaceutical composition comprising an immune response checkpoint inhibitor that is different from the immune response checkpoint inhibitor of the second pharmaceutical composition, and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is selected from a CTLA-4 receptor inhibitor, a receptor inhibitor PD-1, LAG-3 receptor inhibitor, TIM-3 receptor inhibitor, BTLA receptor inhibitor, KIR receptor inhibitor, PD-L1 inhibitor, or PD-L2 inhibitor.

Embodiment 654. Use of a pharmaceutical combination for the treatment of a solid tumor, wherein the pharmaceutical combination contains:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 0.5-2 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy )ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles characterized by an aluminum content of 1-4 mg/ml, 5-20 mM Tris buffer and 5-10% (w/v) sucrose, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is selected from a CTLA-4 receptor inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor inhibitor, a TIM-3 receptor inhibitor , a BTLA receptor inhibitor, a KIR receptor inhibitor, a PD-L1 inhibitor, or a PD-L2 inhibitor, and

c) a third pharmaceutical composition comprising an immune response checkpoint inhibitor that is different from the immune response checkpoint inhibitor of the second pharmaceutical composition, and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is selected from a CTLA-4 receptor inhibitor, a receptor inhibitor PD-1, LAG-3 receptor inhibitor, TIM-3 receptor inhibitor, BTLA receptor inhibitor, KIR receptor inhibitor, PD-L1 inhibitor, or PD-L2 inhibitor.

Embodiment 655 Use of a pharmaceutical combination for the treatment of a solid tumor, wherein the pharmaceutical combination contains:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 1 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)- 2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles characterized by an aluminum content of 2 mg/ml, 16 mM Tris buffer and 7.5% (weight/volume) mannitol, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is selected from a CTLA-4 receptor inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor inhibitor, a TIM-3 receptor inhibitor , a BTLA receptor inhibitor, a KIR receptor inhibitor, a PD-L1 inhibitor, or a PD-L2 inhibitor, and

c) a third pharmaceutical composition comprising an immune response checkpoint inhibitor that is different from the immune response checkpoint inhibitor of the second pharmaceutical composition, and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is selected from a CTLA-4 receptor inhibitor, a receptor inhibitor PD-1, LAG-3 receptor inhibitor, TIM-3 receptor inhibitor, BTLA receptor inhibitor, KIR receptor inhibitor, PD-L1 inhibitor, or PD-L2 inhibitor.

Embodiment 656 Use of a pharmaceutical combination for the treatment of a solid tumor, wherein the pharmaceutical combination comprises:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 1 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)- 2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles characterized by an aluminum content of 2 mg/ml, 16 mM Tris buffer and 7.5% (weight/volume) sucrose, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is selected from a CTLA-4 receptor inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor inhibitor, a TIM-3 receptor inhibitor , a BTLA receptor inhibitor, a KIR receptor inhibitor, a PD-L1 inhibitor, or a PD-L2 inhibitor, and

c) a third pharmaceutical composition comprising an immune response checkpoint inhibitor that is different from the immune response checkpoint inhibitor of the second pharmaceutical composition, and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is selected from a CTLA-4 receptor inhibitor, a receptor inhibitor PD-1, LAG-3 receptor inhibitor, TIM-3 receptor inhibitor, BTLA receptor inhibitor, KIR receptor inhibitor, PD-L1 inhibitor, or PD-L2 inhibitor.

Embodiment 657. Use of a pharmaceutical combination for the treatment of a solid tumor, wherein the pharmaceutical combination contains:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 1 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)- 2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles characterized by an aluminum content of 2 mg/ml, 5 mM Tris buffer and 8.25% (weight/volume) mannitol, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is selected from a CTLA-4 receptor inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor inhibitor, a TIM-3 receptor inhibitor , a BTLA receptor inhibitor, a KIR receptor inhibitor, a PD-L1 inhibitor, or a PD-L2 inhibitor, and

c) a third pharmaceutical composition comprising an immune response checkpoint inhibitor that is different from the immune response checkpoint inhibitor of the second pharmaceutical composition, and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is selected from a CTLA-4 receptor inhibitor, a receptor inhibitor PD-1, LAG-3 receptor inhibitor, TIM-3 receptor inhibitor, BTLA receptor inhibitor, KIR receptor inhibitor, PD-L1 inhibitor, or PD-L2 inhibitor.

Embodiment 658. Use of a pharmaceutical combination for the treatment of a solid tumor, wherein the pharmaceutical combination contains:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 1 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)- 2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles characterized by an aluminum content of 2 mg/ml, 5 mM Tris buffer and 8.25% (weight/volume) sucrose, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is selected from a CTLA-4 receptor inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor inhibitor, a TIM-3 receptor inhibitor , a BTLA receptor inhibitor, a KIR receptor inhibitor, a PD-L1 inhibitor, or a PD-L2 inhibitor, and

c) a third pharmaceutical composition comprising an immune response checkpoint inhibitor that is different from the immune response checkpoint inhibitor of the second pharmaceutical composition, and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is selected from a CTLA-4 receptor inhibitor, a receptor inhibitor PD-1, LAG-3 receptor inhibitor, TIM-3 receptor inhibitor, BTLA receptor inhibitor, KIR receptor inhibitor, PD-L1 inhibitor, or PD-L2 inhibitor.

Embodiment 659. Use of a pharmaceutical combination for the treatment of a solid tumor, wherein the pharmaceutical combination contains:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 0.5-2 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy )ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles, characterized by an aluminum content of 1-4 mg/ml, 5-100 mM tris buffer and 5-10% (w/v) mannitol, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-PD-L1 antibody, and

c) a third pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is selected from a CTLA-4 receptor inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor inhibitor, a TIM-3 receptor inhibitor , a BTLA receptor inhibitor, a KIR receptor inhibitor, a PD-L1 inhibitor, or a PD-L2 inhibitor.

Embodiment 660. Use of a pharmaceutical combination for the treatment of a solid tumor, wherein the pharmaceutical combination contains:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 0.5-2 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy )ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles, characterized by an aluminum content of 1-4 mg/ml, 5-100 mM Tris buffer and 5-10% (w/v) sucrose, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-PD-L1 antibody, and

c) a third pharmaceutical composition comprising an immune response checkpoint inhibitor that is different from the immune response checkpoint inhibitor of the second pharmaceutical composition, and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is selected from a CTLA-4 receptor inhibitor, a receptor inhibitor PD-1, LAG-3 receptor inhibitor, TIM-3 receptor inhibitor, BTLA receptor inhibitor, KIR receptor inhibitor, PD-L1 inhibitor, or PD-L2 inhibitor.

Embodiment 661. Use of a pharmaceutical combination for the treatment of a solid tumor, wherein the pharmaceutical combination contains:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 0.5-2 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy )ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles, characterized by an aluminum content of 1-4 mg/ml, 5-50 mM tris buffer and 5-10% (w/v) mannitol, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-PD-L1 antibody, and

c) a third pharmaceutical composition comprising an immune response checkpoint inhibitor that is different from the immune response checkpoint inhibitor of the second pharmaceutical composition, and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is selected from a CTLA-4 receptor inhibitor, a receptor inhibitor PD-1, LAG-3 receptor inhibitor, TIM-3 receptor inhibitor, BTLA receptor inhibitor, KIR receptor inhibitor, PD-L1 inhibitor, or PD-L2 inhibitor.

Embodiment 662. Use of a pharmaceutical combination for the treatment of a solid tumor, wherein the pharmaceutical combination contains:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 0.5-2 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy )ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles, characterized by an aluminum content of 1-4 mg/ml, 5-50 mM Tris buffer and 5-10% (w/v) sucrose, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-PD-L1 antibody, and

c) a third pharmaceutical composition comprising an immune response checkpoint inhibitor that is different from the immune response checkpoint inhibitor of the second pharmaceutical composition, and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is selected from a CTLA-4 receptor inhibitor, a receptor inhibitor PD-1, LAG-3 receptor inhibitor, TIM-3 receptor inhibitor, BTLA receptor inhibitor, KIR receptor inhibitor, PD-L1 inhibitor, or PD-L2 inhibitor.

Embodiment 663 Use of a pharmaceutical combination for the treatment of a solid tumor, wherein the pharmaceutical combination contains:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 0.5-2 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy )ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles characterized by an aluminum content of 1-4 mg/ml, 5-20 mM tris buffer and 5-10% (w/v) mannitol, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-PD-L1 antibody, and

c) a third pharmaceutical composition comprising an immune response checkpoint inhibitor that is different from the immune response checkpoint inhibitor of the second pharmaceutical composition, and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is selected from a CTLA-4 receptor inhibitor, a receptor inhibitor PD-1, LAG-3 receptor inhibitor, TIM-3 receptor inhibitor, BTLA receptor inhibitor, KIR receptor inhibitor, PD-L1 inhibitor, or PD-L2 inhibitor.

Embodiment 664 Use of a pharmaceutical combination for the treatment of a solid tumor, wherein the pharmaceutical combination contains:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 0.5-2 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy )ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles characterized by an aluminum content of 1-4 mg/ml, 5-20 mM Tris buffer and 5-10% (w/v) sucrose, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-PD-L1 antibody, and

c) a third pharmaceutical composition comprising an immune response checkpoint inhibitor that is different from the immune response checkpoint inhibitor of the second pharmaceutical composition, and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is selected from a CTLA-4 receptor inhibitor, a receptor inhibitor PD-1, LAG-3 receptor inhibitor, TIM-3 receptor inhibitor, BTLA receptor inhibitor, KIR receptor inhibitor, PD-L1 inhibitor, or PD-L2 inhibitor.

Embodiment 665 Use of a pharmaceutical combination for the treatment of a solid tumor, wherein the pharmaceutical combination contains:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 1 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)- 2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles characterized by an aluminum content of 2 mg/ml, 16 mM Tris buffer and 7.5% (weight/volume) mannitol, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-PD-L1 antibody, and

c) a third pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-CTLA-4 antibody.

Embodiment 666 Use of a pharmaceutical combination for the treatment of a solid tumor, wherein the pharmaceutical combination comprises:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 1 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)- 2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles characterized by an aluminum content of 2 mg/ml, 16 mM Tris buffer and 7.5% (weight/volume) sucrose, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-PD-L1 antibody, and

c) a third pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-CTLA-4 antibody.

Embodiment 667. Use of a pharmaceutical combination for the treatment of a solid tumor, wherein the pharmaceutical combination contains:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 1 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)- 2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles characterized by an aluminum content of 2 mg/ml, 5 mM Tris buffer and 8.25% (weight/volume) mannitol, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-PD-L1 antibody, and

c) a third pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-CTLA-4 antibody.

Embodiment 668. Use of a pharmaceutical combination for the treatment of a solid tumor, wherein the pharmaceutical combination contains:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 1 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)- 2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles characterized by an aluminum content of 2 mg/ml, 5 mM Tris buffer and 8.25% (weight/volume) sucrose, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-PD-L1 antibody, and

c) a third pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-CTLA-4 antibody.

Embodiment 669 Use according to any one of Embodiments 649-668, wherein the anti-PD-L1 antibody is an anti-PD-L1 antibody from Table 2.

Embodiment 670. Use according to any one of embodiments 649-668, wherein the anti-PD-L1 antibody is an anti-PD-L1 antibody comprising a heavy chain variable domain that comprises the amino acid sequence of SEQ ID NO: 7 and the variable domain light chain which contains the amino acid sequence of SEQ ID NO: 17.

Embodiment 671. Use of a pharmaceutical combination for the treatment of a solid tumor, wherein the pharmaceutical combination contains:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 0.5-2 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy )ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles, characterized by an aluminum content of 1-4 mg/ml, 5-100 mM tris buffer and 5-10% (w/v) mannitol, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-PD-1 antibody, and

c) a third pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is selected from a CTLA-4 receptor inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor inhibitor, a TIM-3 receptor inhibitor , a BTLA receptor inhibitor, a KIR receptor inhibitor, a PD-L1 inhibitor, or a PD-L2 inhibitor.

Embodiment 672. Use of a pharmaceutical combination for the treatment of a solid tumor, wherein the pharmaceutical combination contains:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 0.5-2 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy )ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles, characterized by an aluminum content of 1-4 mg/ml, 5-100 mM Tris buffer and 5-10% (w/v) sucrose, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-PD-1 antibody, and

c) a third pharmaceutical composition comprising an immune response checkpoint inhibitor that is different from the immune response checkpoint inhibitor of the second pharmaceutical composition, and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is selected from a CTLA-4 receptor inhibitor, a receptor inhibitor PD-1, LAG-3 receptor inhibitor, TIM-3 receptor inhibitor, BTLA receptor inhibitor, KIR receptor inhibitor, PD-L1 inhibitor, or PD-L2 inhibitor.

Embodiment 673 Use of a pharmaceutical combination for the treatment of a solid tumor, wherein the pharmaceutical combination contains:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 0.5-2 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy )ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles, characterized by an aluminum content of 1-4 mg/ml, 5-50 mM tris buffer and 5-10% (w/v) mannitol, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-PD-1 antibody, and

c) a third pharmaceutical composition comprising an immune response checkpoint inhibitor that is different from the immune response checkpoint inhibitor of the second pharmaceutical composition, and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is selected from a CTLA-4 receptor inhibitor, a receptor inhibitor PD-1, LAG-3 receptor inhibitor, TIM-3 receptor inhibitor, BTLA receptor inhibitor, KIR receptor inhibitor, PD-L1 inhibitor, or PD-L2 inhibitor.

Embodiment 674 Use of a pharmaceutical combination for the treatment of a solid tumor, wherein the pharmaceutical combination comprises:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 0.5-2 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy )ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles, characterized by an aluminum content of 1-4 mg/ml, 5-50 mM Tris buffer and 5-10% (w/v) sucrose, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-PD-1 antibody, and

c) a third pharmaceutical composition comprising an immune response checkpoint inhibitor that is different from the immune response checkpoint inhibitor of the second pharmaceutical composition, and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is selected from a CTLA-4 receptor inhibitor, a receptor inhibitor PD-1, LAG-3 receptor inhibitor, TIM-3 receptor inhibitor, BTLA receptor inhibitor, KIR receptor inhibitor, PD-L1 inhibitor, or PD-L2 inhibitor.

Embodiment 675. Use of a pharmaceutical combination for the treatment of a solid tumor, wherein the pharmaceutical combination contains:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 0.5-2 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy )ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles characterized by an aluminum content of 1-4 mg/ml, 5-20 mM tris buffer and 5-10% (w/v) mannitol, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-PD-1 antibody, and

c) a third pharmaceutical composition comprising an immune response checkpoint inhibitor that is different from the immune response checkpoint inhibitor of the second pharmaceutical composition, and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is selected from a CTLA-4 receptor inhibitor, a receptor inhibitor PD-1, LAG-3 receptor inhibitor, TIM-3 receptor inhibitor, BTLA receptor inhibitor, KIR receptor inhibitor, PD-L1 inhibitor, or PD-L2 inhibitor.

Embodiment 676 Use of a pharmaceutical combination for the treatment of a solid tumor, wherein the pharmaceutical combination contains:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 0.5-2 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy )ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles characterized by an aluminum content of 1-4 mg/ml, 5-20 mM Tris buffer and 5-10% (w/v) sucrose, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-PD-1 antibody, and

c) a third pharmaceutical composition comprising an immune response checkpoint inhibitor that is different from the immune response checkpoint inhibitor of the second pharmaceutical composition, and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is selected from a CTLA-4 receptor inhibitor, a receptor inhibitor PD-1, LAG-3 receptor inhibitor, TIM-3 receptor inhibitor, BTLA receptor inhibitor, KIR receptor inhibitor, PD-L1 inhibitor, or PD-L2 inhibitor.

Embodiment 677. Use of a pharmaceutical combination for the treatment of a solid tumor, wherein the pharmaceutical combination contains:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 1 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)- 2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles characterized by an aluminum content of 2 mg/ml, 16 mM Tris buffer and 7.5% (weight/volume) mannitol, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-PD-1 antibody, and

c) a third pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-CTLA-4 antibody.

Embodiment 678. Use of a pharmaceutical combination for the treatment of a solid tumor, wherein the pharmaceutical combination contains:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 1 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)- 2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles characterized by an aluminum content of 2 mg/ml, 16 mM Tris buffer and 7.5% (weight/volume) sucrose, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-PD-1 antibody, and

c) a third pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-CTLA-4 antibody.

Embodiment 679 Use of a pharmaceutical combination for the treatment of a solid tumor, wherein the pharmaceutical combination contains:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 1 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)- 2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles characterized by an aluminum content of 2 mg/ml, 5 mM Tris buffer and 8.25% (weight/volume) mannitol, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-PD-1 antibody, and

c) a third pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-CTLA-4 antibody.

Embodiment 680. Use of a pharmaceutical combination for the treatment of a solid tumor, wherein the pharmaceutical combination contains:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 1 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)- 2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles characterized by an aluminum content of 2 mg/ml, 5 mM Tris buffer and 8.25% (weight/volume) sucrose, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-PD-1 antibody, and

c) a third pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-CTLA-4 antibody.

Embodiment 681 Use according to any one of Embodiments 671-680, wherein the anti-PD-1 antibody is an anti-PD-1 antibody from Table 3.

Embodiment 682. Use according to any of embodiments 671-680, wherein the anti-PD1 antibody is an anti-PD-1 antibody comprising a heavy chain variable domain that comprises the amino acid sequence of SEQ ID NO: 27 and a light chain variable domain , which contains the amino acid sequence under SEQ ID NO: 37.

Embodiment 683 A pharmaceutical combination according to any one of Embodiments 295-352 for use in the treatment of a solid tumor.

Embodiment 684 A pharmaceutical combination for use in the treatment of a solid tumor, wherein the pharmaceutical combination comprises:

a) a first pharmaceutical composition containing a compound of formula (A) or a pharmaceutically acceptable salt thereof, aluminum particles, a buffering agent and one or more pharmaceutically acceptable excipients,

b) a second pharmaceutical composition comprising an immune checkpoint inhibitor and one or more pharmaceutically acceptable excipients, and

c) a third pharmaceutical composition comprising an immune checkpoint inhibitor that is different from the immune checkpoint inhibitor of the second pharmaceutical composition and one or more pharmaceutically acceptable excipients.

Embodiment 685 A pharmaceutical combination for use in the treatment of a solid tumor, wherein the pharmaceutical combination comprises:

a) a first pharmaceutical composition comprising a compound of formula (A) or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffering agent and one or more pharmaceutically acceptable excipients,

b) a second pharmaceutical composition comprising an immune checkpoint inhibitor and one or more pharmaceutically acceptable excipients, and

c) a third pharmaceutical composition comprising an immune checkpoint inhibitor that is different from the immune checkpoint inhibitor of the second pharmaceutical composition and one or more pharmaceutically acceptable excipients.

Embodiment 686 A pharmaceutical combination for use in the treatment of a solid tumor, wherein the pharmaceutical combination comprises:

a) a first pharmaceutical composition comprising a compound of formula (A) or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffering agent and one or more pharmaceutically acceptable excipients,

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is selected from a CTLA-4 receptor inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor inhibitor, a TIM-3 receptor inhibitor , a BTLA receptor inhibitor, a KIR receptor inhibitor, a PD-L1 inhibitor, or a PD-L2 inhibitor, and

c) a third pharmaceutical composition comprising an immune response checkpoint inhibitor that is different from the immune response checkpoint inhibitor of the second pharmaceutical composition, and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is selected from a CTLA-4 receptor inhibitor, a receptor inhibitor PD-1, LAG-3 receptor inhibitor, TIM-3 receptor inhibitor, BTLA receptor inhibitor, KIR receptor inhibitor, PD-L1 inhibitor, or PD-L2 inhibitor.

Embodiment 687 A pharmaceutical combination for use in the treatment of a solid tumor, wherein the pharmaceutical combination comprises:

a) a first pharmaceutical composition comprising a compound of formula (A) or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffering agent and one or more pharmaceutically acceptable excipients,

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is selected from a CTLA-4 receptor inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor inhibitor, a TIM-3 receptor inhibitor , a BTLA receptor inhibitor, a KIR receptor inhibitor, a PD-L1 inhibitor, or a PD-L2 inhibitor, and

c) a third pharmaceutical composition comprising an immune response checkpoint inhibitor that is different from the immune response checkpoint inhibitor of the second pharmaceutical composition, and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is selected from a CTLA-4 receptor inhibitor, a receptor inhibitor PD-1, LAG-3 receptor inhibitor, TIM-3 receptor inhibitor, BTLA receptor inhibitor, KIR receptor inhibitor, PD-L1 inhibitor, or PD-L2 inhibitor.

Embodiment 688 A pharmaceutical combination for use in the treatment of a solid tumor, wherein the pharmaceutical combination comprises:

a) a first pharmaceutical composition comprising a compound of formula (A) or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffering agent and one or more pharmaceutically acceptable excipients,

b) a second pharmaceutical composition comprising a CTLA-4 receptor inhibitor and one or more pharmaceutically acceptable excipients, and

c) a third pharmaceutical composition containing a PD-L1 inhibitor and one or more pharmaceutically acceptable excipients.

Embodiment 689 A pharmaceutical combination for use in the treatment of a solid tumor, wherein the pharmaceutical combination comprises:

a) a first pharmaceutical composition comprising a compound of formula (A) or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffering agent and one or more pharmaceutically acceptable excipients,

b) a second pharmaceutical composition comprising an anti-CTLA-4 antibody and one or more pharmaceutically acceptable excipients, and

c) a third pharmaceutical composition comprising an anti-PD-L1 antibody and one or more pharmaceutically acceptable excipients.

Embodiment 690 A pharmaceutical combination for use in the treatment of a solid tumor, wherein the pharmaceutical combination comprises:

a) a first pharmaceutical composition comprising a compound of formula (A) or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffering agent and one or more pharmaceutically acceptable excipients,

b) a second pharmaceutical composition comprising an anti-CTLA-4 antibody and one or more pharmaceutically acceptable excipients, and

c) a third pharmaceutical composition comprising an anti-PD-L1 antibody from Table 2 and one or more pharmaceutically acceptable excipients.

Embodiment 691 A pharmaceutical combination for use in the treatment of a solid tumor, wherein the pharmaceutical combination comprises:

a) a first pharmaceutical composition comprising a compound of formula (A) or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffering agent and one or more pharmaceutically acceptable excipients,

b) a second pharmaceutical composition comprising an anti-CTLA-4 antibody and one or more pharmaceutically acceptable excipients, and

c) a third pharmaceutical composition comprising an anti-PD-L1 antibody comprising a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 7 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 17, and one or several pharmaceutically acceptable excipients.

Embodiment 692 A pharmaceutical combination for use in the treatment of a solid tumor, wherein the pharmaceutical combination comprises:

a) a first pharmaceutical composition comprising a compound of formula (A) or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffering agent and one or more pharmaceutically acceptable excipients,

b) a second pharmaceutical composition comprising a CTLA-4 receptor inhibitor and one or more pharmaceutically acceptable excipients, and

c) a third pharmaceutical composition containing a PD-1 inhibitor and one or more pharmaceutically acceptable excipients.

