WO2022100659A1 - Combination therapy and methods utilizing the same - Google Patents
Combination therapy and methods utilizing the same Download PDFInfo
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- WO2022100659A1 WO2022100659A1 PCT/CN2021/130026 CN2021130026W WO2022100659A1 WO 2022100659 A1 WO2022100659 A1 WO 2022100659A1 CN 2021130026 W CN2021130026 W CN 2021130026W WO 2022100659 A1 WO2022100659 A1 WO 2022100659A1
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Definitions
- Immune checkpoint blockade with antagonistic monoclonal antibodies (mAbs) targeting B7 immunoglobulin superfamily molecules (CTLA-4, PD-1, and PD-L1) generate long lasting anti-tumor immune responses translating into clinical benefit across many cancer types.
- mAbs antagonistic monoclonal antibodies
- CTLA-4, PD-1, and PD-L1 B7 immunoglobulin superfamily molecules
- the present disclosure provides novel compositions and methods thereof for overcoming primary and secondary resistance to immunotherapy across numerous cancer types.
- New immunostimulatory targets such as the tumor necrosis factor receptor superfamily comprising many other immune checkpoints, can be used as the next generation immunomodulators.
- OX40 CD134
- a co-stimulatory molecule that can be expressed by activated immune cells can be utilized as a new immunostimulatory target.
- the present disclosure provides a method for treating a subject in need thereof, comprising: (a) administering to the subject a polypeptide comprising an antigen binding moiety exhibiting binding specificity to OX40, wherein the antigen binding moiety comprises at least one heavy chain CDR (CDRH) selected from the group consisting of (i) - (iii) and at least one light chain CDR (CDRL) selected from the group consisting of (iv) - (vi) , wherein: (i) a CDRH1 having at least 80% sequence identity to a sequence selected from the group consisting of SEQ ID NOs: 1, 7, 13, 15, 21 and 27; (ii) a CDRH2 having at least 80% sequence identity to a sequence selected from the group consisting of SEQ ID NOs: 3, 9, 17, 23 and 29; (iii) a CDRH3 having at least 80% sequence identity to a sequence selected from the group consisting of SEQ ID NOs: 5, 11, 19, 25 and 31; (iv) a
- the antigen binding moiety comprises: (1) a heavy chain variable region (VH) having at least 80% sequence identity to a sequence selected from the group consisting of SEQ ID NOs: 33, 35, 37, 39, 41 and 43; and (2) a light chain variable region (VL) having at least 80% sequence identity to a sequence selected from the group consisting of SEQ ID NOs: 34, 36, 38, 40, 42 and 44.
- VH heavy chain variable region
- VL light chain variable region
- the antigen binding moiety comprises (1) a VH having at least 80% sequence identity to SEQ ID NO: 39 and (2) a VL having at least 80% sequence identity to SEQ ID NO: 40.
- the inhibitor against PI3K comprises one or more small molecule inhibitors against PI3K alpha, PI3K beta, PI3K delta, or PI3K gamma. In some embodiments of any one of the methods disclosed herein, the inhibitor against PI3K comprises one or more small molecule inhibitors against PI3K delta or PI3K gamma.
- the present disclosure provides a method comprising treating a subject in need thereof, comprising: (a) administering to the subject a polypeptide comprising an antigen binding moiety exhibiting binding specificity to OX40; and (b) administering to the subject an inhibitor against PI3K comprising one or more members selected from the group consisting of Wortmannin, LY294002, hibiscone C, Idelalisib, Copanlisib, Duvelisib, Alpelisib, Taselisib, Perifosine, Buparlisib, Umbralisib, PX-866, Dactolisib, CUDC-907, Voxtalisib, CUDC-907, ME-401, IPI-549, SF1126, Tenalisib, INK1117, pictilisib, XL147, Palomid 529, GSK1059615, ZSTK474, PWT33597, IC87114, TG100
- the inhibitor against PI3K comprises one or more members selected from the group consisting of Idelalisib, Copanlisib, Duvelisib, Alpelisib, Taselisib, Perifosine, Buparlisib, Umbralisib, Tenalisib, modifications thereof, and combinations thereof. In some embodiments, the inhibitor against PI3K comprises Tenalisib.
- the polypeptide comprises an antibody, a fragment thereof, or a functional variant thereof.
- administration of the polypeptide occurs prior to, simultaneously with, or subsequent to administration of the inhibitor against PI3K.
- the polypeptide and the inhibitor against PI3K are administered in a same unit dose.
- the polypeptide and the inhibitor against PI3K are administered in different unit doses.
- the diseased cell comprises a tumor cell or a cancer cell. In some embodiments of any one of the methods disclosed herein, the diseased cell comprises a colorectal cancer cell. In some embodiments of any one of the methods disclosed herein, the diseased cell comprises a lymphoma cell.
- the method further comprises administering to the subject a co-therapeutic agent.
- the subject has or is suspected of having a disease.
- the disease comprises tumor or cancer. In some embodiments of any one of the methods disclosed herein, the disease comprises colorectal cancer. In some embodiments of any one of the methods disclosed herein, the disease comprises lymphoma. In some embodiments of any one of the methods disclosed herein, the disease comprises B cell lymphoma.
