CN116829158A - Treatment of cancer and diseases associated with defects in phagocytosis - Google Patents

Treatment of cancer and diseases associated with defects in phagocytosis Download PDF

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CN116829158A
CN116829158A CN202180073606.6A CN202180073606A CN116829158A CN 116829158 A CN116829158 A CN 116829158A CN 202180073606 A CN202180073606 A CN 202180073606A CN 116829158 A CN116829158 A CN 116829158A
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combination
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cancer
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稻叶太郎
野野村和彦
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R Discovery Co ltd
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R Discovery Co ltd
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Priority claimed from PCT/US2021/057698 external-priority patent/WO2022098642A1/en
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    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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Abstract

Methods for treating diseases and conditions associated with defects in phagocytosis and methods for treating cancer with a phagocytosis activator and a mitochondrial fission inhibitor, respectively, as monotherapy or in combination with one or more additional agents, and agents, combinations of agents, and compositions for treating diseases and conditions associated with defects in phagocytosis.

Description

Treatment of cancer and diseases associated with defects in phagocytosis
1. Cross-reference to related applications
The present application claims priority from U.S. provisional application No. 63/109,111 filed on 3 months 11 and 2021 to U.S. provisional application No. 63/145,681 filed on 4 months 2, 2020, each of which is incorporated herein by reference in its entirety.
2. Background art
CD47 is a widely expressed cell surface protein that binds to signal-regulating protein alpha (sirpa) on macrophages to protect healthy cells from phagocytosis by macrophages. The interaction between CD47 and sirpa is called a "don't eat me" signal. CD47 is typically upregulated in cancer cells, enabling the cancer cells to evade innate immunity detection. Morissey and Vale,2019,bioRxiv 752311; ori/10.1101/752311. By blocking the interaction between CD47 and sirpa, for example by anti-CD 47 or anti-sirpa antibodies, "don't eat me" signals are attenuated and phagocytic function of macrophages and other phagocytes should be activated. anti-CD 47 and anti-sirpa antibodies have generated promising clinical and non-clinical data in the oncology field. However, a significant number of patients do not respond to therapies targeting CD 47-SIRPalpha interactions (see, e.g., advani et al, 2018,N Engl J Med.379 (18): 1711-1721).
In addition to cancer, defects in phagocytosis have been associated with other diseases, such as infectious diseases, neurodegenerative diseases, inflammatory and lysosomal diseases (see, e.g., engelich et al 2001,Clinical Infectious Diseases 33 (12): 2040-2048; andrews and Sullivan,2003,Clin Microbiol Rev.16 (4): 597-621; galloway et al 2019,Front Immunol.10:790;Kourtzelis et al 2020,Front Immunol.2020;11:553;Maderna and Godson,2003,Biochimica et Biophysica Acta (BBA) -Molecular Basis of Disease,1639 (3): 141-151; marques and Saftig,2019,Journal of Cell Science 132:jcs221739;Parkinson-Lawrence et al 2010,Physiology 25:102-115).
There remains a need for new therapies for the treatment of cancer and diseases and conditions associated with defects in phagocytosis.
3. Summary of the invention
Without being bound by theory, it is believed that the limited clinical and non-clinical effects of CD 47-sirpa targeted therapies are associated with defects in phagocytic capacity of phagocytes such as monocytes, macrophages and microglia, at least in some cases. It is believed that defects in phagocytes may be due to a variety of causes, including nutritional conditions, poor innate immune stimulation, phagocyte polarization, aging associated with the aging of hematopoietic stem cells and cells of their lineages, including monocytes. It is believed that when phagocytic capacity of phagocytes is not ideal, the blockade of CD47 and sirpa interactions may not be sufficient for phagocytes to eliminate cancer cells or induce the adaptive immune system to develop immunity against cancer cells.
It is further believed, again without being bound by theory, that enhancing phagocytic activity of phagocytes by phagocytosis activators may improve the outcome of non-cancerous phagocytosis-defect related diseases and conditions, such as infectious diseases, neurodegenerative diseases, inflammation, inflammatory diseases, lysosomal diseases and musculoskeletal degenerative diseases, such as Duchenne Muscular Dystrophy (DMD).
Thus, in one aspect, the present disclosure provides methods of treating phagocytosis-defect related diseases and disorders (e.g., cancer) with agents that activate phagocytosis (e.g., mitochondrial fission inhibitors such as cilnidipine, P110, metformin, mdivi-1, or berberine). The present disclosure is based in part on the discovery that the mitochondrial fission inhibitor cilnidipine can enhance phagocytic activity of macrophages. The phagocytosis activator may be administered as monotherapy or, alternatively, may be administered in combination with another agent or combination of agents, such as an anti-CD 47 antibody and/or an anti-sirpa antibody. In some embodiments, the disease associated with a defect in phagocytosis is cancer. In other embodiments, the phagocytosis-defect related disease is a non-cancer disease associated with phagocytosis dysfunction, such as an infectious disease, a neurodegenerative disease, an inflammatory disease, a lysosomal disease, or a musculoskeletal degenerative disease such as DMD.
Exemplary phagocytosis activators are described below in section 5.1 and embodiments 2 through 89. Exemplary additional agents and combinations of agents that may be used in combination with the phagocytosis activator or combination of phagocytosis activators are described below in section 5.2 and embodiments 111-148. Exemplary diseases associated with defects in phagocytosis are described below in section 5.4 and embodiments 1 and 149 to 186.
In another aspect, the present disclosure provides methods of treating cancer (which may or may not be associated with a phagocytosis defect) with a mitochondrial fission inhibitor, such as cilnidipine, a cilnidipine derivative (e.g., as described in WO 2020/241638), P110, metformin, mdivi-1, or berberine. In some embodiments, the cancer has a KRAS mutation. KRAS mutations can drive cancer cell growth and spread in vivo, and without being bound by theory, it is believed that mitochondrial fission inhibitors can inhibit proliferation signals in tumor cells caused by KRAS mutations.
The mitochondrial fission inhibitor may be administered as monotherapy for the cancer or alternatively as part of a combination therapy, e.g., with an anti-PD 1 or anti-PD-L1 antibody. In some embodiments, the combination therapy comprises a mitochondrial fission inhibitor, such as cilnidipine, administered with standard of care therapy. Exemplary mitochondrial fission inhibitors are described below in section 5.1.1 and embodiments 5 through 54. Exemplary cancers that may be treated are described below in section 5.4.1 and embodiments 90 through 109.
In a further aspect, the present disclosure provides reagents and combinations of reagents for use in the methods described herein. The agent and the combination of agents may be in a pharmaceutical composition. Exemplary agents, combinations of agents, and pharmaceutical compositions are described below in sections 5.1 through 5.3 and in specific embodiments 187 through 237.
In a further aspect, the present disclosure provides a pharmaceutical composition comprising phagocytes having enhanced phagocytic activity. Phagocytes with enhanced phagocytic activity may be obtained by ex vivo treatment of phagocytes with mitochondrial fission inhibitors such as cilnidipine. Such pharmaceutical compositions are useful in methods of treating a subject suffering from a phagocytosis-defect related disease or disorder, such as cancer or other diseases or disorders disclosed herein. The phagocytes may be autologous to the subject to be treated or alternatively, the phagocytes may be allogenic to the subject to be treated. Exemplary pharmaceutical compositions comprising phagocytes having enhanced phagocytic activity, methods for their production, and mitochondrial fission inhibitors for preparing such pharmaceutical compositions are described below in section 5.3 and embodiments 238-255.
4. Description of the drawings
FIG. 1 shows enhancement of phagocytic activity of macrophages exposed to DMSO vehicle or cilnidipine at a concentration of 0.3. Mu.M, 1. Mu.M or 3. Mu.M. Phagocytosis is the ratio of cells that engulf a specified number of fluorescent-labeled particles (one or more, two or more, three or more, or four or more particles).
FIG. 2 shows the average fluorescence intensity of fluorescent-labeled beads derived from macrophage uptake of cilnidipine exposed to DMSO vehicle or at a concentration of 0.3. Mu.M, 1. Mu.M, or 3. Mu.M.
Figure 3 shows the animal body weight of example 4.
Fig. 4 shows the results of the rotarod incubation period for the animals of example 4. Data are expressed as mean ± SEM.
Figure 5 shows plasma LDH levels of the animals of example 4. Data are expressed as mean ± SEM; # # # represents p <0.001, by unpaired t-test with WT; * P <0.05 is indicated by unpaired t-test with MDX-vehicle.
Figure 6 shows plasma CK levels for the animals of example 4. Data are expressed as mean ± SEM; # # # represents that p <0.001 passes unpaired t-test with WT; * P <0.05 is indicated by unpaired t-test with MDX-vehicle.
Figures 7A-7B show the average body weight (figure 7A) and percent change in body weight (figure 7B) of the animals of example 5.
Figures 8A-8B show the average tumor volume (figure 8A) and percent tumor volume inhibition (figure 8B) for the animals of example 5.
5. Detailed description of the invention
In one aspect, the present disclosure provides methods of treating phagocytosis-deficiency related diseases and disorders, such as cancer, with agents that activate phagocytosis as monotherapy, or alternatively in combination with additional agents or combinations of agents, such as anti-CD 47 antibodies and/or anti-sirpa antibodies. Exemplary phagocytosis activators are described in section 5.1. Exemplary additional reagents and combinations of reagents are described in section 5.2. Pharmaceutical compositions useful in the methods of the present disclosure are described in section 5.3. Exemplary diseases associated with defects in phagocytosis are described in section 5.4.
In another aspect, the present disclosure provides methods of treating cancer (which may or may not be associated with a phagocytosis defect) with a mitochondrial fission inhibitor, such as cilnidipine or a cilnidipine derivative. Exemplary mitochondrial fission inhibitors are described in section 5.1.1. Exemplary cancers that may be treated are described in section 5.4.1. In some embodiments, a method of treating cancer can include administering an agent or combination of agents in an amount effective to slow the progression of cancer (e.g., slow the rate of tumor growth) in a subject.
In another aspect, the present disclosure provides methods of treating non-cancer diseases associated with phagocytic dysfunction, such as infectious diseases, neurodegenerative diseases, inflammatory diseases, and lysosomal diseases, with a mitochondrial fission inhibitor, such as cilnidipine or a cilnidipine derivative. Exemplary non-cancer indications are described in section 5.4.2. In some embodiments, a method of treating a non-cancer disease may comprise administering an agent or combination of agents in an amount effective to ameliorate one or more symptoms of the disease. In some embodiments, a method of treating a non-cancer disease may comprise administering an agent or combination of agents in an amount effective to ameliorate one or more biomarkers of the disease.
In further aspects, the present disclosure provides reagents and combinations of reagents for use in the methods described herein, as well as pharmaceutical compositions comprising such reagents. Exemplary agents, combinations of agents, and pharmaceutical compositions are described in sections 5.1 through 5.3.
In some embodiments of the methods of the present disclosure, the subject has a phagocyte defect. Phagocytic defects may be measured, for example, phagocytic activity using an in vitro assay. Example 1 describes an in vitro assay that may be suitable for measuring phagocytic activity in a subject (e.g., macrophages and/or other types of phagocytes of a subject may be isolated and used in an assay as described in example 1, but in the absence of cilnidipine). Phagocytic activity of phagocytes of a subject can be compared to a control phagocytic activity value, e.g., a phagocytic activity value obtained using phagocytes from a healthy subject population.
The subject treated by the methods described herein is preferably a mammal, most preferably a human.
5.1. Phagocytosis activating agent
A variety of phagocytosis activators may be used in the methods of the present disclosure. For example, the agent may be a mitochondrial fission inhibitor (e.g., drp1 inhibitor), pgc1α activator, inhibitor of PI3K-AKT-mTOR pathway, or a single component or a combination of components from the lactic acid releasing bacteria medium. Combinations of such agents may also be used (e.g., combinations of two or more mitochondrial fission inhibitors, combinations of mitochondrial fission inhibitors and pgc1α activators, combinations of mitochondrial fission inhibitors and inhibitors of the PI3K-AKT-mTOR pathway, etc. may be used). It will be appreciated that the classification of phagocytosis activators into specific types of agents is for convenience and that agents may have more than one mechanism of action. Thus, it should be understood that the methods of the present disclosure, including administration of a particular agent to a subject, are not limited to a particular mechanism of action.
5.1.1. Mitochondrial fission inhibitors
Mitochondria are organelles that can be found in almost all eukaryotic cells, mainly involved in ATP production due to oxidative phosphorylation occurring in the electron transport system. Mitochondria undergo repeated fusion and division, an abnormality of which is known to be associated with cancer. Mitochondrial fission is induced by activation of Drp1, drp1 being a GTP binding protein. Cilnidipine has the effect of blocking both L-type and N-type calcium channels, has been used as a drug for the treatment of hypertension, and has also been found to inhibit Drp-filamin complex formation, thereby inhibiting mitochondrial fission. Nishimura et al 2018, sci.Signal.11 (556): eaat5185. Example 1 of the present invention shows that cilnidipine can also enhance phagocytic activity of macrophages. Thus, in some embodiments, the phagocytosis activator or combination of phagocytosis activators comprises a Drp-1 inhibitor, such as cilnidipine or derivatives thereof.