Embodiment 693 A pharmaceutical combination for use in the treatment of a solid tumor, wherein the pharmaceutical combination comprises:

a) a first pharmaceutical composition comprising a compound of formula (A) or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffering agent and one or more pharmaceutically acceptable excipients,

b) a second pharmaceutical composition comprising an anti-CTLA-4 antibody and one or more pharmaceutically acceptable excipients, and

c) a third pharmaceutical composition comprising an anti-PD-1 antibody and one or more pharmaceutically acceptable excipients.

Embodiment 694 A pharmaceutical combination for use in the treatment of a solid tumor, wherein the pharmaceutical combination comprises:

a) a first pharmaceutical composition comprising a compound of formula (A) or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffering agent and one or more pharmaceutically acceptable excipients,

b) a second pharmaceutical composition comprising an anti-CTLA-4 antibody and one or more pharmaceutically acceptable excipients, and

c) a third pharmaceutical composition comprising an anti-PD-1 antibody from Table 3 and one or more pharmaceutically acceptable excipients.

Embodiment 695 A pharmaceutical combination for use in the treatment of a solid tumor, wherein the pharmaceutical combination comprises:

a) a first pharmaceutical composition comprising a compound of formula (A) or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffering agent and one or more pharmaceutically acceptable excipients,

b) a second pharmaceutical composition comprising an anti-CTLA-4 antibody and one or more pharmaceutically acceptable excipients, and

c) a third pharmaceutical composition comprising an anti-PD-1 antibody comprising a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 27 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 37, and one or several pharmaceutically acceptable excipients.

Embodiment 696 A pharmaceutical combination for use in the treatment of a solid tumor, wherein the pharmaceutical combination comprises:

a) a first pharmaceutical composition containing 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridine -8-yl) propanoic acid or a pharmaceutically acceptable salt thereof, aluminum particles, a buffering agent and one or more pharmaceutically acceptable excipients,

b) a second pharmaceutical composition comprising an immune checkpoint inhibitor and one or more pharmaceutically acceptable excipients, and

c) a third pharmaceutical composition comprising an immune checkpoint inhibitor that is different from the immune checkpoint inhibitor of the second pharmaceutical composition and one or more pharmaceutically acceptable excipients.

Embodiment 697 A pharmaceutical combination for use in the treatment of a solid tumor, wherein the pharmaceutical combination comprises:

a) a first pharmaceutical composition containing 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridine -8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffering agent and one or more pharmaceutically acceptable excipients,

b) a second pharmaceutical composition comprising an immune checkpoint inhibitor and one or more pharmaceutically acceptable excipients, and

c) a third pharmaceutical composition comprising an immune checkpoint inhibitor that is different from the immune checkpoint inhibitor of the second pharmaceutical composition and one or more pharmaceutically acceptable excipients.

Embodiment 698 A pharmaceutical combination for use in the treatment of a solid tumor, wherein the pharmaceutical combination comprises:

a) a first pharmaceutical composition containing 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridine -8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffering agent and one or more pharmaceutically acceptable excipients,

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is selected from a CTLA-4 receptor inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor inhibitor, a TIM-3 receptor inhibitor , a BTLA receptor inhibitor, a KIR receptor inhibitor, a PD-L1 inhibitor, or a PD-L2 inhibitor, and

c) a third pharmaceutical composition comprising an immune response checkpoint inhibitor that is different from the immune response checkpoint inhibitor of the second pharmaceutical composition, and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is selected from a CTLA-4 receptor inhibitor, a receptor inhibitor PD-1, LAG-3 receptor inhibitor, TIM-3 receptor inhibitor, BTLA receptor inhibitor, KIR receptor inhibitor, PD-L1 inhibitor, or PD-L2 inhibitor.

Embodiment 699 A pharmaceutical combination for use in the treatment of a solid tumor, wherein the pharmaceutical combination comprises:

a) a first pharmaceutical composition containing 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridine -8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffering agent and one or more pharmaceutically acceptable excipients,

b) a second pharmaceutical composition comprising a CTLA-4 receptor inhibitor and one or more pharmaceutically acceptable excipients, and

c) a third pharmaceutical composition containing a PD-L1 inhibitor and one or more pharmaceutically acceptable excipients.

Embodiment 700 A pharmaceutical combination for use in the treatment of a solid tumor, wherein the pharmaceutical combination comprises:

a) a first pharmaceutical composition containing 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridine -8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffering agent and one or more pharmaceutically acceptable excipients,

b) a second pharmaceutical composition comprising an anti-CTLA-4 antibody and one or more pharmaceutically acceptable excipients, and

c) a third pharmaceutical composition comprising an anti-PD-L1 antibody and one or more pharmaceutically acceptable excipients.

Embodiment 701 A pharmaceutical combination for use in the treatment of a solid tumor, wherein the pharmaceutical combination contains:

a) a first pharmaceutical composition containing 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridine -8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffering agent and one or more pharmaceutically acceptable excipients,

b) a second pharmaceutical composition comprising an anti-CTLA-4 antibody and one or more pharmaceutically acceptable excipients, and

c) a third pharmaceutical composition comprising an anti-PD-L1 antibody from Table 2 and one or more pharmaceutically acceptable excipients.

Embodiment 702 A pharmaceutical combination for use in the treatment of a solid tumor, wherein the pharmaceutical combination contains:

a) a first pharmaceutical composition containing 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridine -8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffering agent and one or more pharmaceutically acceptable excipients,

b) a second pharmaceutical composition comprising an anti-CTLA-4 antibody and one or more pharmaceutically acceptable excipients, and

c) a third pharmaceutical composition comprising an anti-PD-L1 antibody comprising a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 7 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 17, and one or several pharmaceutically acceptable excipients.

Embodiment 703 A pharmaceutical combination for use in the treatment of a solid tumor, wherein the pharmaceutical combination comprises:

a) a first pharmaceutical composition containing 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridine -8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffering agent and one or more pharmaceutically acceptable excipients,

b) a second pharmaceutical composition comprising a CTLA-4 receptor inhibitor and one or more pharmaceutically acceptable excipients, and

c) a third pharmaceutical composition containing a PD-1 inhibitor and one or more pharmaceutically acceptable excipients.

Embodiment 704 A pharmaceutical combination for use in the treatment of a solid tumor, wherein the pharmaceutical combination contains:

a) a first pharmaceutical composition containing 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridine -8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffering agent and one or more pharmaceutically acceptable excipients,

b) a second pharmaceutical composition comprising an anti-CTLA-4 antibody and one or more pharmaceutically acceptable excipients, and

c) a third pharmaceutical composition comprising an anti-PD-1 antibody and one or more pharmaceutically acceptable excipients.

Embodiment 705 A pharmaceutical combination for use in the treatment of a solid tumor, wherein the pharmaceutical combination comprises:

a) a first pharmaceutical composition containing 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridine -8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffering agent and one or more pharmaceutically acceptable excipients,

b) a second pharmaceutical composition comprising an anti-CTLA-4 antibody and one or more pharmaceutically acceptable excipients, and

c) a third pharmaceutical composition comprising an anti-PD-1 antibody from Table 3 and one or more pharmaceutically acceptable excipients.

Embodiment 706 A pharmaceutical combination for use in the treatment of a solid tumor, wherein the pharmaceutical combination comprises:

a) a first pharmaceutical composition containing 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridine -8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffering agent and one or more pharmaceutically acceptable excipients,

b) a second pharmaceutical composition comprising an anti-CTLA-4 antibody and one or more pharmaceutically acceptable excipients, and

c) a third pharmaceutical composition comprising an anti-PD-L1 antibody comprising a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 27 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 37, and one or several pharmaceutically acceptable excipients.

Embodiment 707 A pharmaceutical combination for use in the treatment of a solid tumor, wherein the pharmaceutical combination comprises:

a) a first pharmaceutical composition comprising a compound of formula (A) or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffering agent and one or more pharmaceutically acceptable excipients,

b) a second pharmaceutical composition comprising ipilimumab and one or more pharmaceutically acceptable excipients, and

c) a third pharmaceutical composition comprising an anti-PD-L1 antibody and one or more pharmaceutically acceptable excipients.

Embodiment 708 A pharmaceutical combination for use in the treatment of a solid tumor, wherein the pharmaceutical combination comprises:

a) a first pharmaceutical composition containing 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridine -8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, aluminum hydroxide particles, a buffering agent and one or more pharmaceutically acceptable excipients,

b) a second pharmaceutical composition comprising ipilimumab and one or more pharmaceutically acceptable excipients, and

c) a third pharmaceutical composition comprising an anti-PD-L1 antibody and one or more pharmaceutically acceptable excipients.

Embodiment 709 A pharmaceutical combination for use in the treatment of a solid tumor, wherein the pharmaceutical combination comprises:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 0.5-2 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy )ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles, characterized by an aluminum content of 1-4 mg/ml, 5-100 mM tris buffer and 5-10% (w/v) mannitol, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is selected from a CTLA-4 receptor inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor inhibitor, a TIM-3 receptor inhibitor , a BTLA receptor inhibitor, a KIR receptor inhibitor, a PD-L1 inhibitor, or a PD-L2 inhibitor, and

c) a third pharmaceutical composition comprising an immune response checkpoint inhibitor that is different from the immune response checkpoint inhibitor of the second pharmaceutical composition, and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is selected from a CTLA-4 receptor inhibitor, a receptor inhibitor PD-1, LAG-3 receptor inhibitor, TIM-3 receptor inhibitor, BTLA receptor inhibitor, KIR receptor inhibitor, PD-L1 inhibitor, or PD-L2 inhibitor.

Embodiment 710 A pharmaceutical combination for use in the treatment of a solid tumor, wherein the pharmaceutical combination contains:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 0.5-2 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy )ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles, characterized by an aluminum content of 1-4 mg/ml, 5-100 mM Tris buffer and 5-10% (w/v) sucrose, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is selected from a CTLA-4 receptor inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor inhibitor, a TIM-3 receptor inhibitor , a BTLA receptor inhibitor, a KIR receptor inhibitor, a PD-L1 inhibitor, or a PD-L2 inhibitor, and

c) a third pharmaceutical composition comprising an immune response checkpoint inhibitor that is different from the immune response checkpoint inhibitor of the second pharmaceutical composition, and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is selected from a CTLA-4 receptor inhibitor, a receptor inhibitor PD-1, LAG-3 receptor inhibitor, TIM-3 receptor inhibitor, BTLA receptor inhibitor, KIR receptor inhibitor, PD-L1 inhibitor, or PD-L2 inhibitor.

Embodiment 711 A pharmaceutical combination for use in the treatment of a solid tumor, wherein the pharmaceutical combination comprises:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 0.5-2 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy )ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles, characterized by an aluminum content of 1-4 mg/ml, 5-50 mM tris buffer and 5-10% (w/v) mannitol, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is selected from a CTLA-4 receptor inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor inhibitor, a TIM-3 receptor inhibitor , a BTLA receptor inhibitor, a KIR receptor inhibitor, a PD-L1 inhibitor, or a PD-L2 inhibitor, and

c) a third pharmaceutical composition comprising an immune response checkpoint inhibitor that is different from the immune response checkpoint inhibitor of the second pharmaceutical composition, and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is selected from a CTLA-4 receptor inhibitor, a receptor inhibitor PD-1, LAG-3 receptor inhibitor, TIM-3 receptor inhibitor, BTLA receptor inhibitor, KIR receptor inhibitor, PD-L1 inhibitor, or PD-L2 inhibitor.

Embodiment 712 A pharmaceutical combination for use in the treatment of a solid tumor, wherein the pharmaceutical combination contains:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 0.5-2 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy )ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles, characterized by an aluminum content of 1-4 mg/ml, 5-50 mM Tris buffer and 5-10% (w/v) sucrose, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is selected from a CTLA-4 receptor inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor inhibitor, a TIM-3 receptor inhibitor , a BTLA receptor inhibitor, a KIR receptor inhibitor, a PD-L1 inhibitor, or a PD-L2 inhibitor, and

c) a third pharmaceutical composition comprising an immune response checkpoint inhibitor that is different from the immune response checkpoint inhibitor of the second pharmaceutical composition, and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is selected from a CTLA-4 receptor inhibitor, a receptor inhibitor PD-1, LAG-3 receptor inhibitor, TIM-3 receptor inhibitor, BTLA receptor inhibitor, KIR receptor inhibitor, PD-L1 inhibitor, or PD-L2 inhibitor.

Embodiment 713 A pharmaceutical combination for use in the treatment of a solid tumor, wherein the pharmaceutical combination comprises:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 0.5-2 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy )ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles characterized by an aluminum content of 1-4 mg/ml, 5-20 mM tris buffer and 5-10% (w/v) mannitol, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is selected from a CTLA-4 receptor inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor inhibitor, a TIM-3 receptor inhibitor , a BTLA receptor inhibitor, a KIR receptor inhibitor, a PD-L1 inhibitor, or a PD-L2 inhibitor, and

c) a third pharmaceutical composition comprising an immune response checkpoint inhibitor that is different from the immune response checkpoint inhibitor of the second pharmaceutical composition, and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is selected from a CTLA-4 receptor inhibitor, a receptor inhibitor PD-1, LAG-3 receptor inhibitor, TIM-3 receptor inhibitor, BTLA receptor inhibitor, KIR receptor inhibitor, PD-L1 inhibitor, or PD-L2 inhibitor.

Embodiment 714 A pharmaceutical combination for use in the treatment of a solid tumor, wherein the pharmaceutical combination comprises:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 0.5-2 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy )ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles characterized by an aluminum content of 1-4 mg/ml, 5-20 mM Tris buffer and 5-10% (w/v) sucrose, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is selected from a CTLA-4 receptor inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor inhibitor, a TIM-3 receptor inhibitor , a BTLA receptor inhibitor, a KIR receptor inhibitor, a PD-L1 inhibitor, or a PD-L2 inhibitor, and

c) a third pharmaceutical composition comprising an immune response checkpoint inhibitor that is different from the immune response checkpoint inhibitor of the second pharmaceutical composition, and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is selected from a CTLA-4 receptor inhibitor, a receptor inhibitor PD-1, LAG-3 receptor inhibitor, TIM-3 receptor inhibitor, BTLA receptor inhibitor, KIR receptor inhibitor, PD-L1 inhibitor, or PD-L2 inhibitor.

Embodiment 715 A pharmaceutical combination for use in the treatment of a solid tumor, wherein the pharmaceutical combination comprises:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 1 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)- 2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles characterized by an aluminum content of 2 mg/ml, 16 mM Tris buffer and 7.5% (weight/volume) mannitol, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is selected from a CTLA-4 receptor inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor inhibitor, a TIM-3 receptor inhibitor , a BTLA receptor inhibitor, a KIR receptor inhibitor, a PD-L1 inhibitor, or a PD-L2 inhibitor, and

c) a third pharmaceutical composition comprising an immune response checkpoint inhibitor that is different from the immune response checkpoint inhibitor of the second pharmaceutical composition, and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is selected from a CTLA-4 receptor inhibitor, a receptor inhibitor PD-1, LAG-3 receptor inhibitor, TIM-3 receptor inhibitor, BTLA receptor inhibitor, KIR receptor inhibitor, PD-L1 inhibitor, or PD-L2 inhibitor.

Embodiment 716 A pharmaceutical combination for use in the treatment of a solid tumor, wherein the pharmaceutical combination contains:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 1 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)- 2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles characterized by an aluminum content of 2 mg/ml, 16 mM Tris buffer and 7.5% (weight/volume) sucrose, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is selected from a CTLA-4 receptor inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor inhibitor, a TIM-3 receptor inhibitor , a BTLA receptor inhibitor, a KIR receptor inhibitor, a PD-L1 inhibitor, or a PD-L2 inhibitor, and

c) a third pharmaceutical composition comprising an immune response checkpoint inhibitor that is different from the immune response checkpoint inhibitor of the second pharmaceutical composition, and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is selected from a CTLA-4 receptor inhibitor, a receptor inhibitor PD-1, LAG-3 receptor inhibitor, TIM-3 receptor inhibitor, BTLA receptor inhibitor, KIR receptor inhibitor, PD-L1 inhibitor, or PD-L2 inhibitor.

Embodiment 717 A pharmaceutical combination for use in the treatment of a solid tumor, wherein the pharmaceutical combination contains:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 1 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)- 2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles characterized by an aluminum content of 2 mg/ml, 5 mM Tris buffer and 8.25% (weight/volume) mannitol, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is selected from a CTLA-4 receptor inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor inhibitor, a TIM-3 receptor inhibitor , a BTLA receptor inhibitor, a KIR receptor inhibitor, a PD-L1 inhibitor, or a PD-L2 inhibitor, and

c) a third pharmaceutical composition comprising an immune response checkpoint inhibitor that is different from the immune response checkpoint inhibitor of the second pharmaceutical composition, and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is selected from a CTLA-4 receptor inhibitor, a receptor inhibitor PD-1, LAG-3 receptor inhibitor, TIM-3 receptor inhibitor, BTLA receptor inhibitor, KIR receptor inhibitor, PD-L1 inhibitor, or PD-L2 inhibitor.

Embodiment 718 A pharmaceutical combination for use in the treatment of a solid tumor, wherein the pharmaceutical combination contains:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 1 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)- 2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles characterized by an aluminum content of 2 mg/ml, 5 mM Tris buffer and 8.25% (weight/volume) sucrose, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is selected from a CTLA-4 receptor inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor inhibitor, a TIM-3 receptor inhibitor , a BTLA receptor inhibitor, a KIR receptor inhibitor, a PD-L1 inhibitor, or a PD-L2 inhibitor, and

c) a third pharmaceutical composition comprising an immune response checkpoint inhibitor that is different from the immune response checkpoint inhibitor of the second pharmaceutical composition, and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is selected from a CTLA-4 receptor inhibitor, a receptor inhibitor PD-1, LAG-3 receptor inhibitor, TIM-3 receptor inhibitor, BTLA receptor inhibitor, KIR receptor inhibitor, PD-L1 inhibitor, or PD-L2 inhibitor.

Embodiment 719 A pharmaceutical combination for use in the treatment of a solid tumor, wherein the pharmaceutical combination comprises:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 0.5-2 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy )ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles, characterized by an aluminum content of 1-4 mg/ml, 5-100 mM tris buffer and 5-10% (w/v) mannitol, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-PD-L1 antibody, and

c) a third pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is selected from a CTLA-4 receptor inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor inhibitor, a TIM-3 receptor inhibitor , a BTLA receptor inhibitor, a KIR receptor inhibitor, a PD-L1 inhibitor, or a PD-L2 inhibitor.

Embodiment 720 A pharmaceutical combination for use in the treatment of a solid tumor, wherein the pharmaceutical combination comprises:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 0.5-2 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy )ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles, characterized by an aluminum content of 1-4 mg/ml, 5-100 mM Tris buffer and 5-10% (w/v) sucrose, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-PD-L1 antibody, and

c) a third pharmaceutical composition comprising an immune response checkpoint inhibitor that is different from the immune response checkpoint inhibitor of the second pharmaceutical composition, and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is selected from a CTLA-4 receptor inhibitor, a receptor inhibitor PD-1, LAG-3 receptor inhibitor, TIM-3 receptor inhibitor, BTLA receptor inhibitor, KIR receptor inhibitor, PD-L1 inhibitor, or PD-L2 inhibitor.

Embodiment 721 A pharmaceutical combination for use in the treatment of a solid tumor, wherein the pharmaceutical combination comprises:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 0.5-2 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy )ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles, characterized by an aluminum content of 1-4 mg/ml, 5-50 mM tris buffer and 5-10% (w/v) mannitol, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-PD-L1 antibody, and

c) a third pharmaceutical composition comprising an immune response checkpoint inhibitor that is different from the immune response checkpoint inhibitor of the second pharmaceutical composition, and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is selected from a CTLA-4 receptor inhibitor, a receptor inhibitor PD-1, LAG-3 receptor inhibitor, TIM-3 receptor inhibitor, BTLA receptor inhibitor, KIR receptor inhibitor, PD-L1 inhibitor, or PD-L2 inhibitor.

Embodiment 722 A pharmaceutical combination for use in the treatment of a solid tumor, wherein the pharmaceutical combination comprises:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 0.5-2 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy )ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles, characterized by an aluminum content of 1-4 mg/ml, 5-50 mM Tris buffer and 5-10% (w/v) sucrose, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-PD-L1 antibody, and

c) a third pharmaceutical composition comprising an immune response checkpoint inhibitor that is different from the immune response checkpoint inhibitor of the second pharmaceutical composition, and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is selected from a CTLA-4 receptor inhibitor, a receptor inhibitor PD-1, LAG-3 receptor inhibitor, TIM-3 receptor inhibitor, BTLA receptor inhibitor, KIR receptor inhibitor, PD-L1 inhibitor, or PD-L2 inhibitor.

Embodiment 723 A pharmaceutical combination for use in the treatment of a solid tumor, wherein the pharmaceutical combination comprises:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 0.5-2 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy )ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles characterized by an aluminum content of 1-4 mg/ml, 5-20 mM tris buffer and 5-10% (w/v) mannitol, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-PD-L1 antibody, and

c) a third pharmaceutical composition comprising an immune response checkpoint inhibitor that is different from the immune response checkpoint inhibitor of the second pharmaceutical composition, and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is selected from a CTLA-4 receptor inhibitor, a receptor inhibitor PD-1, LAG-3 receptor inhibitor, TIM-3 receptor inhibitor, BTLA receptor inhibitor, KIR receptor inhibitor, PD-L1 inhibitor, or PD-L2 inhibitor.

Embodiment 724 A pharmaceutical combination for use in the treatment of a solid tumor, wherein the pharmaceutical combination comprises:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 0.5-2 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy )ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles characterized by an aluminum content of 1-4 mg/ml, 5-20 mM Tris buffer and 5-10% (w/v) sucrose, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-PD-L1 antibody, and

c) a third pharmaceutical composition comprising an immune response checkpoint inhibitor that is different from the immune response checkpoint inhibitor of the second pharmaceutical composition, and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is selected from a CTLA-4 receptor inhibitor, a receptor inhibitor PD-1, LAG-3 receptor inhibitor, TIM-3 receptor inhibitor, BTLA receptor inhibitor, KIR receptor inhibitor, PD-L1 inhibitor, or PD-L2 inhibitor.

Embodiment 725 A pharmaceutical combination for use in the treatment of a solid tumor, wherein the pharmaceutical combination comprises:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 1 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)- 2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles characterized by an aluminum content of 2 mg/ml, 16 mM Tris buffer and 7.5% (weight/volume) mannitol, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-PD-L1 antibody, and

c) a third pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-CTLA-4 antibody.

Embodiment 726 A pharmaceutical combination for use in the treatment of a solid tumor, wherein the pharmaceutical combination comprises:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 1 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)- 2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles characterized by an aluminum content of 2 mg/ml, 16 mM Tris buffer and 7.5% (weight/volume) sucrose, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-PD-L1 antibody, and

c) a third pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-CTLA-4 antibody.

Embodiment 727 A pharmaceutical combination for use in the treatment of a solid tumor, wherein the pharmaceutical combination comprises:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 1 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)- 2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles characterized by an aluminum content of 2 mg/ml, 5 mM Tris buffer and 8.25% (weight/volume) mannitol, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-PD-L1 antibody, and

c) a third pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-CTLA-4 antibody.