- the present disclosure provides a composition
- a composition comprising: (a) a polypeptide comprising an antigen binding moiety exhibiting binding specificity to OX40, wherein the antigen binding moiety comprises at least one heavy chain CDR (CDRH) selected from the group consisting of (i) - (iii) and at least one light chain CDR (CDRL) selected from the group consisting of (iv) - (vi) , wherein: (i) a CDRH1 having at least 80% sequence identity to a sequence selected from the group consisting of SEQ ID NOs: 1, 7, 13, 15, 21 and 27; (ii) a CDRH2 having at least 80% sequence identity to a sequence selected from the group consisting of SEQ ID NOs: 3, 9, 17, 23 and 29; (iii) a CDRH3 having at least 80% sequence identity to a sequence selected from the group consisting of SEQ ID NOs: 5, 11, 19, 25 and 31; (iv) a CDRL1 having at least 80% sequence identity to
- the antigen binding moiety comprises: (1) a heavy chain variable region (VH) having at least 80% sequence identity to a sequence selected from the group consisting of SEQ ID NOs: 33, 35, 37, 39, 41 and 43; and (2) a light chain variable region (VL) having at least 80% sequence identity to a sequence selected from the group consisting of SEQ ID NOs: 34, 36, 38, 40, 42 and 44.
- VH heavy chain variable region
- VL light chain variable region
- the antigen binding moiety comprises (1) a VH having at least 80% sequence identity to SEQ ID NO: 39 and (2) a VL having at least 80% sequence identity to SEQ ID NO: 40.
- the inhibitor against PI3K comprises one or more small molecule inhibitors against PI3K alpha, PI3K beta, PI3K delta, or PI3K gamma. In some embodiments of any one of the compositions disclosed herein, the inhibitor against PI3K comprises one or more small molecule inhibitors against PI3K delta or PI3K gamma.
- the present disclosure provides a composition
- a composition comprising: (a) a polypeptide comprising an antigen binding moiety exhibiting binding specificity to OX40; and (b) an inhibitor against PI3K comprising one or more members selected from the group consisting of Wortmannin, LY294002, hibiscone C, Idelalisib, Copanlisib, Duvelisib, Alpelisib, Taselisib, Perifosine, Buparlisib, Umbralisib, PX-866, Dactolisib, CUDC-907, Voxtalisib, CUDC-907, ME-401, IPI-549, SF1126, Tenalisib, INK1117, pictilisib, XL147, Palomid 529, GSK1059615, ZSTK474, PWT33597, IC87114, TG100–115, CAL263, RP6503, PI-103, GNE
- the inhibitor against PI3K comprises one or more members selected from the group consisting of Idelalisib, Copanlisib, Duvelisib, Alpelisib, Taselisib, Perifosine, Buparlisib, Umbralisib, Tenalisib, modifications thereof, and combinations thereof. In some embodiments, the inhibitor against PI3K comprises Tenalisib.
- the polypeptide comprises an antibody, a fragment thereof, or a functional variant thereof.
- the polypeptide and the inhibitor against PI3K are prepared in a same unit dose. In some embodiments of any one of the compositions disclosed herein, the polypeptide and the inhibitor against PI3K are prepared in different unit doses.
- the composition further comprises a co-therapeutic agent.
- FIG. 1A Antitumor activity of Tenalisib (CN401) in combination with ⁇ -mOX40 mAb and anti-mPD1 mAb in MC38 syngeneic model.
- MC38 cells 0.5million/mouse were injected into the right flank of c57bl/6 mice. 6 days after cell implantation, when average tumor size reached about 70 mm 3 , mice were administered vehicle, CN401 (15mg/kg, 50mg/kg and 150mg/kg p.o. BID) , ⁇ -OX40 mAb (100ug/mouse I.p. BIW) , ⁇ -PD-1 mAb (60ug/mouse i.p. BIW) and their combination.
- FIG. 1B shows body weight growth of each group, mouse body weight was measured thrice a week.
- FIG. 2A shows antitumor activity of Tenalisib (CN401) in combination with ⁇ -mOX40 mAb and anti-mPD1 mAb in MC38 syngeneic model.
- the panel shows individual tumor growth curve of tumor from vehicle treated mice.
- FIG. 2B shows the individual tumor growth curve for CN401 (150mg/kg) treated mice.
- FIG. 2C shows the individual tumor growth curve for ⁇ -OX40 mAb (100ug/kg) treated mice.
- FIG. 2D shows individual tumor growth curve of ⁇ -OX40 mAb (100ug/kg) +CN410 (150mg/kg) treated mice.
- FIG. 2E shows individual tumor growth curve of ⁇ -OX40 mAb (100ug/kg) + CN401 (50mg/kg) treated mice.
- FIG. 2F shows individual tumor growth curve of ⁇ -OX40 mAb (100ug/kg) +CN410 (15mg/kg) treated mice.
- FIG. 2G shows individual tumor growth curve of ⁇ -OX40 mAb (100ug/kg) +CN410 (150mg/kg) + -PD1 mAb (3mg/kg) treated mice.
- FIG. 3A shows antitumor activity of Tenalisib (CN401) in combination with ⁇ -OX40 mAb and anti-PD1 mAb in A20 syngeneic model.
- A20 cells 0.5million/mouse
- mice were administered vehicle, CN401 (150mg/kg and 300mg/kg p.o. BID) , ⁇ -OX40 mAb (100ug/mouse I.p. BIW) , ⁇ -PD-1 mAb (60ug/mouse i.p. BIW) and their combination.
- FIG. 3B shows body weight growth of each group, mouse body weight was measured thrice a week.
- FIG. 4A shows antitumor activity of Tenalisib (CN401) in combination with ⁇ -OX40 mAb and anti-PD1 mAb in A20 syngeneic model.
- the panel shows the individual tumor growth curve of tumor from vehicle treated mice.