Cilnidipine has the following structure:
exemplary cilnidipine derivatives are described in WO 2020/241638, the contents of which are incorporated herein by reference in their entirety.
In some embodiments, the phagocytosis activating agent is a compound of formula (I):
or a pharmacologically acceptable salt thereof or a solvate thereof, wherein:
R 1 for phenyl substituted with 1 to 3 substituents, each substituent is independently NO 2 、NH 2 、OH、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, or C 1 -C 6 Alkoxyalkyl groups, provided that at least one substituent is NO 2 Or NH 2 ；
R 2 H, C of a shape of H, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, or C 1 -C 6 An alkoxyalkyl group;
R 3 h, C of a shape of H, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, or C 1 -C 6 An alkoxyalkyl group;
R 4 is C 1 -C 6 Alkyl or C 1 -C 6 A haloalkyl group;
R 5 is phenyl or pyridinyl, wherein the phenyl or pyridinyl is unsubstituted or substituted with 1 to 3 substituents, each substituent independently being NO 2 、NH 2 、OH、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, or C 1 -C 6 An alkoxyalkyl group;
(i) Bond a is present and bonds b and c are absent or (ii) bonds b and c are present and bond a is absent;
a is NH when bond a is present and N when bonds b and c are present;
m is an integer from 1 to 4; and
n is an integer from 1 to 3.
In some embodiments, the compound of formula (I) is not cilnidipine. Such compounds of formula (I) are examples of cilnidipine derivatives.
Further features of the compounds of formula (I) are described in the following embodiments 9 to 50.
In some embodiments, the compound of formula (I) is(referred to as "NS4-019" in WO 2020/241638), or a pharmacologically acceptable salt thereof or a solvate thereof.
In other embodiments, the compound of formula (I) is(referred to as "NS4-238" in WO 2020/241638), or a pharmacologically acceptable salt thereof or a solvate thereof.
In other embodiments, the compound of formula (I) is(referred to as "NS4-043" in WO 2020/241638), or a pharmacologically acceptable salt thereof or a solvate thereof.
In other embodiments, the compound of formula (I) is(referred to as "NS4-700" in WO 2020/241638), or a pharmacologically acceptable salt thereof or a solvate thereof.
In other embodiments, the compound of formula (I) is(referred to as "NS4-021" in WO 2020/241638), or a pharmacologically acceptable salt thereof or a solvate thereof.
In other embodiments, the compound of formula (I) is(designated "JYK-002" in WO 2020/241638), or a pharmacologically acceptable salt thereof or a solvate thereof.
In other embodiments, the compound of formula (I) is (designated "JYK-003" in WO 2020/241638), or a pharmacologically acceptable salt thereof or a solvate thereof.
In other embodiments, the compound of formula (I) is(designated "JYK-001" in WO 2020/241638), or a pharmacologically acceptable salt thereof or a solvate thereof.
In other embodiments, the compound of formula (I) is(referred to as "JYK-004" in WO 2020/241638), or a pharmacologically acceptable salt thereof or a solvate thereof.
Additional mitochondrial fission inhibitors include P110 (YGRKKRRQRRRGGDLLPRGS-NH 2 The method comprises the steps of carrying out a first treatment on the surface of the See Qi et al, 2013,J Cell Sci,126 (Pt 3): 789-802; U.S. patent No. 10,245,297; WO 2018/195491), metformin, mdivi-1, or berberine. Additional mitochondrial fission inhibitors, including Drp inhibitors, are described in WO 2012/158624, WO 2016/130143, WO 2018/052891, and WO 2019/126179, the respective contents of each of which are incorporated herein by reference in their entirety.
5.1.2. Additional phagocytosis activators
Additional phagocytosis activators (e.g., alone or in combination with the agents described in 5.1.1 and/or with the agents described in 5.1.2) that may be used in the methods of the present disclosure include agents that activate toll-like receptors (TLRs), dectin-1, mannose receptors, scavenger receptors A, CD, CD36, opsonin receptors, or apoptotic body receptors (e.g., as agonists of these).
TLR agonists activate TLRs, including, for example, TLR3, TLR4, or RIG1. Examples of TLR agonists include pathogen-associated molecular patterns (PAMPs) and mimics thereof. These microbial molecular markers may be composed of proteins, carbohydrates, lipids, nucleic acids, and/or combinations thereof, and may be internal or external, as is known in the art. Examples include LPS, zymosan, peptidoglycan, flagellin, synthetic TLR2 agonists Pam3cys, pam3CSK4, MALP-2, imiquimod, cpG ODN, and the like.
TLR3 agonists include double stranded RNA; poly (I: C), poly (A.U), etc., wherein such nucleic acids typically have a size of at least about 10bp, at least about 20bp, at least about 50bp and may have a high molecular weight of from about 1 to about 20kb, typically no more than about 50 to 100 kb. Alternative TLR3 agonists may bind directly to a protein, for example an antibody or small molecule that selectively binds and activates TLR 3. Other TLR3 agonists include retroviruses, e.g., retroviruses designed to lack the ability to integrate into the genome.
TLR3, 4, 7/8 and 9 agonists include: 852A: synthesizing imidazole quinoline simulating the ssRNA of the virus; VTX-2337: small molecule selective TLR8 agonists that mimic viral ssrnas; BCG: BCG (Bacillus of Calmette-Guerin), mycobacterium bovis; cpG ODN: cpG oligodeoxynucleotide; imiquimod: synthesizing imidazole quinoline simulating the ssRNA of the virus; LPS: lipopolysaccharide; MPL: monophosphoryl lipid a; poly l: C: polyribocytidine-polyribocytidine acid (Polyriboinosinic-Polyribocytidylic Acid); polylCLC: poly-l-lysine; raschimod: synthesis of imidazoquinolines mimicking viral ssRNA.
Imiquimod is a synthetic imidazoquinoline, targeting TLR7. Newer imidazoquinoline TLR7 agonists 852A show modest clinical efficacy and disease stability as monotherapy by parenteral administration. Leixomadine is an imidazoquinoline TLR7/8 agonist in humans.
CpG is a single stranded Oligodeoxynucleotide (ODN) characterized by containing a motif of cytosine and guanine. Based on their immune effects, cpG ODNs fall into three distinct categories: ext> CpGext> -ext> Aext>,ext> aext> potentext> NKext> cellext> stimulatorext>,ext> becauseext> itext> hasext> anext> effectext> onext> IFNext> -ext> aext> ofext> pDCext>;ext> CpG-B, a moderate IFN-a inducer and enhancer of antigen specific immune responses (costimulatory molecules on up-regulate pDC and B cells, induce production of Th 1 cytokines and stimulate antigen presentation of pDC); ext> andext> CpGext> -ext> Cext>,ext> whichext> combinesext> theext> stimulatoryext> capabilitiesext> ofext> CpGext> -ext> Aext> andext> CpGext> -ext> Bext>.ext> CpG 7909 (PF-3512676, a type B CpG and TLR9 agonist) has been evaluated in a variety of tumor types, including renal cell carcinoma, glioblastoma, melanoma, cutaneous T-cell lymphoma, and non-Hodgkin's lymphoma.
Polyribocytidine-polyribocytidine acid (Poly l: C) is a synthetic analog of viral dsRNA that stimulates endosomes (TLR 3) and/or cytosolic melanoma differentiation associated gene 5 (MDA 5) to increase type I IFN production.
Lipid a molecules targeting TLR4 complexes include monophosphoryl lipid a (MPL), a derivative of lipid a from salmonella minnesota.
Dectin-1 agonists include beta-glucan, heat-inactivated Candida albicans, heat-inactivated Saccharomyces cerevisiae, whole Glucan Particles (WGP), and zymosan (a cell wall preparation of Saccharomyces cerevisiae).
Mannose receptor activators include RP-182 (Jaynes et al 2020,Science Translational Medicine 12 (530): eaax 6337).
Scavenger receptor A activators include low endotoxin acetylated LDL (AcLDL) (J. Tsuzefowski et al, 2014,Innate Immun.20 (8): 826-47).
CD14 activators include the flavivirus NS1 protein, LPS and oxPAPC (oxidized 1-palmitoyl-2-arachidonyl-sn-glycero-3-phosphorylcholine).
CD36 activators include NKS-3 (see WO 2019/229005) and ABT-510, a CD36 agonist peptide.
Receptor activators of opsonin include aggregated C3 proteins and aggregated C3b proteins.
Other examples of phagocytosis activators include 1, 3-beta glucan, mannan, lipopolysaccharide (LPS), lipoteichoic acid, lipopolysaccharide binding proteins, plasmodium falciparum infected erythrocytes, igG, igA, igE and phosphatidylserine. In some embodiments, the phagocytosis activator or combination of phagocytosis activators comprises 1, 3-beta glucan. In some embodiments, the phagocytosis activator or combination of phagocytosis activators comprises mannans. In some embodiments, the phagocytosis activator or combination of phagocytosis activators comprises Lipopolysaccharide (LPS). In some embodiments, the phagocytosis activator or combination of phagocytosis activators comprises lipoteichoic acid. In some embodiments, the phagocytosis activator or combination of phagocytosis activators comprises a lipopolysaccharide binding protein. In some embodiments, the phagocytosis activator or combination of phagocytosis activators comprises plasmodium falciparum infected erythrocytes. In some embodiments, the phagocytosis activator or combination of phagocytosis activators comprises IgG. In some embodiments, the phagocytosis activator or combination of phagocytosis activators comprises IgA. In some embodiments, the phagocytosis activator or combination of phagocytosis activators comprises IgE. In some embodiments, the phagocytosis activator or combination of phagocytosis activators comprises phosphatidylserine.
In a further embodiment, the phagocytosis activator comprises an agent that activates PPARG coactivator 1 alpha (PGC 1 alpha). Exemplary PGC1α activators include metformin, ZLN005 (Zhang et al, 2013, diabetes.62 (4): 1297-307) and mogroside VI B (Niu et al, 2017,J Nat Prod.80 (5): 1428-1435). Other agents that increase pgc1α activity include peroxisome proliferator-activated receptor (PPAR) -gamma agonists, AMPK activators and deacetylase (sirtuin) activators. Exemplary PPAR-gamma agonists include Thiazolidinedione (TZD), aloglizab, faglizab, moglizab, and tigglizab. Exemplary TZDs include pioglitazone, rosiglitazone, pioglitazone, and troglitazone. Exemplary AMPK activators include 5-aminoimidazole-4-carboxamide ribonucleotides (AICAR). Exemplary deacetylase activators include resveratrol, SRT1720, SRT2104, SRT2183, SRT1460, and combinations thereof.
In a further embodiment, the phagocytosis activator or combination of phagocytosis activators comprises an agent that inhibits the PI3K-AKT-mTOR pathway. The PI3K-AKT-mTOR pathway is an intracellular signaling pathway important in regulating phagocytic capacity of macrophages (Weichhart et al 2015,Nat Rev Immunol.15 (10): 599-61). The agent that inhibits the PI3K-AKT-mTOR pathway may be, for example, an agent that inhibits PI3K, an agent that inhibits AKT, or an agent that inhibits mTOR. Exemplary PI3K inhibitors include pictilisib, buparlisib, idelalisib, copanlisib, duvelisib, gedatolisib and apitolisib. Exemplary AKT inhibitors include ipatasertib, MK-2206 and ARQ-092. Exemplary mTOR inhibitors include rapamycin, everolimus, 32-deoxorapamycin, 16-pent-2-ynyloxy-32-deoxorapamycin, 16-pent-2-yloxy-32 (S) -dihydro-rapamycin, 16-pent-2-yloxy-32 (S) -dihydro-O-40-O- (2-hydroxyethyl) -rapamycin, rapamycin 42-ester with 3-hydroxy-2- (hydroxymethyl) -2-methylpropanoic acid (CCI-779), 40- [ 3-hydroxy-2- (hydroxymethyl) -2-methylpropanoic acid ester ] -rapamycin, or a pharmaceutically acceptable salt thereof, as disclosed in U.S. Pat. No. 5,362,718, ABT578 or 40- (tetrazolyl) -rapamycin, 40-epi- (tetrazolyl) -rapamycin, e.g., as disclosed in WO 99/15530, or rapamycin analogues, as disclosed in WO 98/024441 and WO 01/87, e.g., AP23573.
In a further embodiment, the phagocytosis activating agent comprises one or more bacterial strains, e.g. one or more probiotic bacterial strains and/or components or combinations of components from a bacterial culture, e.g. a probiotic culture. Probiotics may activate phagocytosis. See, e.g., gorska et al, 2019,Curr Microbiol.76 (8): 939-949. Bacteria may include, for example, lactic acid producing bacteria. In some embodiments, the phagocytosis activating agent comprises a component or combination of components from a cell-free extract of lactic acid releasing bacteria culture medium. Exemplary lactic acid releasing bacteria include Lactobacillus, leuconostoc, pediococcus, lactococcus and Streptococcus, balloon, carnivorous, enterococcus, wine, lactobacillus, tetracoccus, roaming and Weissella. In some embodiments, the lactic acid bacteria include bifidobacteria and/or lactobacillus, such as lactobacillus acidophilus. Exemplary bacterial formulations are described in WO 2016/196605 and WO 2004/087178, the contents of which are incorporated herein by reference in their entirety. The formulation comprising the living bacteria may be administered by any suitable route, for example orally, by intravenous injection or by intratumoral injection.