Embodiment 728 A pharmaceutical combination for use in the treatment of a solid tumor, wherein the pharmaceutical combination comprises:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 1 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)- 2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles characterized by an aluminum content of 2 mg/ml, 5 mM Tris buffer and 8.25% (weight/volume) sucrose, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-PD-L1 antibody, and

c) a third pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-CTLA-4 antibody.

Embodiment 729 A pharmaceutical combination according to any of embodiments 709-728, wherein the anti-PD-L1 antibody is an anti-PD-L1 antibody from Table 2.

Embodiment 730. The pharmaceutical combination according to any of embodiments 709-728, wherein the anti-PD-L1 antibody is an anti-PD-L1 antibody comprising a heavy chain variable domain that comprises the amino acid sequence of SEQ ID NO: 7, and the variable a light chain domain that contains the amino acid sequence of SEQ ID NO: 17.

Embodiment 731 A pharmaceutical combination for use in the treatment of a solid tumor, wherein the pharmaceutical combination comprises:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 0.5-2 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy )ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles, characterized by an aluminum content of 1-4 mg/ml, 5-100 mM tris buffer and 5-10% (w/v) mannitol, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-PD-1 antibody, and

c) a third pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is selected from a CTLA-4 receptor inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor inhibitor, a TIM-3 receptor inhibitor , a BTLA receptor inhibitor, a KIR receptor inhibitor, a PD-L1 inhibitor, or a PD-L2 inhibitor.

Embodiment 732 A pharmaceutical combination for use in the treatment of a solid tumor, wherein the pharmaceutical combination comprises:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 0.5-2 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy )ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles, characterized by an aluminum content of 1-4 mg/ml, 5-100 mM Tris buffer and 5-10% (w/v) sucrose, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-PD-1 antibody, and

c) a third pharmaceutical composition comprising an immune response checkpoint inhibitor that is different from the immune response checkpoint inhibitor of the second pharmaceutical composition, and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is selected from a CTLA-4 receptor inhibitor, a receptor inhibitor PD-1, LAG-3 receptor inhibitor, TIM-3 receptor inhibitor, BTLA receptor inhibitor, KIR receptor inhibitor, PD-L1 inhibitor, or PD-L2 inhibitor.

Embodiment 733 A pharmaceutical combination for use in the treatment of a solid tumor, wherein the pharmaceutical combination comprises:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 0.5-2 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy )ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles, characterized by an aluminum content of 1-4 mg/ml, 5-50 mM tris buffer and 5-10% (w/v) mannitol, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-PD-1 antibody, and

c) a third pharmaceutical composition comprising an immune response checkpoint inhibitor that is different from the immune response checkpoint inhibitor of the second pharmaceutical composition, and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is selected from a CTLA-4 receptor inhibitor, a receptor inhibitor PD-1, LAG-3 receptor inhibitor, TIM-3 receptor inhibitor, BTLA receptor inhibitor, KIR receptor inhibitor, PD-L1 inhibitor, or PD-L2 inhibitor.

Embodiment 734 A pharmaceutical combination for use in the treatment of a solid tumor, wherein the pharmaceutical combination comprises:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 0.5-2 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy )ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles, characterized by an aluminum content of 1-4 mg/ml, 5-50 mM Tris buffer and 5-10% (w/v) sucrose, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-PD-1 antibody, and

c) a third pharmaceutical composition comprising an immune response checkpoint inhibitor that is different from the immune response checkpoint inhibitor of the second pharmaceutical composition, and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is selected from a CTLA-4 receptor inhibitor, a receptor inhibitor PD-1, LAG-3 receptor inhibitor, TIM-3 receptor inhibitor, BTLA receptor inhibitor, KIR receptor inhibitor, PD-L1 inhibitor, or PD-L2 inhibitor.

Embodiment 735 A pharmaceutical combination for use in the treatment of a solid tumor, wherein the pharmaceutical combination comprises:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 0.5-2 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy )ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles characterized by an aluminum content of 1-4 mg/ml, 5-20 mM tris buffer and 5-10% (w/v) mannitol, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-PD-1 antibody, and

c) a third pharmaceutical composition comprising an immune response checkpoint inhibitor that is different from the immune response checkpoint inhibitor of the second pharmaceutical composition, and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is selected from a CTLA-4 receptor inhibitor, a receptor inhibitor PD-1, LAG-3 receptor inhibitor, TIM-3 receptor inhibitor, BTLA receptor inhibitor, KIR receptor inhibitor, PD-L1 inhibitor, or PD-L2 inhibitor.

Embodiment 736 A pharmaceutical combination for use in the treatment of a solid tumor, wherein the pharmaceutical combination comprises:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 0.5-2 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy )ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles characterized by an aluminum content of 1-4 mg/ml, 5-20 mM Tris buffer and 5-10% (w/v) sucrose, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-PD-1 antibody, and

c) a third pharmaceutical composition comprising an immune response checkpoint inhibitor that is different from the immune response checkpoint inhibitor of the second pharmaceutical composition, and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is selected from a CTLA-4 receptor inhibitor, a receptor inhibitor PD-1, LAG-3 receptor inhibitor, TIM-3 receptor inhibitor, BTLA receptor inhibitor, KIR receptor inhibitor, PD-L1 inhibitor, or PD-L2 inhibitor.

Embodiment 737 A pharmaceutical combination for use in the treatment of a solid tumor, wherein the pharmaceutical combination comprises:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 1 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)- 2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles characterized by an aluminum content of 2 mg/ml, 16 mM Tris buffer and 7.5% (weight/volume) mannitol, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-PD-1 antibody, and

c) a third pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-CTLA-4 antibody.

Embodiment 738 A pharmaceutical combination for use in the treatment of a solid tumor, wherein the pharmaceutical combination contains:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 1 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)- 2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles characterized by an aluminum content of 2 mg/ml, 16 mM Tris buffer and 7.5% (weight/volume) sucrose, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-PD-1 antibody, and

c) a third pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-CTLA-4 antibody.

Embodiment 739 A pharmaceutical combination for use in the treatment of a solid tumor, wherein the pharmaceutical combination comprises:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 1 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)- 2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles characterized by an aluminum content of 2 mg/ml, 5 mM Tris buffer and 8.25% (weight/volume) mannitol, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-PD-1 antibody, and

c) a third pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-CTLA-4 antibody.

Embodiment 740 A pharmaceutical combination for use in the treatment of a solid tumor, wherein the pharmaceutical combination comprises:

a) the first pharmaceutical composition, characterized by pH 7.0-8.0, containing 1 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)- 2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles characterized by an aluminum content of 2 mg/ml, 5 mM Tris buffer and 8.25% (weight/volume) sucrose, and

b) a second pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-PD-1 antibody, and

c) a third pharmaceutical composition comprising an immune response checkpoint inhibitor and one or more pharmaceutically acceptable excipients, wherein the checkpoint inhibitor is an anti-CTLA-4 antibody.

Embodiment 741 A pharmaceutical combination according to any one of Embodiments 731-740, wherein the anti-PD-1 antibody is an anti-PD-1 antibody from Table 3.

Embodiment 742. The pharmaceutical combination according to any one of embodiments 731-740, wherein the anti-PD1 antibody is an anti-PD-1 antibody comprising a heavy chain variable domain that comprises the amino acid sequence of SEQ ID NO: 27 and a light variable domain. chain which contains the amino acid sequence under SEQ ID NO: 37.

Embodiment 743. The method according to any of Embodiments 165-189, or Embodiments 353-363, or Embodiments 382-434, or Embodiments 519-622, wherein the solid tumor is head and neck squamous cell carcinoma (HNSCC) , melanoma or visceral tumor.

Embodiment 744 Use according to any of Embodiments 190-211 or Embodiments 364-371 or Embodiments 435-476 or according to any of Embodiments 623-682 wherein the solid tumor is a squamous cell carcinoma of the head and neck (HNSCC), melanoma or visceral tumor.

Embodiment 745. The pharmaceutical composition according to any of Embodiments 212-234 or Embodiments 372-381, wherein the solid tumor is head and neck squamous cell carcinoma (HNSCC), melanoma, or visceral tumor.

Embodiment 746. The pharmaceutical combination according to any one of Embodiments 478-518 or Embodiments 683-742, wherein the solid tumor is head and neck squamous cell carcinoma (HNSCC), melanoma, or visceral tumor.

Embodiment 747. The use of a pharmaceutical composition according to any of Embodiments 1-4, Embodiments 10-83, or Embodiments 161-164 for the manufacture of a medicament for the treatment of a solid tumor.

Embodiment 748. Use according to embodiment 747, wherein the solid tumor is head and neck squamous cell carcinoma (HNSCC), melanoma, or visceral tumor.

Embodiment 749. The use of a pharmaceutical combination according to any of Embodiments 235-352 for the manufacture of a medicament for the treatment of a solid tumor.

Embodiment 750. Use according to embodiment 749, wherein the solid tumor is head and neck squamous cell carcinoma (HNSCC), melanoma, or visceral tumor.

The effect on tumor volume of administering a compound of formula (A) in the presence of aluminum containing particles with and without administration of one or more checkpoint inhibitors is shown in Example 14. It was found that administration of a pharmaceutical composition containing a compound of formula (A) or a pharmaceutically acceptable compound thereof salt and aluminum-containing particles, proved to be as effective in enhancing the immune response to the tumor, when administered alone (not in combination), as the effect obtained by introducing a pharmaceutical composition containing a compound of formula (A) or its pharmaceutically acceptable salt and aluminum-containing particles in combinations with the introduction of an immune response checkpoint inhibitor. Figure 9A shows the efficacy achieved in a syngeneic tumor model using colonic MC38 cells for a pharmaceutical composition containing Compound 15 and aluminum hydroxide administered alone (not in combination) or administered in combination with administration of a pharmaceutical composition containing either a CTLA4 receptor inhibitor (anti-CTLA4 antibody) or a PD-L1 ligand inhibitor (anti-PD-L1 antibody). It is also apparent from Figure 9A that administering a pharmaceutical composition containing compound 15 and aluminum hydroxide alone is more effective than administering either a CTLA4 receptor inhibitor alone (not in combination) or administering a PD-L1 ligand inhibitor alone (not in combination) .

In addition, it was found that the immune response to the tumor was even further enhanced by the administration of a pharmaceutical composition containing a compound of formula (A) or a pharmaceutically acceptable salt thereof and aluminum particles in combination with the administration of two different checkpoint inhibitors. Figure 9 further shows the enhanced efficacy provided by the triple combination of two different checkpoint inhibitors and a pharmaceutical composition containing a compound of formula (A) or a pharmaceutically acceptable salt thereof and aluminum particles. In particular, Figure 9A shows the efficacy achieved by intratumoral administration of a pharmaceutical composition containing compound 15 and aluminum hydroxide in combination with a systemic (ip) CTLA4 receptor inhibitor and a separate systemic (ip) PD-L1 ligand inhibitor.

Figure 9A shows the data obtained from the injection site, while Figure 9B shows the data obtained from the site remote from the injection site. Figure 9B shows the same situation as described above for Figure 9A, which demonstrates the systemic antitumor efficacy of the compound of formula (A) adsorbed on aluminum hydroxide.

EXAMPLES

Compounds, pharmaceutical compositions containing such compounds, pharmaceutical combinations containing such compounds, methods of using such pharmaceutical compositions and pharmaceutical combinations and the use of such pharmaceutical compositions and pharmaceutical combinations of the present invention are shown in the following examples, which are intended to illustrate the present invention, and they are not should be interpreted as limiting it.

Materials and methods

Suspensions Compound 15/Alhydrogel ®

2% Alhydrogel® (aluminum hydroxide gel: 10 mg/ml aluminium) was obtained from Brenntag Biosector A/S, Elsenbakken 23, 3600 Frederikssund, Kingdom of Denmark and used as stock solution to dilute to obtain the required concentration of aluminum. As an example, Table 5 shows the volume of stock solution at a concentration of 20 mg/ml of compound 15 in 200 mm Tris buffer (pH 7.4), the volume of 2% Alhydrogel® and the volume of water used to form a final volume of 10 ml, with the required concentrations of aluminum and compound 15 in 20 mM Tris buffer.

Table 5

Final conc.
compounds 15
(mg/ml) Final conc.
aluminum
(mg/ml) Ratio of aluminum and compound 15 Volume
stock solution of compound 15
(ml) Volume
2% Alhydrogel® (ml) Water volume
(ml) 0.25 0.013 0.05:1 0.125 0.013 9.86 0.25 0.025 0.1:1 0.125 0.025 9.85 0.25 0.063 0.25:1 0.125 0.063 9.81 0.25 0.125 0.5:1 0.125 0.125 9.75 0.25 0.250 1:1 0.125 0.250 9.63 0.25 0.375 1.5:1 0.125 0.375 9.50 0.25 0.500 2:1 0.125 0.500 9.38 0.30 0.015 0.05:1 0.150 0.015 9.84 0.30 0.030 0.1:1 0.150 0.030 9.82 0.30 0.075 0.25:1 0.150 0.075 9.78 0.30 0.150 0.5:1 0.150 0.150 9.70 0.30 0.300 1:1 0.150 0.300 9.55 0.30 0.450 1.5:1 0.150 0.450 9.40 0.30 0.600 2:1 0.150 0.600 9.25 0.50 0.025 0.05:1 0.250 0.025 9.73 0.50 0.050 0.1:1 0.250 0.050 9.70 0.50 0.125 0.25:1 0.250 0.125 9.63 0.50 0.250 0.5:1 0.250 0.250 9.50 0.50 0.500 1:1 0.250 0.500 9.25 0.50 0.750 1.5:1 0.250 0.750 9.00 0.50 1,000 2:1 0.250 1,000 8.75 1.00 0.050 0.05:1 0.500 0.050 9.45 1.00 0.100 0.1:1 0.500 0.100 9.40 1.00 0.250 0.25:1 0.500 0.250 9.25 1.00 0.500 0.5:1 0.500 0.500 9.00 1.00 1,000 1:1 0.500 1,000 8.50 1.00 1,500 1.5:1 0.500 1,500 8.00 1.00 2,000 2:1 0.500 2,000 7.50 2.00 0.100 0.05:1 1,000 0.100 8.90 2.00 0.200 0.1:1 1,000 0.200 8.80 2.00 0.500 0.25:1 1,000 0.500 8.50 2.00 1,000 0.5:1 1,000 1,000 8.00 2.00 2,000 1:1 1,000 2,000 7.00 2.00 3,000 1.5:1 1,000 3,000 6.00 2.00 4,000 2:1 1,000 4,000 5.00 3.00 0.150 0.05:1 1,500 0.150 8.35 3.00 0.300 0.1:1 1,500 0.300 8.20 3.00 0.750 0.25:1 1,500 0.750 7.75 3.00 1,500 0.5:1 1,500 1,500 7.00 3.00 3,000 1:1 1,500 3,000 5.50 3.00 4,500 1.5:1 1,500 4,500 4.00 3.00 6,000 2:1 1,500 6,000 2.50 5.00 0.250 0.05:1 2,500 0.250 7.25 5.00 0.500 0.1:1 2,500 0.500 7.00 5.00 1,250 0.25:1 2,500 1,250 6.25 5.00 2,500 0.5:1 2,500 2,500 5.00 5.00 5,000 1:1 2,500 5,000 2.50 5.00 7,500 1.5:1 2,500 7,500 0.00

In preparing the Compound 15/Alhydrogel® suspension used in the examples herein, the Alhydrogel® stock suspension was filtered by gravity filtration through a 100 µm filter before being mixed with the stock solution containing Compound 15. The resulting mixture/suspension was stirred for 5 minutes to allow compound 15 to adsorb/bind to aluminum from Alhydrogel®.

To determine the degree of binding of Compound 15 to Alhydrogel® (i.e. % binding) in the Compound 15/Alhydrogel® suspension used in the examples herein, aliquots of the suspension were centrifuged to precipitate bound Compound 15/Alhydrogel® (e.g., 21,000 x g for 10 min.), and the amount of free compound 15 in the supernatant was analyzed by HPLC/UV or LC/MS/MS.

Animals.

All procedures related to animals were carried out in accordance with the provisions of the animal welfare law and the guidelines for the care and use of laboratory animals.

C57/Bl6 mice were purchased from Jackson Laboratory, Bar Harbor, Maine, USA.

Male Wistar rats (weight range 250~300 g) were purchased from Envigo, Indianapolis, IN,

USA.

Balb/c female mice from Charles River Laboratories (6-8 weeks old) were purchased from Jackson Laboratory, Bar Harbor, Maine, USA

cell lines

Cell lines MC38 and A20 were purchased from ATCC (American Type Culture Collection, Manassas, Virginia).

Pharmacokinetic regression analysis

Pharmacokinetic parameters were calculated using non-compartmental regression analysis using an in-house fitting program. Recorded the highest concentration of compound 15 (Cmax) in plasma and the corresponding time (T _max ). The area under each concentration-time curve, AUC0-t or AUC0-∞ was calculated using the linear trapezoidal rule. Clearance (CL), volume of distribution at steady state (Vss), and mean retention time (MRT) of compound 15 were calculated using data from the intravenous dose and the following equations:

CL=Dose/AUC _0-∞

Vss = (Dose* AUMC _0-∞ )/(AUC _0-∞ )

MRT = (AUMC _0-∞ )/(AUMC _0-∞ ) = Vss/CL

where AUC _0-∞ and AUMC _0-∞ are the area under the concentration versus time curve and the area under the first moment of the concentration versus time curve from time 0 to infinity, respectively.

Bioavailability after subcutaneous injection of free or adsorbed Alhydrogel LHC165 was assessed as follows:

F = (AUMC _0-∞,sc )/(AUMC _0-∞,iv ) * (Dose _iv /Dose _sc )

Percent Processing/Control (T/C)

Tumor treatment/control (T/C) percentages were calculated using the following formula:

%T/C=100×ΔT/ΔC if ΔT >0

% regression=100 × ΔT/T _original if ΔT <0,

where

T=mean tumor volume in the drug-treated group on the last day of the study;

ΔT=mean tumor volume in the drug-treated group on the last day of the study minus the mean tumor volume in the drug-treated group on the first day of dosing;

T _baseline = mean tumor volume in the drug-treated group on the first day of dosing;

C=mean tumor volume in the control group on the last day of the study;

ΔC=mean tumor volume on the last day of the study minus the mean tumor volume in the control group on the first day of dosing.

All data are expressed as mean ± standard error of the mean (SEM). Change in tumor volume

and body weights were used for statistical analysis. Comparisons between groups were made

using one-way ANOVA followed by Tukey's or Dunn's post hoc test. For all statistical

assessments, the significance level was set at p < 0.05. Significance compared to control group is given

with carrier medium, unless otherwise indicated.

Example 1 Synthesis of Exemplary Compounds

Compounds Nos. 1-28 of Table 1 were synthesized using the methods described in WO2011/049677.

Example 2 TLR7 Activation Assay

The EC _50s for TLR-7 stimulation with exemplary compounds of formula (A) are shown in Table 6. These EC _50s were obtained using a reporter gene assay where human embryonic kidney 293 (HEK 293) cells were stably transfected with human TLR7 and a vector with a NF-kB driven luciferase reporter gene (pNifty-Luciferase). Normal Hek293 transfected with pNifty-Luc was used as a control assay. Cells were cultured in DMEM supplemented with 2 mM L-glutamine, 10% heat-inactivated FBS, 1% penicillin and streptomycin, 2 µg/ml puromycin (InvivoGen no. ant-pr-5) and 5 µg/ml blasticidin (Invitrogen no. 46-1120) . Buffer and substrate for Bright-Glo™ luciferase assay were supplied from Promega #E263B and #E264B (substrate and assay buffer, respectively). Clear bottom 384 well plates were supplied from Greiner bio-one (#789163-G) and were individually barcoded plates. Cells were seeded at 25,000 cells/well in 384-well plates in a final volume of 50 μl of medium. The cells were allowed to adhere to the plates after overnight (18 hours) culture at 37° C. and 5% CO ₂ . Serially diluted test compounds and positive control compounds were then added to each well and incubated for 7 hours at 37° C. and 5% CO ₂ . Cells stimulated with DMSO alone also served as negative controls. After incubation, 30 µl of premixed assay buffer and substrate buffer was added to each well according to the manufacturer's instructions. The luminescent signal was read on a CLIPR instrument with an integration time of 20 seconds per plate. Dose-response curves were generated for each compound and EC ₅₀ values were defined as the concentration that provides 50% of the maximum signal. These EC ₅₀ values were obtained relative to resiquimod activity set at 100%.

Table 6

Number
connections EC ₅₀ (nM) human TLR7
HEK293 Number
connections EC ₅₀ (nM) human TLR7
HEK293 Number
connections EC ₅₀ (nM) human TLR7
HEK293 1 1640 eleven 90 21 204 2 226 12 201 22 1160 3 315 13 1051 23 791 four 3170 fourteen 885 24 4260 five 559 15 96 25 975 6 308 sixteen 65 26 2592 7 1010 17 137 27 921 8 375 eighteen five 28 524 nine 390 nineteen 964 10 153 20 384

Example 3 Adsorption of Compounds of Formula (A) onto Aluminum-Containing Particles

As an example, the percentage (%) binding of compounds 6, 15, 17, 18 and 20 with aluminum hydroxide in histidine buffer (pH 6.8) is shown in Table 7. The percentage (%) binding for compounds 6, 15, 17, 18 and 20 was prepared as follows: to three volume equivalents of aqueous aluminum hydroxide (2 mg/ml) was added one volume equivalent of the compound in 10 mM histidine buffer (4 mg/ml) at pH 6.8. The resulting solution was diluted 10-fold with blank histidine buffer to a final compound concentration of 0.1 mg/mL. The diluted solutions were incubated at 37°C for 5 hours. Samples were centrifuged at 14,000 rpm. for 10 minutes to precipitate insoluble substances. The supernatant (along with an internal standard) was then evaluated by LC-MS/MS using a superfast gradient (from 5% CH ₃ CN-0.5% formic acid to 95% CH ₃ CN-1.0% formic acid in 3 .5 minutes) on a Waters Atlantis dC18 column (50 mm x 2.1 mm) at room temperature compared to a calibration curve obtained with known compound concentrations ranging from 0.005 µM to 50 µM. Supernatant concentration was calculated as % unbound compound with aluminum hydroxide compared to control; % bound compound with aluminum hydroxide was calculated as 100% minus % unbound compound.

Table 7

Compound % binding 1 98.2 15 96.0 17 94.5 eighteen 96.2 20 97.0

Example 4 Bonding Efficiency of Compounds of Formula (A) to Aluminum-Containing Particles

The binding efficiency of the compounds of formula (A) to the aluminum containing particles, expressed as percentage (%) binding to the aluminum containing particles, depends on the ratio (w/w) of the aluminum containing particles to the compound and the final concentration (mg/mL) of the compound in suspension with aluminum hydroxide. As an example, the dependence of binding efficiency on the ratio (w/w) of aluminum-containing particles and compound is shown in Table 8, where the final concentration of compound 15 is fixed at 2 mg/ml, and the amount of aluminum hydroxide is changed to obtain the desired ratio. Percent bound Compound 15 was prepared as described above in the Materials and Methods section, and Compound 15/Alhydrogel® suspensions were prepared in 20 mM Tris buffer (pH 7.4) as described above in Compound 15/Alhydrogel® Suspensions .