- FIG. 4B shows the individual tumor growth curve of tumor from CN401 (300mg/kg) treated mice.
- FIG. 4C shows the individual tumor growth curve of tumor from CN401 (150mg/kg) treated mice.
- FIG. 4D shows the individual tumor growth curve of tumor from ⁇ -OX40 mAb (100ug/kg) treated mice.
- FIG. 4E shows the individual tumor growth curve of tumor from ⁇ -OX40 mAb treated mice.
- FIG. 4F shows the individual tumor growth curve of tumor from ⁇ -OX40 mAb (100ug/kg) +CN410 (150mg/kg) treated mice. Of note, 1/6 mice achieved complete responses.
- FIG. 4G shows the individual tumor growth curve of tumors from ⁇ -OX40 mAb (100ug/kg) + ⁇ -PD1 mAb (60ug/mouse) treated mice. Of note, are that 3/6 mice achieved complete responses.
- FIG. 4H shows individual tumor growth curve of tumor from ⁇ -OX40 mAb (100ug/kg) +CN410 (150mg/kg) + -PD1 mAb (60ug/mouse) treated mice. Of note, are that 4/6 mice achieved complete responses.
- FIG. 5A shows antitumor activity of Tenalisib (CN401) in combination with CN1 Ab in A20 humanized transgenic mice.
- A20 cells 0.5million/mouse
- mice were administered vehicle, CN401 (150mg/kg p.o. BID) , CN1 (1mg/kg i.p. BIW and their combination.
- FIG. 5B shows the body weight growth of each group, mouse body weight was measured thrice a week.
- FIG. 6A shows antitumor activity of Tenalisib (CN401) in combination with CN1 in A20 humanized Ox40 transgenic mouse syngeneic model.
- the panel shows the individual tumor growth curve of tumor from vehicle treated mice.
- FIG. 6B shows individual tumor growth curve of tumor from CN401 (1mg/kg) treated mice. Of note is that 4/8 treated mice achieved complete responses.
- FIG. 6C shows individual tumor growth curve of tumor from CN401 (150mg/kg) treated mice. Of note is that 1/8 treated mice achieved complete responses.
- FIG. 6D shows individual growth curve from CN1 (1mg/kg) +CN401 (150mg/kg) treated mice. Of note is that 5/8 treated mice achieved complete responses.
- FIG. 7A shows results of different tumor cell lines treated with 10 ⁇ M Tenalisib for 72 hr. and the effects on cell proliferation were measured as percentage of control.
- Two cell lines (MV-4-11, human leukemia cells; A20, mouse B cell lymphoma) showed inhibition greater than 50%.
- FIG. 7B shows a chemical structure of Tenalisib (RP6530) .
- FIG. 7C shows results of different tumor cell lines treated with Duvelishib (The range of compound concentration was from 0.002 ⁇ M 10 ⁇ M to with 3 fold serial dilution ) for 72 hours and the effects on cell proliferation were measured as percentage of control.
- FIG. 7D shows a chemical structure of Duvelishib.
- FIG. 8A shows antitumor activity of Tenalisib (CN401) and duvelisib in combination with ⁇ -OX40 mAb and anti-PD1 mAb in MC38 syngeneic model.
- MC38 cells 0.5million/mouse
- mice were administered vehicle, CN401 (15mg/kg, 50mg/kg and 150mg/kg p.o. BID)
- ⁇ -OX40 mAb 100ug/mouse I.p. BIW
- ⁇ -PD-1 mAb 60ug/mouse i.p.
- BIW Duvelisib
- Duvelisib 50mg/kg p.o. BID
- FIG. 8B shows body weight growth of each group, mouse body weight was measured thrice a week.
- FIG. 9A shows antitumor activity of Tenalisib (CN401) & duvelisib in combination with ⁇ -OX40 mAb and anti-PD1 mAb in MC38 syngeneic model.
- the panel shows the individual tumor growth curve of tumor from vehicle treated mice.
- FIG. 9B shows the individual tumor growth curve of tumor from CN401 (150mg/kg) treated mice.
- FIG. 9C shows the individual tumor growth curve of tumor from ⁇ -OX40 mAb (100ug/mouse) treated mice.
- FIG. 9D shows the individual tumor growth curve of tumor from duvelisib (50mg/kg) treat mice.
- FIG. 9A shows antitumor activity of Tenalisib (CN401) & duvelisib in combination with ⁇ -OX40 mAb and anti-PD1 mAb in MC38 syngeneic model.
- the panel shows the individual tumor growth curve of tumor from vehicle treated mice.
- FIG. 9B shows the individual tumor
- FIG. 9E shows the individual tumor growth curve of tumor from ⁇ -OX40 mAb (100ug/mouse) +CN410 (150mg/kg) treated mice.
- FIG. 9F shows the individual tumor growth curve of tumor from ⁇ -OX40 mAb (100ug/mouse) + CN401 (50mg/kg) treated mice.
- FIG. 9G shows the individual tumor growth curve of tumor from ⁇ -OX40 mAb (100ug/mouse) +CN410 (15mg/kg) treated mice.
- FIG. 9E shows the individual tumor growth curve of tumor from ⁇ -OX40 mAb (100ug/mouse) +CN410 (150mg/kg) treated mice.
- FIG. 9F shows the individual tumor growth curve of tumor from ⁇ -OX40 mAb (100ug/mouse) + CN401 (50mg/kg) treated mice.