5.2. Second agent and combination of second agents
In some embodiments, the phagocytosis activator or combination of phagocytosis activators is administered in combination with one or more additional agents, e.g., one or more standard of care therapies for the disease of the subject or one or more additional agents described herein.
As used herein, "combined" administration refers to delivering two (or more) different treatments to a subject during the subject's suffering from a disorder, e.g., two or more treatments are delivered after the subject is diagnosed with a disorder and before the disorder is cured or eliminated or the treatment is otherwise stopped. In some embodiments, when delivery of the second treatment begins, delivery of one treatment is still ongoing such that there is overlap in administration. This may be referred to as "simultaneous" or "concurrent delivery. The term "simultaneously" is not limited to a complete simultaneous administration of therapy (e.g., a phagocytosis activator and an additional agent), but rather refers to a pharmaceutical composition comprising one agent being administered to a subject in a sequence and at intervals such that the agent may act with the additional agent to provide a greater benefit than when administered otherwise. For example, each agent in the combination may be administered to the subject simultaneously or sequentially in any order at different time points; however, if not administered simultaneously, they should be administered at a time sufficiently close to provide the desired therapeutic effect.
The methods of treating cancer disclosed herein can include the combined administration of a phagocytosis activator and a CD47 inhibitor, such as an anti-CD 47 antibody and/or a sirpa inhibitor, such as an anti-sirpa antibody.
Phagocytosis activators, e.g., mitochondrial fission inhibitors, e.g., cilnidipine and cilnidipine derivatives, e.g., as described in section 5.1.1, may be used in combination with one or more additional anti-cancer therapies (e.g., standard of care therapies for the particular cancer being treated). For example, a subject having pancreatic cancer may be treated with cilnidipine, a salt thereof or a solvate thereof in combination with gemcitabine.
5.2.1. inhibitors of cd47
CD47 inhibitors include anti-CD 47 antibodies such as AO-176 (see Puro et al, 2020,Molecular Cancer Therapeutics 19 (3): 835-846), magrolimab (also known as hu5F9-G4; gilead), CC-90002 (Celgene; see Zeidan et al, 2019, blood 134 (supplement_1): 1320), IBI-188 (Innovent Biologics), SHR-1063 (Gao et al, 2019,J Pharm Biomed Anal 175:112792), and AMMS4-G4 (Zeng et al, 2016,Oncotarget 7:83040-50). Other examples of anti-CD 47 antibodies include clones B6H12, 5F9, 886 and C3 (as described in WO 2011/143624, for example.) further anti-CD 47 antibodies are described in WO 2015/191861 and WO 2016/423. Anti-CD 47 antibodies may be, for example, fully humanized, humanized or chimeric versions of such antibodies.
Other CD47 inhibitors include TTI-621, a recombinant fusion protein consisting of the N-terminus of human sirpa linked to the Fc of IgG1, ALX148, another sirpa-Fc fusion protein (ALX Oncology) and CV1, a sirpa variant, with high affinity for CD47 that competes for CD47 binding with endogenous sirpa (Huang et al 2017,J Thorac Dis.2017Feb;9 (2): E168-E174).
SIRPalpha inhibitors
SIRPalpha inhibitors include anti-SIRPalpha antibodies, for example, KWAR23 (Ring et al, 2017,Proc Natl Acad Sci 114 (49): E10578-E10585), CC-95251 (Celgene), BI 765063 (also known as OSE-172; OSE immunotherapy). Other examples of anti-SIRPalpha antibodies are described in WO 2019/023473, WO 2013/056352 and WO 2018/190719.
In some embodiments, the sirpa inhibitor is a soluble CD47 polypeptide, e.g., as described in US 2010/0239979. In certain embodiments, the soluble CD47 polypeptide comprises the extracellular domain of CD47, including a signal peptide (SEQ ID NO:2 of WO 2016/118754) such that the extracellular portion of CD47 is typically 142 amino acids in length and has the amino acid sequence set forth in SEQ ID NO:3 of WO 2016/118754. The soluble CD47 polypeptides described herein also include CD47 ectodomain variants that comprise at least 65% -75%, 75% -80%, 80-85%, 85% -90% or 95% -99% amino acid sequence (or any percentage of identity not specifically recited between 65% and 100%) that retain the ability to bind sirpa without stimulating sirpa signaling.
5.2.3. Other reagents
The phagocytosis activators described herein, e.g., mitochondrial fission inhibitors, may be administered as monotherapy. Alternatively, the phagocytosis activating agent may be administered to the subject together with an additional agent or combination of agents for treating a disease in the subject. For example, one or more chemotherapeutic agents and/or one or more immunotherapeutic agents may be administered to a subject having cancer, e.g., an anti-PD 1 antibody (e.g., cemiplimab, nivolumab, or pembrolizumab) and/or an anti-PD-L1 antibody (e.g., avilamunomab, dewaruzumab, or altt Zhu Shankang). In some embodiments, the additional agent or combination of agents comprises standard of care therapy for the subject's disease.
For subjects with pancreatic cancer, the additional agent or combination of agents may include, for example, gemcitabine and/or paclitaxel (paclitaxel).
For subjects with lung adenocarcinoma, the additional agent or combination of agents may include, for example, cisplatin and/or carboplatin.
For subjects with colorectal cancer, the additional agent or combination of agents may include, for example, cetuximab and/or panitumumab.
5.3. Pharmaceutical composition
The present disclosure provides pharmaceutical compositions comprising one or more agents as described herein. Pharmaceutical compositions are useful in the methods of the present disclosure. Pharmaceutical compositions comprising the agents described herein, e.g., including sub-portions thereof, as described in sections 5.1 and 5.2, may be formulated according to techniques known in the art. For example, the agents described herein may be combined with one or more carriers, excipients, stabilizers, or combinations thereof, e.g., in the form of lyophilized powders, slurries, aqueous solutions, lotions, or suspensions (see, e.g., hardman et al, 2001, goodman and Gilman The Pharmacological Basis of Therapeutics, mcGraw-Hill, new York, N.Y., gennaro,2000,Remington:The Science and Practice of Pharmacy,Lippincott, williams and Wilkins, new York, N.Y., avis et al, (eds.), 1993,Pharmaceutical Dosage Forms:General Medications,Marcel Dekker,NY;Lieberman et al, (eds.), 1990,Pharmaceutical Dosage Forms:Tablets,Marcel Dekker,NY;Lieberman et al, (eds.), 1990,Pharmaceutical Dosage Forms:Disperse Systems,Marcel Dekker,NY;Weiner and Kotkoskie,2000,Excipient Toxicity and Safety,Marcel Dekker,Inc, new York, NY.).
In one aspect, the present disclosure provides a pharmaceutical composition comprising a phagocytosis activating agent and/or an additional agent or combination of additional agents as described herein and a pharmacologically acceptable diluent, carrier or excipient.
The amount of phagocytosis activator and/or additional agent or combination of additional agents in the pharmaceutical composition may be suitably selected, typically in the range of 0.01 to 100% by weight (e.g. 1% to 99%, 1% to 90%, 5% to 80%, 10% to 75%, or 15% to 50% by weight of the pharmaceutical composition, or any weight percentage range defined by any two of the above values).
Phagocytosis activators (e.g., mitochondrial fission inhibitors) and/or additional agents or combinations of agents may be formulated in pharmaceutical compositions comprising one or more agents designed to target delivery of the phagocytosis activator and/or additional agent or combination of agents to the tumor microenvironment and/or phagocytes. For example, the agent or combination of agents may be formulated with bile acids and/or bile acid derivatives such as ursodeoxycholic acid. Such formulations may be used, for example, to enhance delivery of agents that are orally available hydrophobic small molecules. See Lozano et al, 2015,J Control Release 216:93-102; mooranian et al, 2020,Sci Rep 10:106; pavlovic et al 2018, front. Phacol.9:1283; US 10,765,751, the contents of each of which are incorporated herein by reference in their entirety.
In a further aspect, the present disclosure provides pharmaceutical compositions comprising phagocytes (e.g., monocytes, macrophages, neutrophils, dendritic cells, mast cells, or any combination thereof) having enhanced phagocytic activity. Enhanced phagocytic activity may be measured, for example, as described in example 1. The pharmaceutical composition comprising phagocytes may contain, for example, a population of phagocytes and one or more additional components, such as a buffer or a cell culture medium.
Phagocytes with enhanced phagocytic activity may be obtained by ex vivo treatment of phagocytes with a mitochondrial fission inhibitor (e.g. cilnidipine and/or another mitochondrial fission inhibitor as described in section 5.1.1). Such pharmaceutical compositions are useful in methods of treating a subject suffering from a disease or disorder associated with a defect in phagocytosis, such as cancer or other disease or disorder disclosed in section 5.4. The phagocytes may be autologous to the subject to be treated or the phagocytes may be allogeneic to the subject to be treated.
The compositions of the present disclosure may also be administered by one or more routes of administration using one or more of a variety of methods known in the art. As will be appreciated by those skilled in the art, the route and/or manner of administration will vary depending upon the desired result. Selected routes of administration include intravenous, intramuscular, intradermal, intraperitoneal, subcutaneous, spinal or other general routes of administration, such as by injection or infusion. General administration may represent modes of administration other than enteral and topical administration, typically by injection, including but not limited to intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intra-articular, subcapsular, subarachnoid, intraspinal, epidural and intrasternal, intratumoral, peritumoral, intralymphatic injection and infusion. Alternatively, the compositions of the present disclosure may be administered by non-general routes, such as topical, epidermal, or mucosal routes of administration, such as intranasal, oral, vaginal, rectal, sublingual, or topical.
In another aspect, the present disclosure provides the use of an agent disclosed herein, e.g., cilnidipine or a pharmacologically acceptable salt thereof or a solvate thereof, in the manufacture of a medicament for the treatment of a disease or disorder disclosed herein (e.g., pancreatic cancer or DMD), optionally wherein the medicament is formulated for administration as a monotherapy or as part of a combination therapy regimen, e.g., with a second agent as described herein.
5.4. Diseases and conditions associated with cancer and defects of phagocytosis
5.4.1. Cancer of the human body
Cancers that may be treated according to the methods of the present disclosure include hematological cancers and solid tumors. Exemplary cancers include pancreatic cancer (e.g., pancreatic ductal adenocarcinoma), lung cancer, small cell lung cancer, or non-small cell lung cancer, e.g., lung adenocarcinoma, colorectal cancer, melanoma (e.g., with BRAF mutations), leukemia, e.g., acute myelogenous leukemia or acute lymphoblastic leukemia, lymphomas, e.g., non-hodgkin's lymphoma, diffuse large B-cell lymphoma (DLBCL), myelomas, e.g., multiple myeloma, leiomyosarcoma, breast cancer, liver cancer, osteosarcoma, and head and neck cancer. In some embodiments, the subject has acute myelogenous leukemia, lymphoma, non-hodgkin's lymphoma, or DLBCL.
In some embodiments, the cancer has a KRAS mutation. KRAS is a protein involved in cell signaling pathways that control cell growth, cell maturation and cell death. Mutated forms of the KRAS gene are found in certain types of cancer, including non-small cell lung cancer (NSCLC), colorectal cancer, lung cancer, and pancreatic cancer. These mutations can drive the growth and spread of cancer cells in vivo.
Without being bound by theory, it is believed that mitochondrial fission inhibitors such as Drp1 inhibitors such as cilnidipine inhibit proliferation signals in tumor cells caused by KRAS mutations by inactivating Drp 1. It is further believed that Drp inhibition can cause metabolic switching from aerobic glycolysis to fatty acid oxidation, reduce oxidative stress in the tumor microenvironment, promote cd8+ T cell infiltration into the tumor, and/or increase T cell durability in the tumor microenvironment. Again, without being bound by theory, it is believed that metabolic switching may restore phagocytic capacity of macrophages and natural killer cells in the tumor microenvironment, promoting tumor depletion and/or T cell activation/activation.
In some aspects, the present disclosure provides methods of treating pancreatic cancer, such as pancreatic ductal adenocarcinoma, with cilnidipine or a pharmacologically acceptable salt thereof or a solvate thereof. In some embodiments, cilnidipine or a pharmacologically acceptable salt thereof or a solvate thereof is administered orally. In some embodiments, cilnidipine or a pharmacologically acceptable salt thereof or a solvate thereof is administered as monotherapy. In other embodiments, cilnidipine or a pharmacologically acceptable salt thereof or a solvate thereof is administered in combination (e.g., intravenously) with one or more additional agents (e.g., gemcitabine). In some embodiments, the amount of cilnidipine or a pharmacologically acceptable salt thereof or a solvate thereof administered as monotherapy is an amount effective to slow tumor growth in the subject. In some embodiments, the amounts of both cilnidipine and gemcitabine together are effective to slow tumor growth in the subject when the cilidipine or a pharmacologically acceptable salt thereof or a solvate thereof is administered in combination with gemcitabine. In some embodiments, the amounts of cilnidipine and gemcitabine together are more effective than when administered alone to slow tumor growth in a subject.