Table 8

Final conc.
compounds 15
(mg/ml) Final conc.
aluminum
(mg/ml) Ratio of aluminum and compound 15 % bound
compounds 15 % free
compounds 15 2 0.1 0.05:1 9.6 90.4 2 0.2 0.1:1 12.5 87.5 2 0.5 0.25:1 25.7 74.3 2 1 0.5:1 43.5 56.5 2 2 1:1 80.8 19.2 2 3 1.5:1 97.6 2.4 2 four 2:1 99.7 0.3

However, at a fixed ratio of aluminum hydroxide and compound 15, it was observed that the binding efficiency also depended on the final concentration of compound 15 (see table 9).

Table 9

Final conc.
compounds 15
(mg/ml) Final conc.
aluminum
(mg/ml) Ratio of aluminum and compound 15 % bound
compounds 15 % free
compounds 15 0.25 0.625 2.5:1 90.7 9.3 0.25 five 20:1 97.6 1.4 1 2.5 2.5:1 93.5 6.5 3 7.5 2.5:1 97.1 2.9 3 five 1.7:1 99.6 0.4

Although, as seen in Table 10, % binding levels >97% were obtained for low final concentrations of Compound 15 by increasing the final aluminum concentration. Sustained release of the compound of formula (A) was observed for % binding >97, which allowed control of the systemic release of cytokines (see examples 5-9).

In addition, for ratios (wt/wt) of aluminum-containing particles and compounds of 1.5:1 and below, the binding efficiency has an obvious dependence on pH. The effect of pH on binding efficiency is seen in Table 10, which shows the binding efficiency of Compound 15 at a ratio of aluminum hydroxide to Compound 15 (w/w) of either 1.5:1 or 2:1. The percentage of bound compound was obtained as described above, despite the use of Tris buffer at different pH values. Compound 15/Alhydrogel® suspensions were prepared in Tris buffer under various conditions as described above under " Compound 15/Alhydrogel® Suspensions ".

Table 10

Ratio of aluminum hydroxide:compound 15 (w/w) pH % bound
compounds 15 1.5:1 7 98.5 1.5:1 7.5 85.9 1.5:1 8 91.1 2:1 7 99.3 2:1 7.5 99.7 2:1 8 99.1

Example 5 Injection Site Retention - Syngeneic Mouse Tumor Model Using MC38 Cells, One Week Study

Pharmacokinetic analysis in mice of free compound 15 and

compound 15 adsorbed on Alhydrogel ®

A syngeneic mouse tumor model using MC38 cells was used to determine systemic exposure to Compound 15 as follows:

a) single intratumoral (i.t.) injection of 100 μg (~4 mg/kg) free form of compound 15 in 20 mM Tris buffer at pH 7.4,

b) single intratumoral (i.t.) injection of Compound 15 adsorbed onto Alhydrogel® Suspension at a 1:1.5 (w/w) ratio of Compound 15 and Alhydrogel®)-Suspension A described below

and

c) a single subcutaneous (s.c.) injection of Compound 15 adsorbed onto Alhydrogel® Suspension at a 1:1.5 (w/w) ratio of Compound 15 and Alhydrogel® Suspension A, described below.

Suspension A:

2 mg/ml compound 15, 3 mg/ml aluminum hydroxide and 7.5% (w/v) sucrose in 16 mM Tris (pH 7.4) - compound 15/Alhydrogel® (ratio 1:1.5)

2% Alhydrogel® (aluminum hydroxide gel: 10 mg/ml aluminium) was obtained from Brenntag Biosector A/S, Elsenbakken 23, 3600 Frederikssund, Kingdom of Denmark and used as stock solution to dilute to obtain the required concentration of aluminum. A stock solution of 2.86 mg/mL Compound 15, 12.5% (w/v) sucrose in 33.4 mM Tris buffer (pH 7.4) was made to dilute with a stock solution of 2% Alhydrogel®. The table below shows the volumes used to prepare a 5 ml suspension containing 2 mg/ml compound 15, 3 mg/ml aluminum hydroxide and 7.5% (w/v) sucrose in 16 mM Tris (pH 7.4) at the ratio 1.5:1 Alhydrogel® and compounds 15.

Final conc.
connections 15
(mg/ml) Final conc.
aluminum
(mg/ml) Ratio of aluminum and compound 15 Volume
stock solution of compound 15
(ml) Volume
2% Alhydrogel® (ml) 2 3 1.5:1 3.5 1.5

Implantation of MC38 tumor cells in C57/BL6 mice

Cells MC38 were grown under sterile conditions in an incubator at 37°C with 5% CO ₂ for two weeks. Cells were cultured in DMEM medium supplemented with 10% FBS, cells were passaged every 2-3 days. On the day of injection, cells were harvested (passage 12) and resuspended in HBSS at a concentration of 2.5×10 ⁶ /ml. Cells were tested with Radil against mycoplasma and mouse viruses.

For each mouse, 0.25×10 ⁶ cells were implanted by subcutaneous injection in the right flank using a 28-1/2 g needle (injection volume 100 μl). Female C57BL/6 mice harboring MC38 tumor cells were randomized into separate groups (n=3-24 mice per group) 10 days after tumor cell implantation with a mean tumor volume in the range of 95.05-194.36 mm ³ .

Dosing and Sampling in MC38 Tumor-bearing C57/BL6 Mice

Approximately 10 days after implantation of MC38 tumor cells, mice bearing tumor cells received a single dose of vehicle medium, 100 μg of a solution of free compound 15 (2 mg/ml) or compound 15 adsorbed on Alhydrogel (1:1.5 w/w ; 97% binding), by direct intratumoral (i.t.) injection or subcutaneous (s.c.) injection. The dose volume was 50 μl per animal. Blood plasma samples were collected up to 7 days post-dose at the time points shown in Table 11 (n=3 animals at each time point).

Table 11

Dose
compound 15 (µg) Composition Points in time of collection of blood plasma samples after dosing (h) 100 (i.t.) 20 mM tris 0.083, 0.5, 1, 3, 6, 24 100 (i.t.) Suspension A 1, 6, 24, 48, 72, 96, 120, 144, 168 100 (s.c.) Suspension A 1, 6, 24, 48, 72, 96, 120, 144, 168

Analysis of Mouse Plasma Samples by LC/MS/MS

Compound 15 plasma concentrations were quantified using liquid chromatography/mass spectrometry (LC/MS/MS) analysis. Compound 20 (100 ng/ml in water) was used as an internal standard. To 20 µl of each blood plasma sample or an appropriately diluted blood plasma sample was added 25 µl of the solution, which was used as an internal standard, then mixed with 150 µl of extraction solvent (methanol/acetonitrile, 80/20 v/v) to precipitate blood plasma proteins . Samples were vortexed for 5 minutes, then centrifuged using an Eppendorf Centrifuge 5810R (Eppendorf, Hamburg, Germany) at a setting of 4000 rpm. for 10 minutes at 4°C. An aliquot of the supernatant (50 µl) was transferred to a clean 96-well plate and mixed with 100 µl of Milli-Q water. The mixed samples were injected (25 µl) into a Waters XBridge C4 analytical column (2.1 x 50 mM, 3.5 µm) and the mobile phases consisted of 0.1% formic acid in water (Solvent A) and 0.1% formic acid. acids in acetonitrile (solvent B). Gradient elution method at a flow rate of 800 µl/min. applied from 20% B to 95% B in 1.5 minutes, held at 95% B for 2 minutes, and reset to 20% B in 2.1 minutes, total run time was 3 minutes.

An HPLC system consisting of an Agilent 1200 series two-component mixture pump (Agilent Technologies Inc.), an Agilent 1200 series microvacuum degasser (Agilent Technologies Inc.), a CTC PAL-HTC automatic dispenser (LEAP Technologies, Carborough, NC, USA) was connected to mass spectrometer AB Sciex API 4000 QTrap (AB Sciex LLC., Framingham, Massachusetts, USA). Mass spectral analyzes were performed using electrospray ionization (ESI) in positive ion detection mode. Compound 15 (604.2>281.0) and internal standard (598.2>263.1) peaks were integrated using AnalystTM 1.4 software. The lower limit of quantification (LLOQ) in plasma was 0.25 ng/mL. Known amounts of Compound 15 were added to blood plasma to form quality control samples at known concentrations of 4, 40, 200 and 1000 ng/mL.

Plasma PK profiles of Compound 15 are shown in Figure 1 and systemic exposures are summarized in Table 12. Direct intratumoral (it) injection of 100 μg of Alhydrogel® soluble or adsorbed Compound 15 in mice harboring MC38 tumor cells resulted in very different PK- profiles. Without Alhydrogel®, the soluble free form of Compound 15 was very rapidly released into the systemic circulation and most of the drugs were eliminated within 24 hours after it injection with a half-life of 2.65 hours. Compound 15 adsorbed on Alhydrogel® (or referred to as Compound 15 /Alhydrogel®) resulted in a controlled release PK profile of compound 15 compared to soluble compound 15. T _max was delayed and C _max was significantly reduced to 2~4% of that after it injection of soluble compound 15.

The half-life of Compound 15 adsorbed to Alhydrogel® was significantly longer and the slow release profile observed for Compound 15 adsorbed to Alhydrogel® demonstrates prolonged retention of Compound 15 in the local tumor environment. In addition, subcutaneous injection of Compound 15/Alhydrogel® resulted in a similar systemic PK profile as that obtained after it injection (FIG. 1), with a similar C _max but greater AUC. AUC after a single sc or it injection of 100 μg compound 15/Alhydrogel® was ~60% and 96% after it injection of 100 μg soluble compound 15, suggesting that most of the compound 15 was desorbed from Alhydrogel® and systematically eliminated 1 week after it or sc injections.

Table 12

Dose
compound 15 (µg) Composition T _1/2 (h) T _max (h) _Cmax (ng/ml) AUC _(0-∞)
(ng*h/ml) 100 (i.t.) 20 mM tris 2.65 0.083 10611 6219 100 (i.t.) Suspension A 56.9 1-6 202 2762 100 (s.c.) Suspension A 29.4 1-6 191 6061

where AUC(0-∞) is the area under the curve starting from moment zero and extrapolated to infinity;

C _max is the maximum observed concentration;

T _max is the time at which the maximum concentration is observed

Note. The pharmacokinetic properties of compound 15 were studied in female C57/BL6 mice after a single intravenous bolus of 2 mg/kg. The compound exhibited a low plasma clearance of 18.1 ml/min/kg, which is ~20% of mouse hepatic blood flow (90 ml/min/kg, Davies and Morris 1993). The mean volume of distribution at steady state was low (0.19 L/kg) compared to total body water (0.725 L/kg, Davies and Morris 1993). Compound 15 had a short retention time (MRT) of 0.17 hours and a half-life of 1 hour in the mouse.

Example 6 Injection Site Retention - Syngeneic Mouse Tumor Model Using MC38 Cells, 2 Week Study

Pharmacokinetic analysis in mice of compound 15 adsorbed on Alhydrogel ®

To evaluate systemic exposure to Compound 15 over a long period of time, a syngeneic mouse tumor model using MC38 cells was used as described in Example 5, where the plasma concentration of Compound 15 was monitored for 2 weeks after a single 50-µl intratumoral (i.t.) or A 50 µl subcutaneous (s.c.) injection of Suspension B (described below), which delivered 100 µg of Compound 15. Suspension B contains Compound 15/Alhydrogel® in a 1:2 ratio.

suspension B.

2 mg/ml compound 15, 4 mg/ml aluminum hydroxide and 7.5% (w/v) sucrose in 16 mM Tris (pH 7.4) - compound 15/Alhydrogel® (ratio 1:2)

2% Alhydrogel® (aluminum hydroxide gel: 10 mg/ml aluminium) was obtained from Brenntag Biosector A/S, Elsenbakken 23, 3600 Frederikssund, Kingdom of Denmark and used as stock solution to dilute to obtain the required concentration of aluminum. A stock solution of 3.34 mg/mL Compound 15, 9.375% (w/v) sucrose in 20 mM Tris buffer (pH 7.4) was made to dilute with a stock solution of 2% Alhydrogel®. The table below shows the volumes used to prepare a 5 ml suspension containing 1 mg/ml compound 15, 2 mg/ml aluminum hydroxide and 7.5% (w/v) sucrose in 16 mM Tris (pH 7.4) at the ratio 2:1 Alhydrogel® and compounds 15.

Final conc.
compounds 15
(mg/ml) Final conc.
aluminum
(mg/ml) Ratio of aluminum and compound 15 Volume
stock solution of compound 15
(ml) Volume
2% Alhydrogel® (ml) 2 four 2:1 3 2

Blood plasma samples were obtained and analyzed as described in example 5. Systemic PK profiles of compound 15 in mice bearing MC38 tumor cells were similar to those shown in figure 1, showing a delayed release of compound 15 into the systemic circulation from compound 15/ Alhydrogel® remaining in local injection sites. Pharmacokinetic parameters (PK) are summarized in Table 13.

Table 13

Dose
compound 15 (µg) Composition T _max (h) _Cmax (ng/ml) AUC _(0-∞)
(ng*h/ml) 100 (i.t.) Suspension B 1 343 8526 100 (s.c.) Suspension B 6 388 9799

where AUC(0-∞) is the area under the curve starting from moment zero and extrapolated to infinity;

C _max is the maximum observed concentration;

T _max is the time at which the maximum concentration is observed

Compound 15/Alhydrogel® Suspension provided a steady, slow and sustained release of Compound 15 into the systemic circulation, retaining Compound 15 at local injection sites for up to 2 weeks after intratumoral (i.t.) injection and thereby prolonging and maximizing local activation, resulting in enhanced antitumor efficacy. The systemic Cmax of Compound 15 was significantly reduced, thereby minimizing the amount of systemically produced cytokines and potential side effects associated with cytokines (see Examples 7 and 8). Subcutaneous (s.c.) and intratumoral (i.t.) injections of Compound 15/Alhydrogel® suspension resulted in similar systemic PK profiles of Compound 15.

Example 7 Cytokine Profiles - Syngeneic Mouse Tumor Model Using MC38 Cells, One Week Study

Pharmacodynamic analysis in mice of free compound 15 and

compound 15 adsorbed on Alhydrogel ®

A syngeneic mouse tumor model using MC38 cells (see Example 5) was used to generate plasma cytokine profiles including TNFa, IL-6 and IP-10 as follows:

a) a single 50 μl intratumoral (i.t.) injection of 100 μg (~4 mg/kg) of the free form of compound 15 in 20 mM Tris buffer at pH 7.4,

b) a single 50 µl intratumoral (i.t.) injection of Compound 15 adsorbed onto Alhydrogel® Suspension at a 1:1.5 (w/w) ratio of Compound 15 and Alhydrogel®)-Suspension A described above,

and

c) a single 50 μl subcutaneous (s.c.) injection of Compound 15 adsorbed onto Alhydrogel® Suspension at a 1:1.5 (w/w) ratio of Compound 15 and Alhydrogel® Suspension A as described above.

Blood plasma samples obtained in Example 5 were analyzed to obtain plasma levels of cytokines such as tumor necrosis factor alpha (TNFα), interleukin 6 (IL-6) and interferon-gamma-induced protein 10 (IP-10).

Cytokine measurements. IP-10 levels measured by ELISA

Plasma levels of IP-10 (the closest biomarker) were measured using the Quantikine CxCL10/IP-10 mouse ELISA kit (R&D Systems, Minneapolis, MN). Blood plasma samples were diluted 1:5 with a calibrator dilution solution. 50 µl of assay diluent/well was added to pre-coated plates followed by standard, control, or diluted samples/well. The plate was incubated for 2 hours at room temperature with shaking. After 2 hours of incubation, the solution was decanted and the wells were washed 5 times with 400 µl of wash buffer. 100 μl mouse IP-10 conjugate/well was added and the plate was incubated for 2 hours at room temperature with shaking. The solution was decanted and the washing step was repeated as described above. 100 μl substrate solution/well was added and the plate was incubated for 30-45 minutes at room temperature protected from light. Finally, 100 μl stop solution/well was added followed by absorbance measurement at 450 nm using a SpectraMax Plus microplate reader (Molecular Devices). The lower limit of detection (LLOQ) for IP-10 from this measurement was 125 pg/mL, the effective LLOQ for unknown plasma samples was 625 pg/mL due to a 5-fold dilution.

Plasma IP-10 levels were also measured using the Platinum IP-10 mouse ELISA kit (eBioscience, San Diego, CA) according to the manufacturer's protocol. Briefly, microplate strips were pre-coated with anti-mouse IP-10 polyclonal antibody and washed 2 times with 400 μl wash buffer. 100 µl of diluted plasma samples (1:10 dilution), standard (1:2 dilution) and blanks/well were added followed by 50 µl of biotin conjugate/well. The plate was incubated on a microplate shaker set at 400 rpm. for 2 hours at room temperature. The supernatant was removed and the wells were washed 6 times with 400 μl wash buffer. 100 μl/well streptavidin-HRP was added and the plate was incubated with shaking for 1 hour at room temperature. The supernatant was removed and the washing step was repeated as described above. 100 μl/well of TMB substrate solution was added and incubated at room temperature for 10 minutes protected from light. The enzymatic reaction was stopped by adding 100 μl/well stop solution followed by absorbance measurement at 450 nm using a SpectraMax Plus microplate reader (Molecular Devices). The lower limit of detection (LLOQ) for IP-10 from this measurement was 7.8 pg/mL, the effective LLOQ for unknown plasma samples was 78 pg/mL due to a 10-fold dilution.

Cytokine measurements. IL-6 and TNFα levels

Levels of IL-6, TNFa, and other cytokines were measured using the MultiPlex Proinflammatory Cytokine 1 Panel ELISA Kit for Mouse (Meso Scale Discovery (MSD), Rockville, MD) according to the manufacturer's protocol. Briefly, 50 μl/well of the resulting control or diluted blood plasma samples (1:2 with diluent 41) was added to a plate pre-coated with immobilized antibodies at independent sites in each well. The plate was incubated for 2 hours at room temperature with shaking, the solution was decanted and the plate was washed 3 times with 200 μl PBS/0.05% Tween 20. Then a detection antibody conjugated with electrochemiluminescent tags (MSD SulfoTag) (25 μl/ well) and the incubation was repeated as described above. The detection antibody solution was removed and the washing step was repeated. Finally, 150 μl of 2x Reading Buffer T was added to each well followed by measurement on a Sector Imager 6000 (Meso Scale Discovery). The effective LLOQ in unknown plasma samples was 0.3 pg/ml for TNFα and 1.8-2.8 pg/ml for IL-6.

Cytokine release profiles

Blood plasma samples from Example 5 were measured for several concentrations of cytokine proteins including IP-10 by ELISA, TNFα, IL-6 and other cytokines by multiplex analysis from Meso scale discovery (MSD).

Blood plasma samples were diluted 2-fold prior to cytokine measurements using multiplex analysis from MSD and TNFα, IL-6 profiles are shown in Figure 2A and Figure 2B. Both after i.t. and after s.c. injection of Compound 15/Alhydrogel® into mice harboring MC38 tumor cells, TNFα and IL-6 levels increased from pre-dose levels, where the maximum induction of production occurred ∼1 hour post-injection, and cytokine levels returned to baseline after 24 hours after dosing. However, in mice injected intratumorally with 15/Alhydrogel®, both TNFα and IL-6 subsequently increased above baseline from 96 hours to 168 hours post-dose, with mice that the introduction was carried out s.c., the levels of cytokines remained at the original value.

The plasma profiles of IP-10 are shown in Figure 2C, the maximum induction of IP-10 production occurred 1~6 hours after it or sc injection of Compound 15/Alhydrogel®, similar to or slightly delayed with respect to the T _max of the systemic concentration of Compound 15 IP-10 levels returned to baseline 24~48 hours post-dose, however, in the it dosed groups, IP-10 levels were elevated again between 72 hours and 168 hours. those observed for TNFα and IL-6.

Example 8 Cytokine Profiles - Syngeneic Mouse Tumor Model Using MC38 Cells, 2 Week Study

Pharmacodynamic analysis in mice of compound 15 adsorbed on Alhydrogel ®

To assess the profiles of plasma cytokines, TNFa, IL-6 and IP-10, over a long period of time, a syngeneic tumor model in mice using MC38 cells was used, as described in example 5, where the levels of TNFa, IL-6 and IP- 10 was monitored for 2 weeks after a single 50 µl intratumoral (i.t.) or 50 µl subcutaneous (s.c.) injection of Suspension B (described above), which delivered 100 µg of Compound 15. Suspension B contains Compound 15/Alhydrogel® in the ratio 1:2.

TNFa, IL-6 and IP-10 levels were generated and analyzed as described in Example 5 and Example 7. The resulting profiles for TNFα and IL-6 are shown in Figure 3A and Figure 3B, where after both i.t. and s.c. injection of Compound 15/Alhydrogel® into mice harboring MC38 tumor cells, TNFα and IL-6 levels increased compared to pre-dose levels, and maximal induction of production occurred ∼1 h post-injection, with cytokine levels returning to baseline after 24 hours after dosing. In mice injected with compound 15/Alhydrogel® intratumorally (i.t.), both TNFα and IL-6 subsequently increased above baseline from 96 hours to 288 hours post-dose, with mice treated with s.c., cytokine levels remained at baseline after 24 h. , was due to the effect of compound 15. In general, the profiles were similar to those observed in the one-week study (example 7). Plasma levels of IP-10 are shown in Figure 3C. Like TNFα and IL-6, plasma levels of IP-10 were induced after i.t. and s.c. compound 15/Alhydrogel® injection.

The free soluble form of compound 15, which was injected intratumorally (i.t.), was rapidly released from the injection site with a Tmax ≤5 min, and 24 hours after injection, essentially the entire volume of injected compound 15 was released and eliminated. However, if Compound 15 is adsorbed onto Alhydrogel®, the high rate of release of Compound 15 into the systemic circulation is minimized and controlled release profiles are observed with Compound 15 slowly released over a period of no more than 2 weeks. Specifically, Cmax was reduced and half-life was increased, suggesting that there is a longer local retention of compound 15/Alhydrogel® at the injection site, thereby minimizing the amount of systemically produced cytokines and potential side effects associated with cytokines. The production of systemic cytokines, TNFα and IL-6, was induced as a result of activation of the TLR7 pathway after i.t. and s.c. Compound 15/Alhydrogel® injections with maximal induction of such cytokines occurring 1~6 hours post-injection, similar to or slightly delayed in relation to Compound 15 systemic PK Tmax. into the systemic circulation, however, the second wave of cytokine induction observed in the period from 96 hours to no more than 2 weeks after a single i.t. Compound 15/Alhydrogel® injections (not observed in mice dosed with Compound 15/Alhydrogel® were injected subcutaneously) may display target recruitment, activation, and changes in the local tumor environment.