- FIG. 9G shows the individual tumor growth curve of tumor from ⁇ -OX40 mAb (
- 9H shows the individual tumor growth curve of tumor from ⁇ -OX40 mAb (100ug/mouse) +duvelisib (50mg/kg) treated mice; (i) ⁇ -OX40 mAb (100ug/mouse) +CN410 (150mg/kg) + -PD1 mAb (60ug/mouse) treated mice.
- FIG. 10A shows antitumor activity of Tenalisib (CN401) and duvelisib in combination with ⁇ -OX40 mAb and anti-PD1 mAb in A20 syngeneic model.
- A20 cells 0.5million/mouse
- mice were administered vehicle, CN401 (150mg/kg and 300mg/kg p.o. BID) , duvelisib (50mg/kg p.o. BID) , ⁇ -OX40 mAb (100ug/mouse I.p.
- BIW ⁇ -PD-1 mAb
- FIG. 10B shows the body weight growth of each group, mouse body weight was measured thrice a week.
- FIG. 11A shows antitumor activity of CN401 and duvelisib in combination with ⁇ -OX40 mAb and anti-PD1 mAb in A20 syngeneic model.
- the panel shows the individual tumor growth curve of tumor from vehicle treated mice.
- FIG. 11B shows the individual tumor growth curve of tumor from CN401 (300mg/kg) treated mice.
- FIG. 11C shows the individual tumor growth curve of tumor from CN401 (150mg/kg) treated mice.
- FIG. 11D shows the individual tumor growth curve of tumor from duvelisib (50mg/kg) treat mice.
- FIG. 11E shows the individual tumor growth curve of tumor from ⁇ -OX40 mAb (100ug/mouse) treated mice.
- FIG. 11F shows the individual tumor growth curve of tumor from ⁇ -OX40 mAb (100ug/kg) + CN401 (300mg/kg) treated mice.
- FIG. 11G shows the individual tumor growth curve of tumor from ⁇ -OX40 mAb (100ug/kg) +CN410 (150mg/kg) treated mice.
- FIG. 11H shows the individual tumor growth curve of tumor from ⁇ -OX40 mAb (100ug/kg) +duvelisib (50mg/kg) treated mice.
- FIG. 11I shows the individual tumor growth curve of tumor from ⁇ -OX40 mAb (100ug/kg) + ⁇ - PD1 mAb (60ug/mouse) treated mice.
- FIG. 11J shows the individual tumor growth curve of tumor from ⁇ -OX40 mAb (100ug/mouse) +CN410 (150mg/kg) + -PD1 mAb (60ug/mouse) treated mice.
- FIG. 12A shows antitumor activity of Tenalisib (CN401) in combination with CN1 and anti-PD1 Ab in A20 humanized transgenic mice.
- A20 cells 0.5million/mouse were injected into right flank of balb/c mice. 9 days after cell implantation, when average tumor size reached about 70 mm 3 , mice were administered vehicle, CN401 (150mg/kg p.o. BID) , CN1 (1mg/kg i.p. BIW and their combination.
- FIG. 12B shows the body weight growth of each group, mouse body weight was measured thrice a week.
- FIG. 13A shows the antitumor activity of Tenalisib (CN401) in combination with CN1 in A20 humanized Ox40 transgenic mouse syngeneic model.
- the panel shows the individual tumor growth curve of tumor from vehicle treated mice.
- FIG. 13B shows individual tumor growth curve of tumor from CN401 (1mg/kg) treated mice. Of note is that 4/8 mice achieved complete responses.
- FIG. 13C shows individual tumor growth curve of tumor from CN401 (150mg/kg) treated mice. Of note is that 1/8 mice achieved complete responses.
- FIG. 13D shows individual tumor growth curve of tumor from CN1 (1mg/kg) +CN401 (150mg/kg) treated mice. Of note, 5/8 mice achieved complete responses.
- FIG. 14A shows antitumor activity of duvelisib in combination with ⁇ -OX40 mAb in MC38 syngeneic model.
- MC38 cells 0.5million/mouse
- ⁇ -OX40 mAb 100ug/mouse I.p. BIW
- Duvelisib 50mg/kg p.o. BID
- FIG. 14B shows the body weight growth of each group, mouse body weight was measured thrice a week.
- C The TGI and p value on day 20 as compared with vehicle group.
- FIG. 15A shows antitumor activity of duvelisib in combination with ⁇ -OX40 mAb in MC38 syngeneic model.
- the panel specifically shows the individual tumor growth curve of tumor from vehicle treated mice.
- FIG. 15B shows the individual tumor growth curve of tumor from ⁇ -OX40 mAb (100ug/mouse) treated mice.
- FIG. 15C shows the individual tumor growth curve of tumor from duvelisib (50mg/kg) treated mice.
- FIG. 15D shows the individual tumor growth curve of tumor from ⁇ -OX40 mAb (100ug/mouse) +duvelisib (50mg/kg) treated mice.
- FIG. 16A shows antitumor activity of duvelisib in combination with ⁇ -OX40 mAb in A20 syngeneic model.
- A20 cells 0.5million/mouse
- mice were administered vehicle, duvelisib (50mg/kg p.o. BID) , ⁇ -OX40 mAb (100ug/mouse I.p. BIW) and their combination.
- FIG. 16B shows the body weight growth of each group, mouse body weight was measured thrice a week.
- FIG. 17A shows antitumor activity of duvelisib in combination with ⁇ -OX40 mAb in A20 syngeneic model.
- the individual tumor growth curve of tumor from vehicle treated mice is shown.
- FIG. 17B shows individual tumor growth curve of tumor from duvelisib (50mg/kg) treated mice.