5.4.2. Non-cancer phagocytosis-defect related diseases and disorders
Defects in phagocytosis have been linked to a variety of diseases and conditions, such as infectious diseases, neurodegenerative diseases, inflammation, inflammatory diseases and lysosomal diseases (see, e.g., engelich et al, 2001,Clinical Infectious Diseases 33 (12): 2040-2048; andrews and Sullivan,2003,Clin Microbiol Rev.16 (4): 597-621; galaway et al, 2019,Front Immunol.10:790;Kourtzelis et al, 2020,Front Immunol.2020;11:553;Maderna and Godson,2003,Biochimica et Biophysica Acta (BBA) -Molecular Basis of Disease,1639 (3): 141-151; abdolmakeki et al, 2018,Front Immunol.9:1645;Marques and Saftig,2019,Journal of Cell Science 132:jcs221739). Phagocytosis also plays a role in musculoskeletal degenerative diseases such as Du's Muscular Dystrophy (DMD) (see, e.g., rosenberg et al, 2015, sci Transl Med.7 (299): 299rv 4).
Infectious diseases include diseases caused by bacteria (e.g., streptococcal infection), viruses (e.g., influenza, hepatitis b, hepatitis c, HIV), fungi (e.g., yeast infection), or parasites (e.g., malaria). Neurodegenerative diseases include Alzheimer's Disease (AD), progressive Supranuclear Palsy (PSP) and other dementias, parkinson's Disease (PD), nasu-Hakola disease, prion disease, amyotrophic Lateral Sclerosis (ALS), friedel-crafts ataxia, huntington's chorea, lewy body disease, adrenoleukodystrophy (ALD), and spinal muscular atrophy. Exemplary inflammatory diseases include autoimmune diseases such as Systemic Lupus Erythematosus (SLE), rheumatoid Arthritis (RA), and autoimmune lymphoproliferative syndrome (ALPS). Lysosomal storage diseases include gaucher's disease, fabry's disease, niemann-pick's disease, hunter syndrome, glycogen storage disease II (pompe disease) and tay-saxophone's disease. Musculoskeletal degenerative diseases include muscular dystrophies, such as DMD. Thus, in some embodiments, a subject treated according to the methods of the present disclosure has a non-cancer disease as described herein.
In some aspects, the present disclosure provides methods of using cilnidipine or a pharmacologically acceptable salt thereof or a solvate thereof for a subject having DMD. In some embodiments, cilnidipine or a pharmacologically acceptable salt thereof or a solvate thereof is administered orally. In some embodiments, cilnidipine or a pharmacologically acceptable salt thereof or a solvate thereof is administered as monotherapy. In some embodiments, the amount of cilnidipine or a pharmacologically acceptable salt thereof or a solvate thereof administered is an amount effective to reduce the level of plasma Creatine Kinase (CK) and/or Lactose Dehydrogenase (LDH).
6. Examples
6.1. Example 1: in vitro study to evaluate the effect of cilnidipine on macrophage phagocytosis
In vitro evaluation of phagocytosis of macrophages by cilnidipine using the J774.1 mouse macrophage lineEffect of use. The cells were treated at 2X10 5 Cells/well/200. Mu.L were seeded in 48-well plates and incubated at 37℃with 5% CO 2 The cells were cultured in DMEM medium containing 10% FBS and antibiotics for 24 hours. Cells were washed once and then incubated with cilnidipine or DMSO (vehicle) at a concentration of 0.3 μm, 1 μm or 3 μm for 20 hours.
By adding 10. Mu.L of a solution containing 4X 10 to cells 6 PE-labeled polystyrene beads [ ]Multicolor red microspheres 2.0 μm) and cultured for 2.5 hours to assess phagocytosis levels. Cells were then washed 3 times with PBS and collected. Phagocytic activity levels were assessed by flow cytometry, and the amount of fluorescent signal from PE-labeled beads taken up by the cells was measured, and cells treated with 0.1% dmso were used as negative controls. The proportion of cells phagocytizing 1 or more, 2 or more, 3 or more, and 4 or more particles was measured. />
As shown in fig. 1, cilnidipine enhances phagocytic activity of macrophages in a dose dependent manner. The average fluorescence intensity for each cilnidipine dose is shown in figure 2.
6.2. Example 2: evaluation of the antiproliferative effect of cilnidipine on cancer cell lines in vitro
The effect of cilnidipine on cell proliferation of eight cancer cell lines was evaluated. Including five pancreatic cancer cell lines, four containing KRAS mutations (AsPC-1 (G12D), cap-1 (G12V), KP4 (M188V, G D) and MIA PaCa-2 (G12C)), one pancreatic cancer cell line with wild-type KRAS, bxPC-3, and three melanoma cell lines, two of which contain B-Raf mutations: a375 (V600E) and SK-MEL-28 (V600E), and a melanoma cell line with wild-type B-Raf, meWo.
Treatment of pancreatic cancer cell lines and melanoma cancer cell lines with cilnidipine has an antiproliferative effect on the cell lines.
6.3. Example 3: in vivo evaluation of the antitumor effect of cilnidipine
Evaluation of in vivo antitumor effects of cilnidipine in C57BL/6 mice bearing MC38 tumorsIs used. Five or seven weeks old C57BL/6 mice were maintained under Specific Pathogen Free (SPF) conditions. Subcutaneous injection of 5X10 into mice 5 MC38 cells (a mouse colon adenocarcinoma cell line) and intrathecal (i.t.) treatment with cilnidipine on day 10 and day 14 after tumor inoculation. Tumor volumes were measured at different time points.
Treatment of mice with cilnidipine reduced tumor growth compared to control mice.
6.4. Example 4: in vivo evaluation of cilnidipine in DMD model
The effect of cilnidipine and cilidipine derivative NS4-043 in mdx mouse model of Duchenne Muscular Dystrophy (DMD) model was evaluated. mdx mice have a point mutation in their DMD gene, changing the glutamine-encoding amino acid to a stop codon, resulting in muscle cells producing a small, nonfunctional dystrophin protein. The study included cilnidipine, NS4-043, idebenone (positive control) and vehicle-treated groups as shown in table 1.
On study day: animals were dosed with vehicle, idebenone or cilnidipine once daily for 0 to 20 days.
Mice were evaluated by the rotarod test on study day 19 and day 20. Body weight was measured throughout the study period. Two DMD biomarkers, creatinine Kinase (CK) and Lactose Dehydrogenase (LDH), were measured on day 21.
No significant effect on body weight was observed for any of the treatment groups (fig. 3; ns4-043 data not shown). Latency (time to drop) was reduced in the rotarod test for mdx mice (all groups) compared to wild type mice, but this reduction did not reach statistical significance for any group (figure 4; data for ns4-043 not shown). LDH was significantly increased in mdx mouse plasma compared to wild type. Both cilnidipine and idebenone significantly reduced plasma LDH (fig. 5). NS4-043 did not significantly reduce plasma LDH in this study (data not shown), possibly due to drug exposure (dose) starvation. CK was significantly increased in mdx mouse plasma compared to wild type. Surprisingly, cilnidipine, but not idebenone, significantly inhibited plasma CK (fig. 6). Plasma CK in NS4-043 treated animals was similar to plasma CK in idebenone treated animals (data not shown). Thus, the present study supports the use of cilnidipine and cilnidipine derivatives such as NS4-043 as a treatment for DMD.
6.5. Example 5: in vivo evaluation of cilnidipine and cilidipine in combination with gemcitabine in pancreatic cancer model
In vivo efficacy studies of cilnidipine as a single drug or in combination with gemcitabine for treatment of a female BALB/c nude mice subcutaneous Capan-1 pancreatic cancer xenograft model were performed.
6.5.1. Materials and methods
6.5.1.1. Animals
Female BALB/c nude mice 7-9 weeks old were used in the study.
6.5.1.2. Study design
The study contained six treatment groups as shown in table 2.
6.5.1.3. Research method
The study contained six treatment groups as shown in table 2.
6.5.1.3.1. Cell culture
Capan-1 human pancreatic ductal adenocarcinoma cells in IMEM medium containing 20% FBS at 37deg.C and 5% CO 2 Culturing in air atmosphere.
6.5.1.3.2. Tumor inoculation
Tumor cells (5X 10) in 0.1ml PBS with Matrigel (1:1) were inoculated subcutaneously in the right upper abdominal region of each mouse 6 Individual cells) are used for tumor development.
6.5.1.3.3. Random grouping
When the average tumor size reached about 254.27mm 3 Random grouping is started at this time. A total of 48 mice participated in the study and were randomly assigned to six studiesGroups of eight mice each were studied. Based on the "matching distribution" method (Study Director TM Software, version 3.1.399.19) for random grouping. The random grouping date is indicated as day 0.
6.5.1.3.4. Observation and data collection
Animals were checked daily for morbidity and mortality following tumor inoculation. During routine monitoring, animals were examined for any effect of tumor growth and treatment on behavior, such as motility, food and water consumption, weight gain/loss (body weight measured twice a week after random grouping), eye/hair mattness (matting), and any other abnormalities. Mortality and observed clinical signs of individual animals were recorded in detail.
Tumor volumes were measured in two dimensions using calipers twice a week after random grouping and in mm using the following formula 3 The indicated volume: v= (l×w×w)/2, where V is tumor volume, L is tumor length (longest tumor size) and W is tumor width (longest tumor size perpendicular to L). Application was performed in a laminar flow cabinet and tumor and weight measurements were taken. Using a student Director TM The software (version 3.1.399.19) measures body weight and tumor volume.
6.5.1.3.5. Pharmaceutical formulations and test article administration
Vehicles for cilnidipine were 5% DMSO and corn oil. The vehicle for gemcitabine is saline. The dose volume was adjusted according to the body weight (dose volume=5/10 μl/g). Treatment was started on day 0 after the randomized group.
6.5.1.3.6. Administration holiday and supplementary gel administration
Study was planned so that (1) mice showing weight loss (BWL) >20% after one measurement would be sacrificed, (2) mice showing BWL >15% after one measurement would be given a holiday alone in separate cages, daily monitoring for 72 hours, while other mice of the same group would be scheduled to receive administration, resuming treatment of the sequestered mice when BWL returns to BWL <10%, and (3) mice showing BWL >10% would receive supplemental gel. BWL is calculated from BW for the first day of treatment.
6.5.1.4. Termination of the study
6.5.1.4.1. Study endpoint
The endpoint of the study was Tumor Growth Inhibition (TGI). TGI% is an indicator of antitumor activity. TGI is expressed as: TGI (%) =100× (1-T/C). T and C are the average tumor volumes of the treatment and control groups, respectively, on a given day.
6.5.1.4.2. Treatment termination
Treatment was performed for 21 days. There was a 2 week follow-up period of non-administration.
6.5.1.4.3. Humane end point
The humane endpoint was based on weight loss, tumor size, tumor appearance monitoring, and general animal welfare monitoring. All animals were monitored for body weight throughout the study, and animals were euthanized if their body weight was lost by more than 20% relative to the body weight of the first day of treatment. When the tumor volume exceeds 3000mm 3 At that time, individual mice will be sacrificed. To prevent autogenous killing, any animals that show ulcers or necrotic tumors will be immediately separated and kept alone and monitored daily before the animals are euthanized or until tumor regression is complete. Mice with about 25% or more of tumor ulcers on the tumor surface will be euthanized.
6.5.1.5. Statistical analysis
To compare tumor volumes of different groups on pre-specified dates, the Bartlett test was used to examine the variance homogeneity assumption for all groups. When p value > =0.05 of Bartlett test, one-way analysis of variance (ANOVA) was performed to test the overall equality (overall equality) of all group averages. If the p-value of the one-way anova was <0.05, a Dunnett test was performed to compare each treatment group to the vehicle group. When the Bartlett test p-value was <0.05, the Kruskal-Wallis test was performed to test the overall equality of the median in all groups. If the p-value of the Kruskal-Wallis test is <0.05, a single step p-value adjustment is used for all pairwise comparisons or for post-hoc comparisons of each treatment group with the vehicle group by running the non-parametric test of Conover.
All statistical analyses were performed in the R-a language and environment for statistical calculations and graphs (version 3.3.1). Unless otherwise indicated, all tests were double-sided, with p values <0.05 considered statistically significant.
6.5.2. Results
The results are shown in FIGS. 7A-7B and 8A-8B.
No signs of cachexia were observed in the vehicle group (group 1). BWL >15% was observed in groups 3, 4, 5 and 6 mice. The average body weight of each group at various time points is shown in fig. 7A. The body weight change curves of each group at different time points are shown in fig. 7B.
Trends in antitumor activity were observed for cilnidipine as a single agent (group 4) and in combination with gemcitabine (groups 5 and 6), with calculated 20-day TGIs of 9.01%, 22.18% and 33.06% (p > 0.05), respectively, even though the observed antitumor activity did not reach statistical significance (fig. 8A-8B and table 3 below).
This study supports the use of cilnidipine alone or in combination with gemcitabine in the treatment of cancer such as pancreatic cancer.