Example 9 Injection Site Retention - Dosing Study in Wistar Rats

Pharmacokinetic analysis in Wistar rats of free compound 15 and

compound 15 adsorbed on aluminum hydroxide

The pharmacokinetic properties of Compound 15 were studied in unexposed male Wistar rats as follows:

a) a single 200 μl subcutaneous (s.c.) injection of 600 μg free form of compound 15 in 100 mM Tris buffer at pH 7.4;

b) a single 200 μl subcutaneous (s.c.) injection of 50 μg of compound 15 adsorbed on aluminum hydroxide at a ratio of 1:2.5 (w/w) of compound 15 and aluminum hydroxide suspension E described below;

c) a single 200 µl subcutaneous (s.c.) injection of 200 µg of compound 15 adsorbed on aluminum hydroxide at a ratio of 1:2.5 (w/w) of compound 15 and aluminum hydroxide suspension D described below,

and

d) a single 200 μl subcutaneous (s.c.) injection of 600 μg of compound 15 adsorbed on aluminum hydroxide at a 1:2.5 (w/w) ratio of compound 15 and aluminum hydroxide suspension C described below.

Suspension C:

3 mg/ml compound 15, 7.5 mg/ml aluminum hydroxide in 100 mM Tris (pH 7.4) - compound 15/Alhydrogel® (ratio 1:2.5)

2% Alhydrogel® (aluminum hydroxide gel: 10 mg/ml aluminium) was obtained from Brenntag Biosector A/S, Elsenbakken 23, 3600 Frederikssund, Kingdom of Denmark and used as stock solution to dilute to obtain the required concentration of aluminum. Prepare a stock solution of 12 mg/mL Compound 15 in 400 mM Tris-HCl buffer (pH 7.4) and mix with a stock solution of 2% Alhydrogel® (10 mg/mL aluminum hydroxide) to prepare Suspension C.

The table below shows the volumes used to prepare 10 ml suspension C containing 3 mg/ml compound 15 and 7.5 mg/ml aluminum hydroxide in 100 mM Tris (pH 7.4) at a ratio of 2.5:1 Alhydrogel® and connections 15.

Final conc.
connections 15
(mg/ml) Final conc.
aluminum
(mg/ml) Ratio of aluminum and compound 15 Volume
stock solution of compound 15
(ml) Volume
2% Alhydrogel® (ml) 3 7.5 2.5:1 2.5 7.5

Suspension D:

1 mg/ml compound 15, 2.5 mg/ml aluminum hydroxide in 100 mM Tris (pH 7.4) - compound 15/Alhydrogel® (ratio 1:2.5)

2% Alhydrogel® (aluminum hydroxide gel: 10 mg/ml aluminium) was obtained from Brenntag Biosector A/S, Elsenbakken 23, 3600 Frederikssund, Kingdom of Denmark and used as stock solution to dilute to obtain the required concentration of aluminum. A stock solution of 4 mg/mL compound 15 in 200 mM Tris-HCl buffer (pH 7.4) was prepared and mixed with a stock solution of 2% Alhydrogel® (10 mg/mL aluminum hydroxide) to form suspension D.

The table below shows the volumes used to prepare 10 ml suspension D containing 1 mg/ml compound 15 and 2.5 mg/ml aluminum hydroxide in 100 mM Tris (pH 7.4) at a ratio of 2.5:1 Alhydrogel® and connections 15.

Final conc.
connections 15
(mg/ml) Final conc.
aluminum
(mg/ml) Ratio of aluminum and compound 15 Volume
stock solution of compound 15
(ml) Volume
2% Alhydrogel (ml) Volume
100 mM tris
(ml) 1 2.5 2.5:1 2.5 2.5 five

Suspension E:

0.25 mg/ml compound 15, 0.625 mg/ml aluminum hydroxide in 100 mM Tris (pH 7.4) - compound 15/Alhydrogel® (ratio 1:2.5)

2% Alhydrogel® (aluminum hydroxide gel: 10 mg/ml aluminium) was obtained from Brenntag Biosector A/S, Elsenbakken 23, 3600 Frederikssund, Kingdom of Denmark and used as stock solution to dilute to obtain the required concentration of aluminum. A stock solution of 1 mg/mL compound 15 in 125 mM Tris-HCl buffer (pH 7.4) was prepared and mixed with a stock solution of 2% Alhydrogel® (10 mg/mL aluminum hydroxide) to form suspension E.

The table below shows the volumes used to prepare 10 ml suspension E containing 0.25 mg/ml compound 15 and 0.625 mg/ml aluminum hydroxide in 100 mM Tris (pH 7.4) at a ratio of 2.5:1 Alhydrogel® and connections 15.

Final conc.
connections 15
(mg/ml) Final conc.
aluminum
(mg/ml) Ratio of aluminum and compound 15 Volume
stock solution of compound 15
(ml) Volume
2% Alhydrogel (ml) Volume
100 mM tris
(ml) 0.25 0.625 2.5:1 2.5 0.625 6.875

In this study, male Wistar rats (n=3 per group) were injected subcutaneously (s.c.) with 600 μg of free compound 15 or increasing doses of 50, 200 and 600 μg of compound 15 absorbed on aluminum hydroxide. An injection volume of 200 μl of Suspension E, Suspension D and Suspension C was used to obtain 50, 200 and 600 μg of Compound 15 absorbed on aluminum hydroxide, respectively. The injection volume of 200 μl per rat was not normalized for the body weight of the rats. As described above, the compound 15/aluminum hydroxide ratio for slurry E, slurry D and slurry C is set to 1:2.5 w/w.

Blood samples (~100 μl each) were collected repeatedly by bloodletting from the saphenous vein of each rat up to 96 hours after dosing (see Table 9, sampling plan). Blood samples were centrifuged to separate blood plasma and plasma samples were frozen at -20°C until analysis using LC/MS/MS (as described in example 5) to obtain systemic concentrations of compound 15.

In addition, blood plasma samples were analyzed for interferon-gamma-induced protein 10 (IP-10) levels as described in Example 7.

Compound 15 plasma PK profiles are shown in Figure 4 and systemic effects are summarized in Table 14.

Table 14

Dose
compound 15 (µg) Composition % free compound 15 T _1/2 (h) T _max (h) _Cmax (ng/ml) AUC _(0-∞)
(ng*h/ml) 50 (s.c.) Suspension
E 9.3 2.2 0.38 45 188 200 (s.c.) Suspension
D 6.5 10.5 1.00 114 937 600 (s.c.) Suspension
C 2.9 21.1 0.83 185 2236 600 (s.c.) 100 mM tris one hundred 2.1 0.25 3655 2560

where AUC(0-∞) is the area under the curve starting from moment zero and extrapolated to infinity; Cmax is the maximum observed concentration; Tmax is the time at which the maximum concentration is observed.

Adsorption efficiency appears to decrease at low compound 15 concentrations (at a fixed compound 15/aluminum hydroxide ratio), resulting in a higher percentage of free compound 15 and hence an increase in systemic IP-10 (see below).

The total AUC increased approximately in proportion to the dose of a single subcutaneous injection of 50-600 µg of compound 15 adsorbed on aluminum hydroxide, with Cmax increasing less proportional to the dose level, probably due to the higher percentage of the free form of compound 15 at a lower dose and resulting more short half-lives at lower doses.

Figure 4 shows that at a dose level of 600 μg, free compound 15 in 100 mM Tris buffer exhibits a rapid release of compound 15 into the systemic circulation after subcutaneous injection (plasma concentration 3655 ng/ml at the first sampling time 0, 25 hours), while if compound 15 was adsorbed on aluminum hydroxide, a sustained release profile was obtained. Also, compared to the free form of compound 15, Cmax was reduced and the half-life was increased for compound 15 adsorbed on aluminum hydroxide.

Note. The pharmacokinetic properties of Compound 15 in 50 mM Tris/0.9% NaCl (pH 7.4) were studied in male Wistar rats after a single intravenous bolus of 1 mg/kg. The compound exhibited a low plasma clearance of 9.2 ml/min/kg, which is ~17% of the rat hepatic plasma flow (55 ml/min/kg, Davies and Morris 1993). The mean volume of distribution at steady state was low (0.11 L/kg) compared to the extracellular fluid volume (0.3 L/kg, Davies and Morris 1993). As a result, the compound exhibited a short retention time (MRT) of 0.2 hours and a terminal half-life of 1.2 hours.

Example 10 Retention at the injection site - Wistar rat study

Pharmacokinetic analysis in Wistar rats of free compound 15 and

compound 15 adsorbed on aluminum hydroxide

The pharmacokinetic properties of Compound 15 were studied in unexposed male Wistar rats as follows:

a) a single 200 μl subcutaneous (s.c.) injection of 600 μg free form of compound 15 in 100 mM Tris buffer at pH 7.4;

b) a single 200 μl subcutaneous (s.c.) injection of 50 μg of compound 15 adsorbed on aluminum hydroxide at a 1:20 (w/w) ratio of compound 15 and aluminum hydroxide suspension G described below;

and

c) a single 200 μl subcutaneous (s.c.) injection of 600 μg of compound 15 adsorbed on aluminum hydroxide at a ratio of 1:1.7 (w/w) of compound 15 and aluminum hydroxide suspension F, described below.

Suspension F:

3 mg/ml compound 15, 5 mg/ml aluminum hydroxide in 100 mM Tris (pH 7.4) - compound 15/Alhydrogel ® (ratio 1:1.7)

2% Alhydrogel® (aluminum hydroxide gel: 10 mg/ml aluminium) was obtained from Brenntag Biosector A/S, Elsenbakken 23, 3600 Frederikssund, Kingdom of Denmark and used as stock solution to dilute to obtain the required concentration of aluminum. A stock solution of 12 mg/mL compound 15 in 300 mM Tris-HCl buffer (pH 7.4) was prepared and mixed with a stock solution of 2% Alhydrogel® (10 mg/mL aluminum hydroxide) to form suspension F.

The table below shows the volumes used to prepare 10 ml suspension F containing 3 mg/ml compound 15 and 5 mg/ml aluminum hydroxide in 100 mM Tris (pH 7.4) at a ratio of 1.7:1 Alhydrogel® and compound 15 .

Final conc.
connections 15
(mg/ml) Final conc.
aluminum
(mg/ml) Ratio of aluminum and compound 15 Volume
stock solution of compound 15
(ml) Volume
2% Alhydrogel (ml) Volume
100 mM tris
(ml) 3 five 1.7:1 2.5 five 2.5

Suspension G:

0.25 mg/ml compound 15, 5 mg/ml aluminum hydroxide in 100 mM Tris (pH 7.4) - compound 15/Alhydrogel® (ratio 1:20)

2% Alhydrogel® (aluminum hydroxide gel: 10 mg/ml aluminium) was obtained from Brenntag Biosector A/S, Elsenbakken 23, 3600 Frederikssund, Kingdom of Denmark and used as stock solution to dilute to obtain the required concentration of aluminum. A stock solution of 1 mg/mL compound 15 in 200 mM Tris-HCl buffer (pH 7.4) was prepared and mixed with a stock solution of 2% Alhydrogel® (10 mg/mL aluminum hydroxide) to form suspension G.

The table below shows the volumes used to prepare 10 ml suspension G containing 0.25 mg/ml compound 15 and 5 mg/ml aluminum hydroxide in 100 mM Tris (pH 7.4) at a ratio of 20:1 Alhydrogel® and compound 15 .

Final conc.
compounds 15
(mg/ml) Final conc.
aluminum
(mg/ml) Ratio of aluminum and compound 15 Volume
stock solution of compound 15
(ml) Volume
2% Alhydrogel (ml) Volume
100 mM tris
(ml) 0.25 five 20:1 2.5 five 2.5

The systemic concentration of compound 15 was assessed after a single 200 μl subcutaneous injection of two different dose levels of compound 15 adsorbed on aluminum hydroxide, where the aluminum hydroxide was at a fixed dose concentration of 5 mg/ml.

In this study, male Wistar rats from two groups (n=3 per group) were injected subcutaneously (s.c.) with either 50 μg or 600 μg of Compound 15 adsorbed on aluminum hydroxide. An injection volume of 200 µl of Suspension G and Suspension F was used to obtain 50 and 600 µg of compound 15 absorbed on aluminum hydroxide, respectively. The injection volume of 200 μl per rat was not normalized for the body weight of the rats. As described above, the ratio compound 15/aluminum hydroxide for slurry F was 1:1.7 w/w, while for slurry G it was 1:20 w/w.

Blood samples (~100 μl each) were collected repeatedly by bloodletting from the saphenous vein of each rat up to 168 hours after dosing (see Table 9, sampling plan). Blood samples were centrifuged to separate blood plasma and plasma samples were frozen at -20°C until analysis using LC/MS/MS (as described in example 5) to obtain systemic concentrations of compound 15.

In addition, blood plasma samples were analyzed for interferon-gamma-induced protein 10 (IP-10) levels as described in Example 7.

In this study, two formulations with a fixed concentration of aluminum hydroxide (5 mg/mL) but differing in the concentration of compound 15 (i.e., two different ratios of compound 15 and aluminum hydroxide) were used to evaluate the binding efficiency for systemic exposure to compound 15. compound 15 after a single s.c. 50 and 600 μg compound 15/aluminum hydroxide injections are summarized in Table 15 and the PK profiles are illustrated in Figure 5A. Data obtained in example 9 for the free form of compound 15 in 100 mm Tris buffer is also included.

Table 15

Dose
compound 15 (µg) Composition % free compound 15 T _1/2 (h) T _max (h) _Cmax (ng/ml) AUC _(0-∞)
(ng*h/
ml) 50 (s.c.) Suspension
G 1.4 12.3 7 7 164 600 (s.c.) Suspension
F 0.4 37.3 7 48 2053 600 (s.c.) 100 mM tris one hundred 2.1 0.25 3655 2560

where AUC(0-∞) is the area under the curve starting from moment zero and extrapolated to infinity;

Cmax is the maximum observed concentration;

Tmax is the time at which the maximum concentration is observed.

As seen in Table 15, the two formulations resulted in a high level of adsorption of compound 15 to aluminum hydroxide (>98%). When comparing the PK data obtained from example 9 and example 10, it becomes apparent that the AUC for dose levels of both 50 μg and 600 μg is similar, with Tmax delayed and Cmax values further reduced in example 10.

Figure 5A shows the systemic PK profiles of Compound 15 obtained from various doses, which show that adsorption of Compound 15 to aluminum hydroxide results in a steady, slow, and sustained release of Compound 15 into the systemic circulation and retains Compound 15 at local injection sites for no more than 1 week after subcutaneous injection.

Figure 5B shows plasma IP-10 profiles in male Wistar rats after a single subcutaneous injection of free compound 15 or compound 15 adsorbed on aluminum hydroxide at dose levels of 50 and 600 μg. The PD response, as measured by the induction of IP-10 production, was delayed relative to plasma Tmax and maximum IP-10 levels were reached between 7-24 hours post s.c. injections of 50 and 600 mcg compound 15/aluminum hydroxide. At the same time, the maximum IP-10 response occurred approximately 3 hours after s.c. injections of 600 µg of free compound 15. Also, compared with the results obtained with 600 µg of compound 15/aluminum hydroxide, the results obtained with 600 µg of free compound 15 showed higher peak levels of IP-10 with a rapid fall rate, which are consistent with the corresponding PK profiles.

Example 11 Systemic exposure to aluminum

ICP-MS was used to analyze serum aluminum levels after administration of compound 15 with aluminum hydroxide and after administration of aluminum hydroxide alone.

Whole blood samples were collected in a serum separation tube (Royal Blue Stopper Covidien Monoject™ trace element blood collection tube, code 8881307006). After collection, the tube was gently inverted 5 times to mix the clotting activator with the blood and allow clotting for at least 30 minutes in an upright position, but not more than 60 minutes at room temperature. The presence of a clot must be visually confirmed before centrifugation. All blood samples were centrifuged at about 1500-2200×g for about 10 minutes at room temperature. The resulting serum was poured/transferred (using metal-free Thomas Brand pipette tips/transfer tips) into uniquely labeled metal-free tubes (Multi Safeseal Sorenson™ microcentrifuge tubes) and frozen as soon as possible over dry ice before transferring to a freezer set to -80°C.

Containers/tubes/tips corresponding to the metal free/trace metal grade (<1 ng/g Al) were used to process the samples and the samples were transferred by transfusion or using metal free tips. The sample processing area was kept clean and free of dust, and the vein puncture site was cleaned with alcohol. Did not use iodine-containing products, including povidone-iodine-treated tampons or pads. Serum samples were not unwrapped with a wooden stick to remove clots and samples were not unwrapped with a wooden stick to promote serum transfer.

All containers, tubes and pipette tips were soaked in 10% Trace Metal Grade nitric acid overnight and then soaked in purified water for at least 12 hours. This was followed by rinsing with purified water at least three times before use.

The animals included in the study were divided into five groups, which received 2 ml/animal buffer without aluminum hydroxide (group 1) or 2 ml/animal buffer containing aluminum hydroxide formulated with compound 15 at a dose of 0 mg/animal (group 2), 0 .3 mg/animal (group 3), 1 mg/animal (group 4) and 2 mg/animal (group 5). The buffer used was 16 mM Tris, 7.5% (w/v) sucrose, pH 7.5 and for groups 2-5 aluminum hydroxide was present at 2 mg/ml.

Groups 1, 2, and 5 consisted of five animals/sex/group; two of which were for sensitivity studies. Groups 3 and 4 consisted of three animals/gender/group. Blood samples were collected from all animals on Day 1 pre-dose and at about 0.5, 3, 6, 24, 72 and 168 hours post-dose. Blood samples were collected from all main animals and animals included in the sensitivity studies on day 29 at about 0.5, 3, 6 and 24 hours after dosing. Blood samples were also collected from animals included in susceptibility studies (Groups 1, 2 and 5) on day 29 72 hours post-dose and on days 36, 43, 50, 57 and 63.

For ICP-MS analysis, 50 µl of sample (matrix substitute (for dual control and control), calibration standards (10-1000 ng/mL), QC samples (30, 300 and 750 ng/mL) and test samples) were added to a defined 1.5 ml metal-free plastic centrifuge tube pre-washed with acid as above. A 20 µl aliquot of the working solution that was used as an internal standard (50 ng/ml) and a 500 µl aliquot of 0.1% HNO3 were added to all tubes. This was followed by vortex mixing for approximately 3 minutes and centrifugation at 12,000 rpm. within 5 min. A 500 μl volume of supernatant from each tube was transferred to a designated plastic sample tube pre-washed with acid as above. All tubes were placed in an automatic dispenser in accordance with a pre-prepared analysis sequence.

Aluminum with a mass/charge of 27 and rhodium with a mass/charge of 103 were measured using an Agilent 7700x ICP-MS instrument (Agilent Technologies UK Ltd) equipped with an Agilent ASX-500 autosampler. Agilent MassHunter software (version C.01.02) was used for data acquisition and integration. Watson LIMS version 7.3 was used for sample management, data management, and calculation of sample concentrations. (Thermo Fisher Scientific, USA).

Automatic adjustment and verification of device settings.

An adjustment solution that contains 1 ng/mL of Ce, Co, Li, Mg, Tl, and Y in 2% HNO3 (Agilent lot #5188-6564 or equivalent) was used for automatic adjustment and adjustment verification. Automatic tuning was carried out when the ICP was ignited. The settings were checked at the beginning of the batch analysis. If the results of checking the settings did not meet certain criteria, the batch was automatically stopped.

Automatic dispenser and operating conditions.

Automatic dispenser Flushing the needle 8 seconds, pump speed 0.5 rpm Purified water Flushing 1 120 sec., pump speed 0.4 rpm 2% HNO ₃ /H ₂ O (v/v) Flushing 2 60 sec, pump speed 0.3 rpm 0.1% HNO ₃ /H ₂ O (v/v) Sample Introduction
20 sec., pump speed 0.4 rpm.
Stabilization 20 sec, pump speed 0.1 rpm

ICP-MS parameters.

Mass spectrometer with ICP Agilent 7700x Spray Concentric MicroMist Nebulizer Pace. spray chamber 2°C Operating mode He Settings* Serum RF power (W) 1550 RF matching (V) 1.8 Sampling depth (mm) 8.0 Carrier gas (l/min.) 1.00 Atomizer pump (r/s) 0.10 Auxiliary gas (l/min.) 0.10 lenses Extract 1 -5.8 Extract 2 -185 Offset Omega -90 Omega lens 7.4 Cell injection -112 Cell excretion -109 Deviation 8.2 Insert offset -104 Cell Gas (helium, ml/min.) 4.5 Offset Octp -18.2 OctP RF 200 Energy Discrimination 4.0 Peak integration pattern: 3 points
Recurrences: 3 Aluminum 0.099 sec. Rhodium ISTD 0.099 sec.

results

Quantifiable aluminum concentrations were not observed in serum samples collected from animals of the control group (group 1), the introduction of which was carried out without aluminum hydroxide and compound 15.

Figure 6 shows serum aluminum concentrations versus time post-dose for group 2 (aluminum hydroxide (2 ml/animal) Al(OH) ₃ in 16 mM Tris, 7.5% (w/v) sucrose, pH 7.5, (0 mg/animal compound 15)) and group 5 (aluminum hydroxide (2 ml/animal) Al(OH) ₃ in 16 mM Tris, 7.5% (w/v) sucrose, pH 7.5 , (2 mg/animal compound 15)). Figure 3 shows the difference in serum aluminum concentration between group 2 (no compound 15) and group 5 (2 mg/animal compound 15), indicating that systemic exposure to aluminum after administration of compound 15 bound to aluminum hydroxide, was significantly lower than systemic exposure after administration of aluminum hydroxide alone.

Example 12. Effect of aluminum on blood serum and urine

The pharmacokinetic properties and mass balance of aluminum and compound 15 were studied after a single subcutaneous (sc) dose (1 ml) of suspension H (compound 15/Alhydrogel® at a 2:1 ratio of aluminum and compound 15) in male Wistar rats. In addition, the pharmacokinetic properties of aluminum were studied after a single intravenous (iv) dose (0.5 ml) of 0.4 mg/ml AlCl ₃ ⋅6H ₂ O (equivalent to 0.2 mg aluminum) in male Wistar rats. Additionally, the control group, which was injected subcutaneously with a dose of saline, was evaluated in relation to the initial level of aluminum under environmental conditions.

Suspension H.

1 mg/ml compound 15, 2 mg/ml aluminum hydroxide and 5.5% (w/v) mannitol in 5 mM Tris (pH 7.5) - compound 15/Alhydrogel® (ratio 1:2)

2% Alhydrogel® (aluminum hydroxide gel: 10 mg/ml aluminium) was obtained from Brenntag Biosector A/S, Elsenbakken 23, 3600 Frederikssund, Kingdom of Denmark and used as stock solution to dilute to obtain the required concentration of aluminum. A 1.25 mg/mL stock solution of Compound 15, 6.875% (w/v) mannitol in 6.25 mM Tris buffer (pH 7.5) was made to dilute with a 2% Alhydrogel® stock solution. The table below shows the volumes used to prepare a 5 ml suspension containing 1 mg/ml compound 15, 2 mg/ml aluminum hydroxide and 5.5% (w/v) mannitol in 5 mM Tris (pH 7.5) at the ratio 2:1 Alhydrogel® and compounds 15.

Final conc.
connections 15
(mg/ml) Final conc.
aluminum
(mg/ml) Ratio of aluminum and compound 15 Volume
stock solution of compound 15
(ml) Volume
2% Alhydrogel® (ml) 1 2 2:1 four 1

Collection and processing of serum and urine samples: groups i.v. and s.c.