- FIG. 17C shows individual tumor growth curve of tumor from ⁇ -OX40 mAb (100ug/mouse) treated mice.
- FIG. 17D shows individual tumor growth curve of tumor from ⁇ -OX40 mAb (100ug/mouse) +duvelisib (50mg/kg) treated mice.
- FIG. 18A shows antitumor activity of CN401 in combination with CN1 in humanized CT26.
- WT cells (0.1 million/mouse) were injected into right flank of mice. 9 days after cell implantation, when average tumor size reached about 70 mm 3 , mice were administered vehicle, CN401 (150mg/kg p.o. BID) , CN1 (5mg/kg mouse i.p. BIW) and their combination.
- FIG. 18B shows the body weight growth of each group, mouse body weight was measured thrice a week.
- FIG. 19A shows antitumor activity of CN401 in combination with CN1 in CT26. WT murine colon carcinoma model. The individual tumor growth curve of tumor from vehicle treated mice is shown.
- FIG. 19B shows individual tumor growth curve of tumor from CN401 (150mg/kg) treated mice.
- FIG. 19C shows individual tumor growth curve of tumor from CN1 (5mg/kg) treated mice.
- FIG. 19D shows individual tumor growth curve of tumor from CN1 (5mg/kg) +CN401 (150mg/kg) treated mice.
- FIG. 20A shows antitumor activity of CN401 in combination with CN1 in humanized B16-F10 murine melanoma tumor model.
- B16-F10 cells 0.1 million/mouse
- mice were administered vehicle, CN401 (150mg/kg p.o. BID) , CN1 (10mg/kg i.p. BIW) and their combination.
- FIG. 20B shows the body weight growth of each group, mouse body weight was measured thrice a week.
- FIG. 21A shows antitumor activity of CN401 in combination with CN1 in B16-F10 melanoma model.
- the individual tumor growth curve of tumor from vehicle treated mice is shown.
- FIG. 20B shows individual tumor growth curve of tumor from CN401 (150mg/kg) treat mice.
- FIG. 20C shows individual tumor growth curve of tumor from CN1 (10mg/kg) treated mice.
- FIG. 20D shows individual tumor growth curve of tumor from CN1 (10mg/kg) +CN401 (150mg/kg) treated mice.
- the term “about” or “approximately” generally means within an acceptable error range for the particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, i.e., the limitations of the measurement system. For example, “about” can mean within 1 or more than 1 standard deviation, per the practice in the art. Alternatively, “about” can mean a range of up to 20%, up to 10%, up to 5%, or up to 1% of a given value. Alternatively, particularly with respect to biological systems or processes, the term can mean within an order of magnitude, preferably within 5-fold, and more preferably within 2- fold, of a value. Where particular values are described in the application and claims, unless otherwise stated, the term “about” meaning within an acceptable error range for the particular value should be assumed.
- a cell generally refers to a biological cell.
- a cell can be the basic structural, functional and/or biological unit of a living organism.
- a cell can originate from any organism having one or more cells. Some non-limiting examples include: a prokaryotic cell, eukaryotic cell, a bacterial cell, an archaeal cell, a cell of a single-cell eukaryotic organism, a protozoa cell, a cell from a plant (e.g.
- algal cell e.g., Botryococcus braunii, Chlamydomonas reinhardtii, Nannochloropsis gaditana, Chlorella pyrenoidosa, Sargassum patens C. Agardh, and the like
- seaweeds e.g., Botryococcus braunii, Chlamydomonas reinhardtii, Nannochloropsis gaditana, Chlorella pyrenoidosa, Sargassum patens C. Agardh, and the like
- seaweeds e.g.
- a fungal cell e.g., a yeast cell, a cell from a mushroom
- an animal cell e.g. fruit fly, cnidarian, echinoderm, nematode, etc.
- a cell from a vertebrate animal e.g., fish, amphibian, reptile, bird, mammal
- a cell from a mammal e.g., a pig, a cow, a goat, a sheep, a rodent, a rat, a mouse, a non-human primate, a human, etc.
- a cell is not originating from a natural organism (e.g. a cell can be a synthetically made, sometimes termed an artificial cell) .
- nucleotide generally refers to a base-sugar-phosphate combination.
- a nucleotide can comprise a synthetic nucleotide.
- a nucleotide can comprise a synthetic nucleotide analog.
- Nucleotides can be monomeric units of a nucleic acid sequence (e.g. deoxyribonucleic acid (DNA) and ribonucleic acid (RNA) ) .
- nucleotide can include ribonucleoside triphosphates adenosine triphosphate (ATP) , uridine triphosphate (UTP) , cytosine triphosphate (CTP) , guanosine triphosphate (GTP) and deoxyribonucleoside triphosphates such as dATP, dCTP, dITP, dUTP, dGTP, dTTP, or derivatives thereof.
- Such derivatives can include, for example, [ ⁇ S] dATP, 7-deaza-dGTP and 7-deaza-dATP, and nucleotide derivatives that confer nuclease resistance on the nucleic acid molecule containing them.
- nucleotide as used herein can refer to dideoxyribonucleoside triphosphates (ddNTPs) and their derivatives.
- ddNTPs dideoxyribonucleoside triphosphates
- Illustrative examples of dideoxyribonucleoside triphosphates can include, but are not limited to, ddATP, ddCTP, ddGTP, ddITP, and ddTTP.
- a nucleotide may be unlabeled or detectably labeled by well-known techniques. Labeling can also be carried out with quantum dots.
- Detectable labels can include, for example, radioactive isotopes, fluorescent labels, chemiluminescent labels, bioluminescent labels and enzyme labels.