7. Detailed description of the preferred embodiments
The present disclosure is exemplified by the following detailed description.
1. A method of treating a subject suffering from a phagocytosis-defect related disease or disorder, optionally cancer, comprising administering to the subject an agent or combination of agents comprising a phagocytosis activating agent.
2. The method of embodiment 1, wherein the agent or combination of agents comprises a mitochondrial fission inhibitor.
3. A method of treating a subject having a disease (being cancer) comprising administering to the subject an agent or combination of agents comprising a mitochondrial fission inhibitor.
4. The method of embodiment 2 or embodiment 3, comprising administering a combination of agents comprising two or more mitochondrial fission inhibitors.
5. The method of any one of embodiments 1 to 4, wherein the agent or combination of agents comprises a Drp1 inhibitor.
6. The method of any of embodiments 1 to 5, wherein the agent or combination of agents comprises cilnidipine, P110, metformin, mdivi-1, berberine, a pharmacologically acceptable salt thereof or a solvate thereof or a combination of any of the foregoing.
7. The method of any of embodiments 1 to 6, wherein the agent or combination of agents comprises cilnidipine or a pharmacologically acceptable salt thereof or a solvate thereof.
8. The method of any of embodiments 1 to 7, wherein the agent or combination of agents comprises a cilnidipine derivative or a pharmacologically acceptable salt thereof or a solvate thereof.
9. The method of any of embodiments 1 to 8, wherein the agent or combination of agents comprises a compound of formula (I):
or a pharmacologically acceptable salt thereof or a solvate thereof, wherein:
R 1 for phenyl substituted with 1 to 3 substituents, each substituent is independently NO 2 、NH 2 、OH、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, or C 1 -C 6 Alkoxyalkyl groups, provided that at least one substituent is NO 2 Or NH 2 ；
R 2 H, C of a shape of H, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, or C 1 -C 6 An alkoxyalkyl group;
R 3 h, C of a shape of H, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, or C 1 -C 6 AlkoxyalkanesA base;
R 4 is C 1 -C 6 Alkyl or C 1 -C 6 A haloalkyl group;
R 5 is phenyl or pyridinyl, wherein the phenyl or pyridinyl is unsubstituted or substituted with 1 to 3 substituents, each substituent independently being NO 2 、NH 2 、OH、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, or C 1 -C 6 An alkoxyalkyl group;
(i) Bond a is present and bonds b and c are absent or (ii) bonds b and c are present and bond a is absent;
a is NH when bond a is present and N when bonds b and c are present;
m is an integer from 1 to 4; and
n is an integer of 1 to 3,
optionally, wherein the compound of formula (I) is not cilnidipine.
10. The method of embodiment 9, wherein the compound of formula (I) is a compound having the structure of formula (Ia):
or a pharmacologically acceptable salt thereof or a solvate thereof.
11. The method of embodiment 9, wherein the compound of formula (I) is a compound having the structure of formula (Ib):
or a pharmacologically acceptable salt thereof or a solvate thereof.
12. The method of any one of embodiments 9 to 11, wherein R 1 The method comprises the following steps:
or->Wherein R is 1a Is NO 2 Or NH 2 And R is 1b And R is 1c Each independently H, NO 2 、NH 2 、OH、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, or C 1 -C 6 An alkoxyalkyl group.
13. The method of embodiment 12, wherein R 1b And R is 1c Each independently H, NO 2 、NH 2 、OH、C 1 -C 3 Alkyl, C 1 -C 3 Haloalkyl, or C 1 -C 3 An alkoxyalkyl group.
14. The method of embodiment 12, wherein R 1 Is that
15. The method of embodiment 12, wherein R 1 Is that
16. The method of embodiment 12, wherein R 1 Is that
17. The method of any one of embodiments 12 to 16, wherein R 1a Is NO 2 。
18. The method of any one of embodiments 12 to 16, wherein R 1a Is NH 2 。
19. The method of any one of embodiments 9 to 18, wherein R 2 H, C of a shape of H, C 1 -C 3 Alkyl, C 1 -C 3 Haloalkyl, or C 1 -C 3 An alkoxyalkyl group.
20. The method of embodiment 19, wherein R 2 Is C 1 -C 3 An alkyl group.
21. The method of embodiment 20, wherein R 2 Is CH 3 。
22. The method of any one of embodiments 9 to 21, wherein R 3 H, C of a shape of H, C 1 -C 3 Alkyl, C 1 -C 3 Haloalkyl, or C 1 -C 3 An alkoxyalkyl group.
23. The method of embodiment 22, wherein R 3 Is C 1 -C 3 An alkyl group.
24. The method of embodiment 23, wherein R 3 Is CH 3 。
25. The method of any one of embodiments 9 to 24, wherein R 4 Is C 1 -C 3 Alkyl or C 1 -C 3 A haloalkyl group.
26. The method of embodiment 25, wherein R 4 Is C 1 -C 3 An alkyl group.
27. The method of embodiment 26, wherein R 4 Is CH 3 。
28. The method of any one of embodiments 9 to 27, wherein R 5 Is phenyl which is unsubstituted or substituted by one to three substituents, each substituent being independently NO 2 、NH 2 、OH、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, or C 1 -C 6 An alkoxyalkyl group.
29. The method of embodiment 28, wherein R 5 Is phenyl which is unsubstituted or substituted by one to three substituents, each substituent being independently NO 2 、NH 2 、OH、C 1 -C 3 Alkyl, C 1 -C 3 Haloalkyl, or C 1 -C 3 An alkoxyalkyl group.
30. The method of embodiment 28, wherein R 5 Is unsubstituted phenyl.
31. The method of any one of embodiments 9 to 27, wherein R 5 Is pyridinyl, which is unsubstituted or substituted with one to three substituents, each substituent being independently NO 2 、NH 2 、OH、C 1 -C 6 Alkyl group、C 1 -C 6 Haloalkyl, or C 1 -C 6 An alkoxyalkyl group.
32. The method of embodiment 31 wherein R 5 Is pyridinyl, which is unsubstituted or substituted with one to three substituents, each substituent being independently NO 2 、NH 2 、OH、C 1 -C 3 Alkyl, C 1 -C 3 Haloalkyl, or C 1 -C 3 An alkoxyalkyl group.
33. The method of embodiment 31 wherein R 5 Is an unsubstituted pyridyl group.
34. The method of any one of embodiments 31 to 33, wherein said R 5 The pyridyl group is a 4-pyridyl group.
35. The method of any one of embodiments 31 to 33, wherein said R 5 Pyridyl is 3-pyridyl.
36. The method of any one of embodiments 31 to 33, wherein said R 5 Pyridyl is 2-pyridyl.
37. The method of any one of embodiments 9 to 36, wherein m is 2.
38. The method of any one of embodiments 9 to 36, wherein n is 1.
39. The method of embodiment 10, wherein:
R 1 is that
Or->Wherein R is 1a Is NO 2 Or NH 2 ；
R 2 、R 3 And R is 4 Is CH 3 ；
R 5 Is unsubstituted phenyl or unsubstituted pyridyl;
m is 2; and
n is 1.
40. The method of embodiment 39, wherein R 5 Is unsubstituted 4-pyridyl.
41. The method of embodiment 9 wherein the compound of formula (I) is cilnidipine or a pharmacologically acceptable salt thereof or a solvate thereof.
42. The method of embodiment 9 wherein the compound of formula (I) is
Or a pharmacologically acceptable salt thereof or a solvate thereof.
43. The method of embodiment 9 wherein the compound of formula (I) is
Or a pharmacologically acceptable salt thereof or a solvate thereof.
44. The method of embodiment 9 wherein the compound of formula (I) is
Or a pharmacologically acceptable salt thereof or a solvate thereof.
45. The method of embodiment 9 wherein the compound of formula (I) is
Or a pharmacologically acceptable salt thereof or a solvate thereof.
46. The method of embodiment 9 wherein the compound of formula (I) is
Or a pharmacologically acceptable salt thereof or a solvate thereof.
47. The method of embodiment 9 wherein the compound of formula (I) is
Or pharmacology thereofAcceptable salts or solvates thereof.
48. The method of embodiment 9 wherein the compound of formula (I) isOr a pharmacologically acceptable salt thereof or a solvate thereof.
49. The method of embodiment 9 wherein the compound of formula (I) isOr a pharmacologically acceptable salt thereof or a solvate thereof.
50. The method of embodiment 9 wherein the compound of formula (I) isOr a pharmacologically acceptable salt thereof or a solvate thereof.
51. The method of any of embodiments 1 to 50, wherein the agent or combination of agents comprises metformin or a pharmacologically acceptable salt thereof or a solvate thereof.
52. The method of any one of embodiments 1 to 51, wherein the agent or combination of agents comprises P110 or a pharmacologically acceptable salt thereof or a solvate thereof.
53. The method of any one of embodiments 1 to 52, wherein the agent or combination of agents comprises mdivi-1 or a pharmacologically acceptable salt thereof or a solvate thereof.
54. The method of any of embodiments 1 to 53, wherein the agent or combination of agents comprises berberine or a pharmacologically acceptable salt thereof or a solvate thereof.
55. The method of any one of embodiments 1 to 54, wherein the agent or combination of agents comprises an agent or combination of agents that activates toll-like receptors (TLRs), dectin-1, mannose receptors, scavenger receptors A, CD, CD36, opsonizing receptors, apoptotic body receptors, or a combination thereof.
56. The method of embodiment 55, wherein the agent or combination of agents comprises an agent that activates a TLR.
57. The method of embodiment 56, comprising administering a combination of agents comprising two or more agents that activate a TLR.
58. The method of any one of embodiments 55 to 57, wherein the agent or combination of agents comprises an agent that activates Dectin-1.
59. The method of embodiment 58, comprising administering a combination of agents comprising two or more agents that activate Dectin-1.
60. The method of any one of embodiments 55 to 59, wherein the agent or combination of agents comprises an agent that activates a mannose receptor.
61. The method of embodiment 60, comprising administering a combination of agents comprising two or more agents that activate mannose receptors.
62. The method of any one of embodiments 55 to 61, wherein the agent or combination of agents comprises an agent that activates scavenger receptor a.
63. The method of embodiment 62, comprising administering a combination comprising two or more agents that activate scavenger receptor a.
64. The method of any one of embodiments 55 to 63, wherein the agent or combination of agents comprises an agent that activates CD 14.
65. The method of embodiment 64, comprising administering a combination of agents comprising two or more agents that activate CD 14.
66. The method of any one of embodiments 55 to 65, wherein the agent or combination of agents comprises an agent that activates CD 36.
67. The method of embodiment 66, comprising administering a combination of agents comprising two or more agents that activate CD 36.
68. The method of any one of embodiments 55 to 67, wherein the agent or combination of agents comprises an agent that activates a modulator receptor.
69. The method of embodiment 68, comprising administering a combination of agents comprising two or more agents that activate the opsonic receptor.
70. The method of embodiment 55, wherein the agent or combination of agents comprises an agent that activates an apoptotic body receptor.
71. The method of embodiment 70, comprising administering a combination of agents comprising two or more agents that activate apoptotic body receptors.
72. The method of any one of embodiments 55 to 71, wherein the agent or combination of agents comprises 1, 3-beta glucan, mannan, lipopolysaccharide, lipoteichoic acid, lipopolysaccharide binding protein, plasmodium falciparum infected erythrocytes, igG, igA, igE, and phosphatidylserine.
73. The method of any one of embodiments 1 to 72, wherein the agent or combination of agents comprises an agent that activates pgc1α.
74. The method of embodiment 73, comprising administering a combination of agents comprising two or more agents that activate pgc1α.
75. The method of embodiment 73 or embodiment 74, wherein the agent or combination of agents comprises metformin or a pharmacologically acceptable salt thereof or a solvate thereof.
76. The method of any one of embodiments 1 to 75, wherein the agent or combination of agents comprises an agent that inhibits the PI3K-AKT-mTOR pathway.
77. The method of embodiment 76, wherein the agent or combination of agents comprises a PI3K inhibitor.
78. The method of embodiment 77, comprising administering a combination of agents comprising two or more PIK3 inhibitors.
79. The method of any one of embodiments 76 to 78, wherein the agent or combination of agents comprises an AKT inhibitor.
80. The method of embodiment 79, comprising administering a combination of agents comprising two or more AKT inhibitors.
81. The method of any one of embodiments 76 to 80, wherein the agent or combination of agents comprises an mTOR inhibitor.
82. The method of embodiment 81, comprising administering a combination of agents comprising two or more mTOR inhibitors.
83. The method of any of embodiments 76 to 82, wherein the agent or combination of agents comprises rapamycin or a pharmacologically acceptable salt thereof or a solvate thereof.
84. The method of any one of embodiments 1 to 83, wherein the agent or combination of agents comprises one or more lactic acid releasing bacterial species.
85. The method of embodiment 84, wherein the agent or combination of agents comprises bifidobacteria and/or lactobacillus acidophilus.
86. The method of any one of embodiments 1 to 85, wherein the agent or combination of agents comprises a component or combination of components of a cell-free extract from a lactic acid releasing bacteria culture medium.
87. The method of embodiment 86, wherein the lactic acid producing bacteria comprise bifidobacteria and/or lactobacillus acidophilus.