Containers/tubes/tips corresponding to the metal free/trace metal grade (<1 ng/g Al) were used to process the sample. The aluminum content was analyzed in blood serum and urine (Frontage Laboratories).

Approximately 0.3-0.5 ml blood samples were collected by carotid cannulation at 0 (pre-dose), 0.083 (IV only), 0.25 (IV only), 0.5, 3, 6, 24, 72, 168, 336, 504, 672 hours post dose.

Urine was collected from each animal during the following periods: 0 (24 hours pre-dose), 0-24, 24-48, 48-72, 72-96, 96-168 hours post-dose, then weekly until 672 hours. Urine samples were stored at -20°C until analysis. Feces were collected from each animal and samples were pooled for the subject at the end of the study at 672 hours.

Compound 15 and aluminum levels were analyzed in serum and urine samples obtained from group s.c., with only aluminum levels analyzed in group i.v.

Collection and processing of serum and urine samples: control groups

Approximately 0.3-0.5 ml blood samples were collected by carotid cannulation at 0 (pre-dosing), 0.5, 3, 24, 168, 336, 504, 672 hours post-dose. The blood samples were left at room temperature for at least 20 minutes. before centrifugation to obtain blood serum. Serum samples were transferred to another tube and stored at -70°C until analysis.

Urine was collected from each animal for the following periods: 0 (24 hours pre-dose), 0-24, 48-72, 96-168 hours post-dose, then weekly up to 672 hours. Urine samples were stored at -20°C before analysis. Feces were collected from each animal and samples were pooled for the subject at the end of the study at 672 hours. Fecal samples were stored at -20°C.

The figure 7 shows the concentration of aluminum in serum depending on the time profile after subcutaneous administration of suspension H and intravenous administration of AlCl ₃ ⋅6H ₂ O in saline.

Pharmacokinetic parameters of aluminum obtained after a single subcutaneous dose of Compound 15/Alhydrogel® (equivalent to 2 mg aluminum per animal) show low systemic exposure, with an average serum aluminum _Cmax of 76.2 ng/mL and an average _Tmax after 3 2 hours after dosing. AUC _last and AUC _inf were 3950 ng.h/ml and 4490 ng/ml, respectively. The half-life was 23.8 hours. Bioavailability was low (0.6%).

The pharmacokinetic parameters of aluminum obtained after a single intravenous dose of AlCl ₃ ⋅6H ₂ O (equivalent to 0.2 mg aluminum per animal) provided an average C _max of aluminum in serum of 26,000 ng/ml and an average T _max after 0.22 hours after dosing. AUC _last and AUC _inf were 67400 ng.h/ml and 67500 ng/ml, respectively. The half-life was 3.40 hours. CL was 0.71 ml/h, mainly via renal excretion based on mass balance data. Vss was the mean at 7.66 ml based on a total body water of 7.8 ml in the rat (Davies B and Morris T (1993) Physiological parameters in laboratory animals and humans, Pharmaceutical Research. Vol. 10, pp 1093-95 ).

After a single intravenous dose of AlCl ₃ ⋅6H ₂ O, urine was the only excretion analyzed and the mean urinary aluminum recovery was nearly complete at ~0.2 mg, suggesting that renal excretion was the major route of clearance. According to the mass balance after a single subcutaneous dose of compound 15/Alhydrogel®, most of the aluminum was found at the injection site (from 71.7% to 85.7%), with ~1% and ~2% of aluminum recovered in urine and feces, respectively . Traces of aluminum (<0.01%) were found in bone, brain, kidney and liver.

Based on the control group, the initial environmental exposure to aluminum in urine and serum was ~10 ng/mL.

Taken together, the obtained pharmacokinetic parameters of aluminum show that systemic levels of aluminum are low after a single subcutaneous dose of Compound 15/Alhydrogel, or after a single intravenous dose of AlCl ₃ ⋅6H ₂ O.

Finally, the pharmacokinetic parameters obtained for compound 15 after a single subcutaneous dose of suspension H were similar to those obtained in example 5, in particular, a mean C _max of 75.8 ng/ml was obtained for compound 15, with a mean T _max of 5 hours after dosing . AUC _last and AUC _inf were 3660 ng.h/ml and 3730 ng/ml, respectively. The half-life was 66.2 hours further demonstrating the controlled release of Compound 15 at the injection site.

Example 13 Efficiency in vivo as a separate tool

Suspension I.

4 mg/ml compound 15, 6 mg/ml aluminum hydroxide and 0.9% NaCl in 50 mM Tris (pH 7.4) - compound 15/Alhydrogel® (ratio 1:1.5)

2% Alhydrogel® (aluminum hydroxide gel: 10 mg/ml aluminium) was obtained from Brenntag Biosector A/S, Elsenbakken 23, 3600 Frederikssund, Kingdom of Denmark and used as stock solution to dilute to obtain the required concentration of aluminum. A 10 mg/mL stock solution of Compound 15, 2.25% (w/v) NaCl in 125 mM Tris buffer (pH 7.4) was made to dilute with a 2% Alhydrogel® stock solution. The table below shows the volumes used to prepare a 5 ml suspension containing 4 mg/ml compound 15, 6 mg/ml aluminum hydroxide and 0.9% NaCl in 50 mM Tris (pH 7.4) at a ratio of 1.5:1 Alhydrogel® and compounds 15.

Final conc.
compounds 15
(mg/ml) Final conc.
aluminum
(mg/ml) Ratio of aluminum and compound 15 Volume
stock solution of compound 15
(ml) Volume
2% Alhydrogel® (ml) Volume
water (ml) four 6 1.5:1 2.0 3.0 0.0

Suspension J.

2 mg/ml compound 15, 3 mg/ml aluminum hydroxide and 0.9% NaCl in 50 mM Tris (pH 7.4) - compound 15/Alhydrogel® (ratio 1:1.5)

2% Alhydrogel® (aluminum hydroxide gel: 10 mg/ml aluminium) was obtained from Brenntag Biosector A/S, Elsenbakken 23, 3600 Frederikssund, Kingdom of Denmark and used as stock solution to dilute to obtain the required concentration of aluminum. A stock solution of 5 mg/mL Compound 15, 2.25% (w/v) NaCl in 125 mM Tris buffer (pH 7.4) was made to dilute with a stock solution of 2% Alhydrogel®. The table below shows the volumes used to prepare a 5 ml suspension containing 2 mg/ml compound 15, 3 mg/ml aluminum hydroxide and 0.9% NaCl in 50 mM Tris (pH 7.4) at a ratio of 1.5:1 Alhydrogel® and compounds 15.

Final conc.
connections 15
(mg/ml) Final conc.
aluminum
(mg/ml) Ratio of aluminum and compound 15 Volume
stock solution of compound 15
(ml) Volume
2% Alhydrogel® (ml) Volume
water (ml) 2 3 1.5:1 2.0 1.5 1.5

suspension K.

1 mg/ml compound 15, 1.5 mg/ml aluminum hydroxide and 0.9% NaCl in 50 mM Tris (pH 7.4) - compound 15/Alhydrogel ® (ratio 1:1.5)

2% Alhydrogel® (aluminum hydroxide gel: 10 mg/ml aluminium) was obtained from Brenntag Biosector A/S, Elsenbakken 23, 3600 Frederikssund, Kingdom of Denmark and used as stock solution to dilute to obtain the required concentration of aluminum. A stock solution of 2.5 mg/mL Compound 15, 2.25% (w/v) NaCl in 125 mM Tris buffer (pH 7.4) was made to dilute with a stock solution of 2% Alhydrogel®. The table below shows the volumes used to prepare a 5 ml suspension containing 1 mg/ml compound 15, 1.5 mg/ml aluminum hydroxide and 0.9% NaCl in 50 mM Tris (pH 7.4) at a ratio of 1.5 :1 Alhydrogel® and compounds 15.

Final conc.
compounds 15
(mg/ml) Final conc.
aluminum
(mg/ml) Ratio of aluminum and compound 15 Volume
stock solution of compound 15
(ml) Volume
2% Alhydrogel® (ml) Volume
water (ml) 1 1.5 1.5:1 2.0 0.75 2.25

Suspension L.

0.5 mg/ml compound 15, 0.75 mg/ml aluminum hydroxide and 0.9% NaCl in 50 mM Tris (pH 7.4) - compound 15/Alhydrogel® (ratio 1:1.5)

2% Alhydrogel® (aluminum hydroxide gel: 10 mg/ml aluminium) was obtained from Brenntag Biosector A/S, Elsenbakken 23, 3600 Frederikssund, Kingdom of Denmark and used as stock solution to dilute to obtain the required concentration of aluminum. A stock solution of 1.25 mg/mL of Compound 15, 2.25% (w/v) NaCl in 125 mM Tris buffer (pH 7.4) was made to dilute with a stock solution of 2% Alhydrogel®. The table below shows the volumes used to prepare a 5 ml suspension containing 0.5 mg/ml compound 15, 0.75 mg/ml aluminum hydroxide and 0.9% NaCl in 50 mM Tris (pH 7.4) at a ratio of 1 ,5:1 Alhydrogel® and compounds 15.

Final conc.
connections 15
(mg/ml) Final conc.
aluminum
(mg/ml) Ratio of aluminum and compound 15 Volume
stock solution of compound 15
(ml) Volume
2% Alhydrogel® (ml) Volume
water (ml) 0.5 0.75 1.5:1 2.0 0.375 2.63

Controls:

a) No treatment

b) Compound 15 only: 2 mg/ml Compound 15 and 0.9% NaCl in 50 mM Tris (pH 7.4)

c) Alhydydrogel® only: 3 mg/ml Alhydrogel® in 50 mM Tris (pH 7.4)

The antitumor efficacy of Compound 15 adsorbed on Alhydrogel® was determined using a bilateral tumor syngeneic mouse lymphoma model using A20 cells in female BALB/c mice.

A20 cells were grown under sterile conditions in an incubator at 37°C with 5% CO ₂ for two weeks. Cells were grown in RPMI 1640 medium with 2 mM L-glutamine adjusted to contain 1.5 g/L sodium bicarbonate, 4.5 g/L glucose, 10 mM HEPES, and 1.0 mM sodium pyruvate and supplemented with 0. 05 mM 2-mercaptoethanol, 10% fetal bovine serum. Cells were passaged every 2-3 days. Cells were floated on the day of implantation (passage 12) and resuspended in HBSS at a concentration of 5×10 ⁶ cells/100 μl. Cells were tested with Radil against mycoplasma and mouse viruses. For each mouse, 5×10 ⁶ cells were implanted by subcutaneous injection in the right and left flank using a 28.5 g needle (injection volume 100 μl). Tumor sizes were assessed three times a week after the tumors became palpable. Tumor dimensions were determined using caliper measurement, with tumor volumes calculated using the formula: (length x width x width)/2.

Female Balb/c mice harboring A20 tumor cells were randomized into 7 groups (n=10 mice per group) 8 days after tumor cell implantation with a mean tumor volume in the range of 111.40 ± 23.57 mm ³ . 50 μl of any of Suspension I, Suspension J, Suspension K, Suspension L, Compound 15 alone control, or Alhydrogel® alone control was intratumorally administered to various groups of animals once a week for two weeks. Table 16 shows the dose of compound 15 obtained by intratumoral administration of 50 μl of controls and suspension.

Table 16

Dose
compound 15 (µg) Compound control 15 one hundred Alhydrogel® control 0 Suspension I 25 Suspension J 50 Suspension K one hundred Suspension L 200

Tumor volumes were measured with a digital caliper 3 times a week, and the body weight of each animal was recorded throughout the study. Mice were sacrificed when tumor volumes exceeded 1500 mm ³ or the mouse was dying.

Figure 8 shows the efficacy and dose response of 0 μg, 25 μg, 50 μg, 100 μg and 200 μg compound 15 adsorbed on aluminum hydroxide (at a fixed ratio of 1:1.5, w/w, and 97% binding) in a syngeneic bilateral tumor mouse model of lymphoma using A20 cells. After two weekly doses of 25 μg, 50 μg, 100 μg and 200 μg of compound 15 adsorbed on aluminum hydroxide, a significant suppression of tumor growth (p<0.05-0.001) was shown at day 21 in the treated tumor site, with a dose-dependent increased antitumor efficacy with intratumoral delivery (i.t.). However, no significant suppression of tumor growth (p>0.05) was observed at day 21 in the distal tumor site. Furthermore, after two weekly doses, Compound 15 adsorbed onto Alhydrogel® showed better efficacy than 100 μg Compound 15 alone, and 100 μg Compound 15 alone had no significant difference at both tumor sites.

Example 14 Efficiency Effect in vivo binding efficiency

suspension M.

2 mg/ml compound 15, 2 mg/ml aluminum hydroxide and 0.9% NaCl in 50 mM Tris (pH 7.4) - compound 15/Alhydrogel® (ratio 1:1)

2% Alhydrogel® (aluminum hydroxide gel: 10 mg/ml aluminium) was obtained from Brenntag Biosector A/S, Elsenbakken 23, 3600 Frederikssund, Kingdom of Denmark and used as stock solution to dilute to obtain the required concentration of aluminum. A stock solution of 5 mg/mL Compound 15, 2.25% (w/v) NaCl in 125 mM Tris buffer (pH 7.4) was made to dilute with a stock solution of 2% Alhydrogel®. The table below shows the volumes used to prepare a 5 ml suspension containing 2 mg/ml compound 15, 32 mg/ml aluminum hydroxide and 0.9% NaCl in 50 mM Tris (pH 7.4) at a ratio of 1:1 Alhydrogel® and connections 15.

Final conc.
connections 15
(mg/ml) Final conc.
aluminum
(mg/ml) Ratio of aluminum and compound 15 Volume
stock solution of compound 15
(ml) Volume
2% Alhydrogel® (ml) Volume
water (ml) 2 2 1:1 2.0 1.0 2.0

suspension N.

2 mg/ml compound 15, 1.0 mg/ml aluminum hydroxide and 0.9% NaCl in 50 mM Tris (pH 7.4) - compound 15/Alhydrogel® (ratio 1:0.5)

2% Alhydrogel® (aluminum hydroxide gel: 10 mg/ml aluminium) was obtained from Brenntag Biosector A/S, Elsenbakken 23, 3600 Frederikssund, Kingdom of Denmark and used as stock solution to dilute to obtain the required concentration of aluminum. A stock solution of 5 mg/mL Compound 15, 2.25% (w/v) NaCl in 125 mM Tris buffer (pH 7.4) was made to dilute with a stock solution of 2% Alhydrogel®. The table below shows the volumes used to prepare a 5 ml suspension containing 2 mg/ml compound 15, 0.5 mg/ml aluminum hydroxide and 0.9% NaCl in 50 mM Tris (pH 7.4) at a ratio of 0.5 :1 Alhydrogel® and compounds 15.

Final conc.
connections 15
(mg/ml) Final conc.
aluminum
(mg/ml) Ratio of aluminum and compound 15 Volume
stock solution of compound 15
(ml) Volume
2% Alhydrogel® (ml) Volume
water (ml) 2 1.0 0.5:1 2.0 0.50 2.50

Control: Alhydydrogel® only: 3 mg/ml Alhydrogel® in 50 mM Tris (pH 7.4)

The effect of binding efficiency of Compound 15 adsorbed on Alhydrogel® on antitumor efficacy was determined using the bilateral tumor syngeneic mouse lymphoma model using A20 cells in female BALB/c mice (described in Example 12). A dose-response study was carried out using Suspension J, Suspension M and Suspension N, characterized by the ratio compound 15/Alhydrogel® and binding efficiency 1:1.5 (approx. 98% binding), 1:1 (approx. 80% binding) and 1:0.5 (approx. 50% binding), respectively.

Balb/c female mice harboring A20 tumor cells were randomized into 4 groups (n=10 mice per group) 9 days after tumor cell implantation with a mean tumor volume in the range of 128.43 ± 23.42 mm ³ . 50 μl of any of Suspension J, Suspension M, Suspension N, or Alhydrogel® control alone was intratumorally administered to various groups of animals. Volume 50 μl intratumoral dose of 100 μg compound 15. Tumor volumes were measured and calculated as in example 12. Mice were sacrificed when the tumor volume exceeded 1500 mm ³ or if the mouse was dying.

Figure 9 shows the efficacy and dose-response relationship of 100 μg of compound 15 adsorbed on aluminum hydroxide at approx. 98% binding (compound 15/Alhydrogel® ratio 1:1.5, w/w), at approx. 80% binding (compound 15/Alhydrogel® ratio 1:1, w/w) and at approx. 50% binding (compound 15/Alhydrogel® ratio 1:0.5, w/w). After a single dose, compound 15 was found to induce tumor regression only if it was approx. 98% bound to Alhydrogel® and showed reduced efficacy with reduced percentages of binding to Alhydrogel®.

Example 15 Efficiency in vivo as an agent in combination with one or more checkpoint inhibitors

Suspension O.

1 mg/ml compound 15, 2 mg/ml aluminum hydroxide and 7.5% (w/v) sucrose in 16 mM Tris (pH 7.4) - compound 15/Alhydrogel® (ratio 1:2)

2% Alhydrogel® (aluminum hydroxide gel: 10 mg/ml aluminium) was obtained from Brenntag Biosector A/S, Elsenbakken 23, 3600 Frederikssund, Kingdom of Denmark and used as stock solution to dilute to obtain the required concentration of aluminum. A stock solution of 1.25 mg/mL Compound 15, 9.375% (w/v) sucrose in 20 mM Tris buffer (pH 7.4) was made to dilute with a stock solution of 2% Alhydrogel®. The table below shows the volumes used to prepare a 5 ml suspension containing 1 mg/ml compound 15, 2 mg/ml aluminum hydroxide and 7.5% (w/v) sucrose in 16 mM Tris (pH 7.4) at the ratio 2:1 Alhydrogel® and compounds 15.

Final conc.
compounds 15
(mg/ml) Final conc.
aluminum
(mg/ml) Ratio of aluminum and compound 15 Volume
stock solution of compound 15
(ml) Volume
2% Alhydrogel® (ml) 1 2 2:1 four 1

Reagents.

Compound 15 was in suspension with Alhydrogel® (suspension N).

Anti-PD-L1 antibody (BAP058-hum13 with heavy chain variable domain of SEQ ID NO: 7 and light chain variable domain of SEQ ID NO: 17).

Anti-CTLA4 antibody was purchased from Bio X Cell. clone 9D9, lot no. 5311-11/1014. cat. no. BE0146.

Formation of a syngeneic tumor model using MC38 cells related to the colon

Cells MC38 were grown under sterile conditions in an incubator at 37°C with 5% CO ₂ for two weeks. Cells were cultured in Dulbecco's Modified Eagle's Medium (DMEM) supplemented with 10% FBS, with cells passaged every 2-3 days. On the day of injection, cells were harvested (passage 12) and resuspended in Hank's balanced salt solution (HBSS) at a concentration of 2.5×10 ⁶ /ml. Cells were tested with Radil against mycoplasma and mouse viruses.

For each mouse, 0.25×10 ⁶ cells were implanted by subcutaneous injection in the right flank using a 28-1/2 g needle (injection volume 100 μl). After the first implantation on day 3 (0.25×10 ⁶ ), cells were implanted by subcutaneous injection into the left block using a 28-1/2 g needle (injection volume 100 μl). Tumor sizes were assessed three times a week after the tumors became palpable. Tumor dimensions were determined using caliper measurement, with tumor volumes calculated using the formula: (length x width x width)/2.

Dosing and Sampling in MC38 Tumor-bearing C57/BL6 Mice

Female C57BL/6 mice harboring MC38 tumor cells were randomized into 7 groups (n=9 mice per group) 9 days after tumor cell implantation with a mean tumor volume in the range of 69.09-142.25 mm ³ , and separate groups of mice tumor-bearing cells received treatment as shown in Table 17.

Table 17

Group Treatment Dose Dose volume Route of administration Scheme 1 No processing --- --- --- --- 2 Compound 15 50 (µg) 50 (µl) (suspension N) Intratumoral
(it) Once a week for 2 weeks 3 Antibody to PD-L1 10 (mg/kg) 10 (µl/g) intraperitoneally
(ip) Twice a week for 2 weeks four Antibody to CTLA4 10 (mg/kg) 10 (µl/g) intraperitoneally
(ip) Twice a week for 2 weeks five Compound 15 50 (µg) 50 (µl) (suspension N) Intratumoral
(it) Once a week for 2 weeks Antibody to PD-L1 10 (mg/kg) 10 (µl/g) intraperitoneally
(ip) Twice a week for 2 weeks 6 Compound 15 50 (µg) 50 (µl) (suspension N) Intratumoral
(it) Once a week for 2 weeks Antibody to CTLA4 10 (mg/kg) 10 (µl/g) intraperitoneally
(ip) Twice a week for 2 weeks 7 Compound 15 50 (µg) 50 (µl) (suspension N) Intratumoral
(it) Once a week for 2 weeks Antibody to PD-L1 10 (mg/kg) 10 (µl/g) intraperitoneally
(ip) Twice a week for 2 weeks Antibody to CTLA4 10 (mg/kg) 10 (µl/g) intraperitoneally
(ip) Twice a week for 2 weeks

where the anti-PD-L1 antibody solution was 10 (mg/mL) in phosphate buffered saline (PBS) (pH 7) and the anti-CTLA4 antibody solution was 10 (mg/mL) in phosphate buffered saline (PBS) (pH 7).

The antitumor efficacy of compound 15 adsorbed on aluminum hydroxide (Alhydrogel®), alone or in combination with checkpoint inhibitors, was determined using a contralateral colon cancer model using MC38 cells. Tumor volume was obtained after two weekly intratumoral injections of compound 15 adsorbed on aluminum hydroxide (50 μg each), or alone (group 2), in double combination with intraperitoneal injection (twice weekly) of anti-PD-L1 antibody (10 mg/kg) ( group 5), in double combination with intraperitoneal injection (twice weekly) of anti-CTLA4 antibody (10 mg/kg) (group 6), or in triple combination with intraperitoneal injection (twice weekly) of anti-PD-L1 antibody (10 mg/kg) and with intraperitoneal injection of anti-CTLA4 antibody (10 mg/kg) (group 7). For comparison, data were obtained after intraperitoneal injection (twice weekly) of anti-PD-L1 antibody (10 mg/kg) alone (group 3) and after intraperitoneal injection (twice weekly) of anti-CTLA4 antibody (10 mg/kg) alone (group 4). Also received data from the untreated control (group 1). Figure 10A shows the tumor volume at the primary site of the intratumoral injection and Figure 10B shows the tumor volume at the distant contralateral site.