- Fluorescent labels of nucleotides may include but are not limited fluorescein, 5-carboxyfluorescein (FAM) , 2′7′-dimethoxy-4′5-dichloro-6-carboxyfluorescein (JOE) , rhodamine, 6-carboxyrhodamine (R6G) , N, N, N′, N′-tetramethyl-6-carboxyrhodamine (TAMRA) , 6-carboxy-X-rhodamine (ROX) , 4- (4′dimethylaminophenylazo) benzoic acid (DABCYL) , Cascade Blue, Oregon Green, Texas Red, Cyanine and 5- (2′-aminoethyl) aminonaphthalene-1-sulfonic acid (EDANS) .
- FAM 5-carboxyfluorescein
- JE 2′7′-dimethoxy-4′5-dichloro-6-carboxyfluorescein
- fluorescently labeled nucleotides can include [R6G] dUTP, [TAMRA] dUTP, [R110] dCTP, [R6G] dCTP, [TAMRA] dCTP, [JOE] ddATP, [R6G] ddATP, [FAM] ddCTP, [R110] ddCTP, [TAMRA] ddGTP, [ROX] ddTTP, [dR6G] ddATP, [dR110] ddCTP, [dTAMRA] ddGTP, and [dROX] ddTTP available from Perkin Elmer, Foster City, Calif.
- Nucleotides can also be labeled or marked by chemical modification.
- a chemically-modified single nucleotide can be biotin-dNTP.
- biotinylated dNTPs can include, biotin-dATP (e.g., bio-N6-ddATP, biotin-14-dATP) , biotin-dCTP (e.g., biotin-11-dCTP, biotin-14-dCTP) , and biotin-dUTP (e.g. biotin-11-dUTP, biotin-16-dUTP, biotin-20-dUTP) .
- polynucleotide oligonucleotide, ” or “nucleic acid, ” as used interchangeably herein, generally refers to a polymeric form of nucleotides of any length, either deoxyribonucleotides or ribonucleotides, or analogs thereof, either in single-, double-, or multi-stranded form.
- a polynucleotide can be exogenous or endogenous to a cell.
- a polynucleotide can exist in a cell-free environment.
- a polynucleotide can be a gene or fragment thereof.
- a polynucleotide can be DNA.
- a polynucleotide can be RNA.
- a polynucleotide can have any three dimensional structure, and can perform any function, known or unknown.
- a polynucleotide can comprise one or more analogs (e.g. altered backbone, sugar, or nucleobase) . If present, modifications to the nucleotide structure can be imparted before or after assembly of the polymer. Some non-limiting examples of analogs include: 5-bromouracil, peptide nucleic acid, xeno nucleic acid, morpholinos, locked nucleic acids, glycol nucleic acids, threose nucleic acids, dideoxynucleotides, cordycepin, 7-deaza-GTP, florophores (e.g.
- rhodamine or flurescein linked to the sugar thiol containing nucleotides, biotin linked nucleotides, fluorescent base analogs, CpG islands, methyl-7-guanosine, methylated nucleotides, inosine, thiouridine, pseudourdine, dihydrouridine, queuosine, and wyosine.
- Non-limiting examples of polynucleotides include coding or non-coding regions of a gene or gene fragment, loci (locus) defined from linkage analysis, exons, introns, messenger RNA (mRNA) , transfer RNA (tRNA) , ribosomal RNA (rRNA) , short interfering RNA (siRNA) , short-hairpin RNA (shRNA) , micro-RNA (miRNA) , ribozymes, cDNA, recombinant polynucleotides, branched polynucleotides, plasmids, vectors, isolated DNA of any sequence, isolated RNA of any sequence, cell-free polynucleotides including cell-free DNA (cfDNA) and cell-free RNA (cfRNA) , nucleic acid probes, and primers.
- the sequence of nucleotides can be interrupted by non-nucleotide components.
- amino acid chains of any length, including full length proteins, and proteins with or without secondary and/or tertiary structure (e.g., domains) .
- the terms also encompass an amino acid polymer that has been modified, for example, by disulfide bond formation, glycosylation, lipidation, acetylation, phosphorylation, oxidation, and any other manipulation such as conjugation with a labeling component.
- amino acid and amino acids, ” as used herein, generally refer to natural and non-natural amino acids, including, but not limited to, modified amino acids and amino acid analogues.
- Modified amino acids can include natural amino acids and non-natural amino acids, which have been chemically modified to include a group or a chemical moiety not naturally present on the amino acid.
- Amino acid analogues can refer to amino acid derivatives.
- amino acid includes both D-amino acids and L-amino acids.
- derivative, ” “variant, ” or “fragment, ” as used herein with reference to a polypeptide generally refers to a polypeptide related to a wild type polypeptide, for example either by amino acid sequence, structure (e.g., secondary and/or tertiary) , activity (e.g., enzymatic activity) and/or function.
- Derivatives, variants and fragments of a polypeptide can comprise one or more amino acid variations (e.g., mutations, insertions, and deletions) , truncations, modifications, or combinations thereof compared to a wild type polypeptide.
- antibody generally refers to a proteinaceous binding molecule with immunoglobulin-like functions.
- the term antibody includes antibodies (e.g., monoclonal and polyclonal antibodies) , as well as derivatives, variants, and fragments thereof.
- Antibodies include, but are not limited to, immunoglobulins (Ig's) of different classes (i.e. IgA, IgG, IgM, IgD and IgE) and subclasses (such as IgG1, IgG2, etc. ) .