88. The method of any one of embodiments 1 to 87, wherein one or more of the agents or combinations of agents are formulated with a bile acid derivative.
89. The method of embodiment 88, wherein said bile acid derivative is ursodeoxycholic acid or a pharmacologically acceptable salt thereof or a solvate thereof.
90. The method of any one of embodiments 1 to 89, wherein the disease is cancer, optionally with KRAS mutations.
91. The method of embodiment 90, wherein the cancer is hematological cancer.
92. The method of embodiment 90, wherein the cancer is a solid tumor.
93. The method of embodiment 90, wherein the cancer is leukemia.
94. The method of embodiment 90, wherein the cancer is lymphoma.
95. The method of embodiment 90, wherein the cancer is myeloma.
96. The method of embodiment 90, wherein the cancer is multiple myeloma.
97. The method of embodiment 90, wherein the cancer is acute myelogenous leukemia.
98. The method of embodiment 90, wherein the cancer is acute lymphoblastic leukemia.
99. The method of embodiment 90, wherein the cancer is non-hodgkin's lymphoma.
100. The method of embodiment 90, wherein the cancer is diffuse large B-cell lymphoma.
101. The method of embodiment 90, wherein the cancer is melanoma, optionally wherein the melanoma has BRAF mutations.
102. The method of embodiment 90, wherein the cancer is leiomyosarcoma.
103. The method of embodiment 90, wherein the cancer is breast cancer.
104. The method of embodiment 90, wherein the cancer is liver cancer.
105. The method of embodiment 90, wherein the cancer is colorectal cancer.
106. The method of embodiment 90, wherein the cancer is pancreatic cancer, optionally wherein the pancreatic cancer is pancreatic ductal adenocarcinoma.
107. The method of embodiment 90, wherein the cancer is lung cancer, optionally small cell lung cancer or non-small cell lung cancer, optionally lung adenocarcinoma.
108. The method of embodiment 90, wherein the cancer is osteosarcoma.
109. The method of embodiment 90, wherein the cancer is head and neck cancer.
110. The method of any one of embodiments 90 to 109, when directly or indirectly dependent on embodiment 3, comprising administering a mitochondrial fission inhibitor as monotherapy for cancer.
111. The method of any one of embodiments 90 to 109, wherein one or more additional agents are administered to the subject.
112. The method of embodiment 111, wherein the one or more additional agents comprise a CD47 inhibitor and/or a sirpa inhibitor.
113. The method of embodiment 112, wherein the one or more additional agents comprise a CD47 inhibitor.
114. The method of embodiment 113, wherein the CD47 inhibitor comprises an antibody or antigen-binding fragment thereof.
115. The method of embodiment 113, wherein the CD47 inhibitor comprises a sirpa-Fc fusion protein.
116. The method of embodiment 113, wherein the CD47 inhibitor comprises a sirpa variant protein.
117. The method of embodiment 113, wherein said CD47 inhibitor is Magrolimab.
118. The method of embodiment 113, wherein said CD47 inhibitor is CC-90002.
119. The method of embodiment 113, wherein said CD47 inhibitor is AO-176.
120. The method of embodiment 113, wherein the CD47 inhibitor is IBI-188.
121. The method of embodiment 113, wherein said CD47 inhibitor is SHR-1063.
122. The method of embodiment 113, wherein the CD47 inhibitor is AMMS4-G4.
123. The method of embodiment 113, wherein the CD47 inhibitor is a sirpa-Fc fusion protein.
124. The method of embodiment 113, wherein the CD47 inhibitor is TTI-621.
125. The method of embodiment 113, wherein the CD47 inhibitor is ALX148.
126. The method of embodiment 113, wherein said CD47 inhibitor is CV1.
127. The method of any one of embodiments 112 to 126, wherein the one or more additional agents comprises a sirpa inhibitor.
128. The method of embodiment 127, wherein the sirpa inhibitor comprises an antibody or antigen-binding fragment thereof.
129. The method of embodiment 127, wherein the sirpa inhibitor is KWAR23.
130. The method of embodiment 127, wherein the SIRPalpha inhibitor is CC-95251.
131. The method of embodiment 127, wherein the sirpa inhibitor is BI 765063.
132. The method of embodiment 127, wherein the sirpa inhibitor comprises a soluble CD47 peptide.
133. The method of any one of embodiments 111 to 132, wherein the one or more additional agents comprise standard of care therapies for cancer.
134. The method of any one of embodiments 111 to 133, wherein when the cancer is pancreatic cancer, the one or more additional agents comprise gemcitabine and/or paclitaxel.
135. The method of any of embodiments 111 to 133, wherein when the cancer is lung adenocarcinoma, the one or more additional agents comprise cisplatin and/or carboplatin.
136. The method of any one of embodiments 111 to 133, wherein when the cancer is colorectal cancer, the one or more additional agents comprise cetuximab and/or panitumumab.
137. The method of any one of embodiments 111 to 136, wherein the one or more additional agents comprise an anti-PD 1 antibody and/or an anti-PD-L1 antibody.
138. The method of embodiment 137, wherein the one or more additional agents comprise an anti-PD 1 antibody.
139. The method of embodiment 138, wherein said anti-PD 1 antibody is cemiplimab.
140. The method of embodiment 138, wherein the anti-PD 1 antibody is nivolumab.
141. The method of embodiment 138, wherein the anti-PD 1 antibody is pembrolizumab.
142. The method of any one of embodiments 137-141, wherein the one or more additional agents comprise an anti-PD-L1 antibody.
143. The method of embodiment 142, wherein the anti-PD-L1 antibody is avermectin.
144. The method of embodiment 142, wherein the anti-PD-L1 antibody is dewarfarin.
145. The method of embodiment 142, wherein the anti-PD-L1 antibody is alt Zhu Shankang.
146. The method of any of embodiments 111 to 145, further comprising administering to the subject one or more additional agents.
147. The method of any one of embodiments 111 to 146, wherein one or more of the one or more additional agents are formulated with the bile acid derivative.
148. The method of embodiment 147, wherein said bile acid derivative is ursodeoxycholic acid or a pharmacologically acceptable salt thereof or a solvate thereof.
149. The method of any one of embodiments 1 to 89, when directly or indirectly dependent on embodiment 1, wherein the phagocytosis defect-related disease or disorder is an infectious disease, a neurodegenerative disease, inflammation, an inflammatory disease, or a lysosomal disease.
150. The method of embodiment 149, wherein the disease or disorder is an infectious disease.
151. The method of embodiment 150, wherein the infectious disease is caused by bacteria.
152. The method of embodiment 150, wherein the infectious disease is caused by a virus.
153. The method of embodiment 149, wherein the disease or disorder is a neurodegenerative disease.
154. The method of embodiment 153, wherein the neurodegenerative disease is Alzheimer's Disease (AD) or other dementia, parkinson's Disease (PD), nasu-Hakola disease, prion disease, amyotrophic Lateral Sclerosis (ALS), friedrich's ataxia, huntington's chorea, lewy body disease, spinal muscular atrophy, progressive Supranuclear Palsy (PSP), or Adrenoleukodystrophy (ALD).
155. The method of embodiment 154, wherein the neurodegenerative disease is Alzheimer's Disease (AD).
156. The method of embodiment 154, wherein the neurodegenerative disease is dementia.
157. The method of embodiment 154, wherein said neurodegenerative disease is Parkinson's Disease (PD).
158. The method of embodiment 154, wherein the neurodegenerative disease is Nasu-Hakola disease.
159. The method of embodiment 154, wherein the neurodegenerative disease is prion disease.
160. The method of embodiment 154, wherein the neurodegenerative disease is Amyotrophic Lateral Sclerosis (ALS).
161. The method of embodiment 154, wherein the neurodegenerative disease is friedrich's ataxia.
162. The method of embodiment 154, wherein the neurodegenerative disease is huntington's disease.
163. The method of embodiment 154, wherein the neurodegenerative disease is lewy body disease.
164. The method of embodiment 154, wherein the neurodegenerative disease is spinal muscular atrophy.
165. The method of embodiment 154, wherein the neurodegenerative disease is Progressive Supranuclear Palsy (PSP).
166. The method of embodiment 154, wherein the neurodegenerative disease is Adrenoleukodystrophy (ALD).
167. The method of embodiment 149, wherein the disease or disorder is inflammation.
168. The method of embodiment 149, wherein the disease is an inflammatory disease.
169. The method of embodiment 168, wherein the inflammatory disease is an autoimmune disease.
170. The method of embodiment 169, wherein the autoimmune disease is Systemic Lupus Erythematosus (SLE), rheumatoid Arthritis (RA), or autoimmune lymphoproliferative syndrome (ALPS).
171. The method of embodiment 170, wherein the autoimmune disease is SLE.
172. The method of embodiment 170, wherein the autoimmune disease is RA.
173. The method of embodiment 170, wherein the autoimmune disease is ALPS.
174. The method of embodiment 149, wherein the disease is a lysosomal storage disease.
175. The method of embodiment 174, wherein the lysosomal storage disease is gaucher disease, fabry disease, niemann-pick disease, hunter syndrome, glycogen storage disease II (pompe disease) or tay-saxophone disease.
176. The method of embodiment 175, wherein the lysosomal storage disease is gaucher disease.
177. The method of embodiment 175, wherein the lysosomal storage disease is fabry disease.
178. The method of embodiment 175, wherein the lysosomal storage disease is niemann-pick disease.
179. The method of embodiment 175, wherein the lysosomal storage disease is hunter syndrome.
180. The method of embodiment 175, wherein the lysosomal storage disease is glycogen storage disease II (pompe disease).
181. The method of embodiment 175, wherein the lysosomal storage disease is tay-saxophone's disease.
182. The method of any one of embodiments 1 to 89, when directly or indirectly dependent on embodiment 1, wherein the phagocytosis defect-related disease or disorder is a musculoskeletal degenerative disease.
183. The method of embodiment 182, wherein the musculoskeletal degenerative disease is muscular dystrophy.
184. The method of embodiment 183, wherein the muscular dystrophy is Duchenne Muscular Dystrophy (DMD).
185. The method of any one of embodiments 1 to 184, wherein the subject has a phagocyte defect.
186. A method of treating a subject suffering from Duchenne Muscular Dystrophy (DMD) comprising administering to the subject a therapeutically effective amount of cilnidipine or a pharmacologically acceptable salt thereof or a solvate thereof.
187. A combination comprising one or more phagocytosis activators and a CD47 and/or sirpa inhibitor, optionally wherein the one or more phagocytosis activators comprise one or more phagocytosis activators described in embodiments 1 to 89, and optionally wherein the CD47 and/or sirpa inhibitor is any CD47 or sirpa inhibitor described in any of embodiments 112 to 132.
188. A combination of embodiment 187, for use in treating a disease or disorder associated with a phagocytosis defect.
189. The combination for use according to embodiment 188, wherein the phagocytosis defect related disease or disorder is a cancer, optionally wherein the cancer is a cancer of any of embodiments 90 to 109.
190. A mitochondrial fission inhibitor or a combination of mitochondrial fission inhibitors for use in the treatment of cancer, optionally wherein the mitochondrial fission inhibitor or combination of mitochondrial fission inhibitors comprises the mitochondrial fission inhibitor or combination of mitochondrial fission inhibitors of any one of embodiments 3 to 54, optionally wherein the cancer is the cancer of any one of embodiments 90 to 109.
191. A mitochondrial fission inhibitor or a combination of mitochondrial fission inhibitors for use according to embodiment 190 for use as monotherapy.
192. A mitochondrial fission inhibitor or a combination of mitochondrial fission inhibitors for use according to embodiment 191 for use in combination with one or more additional agents.
193. The mitochondrial fission inhibitor or combination of mitochondrial fission inhibitors for use according to embodiment 192, wherein the one or more additional agents include one or more agents of any of embodiments 55 to 89 and 111 to 148.
194. A mitochondrial fission inhibitor or a combination of mitochondrial fission inhibitors for use in treating a phagocytosis defect related disease or disorder, optionally wherein the mitochondrial fission inhibitor or combination of mitochondrial fission inhibitors comprises the mitochondrial fission inhibitor or combination of mitochondrial fission inhibitors of any of embodiments 3 to 54.
195. A mitochondrial fission inhibitor or a combination of mitochondrial fission inhibitors for use according to embodiment 194 for use in combination with one or more additional agents.
196. The mitochondrial fission inhibitor or combination of mitochondrial fission inhibitors for use according to embodiment 195, wherein the one or more additional agents include one or more agents of any of embodiments 55 to 89.
197. The mitochondrial fission inhibitor for use according to any of embodiments 194-196, wherein the phagocytosis defect related disease or disorder is a disease or disorder described in any of embodiments 149-184.
198. An agent or combination of agents for use in a method of treating a subject suffering from a phagocytosis-defect related disease or disorder, wherein the agent or combination of agents comprises a phagocytosis activating agent, optionally wherein:
(a) The phagocytosis-defect related disease or disorder is cancer, optionally wherein the cancer is pancreatic cancer; and/or
(b) The agent or combination of agents comprises cilnidipine or a pharmacologically acceptable salt thereof or a solvate thereof.