The antitumor efficacy of Compound 15 alone (without aluminum hydroxide (Alhydrogel®)) or in combination with checkpoint inhibitors was determined using a contralateral colon cancer model using MC38 cells. Tumor volume was obtained after two weekly intratumoral injections of compound 15 alone (without aluminum hydroxide (Alhydrogel®) (50 μg each)) or in triplicate with intraperitoneal injection (twice weekly) of anti-PD-L1 antibody (10 mg/kg) and anti-PD-L1 antibody (10 mg/kg) CTLA4 (10 mg/kg). For comparison, data were obtained after intraperitoneal injection (twice weekly) of a combination of anti-PD-L1 antibody (10 mg/kg) and anti-CTLA4 antibody (10 mg/kg) alone. In addition, the antitumor efficacy of Compound 15 adsorbed on aluminum hydroxide (Alhydrogel®), alone or in triple combination with checkpoint inhibitors, was determined using a contralateral colon cancer model using MC38 cells. Tumor volume was obtained after two weekly intratumoral injections of compound 15 adsorbed on aluminum hydroxide (Alhydrogel®) (50 μg each) alone or in triple combination with intraperitoneal injection (twice weekly) of anti-PD-L1 antibody (10 mg/kg) and antibodies to CTLA4 (10 mg/kg). For comparison, data were obtained after intraperitoneal injection (twice weekly) of a combination of anti-PD-L1 antibody (10 mg/kg) and anti-CTLA4 antibody (10 mg/kg) alone. Raw control data were also obtained. Figure 10C shows the tumor volume obtained at the primary intratumoral injection site and Figure 10D shows the tumor volume obtained at the distant contralateral site.

The introduction of doses in the form of separate means .

At the primary site of injection, CTLA4 antibody alone was not significantly different from the untreated group, (p>0.05) with a %T/C of 99.98%. Similarly, compound 15 alone (without aluminum hydroxide (Alhydrogel®) showed no difference from the untreated group. However, anti-PD-L1 antibody alone was significantly different (p<0.05), with %T/C 56.22 % and Compound 15/Alhydrogel® alone also differed significantly (p < 0.0001), with a %T/C of 25.22% Compound 15 adsorbed on aluminum hydroxide appeared to have improved performance as a hotel agent. at the injection site with respect to any antibody administered as separate agents.

In the contralateral site of the tumor, anti-CTLA4 antibody alone was not significantly different from the untreated group (p>0.05), with a %T/C of 79.72%. Similarly, compound 15 alone (without aluminum hydroxide (Alhydrogel®) showed no difference from the untreated group. However, anti-PD-L1 antibody alone was significantly different (p<0.001), with a %T/C of 27.02%, and Compound 15/Alhydrogel® alone were also significantly different (p<0.01), with a T/C of 29.50% Compound 15 adsorbed on aluminum hydroxide appeared to have improved efficacy as a remote site hotel with respect to any antibody administered as separate agents.

Dosing in combination with a checkpoint inhibitor.

The combination of intratumoral administration of compound 15 adsorbed on aluminum hydroxide with intraperitoneal injection of antibody to PD-L1 showed a significant improvement in antitumor efficacy both at the primary site of intratumoral injection and at the contralateral site, while obtaining (p<0.0001) with T/ C 8.93% and (p<0.0001) with %T/C 5.39% for the primary intratumoral injection site and the contralateral site, respectively.

In the primary site for intratumoral administration, the combination of intratumoral administration of compound 15 adsorbed on aluminum hydroxide and intraperitoneal administration of antibody to CTLA4 showed similar behavior as obtained from compound 15 adsorbed on aluminum hydroxide administered alone, while in the contralateral site, the combination was less effective. than compound 15 adsorbed on aluminum hydroxide administered separately. However, a significant difference from the untreated group was observed, with (p<0.0001) with a %T/C of 26.74% and (p<0.05) with a %T/C of 48.70% for the primary intratumor site and contralateral region, respectively.

In addition, dosing of anti-PD-L1 antibody and anti-CTLA-4 antibody in combination did not result in complete tumor regression (data not shown).

Dosing in combination with two checkpoint inhibitors.

A triple combination of intratumoral injection of compound 15 adsorbed on aluminum hydroxide, intraperitoneal injection of anti-PD-L1 antibody, and intraperitoneal injection of anti-CTLA4 antibody showed complete tumor regression in 7 of 9 animals, with (p<0.0001) with T/C - 38.51% and (p<0.0001) with a T/C of -9.60% for the primary intratumoral injection site and the contralateral site, respectively.

It should be understood that the examples and embodiments described herein are for illustrative purposes only, and that various modifications or changes in light thereof will be made to those skilled in the art and should be included within the spirit and scope of this application and the scope of the appended invention formulas.

--->

SEQUENCE LIST

<110> Novartis AG

Cooke, Michael Paul

Kasibhatla, Shailaja

Miller, Andrew Todd

Wu, Tom Yao-Hsiang

<120> COMPOSITIONS CONTAINING NAPHTHIRIDINE DERIVATIVES AND ALUMINUM CONTAINING

ADDITIONAL MEDICINE INTENDED FOR USE IN THE TREATMENT OF SOLID

TUMORS

<130> PAT057568-WO-PCT

<160> 61

<170> PatentIn version 3.5

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Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val

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Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile

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Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro

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Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn

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Gly Ala Ala Gly Ala Ala Gly Cys Cys Thr Gly Gly Gly Gly Cys Thr

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Ala Thr Ala Gly Thr Gly Gly Gly Ala Gly Thr Ala Cys Thr Ala Ala

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Ala Ala Gly Ala Ala Cys Ala Gly Ala Thr Thr Cys Ala Cys Cys Ala

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Thr Cys Thr Cys Cys Ala Gly Ala Gly Ala Cys Ala Ala Thr Thr Cys

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Cys Ala Ala Gly Ala Ala Cys Ala Cys Gly Cys Thr Gly Thr Ala Thr

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Thr Thr Cys Cys Cys Cys Cys Thr Gly Gly Cys Gly Cys Cys Cys Thr

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Ala Cys Cys Gly Gly Thr Gly Ala Cys Gly Gly Thr Gly Thr Cys Gly

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Cys Ala Cys Cys Thr Thr Cys Cys Cys Gly Gly Cys Thr Gly Thr Cys

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Cys Thr Ala Cys Ala Gly Thr Cys Cys Thr Cys Ala Gly Gly Ala Cys

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Thr Cys Thr Ala Cys Thr Cys Cys Cys Thr Cys Ala Gly Cys Ala Gly

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Cys Cys Cys Ala Gly Cys Ala Ala Cys Ala Cys Cys Ala Ala Gly Gly

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Cys Cys Ala Thr Gly Cys Cys Cys Ala Cys Cys Gly Thr Gly Cys Cys

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Cys Ala Gly Cys Ala Cys Cys Thr Gly Ala Gly Thr Thr Cys Cys Thr

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Gly Gly Gly Gly Gly Gly Ala Cys Cys Ala Thr Cys Ala Gly Thr Cys

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Thr Thr Cys Cys Thr Gly Thr Thr Cys Cys Cys Cys Cys Cys Ala Ala

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Ala Ala Cys Cys Cys Ala Ala Gly Gly Ala Cys Ala Cys Thr Cys Thr

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Cys Cys Thr Gly Ala Gly Gly Thr Cys Ala Cys Gly Thr Gly Cys Gly

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Thr Gly Gly Thr Gly Gly Thr Gly Gly Ala Cys Gly Thr Gly Ala Gly

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Cys Cys Ala Gly Gly Ala Ala Gly Ala Cys Cys Cys Cys Gly Ala Gly

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Gly Thr Cys Cys Ala Gly Thr Thr Cys Ala Ala Cys Thr Gly Gly Thr

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Ala Cys Gly Thr Gly Gly Ala Thr Gly Gly Cys Gly Thr Gly Gly Ala

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Gly Gly Thr Gly Cys Ala Thr Ala Ala Thr Gly Cys Cys Ala Ala Gly

850 855 860

Ala Cys Ala Ala Ala Gly Cys Cys Gly Cys Gly Gly Gly Ala Gly Gly

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Ala Gly Cys Ala Gly Thr Thr Cys Ala Ala Cys Ala Gly Cys Ala Cys

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Gly Thr Ala Cys Cys Gly Thr Gly Thr Gly Gly Thr Cys Ala Gly Cys

900 905 910

Gly Thr Cys Cys Thr Cys Ala Cys Cys Gly Thr Cys Cys Thr Gly Cys

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Ala Cys Cys Ala Gly Gly Ala Cys Thr Gly Gly Cys Thr Gly Ala Ala

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Cys Gly Gly Cys Ala Ala Gly Gly Ala Gly Thr Ala Cys Ala Ala Gly

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Thr Gly Cys Ala Ala Gly Gly Thr Gly Thr Cys Cys Ala Ala Cys Ala

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Ala Ala Gly Gly Cys Cys Thr Cys Cys Cys Gly Thr Cys Cys Thr Cys

980 985 990

Cys Ala Thr Cys Gly Ala Gly Ala Ala Ala Ala Cys Cys Ala Thr Cys

995 1000 1005

Thr Cys Cys Ala Ala Ala Gly Cys Cys Ala Ala Ala Gly Gly Gly

1010 1015 1020

Cys Ala Gly Cys Cys Cys Cys Gly Ala Gly Ala Gly Cys Cys Ala

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Cys Ala Gly Gly Thr Gly Thr Ala Cys Ala Cys Cys Cys Thr Gly

1040 1045 1050

Cys Cys Cys Cys Cys Ala Thr Cys Cys Cys Ala Gly Gly Ala Gly

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Gly Ala Gly Ala Thr Gly Ala Cys Cys Ala Ala Gly Ala Ala Cys

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Cys Ala Gly Gly Thr Cys Ala Gly Cys Cys Thr Gly Ala Cys Cys

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Thr Gly Cys Cys Thr Gly Gly Thr Cys Ala Ala Ala Gly Gly Cys

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Thr Thr Cys Thr Ala Cys Cys Cys Cys Ala Gly Cys Gly Ala Cys

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Ala Thr Cys Gly Cys Cys Gly Thr Gly Gly Ala Gly Thr Gly Gly

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Gly Ala Gly Ala Gly Cys Ala Ala Thr Gly Gly Gly Cys Ala Gly

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Cys Cys Gly Gly Ala Gly Ala Ala Cys Ala Ala Cys Thr Ala Cys

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Ala Ala Gly Ala Cys Cys Ala Cys Gly Cys Cys Thr Cys Cys Cys

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Gly Thr Gly Cys Thr Gly Gly Ala Cys Thr Cys Cys Gly Ala Cys

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Gly Gly Cys Thr Cys Cys Thr Thr Cys Thr Thr Cys Cys Thr Cys

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Thr Ala Cys Ala Gly Cys Ala Gly Gly Cys Thr Ala Ala Cys Cys

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Gly Thr Gly Gly Ala Cys Ala Ala Gly Ala Gly Cys Ala Gly Gly

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Thr Gly Gly Cys Ala Gly Gly Ala Gly Gly Gly Gly Ala Ala Thr

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Gly Thr Cys Thr Thr Cys Thr Cys Ala Thr Gly Cys Thr Cys Cys

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Gly Thr Gly Ala Thr Gly Cys Ala Thr Gly Ala Gly Gly Cys Thr

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Cys Thr Gly Cys Ala Cys Ala Ala Cys Cys Ala Cys Thr Ala Cys

1295 1300 1305

Ala Cys Ala Cys Ala Gly Ala Ala Gly Ala Gly Cys Cys Thr Cys

1310 1315 1320

Thr Cys Cys Cys Thr Gly Thr Cys Thr Cys Thr Gly Gly Gly Thr

1325 1330 1335

Ala Ala Ala

1340

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Lys Ala Ser Gln Asp Val Gly Thr Ala Val Ala

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Trp Ala Ser Thr Arg His Thr

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Gln Gln Tyr Asn Ser Tyr Pro Leu Thr

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Trp Ala Ser

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Glu Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Tyr Asn Ser Tyr Pro Leu

85 90 95

Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala

100 105 110

Pro Ser Val Phe Ile Phe Pro Ser Asp Glu Gln Leu Lys Ser Gly

115 120 125

Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala

130 135 140

Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln

145 150 155 160

Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser

165 170 175

Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr

180 185 190

Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser

195 200 205

Phe Asn Arg Gly Glu Cys

210

<210> 20

<211> 642

<212> DNA

<213> Artificial sequence

<220>

<223> Artificial sequence description: Synthetic polynucleotide

<400> 20

gccatccagt tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60

atcacttgca aggccagtca ggatgtgggt actgctgtag cctggtacct gcagaagcca 120

gggcagtctc cacagctcct gatctattgg gcatccaccc ggcacactgg ggtcccctcg 180

aggttcagtg gcagtggatc tgggacagat ttcaccttta ccatcagtag cctggaagct 240

gaagatgctg caacatatta ctgtcagcag tataacagct atcctctcac gttcggccaa 300

gggaccaagg tggaaatcaa acgtacggtg gctgcaccat ctgtcttcat cttcccgcca 360

tctgatgagc agttgaaatc tggaactgcc tctgttgtgt gcctgctgaa taacttctat 420

cccagagagg ccaaagtaca gtggaaggtg gataacgccc tccaatcggg taactcccag 480

gagagtgtca cagagcagga cagcaaggac agcacctaca gcctcagcag caccctgacg 540

ctgagcaaag cagactacga gaaacacaaa gtctacgcct gcgaagtcac ccatcagggc 600

ctgagctcgc ccgtcacaaa gagcttcaac aggggagagt gt 642

<210> 21

<211> 10

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Artificial sequence description: Synthetic peptide

<400> 21

Gly Tyr Thr Phe Thr Thr Tyr Trp Met His

1 5 10

<210> 22

<211> 5

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Artificial sequence description: Synthetic peptide

<400> 22

Thr Tyr Trp Met His

15

<210> 23

<211> 17

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Artificial sequence description: Synthetic peptide

<400> 23

Asn Ile Tyr Pro Gly Thr Gly Gly Ser Asn Phe Asp Glu Lys Phe Lys

1 5 10 15

Asn

<210> 24

<211> 8

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Artificial sequence description: Synthetic peptide

<400> 24

Trp Thr Thr Gly Thr Gly Ala Tyr

15

<210> 25

<211> 7

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Artificial sequence description: Synthetic peptide

<400> 25

Gly Tyr Thr Phe Thr Thr Tyr

15

<210> 26

<211> 6

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Artificial sequence description: Synthetic peptide

<400> 26

Tyr Pro Gly Thr Gly Gly

15

<210> 27

<211> 117

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Artificial sequence description: Synthetic polypeptide

<400> 27

Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu

1 5 10 15

Ser Leu Arg Ile Ser Cys Lys Gly Ser Gly Tyr Thr Phe Thr Thr Tyr

20 25 30

Trp Met His Trp Val Arg Gln Ala Thr Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Asn Ile Tyr Pro Gly Thr Gly Gly Ser Asn Phe Asp Glu Lys Phe

50 55 60

Lys Asn Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr

65 70 75 80

Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Thr Arg Trp Thr Thr Gly Thr Gly Ala Tyr Trp Gly Gln Gly Thr Thr

100 105 110

Val Thr Val Ser Ser

115

<210> 28

<211> 351

<212> DNA

<213> Artificial sequence

<220>

<223> Artificial sequence description: Synthetic polynucleotide

<400> 28

gaggtgcagc tggtgcagtc aggcgccgaa gtgaagaagc ccggcgagtc actgagaatt 60

agctgtaaag gttcaggcta caccttcact acctactgga tgcactgggt ccgccaggct 120

accggtcaag gcctcgagtg gatgggtaat atctaccccg gcaccggcgg ctctaacttc 180

240 gacgagaagt ttaagaatag agtgactatc accgccgata

atggaactgt ctagcctgag atcagaggac accgccgtct actactgcac taggtggact 300

accggcacag gcgcctactg gggtcaaggc actaccgtga ccgtgtctag c 351

<210> 29

<211> 443

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Artificial sequence description: Synthetic polypeptide

<400> 29

Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu

1 5 10 15

Ser Leu Arg Ile Ser Cys Lys Gly Ser Gly Tyr Thr Phe Thr Thr Tyr

20 25 30

Trp Met His Trp Val Arg Gln Ala Thr Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Asn Ile Tyr Pro Gly Thr Gly Gly Ser Asn Phe Asp Glu Lys Phe

50 55 60

Lys Asn Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr

65 70 75 80

Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Thr Arg Trp Thr Thr Gly Thr Gly Ala Tyr Trp Gly Gln Gly Thr Thr

100 105 110

Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu

115 120 125

Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys

130 135 140

Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser

145 150 155 160

Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser

165 170 175

Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser

180 185 190

Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn

195 200 205

Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro

210 215 220

Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe

225 230 235 240

Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val

245 250 255

Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe

260 265 270

Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro

275 280 285

Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr

290 295 300

Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val

305 310 315 320

Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala

325 330 335

Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln

340 345 350

Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly

355 360 365

Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro

370 375 380

Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser

385 390 395 400

Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu

405 410 415

Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His

420 425 430

Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly

435 440

<210> 30

<211> 1329

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Artificial sequence description: Synthetic polypeptide