- a derivative, variant or fragment thereof can refer to a functional derivative or fragment which retains the binding specificity (e.g., complete and/or partial) of the corresponding antibody.
- Antigen-binding fragments include Fab, Fab′, F (ab′) 2, variable fragment (Fv) , single chain variable fragment (scFv) , minibodies, diabodies, and single-domain antibodies ( “sdAb” or “nanobodies” or “camelids” ) .
- the term antibody includes antibodies and antigen-binding fragments of antibodies that have been optimized, engineered or chemically conjugated. Examples of antibodies that have been optimized include affinity-matured antibodies. Examples of antibodies that have been engineered include Fc optimized antibodies (e.g., antibodies optimized in the fragment crystallizable region) and multispecific antibodies (e.g., bispecific antibodies) .
- an antigen binding domain generally refers to a construct exhibiting preferential binding to a specific target antigen.
- An antigen binding domain can be a polypeptide construct, such as an antibody, modification thereof, fragment thereof, or a combination thereof.
- the antigen binding domain can be any antibody as disclosed herein, or a functional variant thereof.
- Non-limiting examples of an antigen binding domain can include a murine antibody, a human antibody, a humanized antibody, a camel Ig, a shark heavy-chain-only antibody (VNAR) , Ig NAR, a chimeric antibody, a recombinant antibody, or antibody fragment thereof.
- Non-limiting examples of antibody fragment include Fab, Fab′, F (ab) ′2, F (ab) ′3, Fv, single chain antigen binding fragment (scFv) , (scFv) 2, disulfide stabilized Fv (dsFv) , minibody, diabody, triabody, tetrabody, single-domain antigen binding fragments (sdAb, Nanobody) , recombinant heavy-chain-only antibody (VHH) , and other antibody fragments that maintain the binding specificity of the whole antibody.
- the term “enhanced activity, ” “increased activity, ” or “upregulated activity” generally refers to activity of a moiety of interest (e.g., a polynucleotide or a polypeptide) that is modified to a level that is above a normal level of activity of the moiety of interest in a host strain (e.g., a host cell) .
- the normal level of activity can be substantially zero (or null) or higher than zero.
- the moiety of interest can comprise a polypeptide construct of the host strain.
- the moiety of interest can comprise a heterologous polypeptide construct that is introduced to or into the host strain.
- a heterologous gene encoding a polypeptide of interest can be knocked-in (KI) to a genome of the host strain for enhanced activity of the polypeptide of interest in the host strain.
- reduced activity, ” “decreased activity, ” or “downregulated activity” generally refers to activity of a moiety of interest (e.g., a polynucleotide or a polypeptide) that is modified to a level that is below a normal level of activity of the moiety of interest in a host strain (e.g., a host cell) .
- the normal level of activity is higher than zero.
- the moiety of interest can comprise an endogenous gene or polypeptide construct of the host strain.
- the moiety of interest can be knocked-out or knocked-down in the host strain.
- reduced activity of the moiety of interest can include a complete inhibition of such activity in the host strain.
- subject generally refers to a vertebrate, preferably a mammal such as a human. Mammals include, but are not limited to, murines, simians, humans, farm animals, sport animals, and pets. Tissues, cells and their progeny of a biological entity obtained in vivo or cultured in vitro are also encompassed.
- treatment generally refers to an approach for obtaining beneficial or desired results including but not limited to a therapeutic benefit and/or a prophylactic benefit.
- a treatment can comprise administering a system or cell population disclosed herein.
- therapeutic benefit is meant any therapeutically relevant improvement in or effect on one or more diseases, conditions, or symptoms under treatment.
- a composition can be administered to a subject at risk of developing a particular disease, condition, or symptom, or to a subject reporting one or more of the physiological symptoms of a disease, even though the disease, condition, or symptom may not have yet been manifested.
- ⁇ ективное amount generally refers to the quantity of a composition, for example a composition (e.g., one or more unit doses) as disclosed herein, that is sufficient to result in a desired activity upon administration to a subject in need thereof.
- therapeutically effective generally refers to that quantity of a composition that is sufficient to delay the manifestation, arrest the progression, relieve or alleviate at least one symptom of a disorder treated by the methods of the present disclosure.
- compositions that comprise antibodies, such an anti-OX40 and/or anti-PD-1 antibodies, and PI3K inhibitors and methods of using the same to treat or prevent cancer.
- therapeutic regimens that comprise administrations of antibodies and PI3K inhibitors.
- Combination therapies can confer increased anti-tumor effects as compared to single-therapy treatments due to synergistic effects associated with the combination therapies.
- compositions that comprise antigen binding moieties.
- Provided herein is also a method for treating a subject in need thereof, comprising (a) administering to the subject a polypeptide comprising an antigen binding moiety exhibiting binding specificity to OX40.
- OX40 is a type 1 transmembrane glycoprotein, is predominantly expressed by T cells (constitutively by regulatory T phenotypes and, after activation, by effector T cells) .
- OX40 induces expression of proteins with anti-apoptotic (Bcl-2, Bcl-xl and Bfl-1) and cell-cycle progression (Survivin) properties.
- Bcl-2, Bcl-xl and Bfl-1 proteins with anti-apoptotic
- Bfl-1 cell-cycle progression
- OX40 counterbalance the inhibition of immune cells (including T lymphocytes CD4 +and CD8+, NK cells and B lymphocytes) while directly stimulating effector T cells.
- OX40 signaling can be triggered by OX40-specific agonistic antibodies, OX40L-Fc fusion proteins, transfection of DC with OX40L mRNA and tumor cells engineered to express OX40L on the surface, and any combination thereof.