199. An agent or combination of agents for use according to embodiment 198, wherein the agent or combination of agents comprises a mitochondrial fission inhibitor.
200. The agent or combination of agents used according to embodiment 198 or embodiment 199, wherein the agent or combination of agents comprises a Drp inhibitor.
201. The agent or combination of agents for use according to any of embodiments 198 to 200, wherein the agent or combination of agents comprises cilnidipine, P110, metformin, mdivi-1, berberine, a pharmacologically acceptable salt thereof or a solvate thereof or a combination of any of the foregoing.
202. The agent or combination of agents for use according to any of embodiments 198 to 201 wherein the agent or combination of agents comprises cilnidipine or a pharmacologically acceptable salt thereof or a solvate thereof.
203. The agent or combination of agents for use according to any of embodiments 198 to 201, wherein the agent or combination of agents comprises a compound of formula (I):
Or a pharmacologically acceptable salt thereof or a solvate thereof, wherein:
R 1 for phenyl substituted with 1 to 3 substituents, each substituent is independently NO 2 、NH 2 、OH、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, or C 1 -C 6 Alkoxyalkyl groups, provided that at least one substituent is NO 2 Or NH 2 ；
R 2 H, C of a shape of H, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, or C 1 -C 6 An alkoxyalkyl group;
R 3 h, C of a shape of H, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, or C 1 -C 6 An alkoxyalkyl group;
R 4 is C 1 -C 6 Alkyl or C 1 -C 6 A haloalkyl group;
R 5 is phenyl or pyridinyl, wherein the phenyl or pyridinyl is unsubstituted or substituted with 1 to 3 substituents, each substituent independently being NO 2 、NH 2 、OH、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, or C 1 -C 6 An alkoxyalkyl group;
(i) Bond a is present and bonds b and c are absent or (ii) bonds b and c are present and bond a is absent;
a is NH when bond a is present and N when bonds b and c are present;
m is an integer from 1 to 4; and
n is an integer of 1 to 3,
optionally, wherein the compound of formula (I) is not cilnidipine.
204. The agent or combination of agents for use according to any of embodiments 198-203, wherein the agent or combination of agents comprises an agent or combination of agents that activates a toll-like receptor (TLR), dectin-1, mannose receptor, scavenger receptor A, CD, CD36, opsonin receptor, apoptotic body receptor, or a combination thereof.
205. The agent or combination of agents used according to embodiment 204, wherein the agent or combination of agents comprises 1, 3-beta glucan, mannan, lipopolysaccharide, lipoteichoic acid, lipopolysaccharide binding protein, plasmodium falciparum infected erythrocytes, igG, igA, igE, and phosphatidylserine.
206. The agent or combination of agents for use according to any of embodiments 198 to 205, wherein the agent or combination of agents comprises an agent that activates pgc1α.
207. An agent or combination of agents for use according to embodiment 206, wherein the agent or combination of agents comprises metformin or a pharmacologically acceptable salt thereof or a solvate thereof.
208. The agent or combination of agents for use according to any of embodiments 198 to 207, wherein the agent or combination of agents comprises an agent that inhibits the PI3K-AKT-mTOR pathway.
209. An agent or combination of agents for use according to embodiment 208, wherein the agent or combination of agents comprises (i) a PI3K inhibitor, (ii) an AKT inhibitor, (iii) an mTOR inhibitor, (iv) rapamycin or a pharmacologically acceptable salt thereof, or a solvate thereof, or (v) a combination of the foregoing.
210. The agent or combination of agents for use according to any of embodiments 198 to 209, wherein the agent or combination of agents comprises one or more lactic acid releasing bacterial species, optionally wherein the agent or combination of agents comprises bifidobacteria and/or lactobacillus acidophilus.
211. The agent or combination of agents for use according to any of embodiments 198 to 210, wherein the agent or combination of agents comprises a component or combination of components of a cell-free extract from a lactic acid releasing bacteria culture medium, optionally wherein the lactic acid releasing bacteria comprises bifidobacteria and/or lactobacillus acidophilus.
212. The agent or combination of agents for use according to any of embodiments 198 to 211, wherein one or more of the agents or combination of agents is formulated with a bile acid derivative, optionally wherein the bile acid derivative is ursodeoxycholic acid or a pharmacologically acceptable salt thereof or a solvate thereof.
213. The agent or combination of agents for use according to any of embodiments 198 to 212, wherein the phagocytosis defect related disease or disorder is a cancer, optionally having a KRAS mutation, optionally wherein the cancer is:
(a) Pancreatic cancer;
(b) Hematological cancer;
(c) Solid tumors;
(d) Leukemia;
(e) Lymphomas;
(f) A myeloma;
(g) Multiple myeloma;
(h) Acute myelogenous leukemia;
(i) Acute lymphoblastic leukemia;
(j) Non-hodgkin's lymphoma;
(k) Diffuse large B-cell lymphomas;
(l) A melanoma, optionally wherein the melanoma has BRAF mutations;
(m) leiomyosarcoma;
(n) breast cancer;
(o) liver cancer;
(p) colorectal cancer;
(q) lung cancer, optionally small cell lung cancer or non-small cell lung cancer, optionally lung adenocarcinoma;
(r) osteosarcoma; or alternatively
(s) head and neck cancer.
214. The agent or combination of agents for use according to embodiment 213, wherein the cancer is pancreatic cancer, optionally wherein the pancreatic cancer is pancreatic ductal adenocarcinoma.
215. The agent or combination of agents used according to embodiment 213 or embodiment 214 that is a mitochondrial fission inhibitor, and wherein the method comprises administering the mitochondrial fission inhibitor as a monotherapy for cancer.
216. The agent or combination of agents for use according to embodiment 213 or embodiment 214, wherein the method comprises administering one or more additional agents to the subject.
217. The agent or combination of agents used according to embodiment 216, wherein the one or more additional agents comprises a CD47 inhibitor and/or a sirpa inhibitor.
218. An agent or combination of agents for use according to embodiment 217, wherein the one or more additional agents comprises a CD47 inhibitor, optionally wherein the CD47 inhibitor is:
(a) An antibody or antigen-binding fragment thereof;
(b) sirpa-Fc fusion proteins;
(c) Sirpa variant proteins;
(d)Magrolimab；
(e)CC-90002；
(f)AO-176；
(g)IBI-188；
(h)SHR-1063；
(i)AMMS4-G4；
(j)TTI-621；
(k) ALX148; or alternatively
(l)CV1。
219. The agent or combination of agents used according to embodiment 217 or embodiment 218, wherein the one or more additional agents comprise a sirpa inhibitor, optionally wherein the sirpa inhibitor is:
(a) An antibody or antigen-binding fragment thereof;
(b)KWAR23；
(c)CC-95251；
(d) BI 765063; or alternatively
(e) Soluble CD47 peptide.
220. The agent or combination of agents for use according to any one of embodiments 216 to 219, wherein the one or more additional agents comprise standard of care therapies for cancer.
221. The agent or combination of agents for use according to any of embodiments 216 to 220, wherein when the cancer is pancreatic cancer, the one or more additional agents comprise gemcitabine and/or paclitaxel.
222. The agent or combination of agents for use according to embodiment 221, wherein when the cancer is pancreatic cancer, the one or more additional agents comprises gemcitabine.
223. The agent or combination of agents for use according to any of embodiments 216 to 220, wherein when the cancer is lung adenocarcinoma, the one or more additional agents comprise cisplatin and/or carboplatin.
224. The agent or combination of agents for use according to any of embodiments 216 to 220, wherein when the cancer is colorectal cancer, the one or more additional agents comprise cetuximab and/or panitumumab.
225. The agent or combination of agents for use according to any of embodiments 216 to 224, wherein the one or more additional agents comprises an anti-PD 1 antibody, optionally wherein the anti-PD 1 antibody is cemiplimab, nivolumab, or pembrolizumab, and/or an anti-PD-L1 antibody, optionally wherein the anti-PD-L1 antibody is avilamab, dewaruzumab, or altr Zhu Shankang.
226. The agent or combination of agents for use according to any of embodiments 216 to 225, further comprising administering one or more additional agents to the subject.
227. The agent or combination of agents for use according to any of embodiments 216 to 226, wherein one or more of the one or more additional agents is formulated with a bile acid derivative, optionally wherein the bile acid derivative is ursodeoxycholic acid or a pharmacologically acceptable salt thereof or a solvate thereof.
228. The agent or combination of agents for use according to any of embodiments 198 to 212, wherein the phagocytosis defect related disease or disorder is:
(a) Musculoskeletal degenerative diseases, optionally muscular dystrophy, such as Duchenne Muscular Dystrophy (DMD);
(b) Infectious disease, optionally caused by bacteria or viruses;
(c) Neurodegenerative diseases, optionally Alzheimer's Disease (AD) or other dementias, parkinson's Disease (PD), nasu-Hakola disease, prion disease, amyotrophic Lateral Sclerosis (ALS), friedel-crafts ataxia, huntington's chorea, lewy body disease, spinal muscular atrophy, progressive Supranuclear Palsy (PSP) or Adrenoleukodystrophy (ALD);
(d) Inflammation;
(e) Inflammatory diseases, which are optionally autoimmune diseases, such as Systemic Lupus Erythematosus (SLE), rheumatoid Arthritis (RA) or autoimmune lymphoproliferative syndrome (ALPS); or alternatively
(f) Lysosomal storage diseases, which are optionally gaucher's disease, fabry's disease, niemann-pick's disease, hunter syndrome, glycogen storage disease II (pompe disease) or tay-saxophone disease.
229. An agent or combination of agents for use according to embodiment 228, wherein the phagocytosis defect related disease or disorder is Duchenne Muscular Dystrophy (DMD).
230. The agent or combination of agents for use according to any one of embodiments 198 to 229, wherein the subject has a phagocytic defect.
231. An agent that is cilnidipine or a pharmacologically acceptable salt thereof or a solvate thereof for use in a method of treating a subject having pancreatic cancer, optionally wherein the pancreatic cancer is pancreatic ductal adenocarcinoma.
232. The agent for use according to embodiment 231, wherein the agent is used as a monotherapy.
233. The agent for use according to embodiment 232, wherein the method comprises administering to the subject an amount of the agent effective to slow tumor growth in the subject.
234. An agent for use according to embodiment 231 wherein the agent is used in combination with gemcitabine.
235. An agent for use according to embodiment 234, wherein the method comprises administering to the subject an amount of the agent and an amount of gemcitabine that together are effective to slow the growth of a tumor in the subject.
236. An agent that is cilnidipine or a pharmacologically acceptable salt thereof or a solvate thereof for use in a method of treating a subject suffering from Duchenne Muscular Dystrophy (DMD).
237. An agent for use according to embodiment 236, wherein the method comprises administering an amount of the agent to reduce Creatinine Kinase (CK) and/or Lactose Dehydrogenase (LDH) in the plasma of the subject.
238. A pharmaceutical composition comprising phagocytes having enhanced phagocytic activity.
239. The pharmaceutical composition of embodiment 238, comprising phagocytes that have been contacted ex vivo with one or more mitochondrial fission inhibitors.
240. The pharmaceutical composition of embodiment 239, wherein the one or more mitochondrial fission inhibitors comprises the mitochondrial fission inhibitor or the combination of mitochondrial fission inhibitors of any of embodiments 3-54.
241. The pharmaceutical composition of embodiment 239 or embodiment 240, wherein the one or more mitochondrial fission inhibitors comprises cilnidipine or a pharmacologically acceptable salt thereof or a solvate thereof.
242. The pharmaceutical composition of any of embodiments 238-241, wherein the phagocytic cell comprises a monocyte, a macrophage, a neutrophil, a dendritic cell, a mast cell, or any combination thereof.
243. The pharmaceutical composition of embodiment 242, wherein the phagocytes comprise monocytes.
244. The pharmaceutical composition of embodiment 242 or embodiment 243, wherein the phagocytic cell comprises a macrophage.
245. The pharmaceutical composition of any one of embodiments 242 to 244, wherein the phagocytic cells comprise neutrophils.
246. The pharmaceutical composition of any one of embodiments 242 to 245, wherein the phagocytic cells comprise dendritic cells.
247. The pharmaceutical composition of any one of embodiments 242 to 246, wherein the phagocytic cells comprise mast cells.
248. The pharmaceutical composition of any one of embodiments 238-247 for use in a method of treating a subject suffering from a phagocytosis-defect related disease or disorder.
249. The pharmaceutical composition for use according to embodiment 248, wherein the phagocytosis defect related disease or disorder is a disease or disorder according to any of embodiments 90 to 109 and 149 to 185.
250. The pharmaceutical composition for use according to embodiment 249, wherein the disease or disorder is cancer.
251. The pharmaceutical composition for use according to any one of embodiments 248 to 250, wherein the phagocytes are autologous to the subject.
252. The pharmaceutical composition for use according to any one of embodiments 248 to 250, wherein the phagocytes are allogeneic to the subject.
253. A method of making the pharmaceutical composition of any of embodiments 239-252, comprising contacting phagocytes ex vivo with one or more mitochondrial fission inhibitors.