<400> 30

Gly Ala Gly Gly Thr Gly Cys Ala Gly Cys Thr Gly Gly Thr Gly Cys

1 5 10 15

Ala Gly Thr Cys Ala Gly Gly Cys Gly Cys Cys Gly Ala Ala Gly Thr

20 25 30

Gly Ala Ala Gly Ala Ala Gly Cys Cys Cys Gly Gly Cys Gly Ala Gly

35 40 45

Thr Cys Ala Cys Thr Gly Ala Gly Ala Ala Thr Thr Ala Gly Cys Thr

50 55 60

Gly Thr Ala Ala Ala Gly Gly Thr Thr Cys Ala Gly Gly Cys Thr Ala

65 70 75 80

Cys Ala Cys Cys Thr Thr Cys Ala Cys Thr Ala Cys Cys Thr Ala Cys

85 90 95

Thr Gly Gly Ala Thr Gly Cys Ala Cys Thr Gly Gly Gly Thr Cys Cys

100 105 110

Gly Cys Cys Ala Gly Gly Cys Thr Ala Cys Cys Gly Gly Thr Cys Ala

115 120 125

Ala Gly Gly Cys Cys Thr Cys Gly Ala Gly Thr Gly Gly Ala Thr Gly

130 135 140

Gly Gly Thr Ala Ala Thr Ala Thr Cys Thr Ala Cys Cys Cys Cys Gly

145 150 155 160

Gly Cys Ala Cys Cys Gly Gly Cys Gly Gly Cys Thr Cys Thr Ala Ala

165 170 175

Cys Thr Thr Cys Gly Ala Cys Gly Ala Gly Ala Ala Gly Thr Thr Thr

180 185 190

Ala Ala Gly Ala Ala Thr Ala Gly Ala Gly Thr Gly Ala Cys Thr Ala

195 200 205

Thr Cys Ala Cys Cys Gly Cys Cys Gly Ala Thr Ala Ala Gly Thr Cys

210 215 220

Thr Ala Cys Thr Ala Gly Cys Ala Cys Cys Gly Cys Cys Thr Ala Thr

225 230 235 240

Ala Thr Gly Gly Ala Ala Cys Thr Gly Thr Cys Thr Ala Gly Cys Cys

245 250 255

Thr Gly Ala Gly Ala Thr Cys Ala Gly Ala Gly Gly Ala Cys Ala Cys

260 265 270

Cys Gly Cys Cys Gly Thr Cys Thr Ala Cys Thr Ala Cys Thr Gly Cys

275 280 285

Ala Cys Thr Ala Gly Gly Thr Gly Gly Ala Cys Thr Ala Cys Cys Gly

290 295 300

Gly Cys Ala Cys Ala Gly Gly Cys Gly Cys Cys Thr Ala Cys Thr Gly

305 310 315 320

Gly Gly Gly Thr Cys Ala Ala Gly Gly Cys Ala Cys Thr Ala Cys Cys

325 330 335

Gly Thr Gly Ala Cys Cys Gly Thr Gly Thr Cys Thr Ala Gly Cys Gly

340 345 350

Cys Thr Ala Gly Cys Ala Cys Thr Ala Ala Gly Gly Gly Cys Cys Cys

355 360 365

Gly Thr Cys Cys Gly Thr Gly Thr Thr Cys Cys Cys Cys Cys Thr Gly

370 375 380

Gly Cys Ala Cys Cys Thr Thr Gly Thr Ala Gly Cys Cys Gly Gly Ala

385 390 395 400

Gly Cys Ala Cys Thr Ala Gly Cys Gly Ala Ala Thr Cys Cys Ala Cys

405 410 415

Cys Gly Cys Thr Gly Cys Cys Cys Thr Cys Gly Gly Cys Thr Gly Cys

420 425 430

Cys Thr Gly Gly Thr Cys Ala Ala Gly Gly Ala Thr Thr Ala Cys Thr

435 440 445

Thr Cys Cys Cys Gly Gly Ala Gly Cys Cys Cys Gly Thr Gly Ala Cys

450 455 460

Cys Gly Thr Gly Thr Cys Cys Thr Gly Gly Ala Ala Cys Ala Gly Cys

465 470 475 480

Gly Gly Ala Gly Cys Cys Cys Thr Gly Ala Cys Cys Thr Cys Cys Gly

485 490 495

Gly Ala Gly Thr Gly Cys Ala Cys Ala Cys Cys Thr Thr Cys Cys Cys

500 505 510

Cys Gly Cys Thr Gly Thr Gly Cys Thr Gly Cys Ala Gly Ala Gly Cys

515 520 525

Thr Cys Cys Gly Gly Gly Cys Thr Gly Thr Ala Cys Thr Cys Gly Cys

530 535 540

Thr Gly Thr Cys Gly Thr Cys Gly Gly Thr Gly Gly Thr Cys Ala Cys

545 550 555 560

Gly Gly Thr Gly Cys Cys Thr Thr Cys Ala Thr Cys Thr Ala Gly Cys

565 570 575

Cys Thr Gly Gly Gly Thr Ala Cys Cys Ala Ala Gly Ala Cys Cys Thr

580 585 590

Ala Cys Ala Cys Thr Thr Gly Cys Ala Ala Cys Gly Thr Gly Gly Ala

595 600 605

Cys Cys Ala Cys Ala Ala Gly Cys Cys Thr Thr Cys Cys Ala Ala Cys

610 615 620

Ala Cys Thr Ala Ala Gly Gly Thr Gly Gly Ala Cys Ala Ala Gly Cys

625 630 635 640

Gly Cys Gly Thr Cys Gly Ala Ala Thr Cys Gly Ala Ala Gly Thr Ala

645 650 655

Cys Gly Gly Cys Cys Cys Ala Cys Cys Gly Thr Gly Cys Cys Cys Gly

660 665 670

Cys Cys Thr Thr Gly Thr Cys Cys Cys Gly Cys Gly Cys Cys Gly Gly

675 680 685

Ala Gly Thr Thr Cys Cys Thr Cys Gly Gly Cys Gly Gly Thr Cys Cys

690 695 700

Cys Thr Cys Gly Gly Thr Cys Thr Thr Thr Cys Thr Gly Thr Thr Cys

705 710 715 720

Cys Cys Ala Cys Cys Gly Ala Ala Gly Cys Cys Cys Ala Ala Gly Gly

725 730 735

Ala Cys Ala Cys Thr Thr Thr Gly Ala Thr Gly Ala Thr Thr Thr Cys

740 745 750

Cys Cys Gly Cys Ala Cys Cys Cys Cys Thr Gly Ala Ala Gly Thr Gly

755 760 765

Ala Cys Ala Thr Gly Cys Gly Thr Gly Gly Thr Cys Gly Thr Gly Gly

770 775 780

Ala Cys Gly Thr Gly Thr Cys Ala Cys Ala Gly Gly Ala Ala Gly Ala

785 790 795 800

Thr Cys Cys Gly Gly Ala Gly Gly Thr Gly Cys Ala Gly Thr Thr Cys

805 810 815

Ala Ala Thr Thr Gly Gly Thr Ala Cys Gly Thr Gly Gly Ala Thr Gly

820 825 830

Gly Cys Gly Thr Cys Gly Ala Gly Gly Thr Gly Cys Ala Cys Ala Ala

835 840 845

Cys Gly Cys Cys Ala Ala Ala Ala Cys Cys Ala Ala Gly Cys Cys Gly

850 855 860

Ala Gly Gly Gly Ala Gly Gly Ala Gly Cys Ala Gly Thr Thr Cys Ala

865 870 875 880

Ala Cys Thr Cys Cys Ala Cys Thr Thr Ala Cys Cys Gly Cys Gly Thr

885 890 895

Cys Gly Thr Gly Thr Cys Cys Gly Thr Gly Cys Thr Gly Ala Cys Gly

900 905 910

Gly Thr Gly Cys Thr Gly Cys Ala Thr Cys Ala Gly Gly Ala Cys Thr

915 920 925

Gly Gly Cys Thr Gly Ala Ala Cys Gly Gly Gly Ala Ala Gly Gly Ala

930 935 940

Gly Thr Ala Cys Ala Ala Gly Thr Gly Cys Ala Ala Ala Gly Thr Gly

945 950 955 960

Thr Cys Cys Ala Ala Cys Ala Ala Gly Gly Gly Ala Cys Thr Thr Cys

965 970 975

Cys Thr Ala Gly Cys Thr Cys Ala Ala Thr Cys Gly Ala Ala Ala Ala

980 985 990

Gly Ala Cys Cys Ala Thr Cys Thr Cys Gly Ala Ala Ala Gly Cys Cys

995 1000 1005

Ala Ala Gly Gly Gly Ala Cys Ala Gly Cys Cys Cys Cys Gly Gly

1010 1015 1020

Gly Ala Ala Cys Cys Cys Cys Ala Ala Gly Thr Gly Thr Ala Thr

1025 1030 1035

Ala Cys Cys Cys Thr Gly Cys Cys Ala Cys Cys Gly Ala Gly Cys

1040 1045 1050

Cys Ala Gly Gly Ala Ala Gly Ala Ala Ala Thr Gly Ala Cys Thr

1055 1060 1065

Ala Ala Gly Ala Ala Cys Cys Ala Ala Gly Thr Cys Thr Cys Ala

1070 1075 1080

Thr Thr Gly Ala Cys Thr Thr Gly Cys Cys Thr Thr Gly Thr Gly

1085 1090 1095

Ala Ala Gly Gly Gly Cys Thr Thr Cys Thr Ala Cys Cys Cys Ala

1100 1105 1110

Thr Cys Gly Gly Ala Thr Ala Thr Cys Gly Cys Cys Gly Thr Gly

1115 1120 1125

Gly Ala Ala Thr Gly Gly Gly Ala Gly Thr Cys Cys Ala Ala Cys

1130 1135 1140

Gly Gly Cys Cys Ala Gly Cys Cys Gly Gly Ala Ala Ala Ala Cys

1145 1150 1155

Ala Ala Cys Thr Ala Cys Ala Ala Gly Ala Cys Cys Ala Cys Cys

1160 1165 1170

Cys Cys Thr Cys Cys Gly Gly Thr Gly Cys Thr Gly Gly Ala Cys

1175 1180 1185

Thr Cys Ala Gly Ala Cys Gly Gly Ala Thr Cys Cys Thr Thr Cys

1190 1195 1200

Thr Thr Cys Cys Thr Cys Thr Ala Cys Thr Cys Gly Cys Gly Gly

1205 1210 1215

Cys Thr Gly Ala Cys Cys Gly Thr Gly Gly Ala Thr Ala Ala Gly

1220 1225 1230

Ala Gly Cys Ala Gly Ala Thr Gly Gly Cys Ala Gly Gly Ala Gly

1235 1240 1245

Gly Gly Ala Ala Ala Thr Gly Thr Gly Thr Thr Cys Ala Gly Cys

1250 1255 1260

Thr Gly Thr Thr Cys Thr Gly Thr Gly Ala Thr Gly Cys Ala Thr

1265 1270 1275

Gly Ala Ala Gly Cys Cys Cys Thr Gly Cys Ala Cys Ala Ala Cys

1280 1285 1290

Cys Ala Cys Thr Ala Cys Ala Cys Thr Cys Ala Gly Ala Ala Gly

1295 1300 1305

Thr Cys Cys Cys Thr Gly Thr Cys Cys Cys Thr Cys Thr Cys Cys

1310 1315 1320

Cys Thr Gly Gly Gly Ala

1325

<210> 31

<211> 17

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Artificial sequence description: Synthetic peptide

<400> 31

Lys Ser Ser Gln Ser Leu Leu Asp Ser Gly Asn Gln Lys Asn Phe Leu

1 5 10 15

Thr

<210> 32

<211> 7

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Artificial sequence description: Synthetic peptide

<400> 32

Trp Ala Ser Thr Arg Glu Ser

15

<210> 33

<211> 9

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Artificial sequence description: Synthetic peptide

<400> 33

Gln Asn Asp Tyr Ser Tyr Pro Tyr Thr

15

<210> 34

<211> 13

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Artificial sequence description: Synthetic peptide

<400> 34

Ser Gln Ser Leu Leu Asp Ser Gly Asn Gln Lys Asn Phe

1 5 10

<210> 35

<211> 3

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Artificial sequence description: Synthetic peptide

<400> 35

Trp Ala Ser

1

<210> 36

<211> 6

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Artificial sequence description: Synthetic peptide

<400> 36

Asp Tyr Ser Tyr Pro Tyr

15

<210> 37

<211> 113

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Artificial sequence description: Synthetic polypeptide

<400> 37

Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Lys Ser Ser Gln Ser Leu Leu Asp Ser

20 25 30

Gly Asn Gln Lys Asn Phe Leu Thr Trp Tyr Gln Gln Lys Pro Gly Lys

35 40 45

Ala Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val

50 55 60

Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr

65 70 75 80

Ile Ser Ser Leu Gln Pro Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Asn

85 90 95

Asp Tyr Ser Tyr Pro Tyr Thr Phe Gly Gln Gly Thr Lys Val Glu Ile

100 105 110

Lys

<210> 38

<211> 339

<212> DNA

<213> Artificial sequence

<220>

<223> Artificial sequence description: Synthetic polynucleotide

<400> 38

gagatcgtcc tgactcagtc acccgctacc ctgagcctga gccctggcga gcgggctaca 60

ctgagctgta aatctagtca gtcactgctg gatagcggta atcagaagaa cttcctgacc 120

tggtatcagc agaagcccgg taaagcccct aagctgctga tctactgggc ctctactaga 180

gaatcaggcg tgccctctag gtttagcggt agcggtagtg gcaccgactt caccttcact 240

atctctagcc tgcagcccga ggatatcgct acctactact gtcagaacga ctatagctac 300

ccctacacct tcggtcaagg cactaaggtc gagattaag 339

<210> 39

<211> 220

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Artificial sequence description: Synthetic polypeptide

<400> 39

Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Lys Ser Ser Gln Ser Leu Leu Asp Ser

20 25 30

Gly Asn Gln Lys Asn Phe Leu Thr Trp Tyr Gln Gln Lys Pro Gly Lys

35 40 45

Ala Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val

50 55 60

Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr

65 70 75 80

Ile Ser Ser Leu Gln Pro Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Asn

85 90 95

Asp Tyr Ser Tyr Pro Tyr Thr Phe Gly Gln Gly Thr Lys Val Glu Ile

100 105 110

Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp

115 120 125

Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn

130 135 140

Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu

145 150 155 160

Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp

165 170 175

Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr

180 185 190

Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser

195 200 205

Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys

210 215 220

<210> 40

<211> 660

<212> DNA

<213> Artificial sequence

<220>

<223> Artificial sequence description: Synthetic polynucleotide

<400> 40

gagatcgtcc tgactcagtc acccgctacc ctgagcctga gccctggcga gcgggctaca 60

ctgagctgta aatctagtca gtcactgctg gatagcggta atcagaagaa cttcctgacc 120

tggtatcagc agaagcccgg taaagcccct aagctgctga tctactgggc ctctactaga 180

gaatcaggcg tgccctctag gtttagcggt agcggtagtg gcaccgactt caccttcact 240

atctctagcc tgcagcccga ggatatcgct acctactact gtcagaacga ctatagctac 300

ccctacacct tcggtcaagg cactaaggtc gagattaagc gtacggtggc cgctcccagc 360

gtgttcatct tcccccccag cgacgagcag ctgaagagcg gcaccgccag cgtggtgtgc 420

ctgctgaaca acttctaccc ccgggaggcc aaggtgcagt ggaaggtgga caacgccctg 480

cagagcggca acagccagga gagcgtcacc gagcaggaca gcaaggactc cacctacagc 540

ctgagcagca ccctgaccct gagcaaggcc gactacgaga agcataaggt gtacgcctgc 600

gaggtgaccc accagggcct gtccagcccc gtgaccaaga gcttcaacag gggcgagtgc 660

<210> 41

<211> 113

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Artificial sequence description: Synthetic polypeptide

<400> 41

Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Lys Ser Ser Gln Ser Leu Leu Asp Ser

20 25 30

Gly Asn Gln Lys Asn Phe Leu Thr Trp Tyr Gln Gln Lys Pro Gly Gln

35 40 45

Ala Pro Arg Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val

50 55 60

Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr

65 70 75 80

Ile Ser Ser Leu Glu Ala Glu Asp Ala Ala Thr Tyr Tyr Cys Gln Asn

85 90 95

Asp Tyr Ser Tyr Pro Tyr Thr Phe Gly Gln Gly Thr Lys Val Glu Ile

100 105 110

Lys

<210> 42

<211> 339

<212> DNA

<213> Artificial sequence

<220>

<223> Artificial sequence description: Synthetic polynucleotide

<400> 42

gagatcgtcc tgactcagtc acccgctacc ctgagcctga gccctggcga gcgggctaca 60

ctgagctgta aatctagtca gtcactgctg gatagcggta atcagaagaa cttcctgacc 120

tggtatcagc agaagcccgg tcaagcccct agactgctga tctactgggc ctctactaga 180

gaatcaggcg tgccctctag gtttagcggt agcggtagtg gcaccgactt caccttcact 240

atctctagcc tggaagccga ggacgccgct acctactact gtcagaacga ctatagctac 300

ccctacacct tcggtcaagg cactaaggtc gagattaag 339

<210> 43

<211> 220

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Artificial sequence description: Synthetic polypeptide

<400> 43

Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Lys Ser Ser Gln Ser Leu Leu Asp Ser

20 25 30

Gly Asn Gln Lys Asn Phe Leu Thr Trp Tyr Gln Gln Lys Pro Gly Gln

35 40 45

Ala Pro Arg Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val

50 55 60

Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr

65 70 75 80

Ile Ser Ser Leu Glu Ala Glu Asp Ala Ala Thr Tyr Tyr Cys Gln Asn

85 90 95

Asp Tyr Ser Tyr Pro Tyr Thr Phe Gly Gln Gly Thr Lys Val Glu Ile

100 105 110

Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp

115 120 125

Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn

130 135 140

Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu

145 150 155 160

Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp

165 170 175

Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr

180 185 190

Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser

195 200 205

Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys

210 215 220

<210> 44

<211> 660

<212> DNA

<213> Artificial sequence

<220>

<223> Artificial sequence description: Synthetic polynucleotide

<400> 44

gagatcgtcc tgactcagtc acccgctacc ctgagcctga gccctggcga gcgggctaca 60

ctgagctgta aatctagtca gtcactgctg gatagcggta atcagaagaa cttcctgacc 120

tggtatcagc agaagcccgg tcaagcccct agactgctga tctactgggc ctctactaga 180

gaatcaggcg tgccctctag gtttagcggt agcggtagtg gcaccgactt caccttcact 240

atctctagcc tggaagccga ggacgccgct acctactact gtcagaacga ctatagctac 300

ccctacacct tcggtcaagg cactaaggtc gagattaagc gtacggtggc cgctcccagc 360

gtgttcatct tcccccccag cgacgagcag ctgaagagcg gcaccgccag cgtggtgtgc 420

ctgctgaaca acttctaccc ccgggaggcc aaggtgcagt ggaaggtgga caacgccctg 480

cagagcggca acagccagga gagcgtcacc gagcaggaca gcaaggactc cacctacagc 540

ctgagcagca ccctgaccct gagcaaggcc gactacgaga agcataaggt gtacgcctgc 600

gaggtgaccc accagggcct gtccagcccc gtgaccaaga gcttcaacag gggcgagtgc 660

<210> 45

<211> 15

<212> DNA

<213> Artificial sequence

<220>

<223> Artificial sequence description: Synthetic polynucleotide

<400> 45

acctactgga tgcac 15

<210> 46

<211> 51

<212> DNA

<213> Artificial sequence

<220>

<223> Artificial sequence description: Synthetic polynucleotide

<400> 46

aatatctacc ccggcaccgg cggctctaac ttcgacgaga agtttaagaa t 51

<210> 47

<211> 24

<212> DNA

<213> Artificial sequence

<220>

<223> Artificial sequence description: Synthetic polynucleotide

<400> 47

tggactaccg gcacaggcgc ctac 24

<210> 48

<211> 21

<212> DNA

<213> Artificial sequence

<220>

<223> Artificial sequence description: Synthetic polynucleotide

<400> 48

ggctacacct tcactaccta c 21

<210> 49

<211> 18

<212> DNA

<213> Artificial sequence

<220>

<223> Artificial sequence description: Synthetic polynucleotide

<400> 49

taccccggca ccggcggc 18

<210> 50

<211> 51

<212> DNA

<213> Artificial sequence

<220>

<223> Artificial sequence description: Synthetic polynucleotide

<400> 50

aaatctagtc agtcactgct ggatagcggt aatcagaaga acttcctgac c 51

<210> 51

<211> 21

<212> DNA

<213> Artificial sequence

<220>

<223> Artificial sequence description: Synthetic polynucleotide

<400> 51

tgggcctcta ctagagaatc a 21

<210> 52

<211> 27

<212> DNA

<213> Artificial sequence

<220>

<223> Artificial sequence description: Synthetic polynucleotide

<400> 52

cagaacgact atagctaccc ctacacc 27

<210> 53

<211> 39

<212> DNA

<213> Artificial sequence

<220>

<223> Artificial sequence description: Synthetic polynucleotide

<400> 53

agtcagtcac tgctggatag cggtaatcag aagaacttc 39

<210> 54

<211> 9

<212> DNA

<213> Artificial sequence

<220>

<223> Artificial sequence description: Synthetic polynucleotide

<400> 54

tgggcctct 9

<210> 55

<211> 18

<212> DNA

<213> Artificial sequence

<220>

<223> Artificial sequence description: Synthetic polynucleotide

<400> 55

gactatagct acccctac 18

<210> 56

<211> 440

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Artificial sequence description: Synthetic polypeptide

<400> 56

Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg

1 5 10 15

Ser Leu Arg Leu Asp Cys Lys Ala Ser Gly Ile Thr Phe Ser Asn Ser

20 25 30

Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ala Val Ile Trp Tyr Asp Gly Ser Lys Arg Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Phe

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Thr Asn Asp Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser

100 105 110

Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser

115 120 125

Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp

130 135 140

Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr

145 150 155 160

Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Ser Gly Leu Tyr

165 170 175

Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys

180 185 190

Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp

195 200 205

Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala

210 215 220

Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro

225 230 235 240

Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val

245 250 255

Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val

260 265 270

Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln

275 280 285

Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln

290 295 300

Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly

305 310 315 320

Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro

325 330 335

Arg Glu Pro Gln Val Tyr Thr Leu Pro Ser Gln Glu Glu Met Thr

340 345 350

Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser

355 360 365

Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr

370 375 380

Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr

385 390 395 400

Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe

405 410 415

Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys

420 425 430

Ser Leu Ser Leu Ser Leu Gly Lys

435 440

<210> 57

<211> 214

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Artificial sequence description: Synthetic polypeptide

<400> 57

Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Tyr

20 25 30

Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile

35 40 45

Tyr Asp Ala Ser Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro

65 70 75 80

Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Ser Ser Asn Trp Pro Arg

85 90 95

Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala

100 105 110

Pro Ser Val Phe Ile Phe Pro Ser Asp Glu Gln Leu Lys Ser Gly

115 120 125

Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala

130 135 140

Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln

145 150 155 160

Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser

165 170 175

Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr

180 185 190

Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser

195 200 205

Phe Asn Arg Gly Glu Cys

210

<210> 58

<211> 447

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Artificial sequence description: Synthetic polypeptide

<400> 58

Gln Val Gln Leu Val Gln Ser Gly Val Glu Val Lys Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr

20 25 30

Tyr Met Tyr Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Gly Ile Asn Pro Ser Asn Gly Gly Thr Asn Phe Asn Glu Lys Phe

50 55 60

Lys Asn Arg Val Thr Leu Thr Thr Asp Ser Ser Thr Thr Thr Ala Tyr

65 70 75 80

Met Glu Leu Lys Ser Leu Gln Phe Asp Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Arg Asp Tyr Arg Phe Asp Met Gly Phe Asp Tyr Trp Gly Gln

100 105 110

Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val

115 120 125

Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala

130 135 140

Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser

145 150 155 160

Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val

165 170 175

Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro

180 185 190

Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys

195 200 205

Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro

210 215 220

Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val

225 230 235 240

Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr

245 250 255

Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu

260 265 270

Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys

275 280 285

Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser

290 295 300

Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys

305 310 315 320

Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile

325 330 335

Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro

340 345 350

Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu

355 360 365

Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn

370 375 380

Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser

385 390 395 400

Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg

405 410 415

Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu

420 425 430

His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys

435 440 445

<210> 59

<211> 218

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Artificial sequence description: Synthetic polypeptide

<400> 59

Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Lys Gly Val Ser Thr Ser

20 25 30

Gly Tyr Ser Tyr Leu His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro

35 40 45

Arg Leu Leu Ile Tyr Leu Ala Ser Tyr Leu Glu Ser Gly Val Pro Ala

50 55 60

Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser

65 70 75 80

Ser Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln His Ser Arg

85 90 95

Asp Leu Pro Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg

100 105 110

Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln

115 120 125

Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr

130 135 140

Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser

145 150 155 160

Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr

165 170 175

Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys

180 185 190

His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro

195 200 205

Val Thr Lys Ser Phe Asn Arg Gly Glu Cys

210 215

<210> 60

<211> 447

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Artificial sequence description: Synthetic polypeptide

<400> 60

Gln Val Gln Leu Val Gln Ser Gly Ser Glu Leu Lys Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr

20 25 30

Gly Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Gln Trp Met

35 40 45

Gly Trp Ile Asn Thr Asp Ser Gly Glu Ser Thr Tyr Ala Glu Glu Phe

50 55 60

Lys Gly Arg Phe Val Phe Ser Leu Asp Thr Ser Val Asn Thr Ala Tyr

65 70 75 80

Leu Gln Ile Thr Ser Leu Thr Ala Glu Asp Thr Gly Met Tyr Phe Cys

85 90 95

Val Arg Val Gly Tyr Asp Ala Leu Asp Tyr Trp Gly Gln Gly Thr Leu

100 105 110

Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu

115 120 125

Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys

130 135 140

Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser

145 150 155 160

Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser

165 170 175

Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser

180 185 190

Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn

195 200 205

Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His

210 215 220

Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val

225 230 235 240

Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr

245 250 255

Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu

260 265 270

Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys

275 280 285

Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser

290 295 300

Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys

305 310 315 320

Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile

325 330 335

Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro

340 345 350

Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu

355 360 365

Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn

370 375 380

Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser

385 390 395 400

Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg

405 410 415

Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu

420 425 430

His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys

435 440 445

<210> 61

<211> 213

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Artificial sequence description: Synthetic polypeptide

<400> 61

Glu Ile Val Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Ser Ala Arg Ser Ser Val Ser Tyr Met

20 25 30

His Trp Phe Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Trp Ile Tyr

35 40 45

Arg Thr Ser Asn Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly Ser

50 55 60

Gly Ser Gly Thr Ser Tyr Cys Leu Thr Ile Asn Ser Leu Gln Pro Glu

65 70 75 80

Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Arg Ser Ser Phe Pro Leu Thr

85 90 95

Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala Pro

100 105 110

Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr

115 120 125

Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys

130 135 140

Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu

145 150 155 160

Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser

165 170 175

Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala

180 185 190

Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe

195 200 205

Asn Arg Gly Glu Cys

210

<---

Claims (22)

1. Pharmaceutical combination for the treatment of a solid tumor, containing: a) an effective amount of the first pharmaceutical composition containing 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1.7 ]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, aluminum particles, a buffering agent and one or more pharmaceutically acceptable excipients, where the buffering agent is Tris buffer; the pharmaceutically acceptable excipient is mannitol; the composition has a pH in the range of 6.5 to 9.0, and the aluminum-containing particles are a suspension of aluminum hydroxide particles, and b) an effective amount of the second pharmaceutical composition containing the anti-PD-L1 antibody. 2. Pharmaceutical combination for the treatment of a solid tumor, containing: a) an effective amount of the first pharmaceutical composition containing 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1.7 ]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, aluminum particles, a buffering agent and one or more pharmaceutically acceptable excipients, where the buffering agent is Tris buffer; the pharmaceutically acceptable excipient is mannitol; the composition has a pH in the range of 6.5 to 9.0, and aluminum-containing particles are a suspension of particles of aluminum hydroxide, b) an effective amount of the second pharmaceutical composition containing the anti-PD-L1 antibody, and c) an effective amount of the third pharmaceutical composition containing the anti-CTLA-4 antibody. 3. Pharmaceutical composition according to claim 1 or 2, where the composition contains 0.5-2 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy) -2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, 5-100 mM tris buffer, 5-10% (w/v) mannitol and hydroxide particle suspension aluminum, characterized by an aluminum content of 1–4 mg/ml. 4. The pharmaceutical composition according to claim 1 or 2, where the pharmaceutical composition contains 1 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2- methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, 5-20 mM Tris buffer, 5-10% (w/v) mannitol, and a suspension of aluminum hydroxide particles characterized by an aluminum content of 2 mg/ml, and where the composition is characterized by a pH in the range of 7.0-8.0. 5. Pharmaceutical composition according to claim 1 or 2, wherein the pharmaceutical composition contains 1 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2- methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, 16 mM Tris buffer, 7.5% (w/v) mannitol, and an aluminum hydroxide particle suspension characterized by aluminum content 2 mg/ml, and where the composition is characterized by a pH in the range of 7.0-8.0. 6. Pharmaceutical composition according to claim 1 or 2, wherein the pharmaceutical composition contains 1 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2- methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, 5 mM Tris buffer, 8.25% (w/v) mannitol, and an aluminum hydroxide particle suspension characterized by aluminum content 2 mg/ml, and where the composition is characterized by a pH in the range of 7.0-8.0. 7. Pharmaceutical composition according to claim. 1 or 2, where the pharmaceutical composition contains 1 mg/ml 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2- methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid or a pharmaceutically acceptable salt thereof, 5 mM tris buffer, 5.5% (w/v) mannitol and a suspension of aluminum hydroxide particles characterized by aluminum content 2 mg/ml, and where the composition is characterized by a pH in the range of 7.0-8.0.

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