254. A mitochondrial fission inhibitor for use in preparing the pharmaceutical composition of any of embodiments 239 to 252, optionally wherein the mitochondrial fission inhibitor comprises the mitochondrial fission inhibitor of any of embodiments 3 to 54.
255. A mitochondrial fission inhibitor for use according to embodiment 254 which is cilnidipine or a pharmacologically acceptable salt thereof or a solvate thereof.
8. Citation of reference
All publications, patents, patent applications, and other documents cited in this disclosure are incorporated by reference in their entirety for all purposes to the same extent as if each individual publication, patent application, or other document was specifically and individually indicated to be incorporated by reference for all purposes. If the teachings of one or more of the references incorporated herein are inconsistent with the present disclosure, the teachings of the present specification control.

Claims (45)

1. An agent or combination of agents for use in a method of treating a subject suffering from a phagocytosis-defect related disease or disorder, wherein the agent or combination of agents comprises a phagocytosis activating agent, optionally wherein:
(a) The phagocytosis-defect related disease or disorder is cancer, optionally wherein the cancer is pancreatic cancer; and/or
(b) The agent or combination of agents comprises cilnidipine or a pharmacologically acceptable salt thereof or a solvate thereof.
2. The agent or combination of agents for use of claim 1, wherein the agent or combination of agents comprises a mitochondrial fission inhibitor.
3. The agent or combination of agents for use of claim 1 or claim 2, wherein the agent or combination of agents comprises a Drp inhibitor.
4. A reagent or combination of reagents for use according to any one of claims 1 to 3, wherein the reagent or combination of reagents comprises cilnidipine, P110, metformin, mdivi-1, berberine, a pharmacologically acceptable salt thereof or a solvate thereof or a combination of any of the foregoing.
5. The agent or combination of agents for use according to any one of claims 1 to 4, wherein the agent or combination of agents comprises cilnidipine or a pharmacologically acceptable salt thereof or a solvate thereof.
6. The agent or combination of agents for use according to any one of claims 1 to 5, wherein the agent or combination of agents comprises a compound of formula (I):
or a pharmacologically acceptable salt thereof or a solvate thereof, wherein:
R 1 For phenyl substituted with 1 to 3 substituents, each substituent is independently NO 2 、NH 2 、OH、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl or C 1 -C 6 Alkoxyalkyl groups, provided that at least one substituent is NO 2 Or NH 2 ；
R 2 H, C of a shape of H, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl or C 1 -C 6 An alkoxyalkyl group;
R 3 h, C of a shape of H, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl or C 1 -C 6 An alkoxyalkyl group;
R 4 is C 1 -C 6 Alkyl or C 1 -C 6 A haloalkyl group;
R 5 is phenyl or pyridinyl, wherein the phenyl or pyridinyl is unsubstituted or substituted with 1 to 3 substituents, each substituent independently being NO 2 、NH 2 、OH、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl or C 1 -C 6 An alkoxyalkyl group;
(i) Bond a is present and bonds b and c are absent or (ii) bonds b and c are present and bond a is absent;
a is NH when bond a is present and N when bonds b and c are present;
m is an integer from 1 to 4; and
n is an integer of 1 to 3,
optionally, wherein the compound of formula (I) is not cilnidipine.
7. The agent or combination of agents for use according to any one of claims 1 to 6, wherein the agent or combination of agents comprises an agent or combination of agents that activates toll-like receptors (TLRs), dectin-1, mannose receptors, scavenger receptors A, CD, CD36, opsonizing receptors, apoptotic body receptors, or combinations thereof.
8. The agent or combination of agents for use according to claim 7, wherein the agent or combination of agents comprises 1, 3-beta glucan, mannan, lipopolysaccharide, lipoteichoic acid, lipopolysaccharide binding protein, plasmodium falciparum infected erythrocytes, igG, igA, igE or phosphatidylserine.
9. The agent or combination of agents for use according to any one of claims 1 to 8, wherein the agent or combination of agents comprises an agent that activates pgc1α.
10. The agent or combination of agents for use according to claim 9, wherein the agent or combination of agents comprises metformin or a pharmacologically acceptable salt thereof or a solvate thereof.
11. The agent or combination of agents for use according to any one of claims 1 to 10, wherein the agent or combination of agents comprises an agent that inhibits the PI3K-AKT-mTOR pathway.
12. The agent or combination of agents for use according to claim 11, wherein the agent or combination of agents comprises (i) a PI3K inhibitor, (ii) an AKT inhibitor, (iii) an mTOR inhibitor, (iv) rapamycin or a pharmacologically acceptable salt thereof or a solvate thereof, or (v) a combination of the foregoing.
13. The agent or combination of agents for use according to any one of claims 1 to 12, wherein the agent or combination of agents comprises one or more lactic acid releasing bacterial species, optionally wherein the agent or combination of agents comprises bifidobacteria and/or lactobacillus acidophilus.
14. The agent or combination of agents for use according to any one of claims 1 to 13, wherein the agent or combination of agents comprises a component or combination of components of a cell-free extract from a lactic acid releasing bacteria medium, optionally wherein the lactic acid releasing bacteria comprises bifidobacteria and/or lactobacillus acidophilus.
15. The agent or combination of agents for use according to any one of claims 1 to 14, wherein one or more of the agents in the combination of agents are formulated with a bile acid derivative, optionally wherein the bile acid derivative is ursodeoxycholic acid or a pharmacologically acceptable salt thereof or a solvate thereof.
16. The agent or combination of agents for use according to any one of claims 1 to 15, wherein the phagocytosis defect related disease or disorder is a cancer, optionally having a KRAS mutation, optionally wherein the cancer is:
(a) Pancreatic cancer;
(b) Hematological cancer;
(c) Solid tumors;
(d) Leukemia;
(e) Lymphomas;
(f) A myeloma;
(g) Multiple myeloma;
(h) Acute myelogenous leukemia;
(i) Acute lymphoblastic leukemia;
(j) Non-hodgkin's lymphoma;
(k) Diffuse large B-cell lymphomas;
(l) A melanoma, optionally wherein the melanoma has BRAF mutations;
(m) leiomyosarcoma;
(n) breast cancer;
(o) liver cancer;
(p) colorectal cancer;
(q) lung cancer, optionally small cell lung cancer or non-small cell lung cancer, optionally lung adenocarcinoma;
(r) osteosarcoma; or alternatively
(s) head and neck cancer.
17. The agent or combination of agents for use according to claim 16, wherein the cancer is pancreatic cancer, optionally wherein the pancreatic cancer is pancreatic ductal adenocarcinoma.
18. The agent for use according to claim 16 or claim 17 which is a mitochondrial fission inhibitor and wherein the method comprises administering the mitochondrial fission inhibitor as monotherapy for cancer.
19. The agent or combination of agents for use according to claim 16 or claim 17, wherein the method comprises administering one or more additional agents to the subject.
20. The agent or combination of agents for use according to claim 19 wherein the one or more additional agents comprise a CD47 inhibitor and/or a sirpa inhibitor.
21. The agent or combination of agents for use according to claim 20, wherein the one or more additional agents comprise a CD47 inhibitor, optionally wherein the CD47 inhibitor is:
(a) An antibody or antigen-binding fragment thereof;
(b) sirpa-Fc fusion proteins;
(c) Sirpa variant proteins;
(d)Magrolimab；
(e)CC-90002；
(f)AO-176；
(g)IBI-188；
(h)SHR-1063；
(i)AMMS4-G4；
(j)TTI-621；
(k) ALX148; or alternatively
(l)CV1。
22. The agent or combination of agents for use according to claim 20 or claim 21, wherein the one or more additional agents comprise a sirpa inhibitor, optionally wherein the sirpa inhibitor is:
(a) An antibody or antigen-binding fragment thereof;
(b)KWAR23；
(c)CC-95251；
(d) BI 765063; or alternatively
(e) Soluble CD47 peptide.
23. The agent or combination of agents for use according to any one of claims 19 to 22, wherein the one or more additional agents comprise standard of care therapies for cancer.
24. The agent or combination of agents for use according to any one of claims 19 to 23, wherein when the cancer is pancreatic cancer, the one or more additional agents comprise gemcitabine and/or paclitaxel (pacritixel).
25. The agent or combination of agents for use according to claim 24, wherein when the cancer is pancreatic cancer, the one or more additional agents comprise gemcitabine.
26. The agent or combination of agents for use according to any one of claims 19 to 23, wherein when the cancer is lung adenocarcinoma, the one or more additional agents comprise cisplatin and/or carboplatin.
27. The agent or combination of agents for use according to any one of claims 19 to 23, wherein when the cancer is colorectal cancer, the one or more additional agents comprise cetuximab and/or panitumumab.
28. The agent or combination of agents for use according to any one of claims 19 to 27, wherein the one or more additional agents comprises an anti-PD 1 antibody, optionally wherein the anti-PD 1 antibody is cemiplimab, nivolumab, or pembrolizumab, and/or an anti-PD-L1 antibody, optionally wherein the anti-PD-L1 antibody is avilamab, devaluzumab, or altrette Zhu Shankang.
29. The agent or combination of agents for use according to any one of claims 19 to 28, further comprising administering one or more additional agents to the subject.
30. The agent or combination of agents for use according to any one of claims 19 to 29, wherein one or more of the one or more additional agents is formulated with a bile acid derivative, optionally wherein the bile acid derivative is ursodeoxycholic acid or a pharmacologically acceptable salt thereof or a solvate thereof.
31. The agent or combination of agents for use according to any one of claims 1 to 15, wherein the phagocytosis defect related disease or disorder is:
(a) Musculoskeletal degenerative diseases, optionally muscular dystrophy, such as Duchenne Muscular Dystrophy (DMD);
(b) Infectious disease, optionally caused by bacteria or viruses;
(c) Neurodegenerative diseases, optionally Alzheimer's Disease (AD) or other dementias, parkinson's Disease (PD), nasu-Hakola disease, prion disease, amyotrophic Lateral Sclerosis (ALS), friedel-crafts ataxia, huntington's chorea, lewy body disease, spinal muscular atrophy, progressive Supranuclear Palsy (PSP) or Adrenoleukodystrophy (ALD);
(d) Inflammation;
(e) Inflammatory diseases, which are optionally autoimmune diseases, such as Systemic Lupus Erythematosus (SLE), rheumatoid Arthritis (RA) or autoimmune lymphoproliferative syndrome (ALPS); or alternatively
(f) Lysosomal storage diseases, which are optionally gaucher's disease, fabry's disease, niemann-pick's disease, hunter syndrome, glycogen storage disease II (pompe disease) or tay-saxophone disease.
32. The agent or combination of agents for use according to claim 31, wherein the phagocytosis defect related disease or disorder is Duchenne Muscular Dystrophy (DMD).
33. The agent or combination of agents for use according to any one of claims 1 to 32, wherein the subject has a phagocytic defect.
34. An agent that is cilnidipine or a pharmacologically acceptable salt thereof or a solvate thereof for use in a method of treating a subject having pancreatic cancer, optionally wherein the pancreatic cancer is pancreatic ductal adenocarcinoma.
35. The agent for use according to claim 34, wherein the agent is used as monotherapy.
36. The agent for use according to claim 35, wherein the method comprises administering to the subject an amount of the agent effective to slow tumor growth in the subject.
37. The agent for use of claim 34, wherein the agent is used in combination with gemcitabine.
38. The agent for use according to claim 37, wherein the method comprises administering to the subject an amount of the agent and an amount of gemcitabine that together are effective to slow the growth of a tumor in the subject.
39. An agent that is cilnidipine or a pharmacologically acceptable salt thereof or a solvate thereof for use in a method of treating a subject suffering from Duchenne Muscular Dystrophy (DMD).
40. The agent for use according to claim 39, wherein the method comprises administering an amount of the agent effective to reduce Creatinine Kinase (CK) and/or Lactose Dehydrogenase (LDH) in the plasma of the subject.
41. A pharmaceutical composition comprising phagocytes having enhanced phagocytic activity, optionally wherein the phagocytes comprise monocytes, macrophages, neutrophils, dendritic cells, mast cells or any combination thereof.
42. The pharmaceutical composition of claim 41 comprising phagocytes that have been contacted ex vivo with one or more mitochondrial fission inhibitors, optionally wherein the one or more mitochondrial fission inhibitors comprise cilnidipine or a pharmacologically acceptable salt thereof or a solvate thereof.
43. The pharmaceutical composition of claim 41 or claim 42 for use in a method of treating a subject suffering from a disease or condition associated with a defect in phagocytosis, optionally wherein the disease or condition is cancer.
44. The pharmaceutical composition for use according to claim 43, wherein the phagocytes are autologous to the subject.
45. The pharmaceutical composition for use according to claim 43, wherein the phagocytes are allogeneic to the subject.
CN202180073606.6A 2020-11-03 2021-11-02 Treatment of cancer and diseases associated with defects in phagocytosis Pending CN116829158A (en)

Applications Claiming Priority (4)

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US63/109,111 2020-11-03
US202163145681P 2021-02-04 2021-02-04
US63/145,681 2021-02-04
PCT/US2021/057698 WO2022098642A1 (en) 2020-11-03 2021-11-02 Therapies for treatment of cancer and phagocytosis-deficiency related diseases

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