- an antigen binding moiety that binds OX40 or a fragment thereof.
- an antigen binding moiety provided herein comprises an antibody or functional fragment there.
- An antibody may include polyclonal antibodies, multiclonal antibodies, monoclonal antibodies, chimeric antibodies, humanized and primatized antibodies, CDR grafted antibodies, human antibodies, recombinantly produced antibodies, intrabodies, multispecific antibodies, bispecific antibodies, monovalent antibodies, multivalent antibodies, anti-idiotypic antibodies, synthetic antibodies, including muteins and variants thereof, ; and derivatives thereof including Fc fusions and other modifications, and any other immunoreactive molecule so long as it exhibits preferential association or binding with a OX40 protein.
- the term further comprises all classes of antibodies (i.e. IgA, IgD, IgE, IgG, and IgM) and all subclasses (i.e., IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2) .
- the antibody is a monoclonal antibody.
- the antibody is a human monoclonal antibody.
- the antibody is a human anti-OX40 monoclonal antibody.
- an antigen binding moiety provided herein comprises an anti-OX40 monoclonal antibody.
- exemplary polypeptides, antigen binding moieties, and combinations thereof can be provided in: WO2019214624, US7960515, US9695246, US9475880, US9040048, and sequences adapted therefrom, all of which are incorporated by reference herein.
- an antigen binding moiety comprises at least about 70%, 72%, 74%, 76%, 78%, 80%, 82%, 84%, 86%, 88%, 90%, 92%, 94%, 96%, 98%, or up to about 100% sequence identity to a CDR sequence of Table 1 or a variable polypeptide sequence of Table 2.
- an antigen binding moiety is encoded by a polynucleotide sequence that comprises at least about 70%, 72%, 74%, 76%, 78%, 80%, 82%, 84%, 86%, 88%, 90%, 92%, 94%, 96%, 98%, or up to about 100% sequence identity to a sequence of Table 3.
- the antigen binding moiety comprises at least one heavy chain CDR (CDRH) selected from the group consisting of (i) - (iii) and at least one light chain CDR (CDRL) selected from the group consisting of (iv) - (vi) , wherein: (i) a CDRH1 having at least 80% sequence identity to a sequence selected from the group consisting of SEQ ID NOs: 1, 7, 13, 15, 21 and 27; (ii) a CDRH2 having at least 80% sequence identity to a sequence selected from the group consisting of SEQ ID NOs: 3, 9, 17, 23 and 29; (iii) a CDRH3 having at least 80% sequence identity to a sequence selected from the group consisting of SEQ ID NOs: 5, 11, 19, 25 and 31; (iv) a CDRL1 having at least 80% sequence identity to a sequence selected from the group consisting of SEQ ID NOs: 2, 8, 14, 16, 22 and 28; (v) a CDRL2 having at least 80% sequence identity to at least 80%
- Table 1 CDR amino acid sequences of fully human anti-OX40 monoclonal antibodies. Designated as “1.62.3-u1-IgG1K” , “1.62.3-u1-3-IgG1K” , “1.7.10-u1-IgG1K” , “1.134.9-u1-IgG1L” , “1.186.19-u1-IgG1K” and “1.214.23-u1-IgG1K” , respectively.
- an antigen binding moiety provided herein comprises an anti-OX40 monoclonal antibody that comprises variable region sequence selected from a polypeptide in Table 2 or any combination thereof.
- an antigen binding moiety comprises (1) a heavy chain variable region (VH) having at least 70%, 72%, 74%, 76%, 78%, 80%, 82%, 84%, 86%, 88%, 90%, 92%, 94%, 96%, 98%, or up to about 100% sequence identity to a sequence selected from the group consisting of SEQ ID NOs: 33, 35, 37, 39, 41 and 43; and/or (2) a light chain variable region (VL) having at least 70%, 72%, 74%, 76%, 78%, 80%, 82%, 84%, 86%, 88%, 90%, 92%, 94%, 96%, 98%, or up to about 100% sequence identity to a sequence selected from the group consisting of SEQ ID NOs: 34, 36, 38, 40, 42 and 44.
- VH heavy chain variable region having at least 70%, 72%, 74%, 76%, 78%, 80%, 82%, 84%, 86%, 88%, 90%, 92%, 94%, 96%, 98%, or up to about
- the antigen binding moiety comprises (1) a VH having at least 70%, 72%, 74%, 76%, 78%, 80%, 82%, 84%, 86%, 88%, 90%, 92%, 94%, 96%, 98%, or up to about 100% sequence identity to SEQ ID NO: 39 and (2) a VL having at least 70%, 72%, 74%, 76%, 78%, 80%, 82%, 84%, 86%, 88%, 90%, 92%, 94%, 96%, 98%, or up to about 100% sequence identity to SEQ ID NO: 40.
- Table 2 Variable region amino acid sequences of fully human anti-OX40 monoclonal antibodies. Designated as “1.62.3-u1-IgG1K” , “1.62.3-u1-3-IgG1K” , “1.7.10-u1-IgG1K” , “1.134.9-u1-IgG1L” , “1.186.19-u1-IgG1K” and “1.214.23-u1-IgG1K” , respectively.
- the disclosure is directed to an isolated nucleic acid molecule, comprising a nucleic acid sequence encoding the heavy chain variable region and/or the light chain variable region of an antigen binding moiety as disclosed herein.
- An exemplary isolated nucleic acid molecule is provided in Table 3.
- Table 3 Variable region nucleotide sequences of fully human anti-OX40 monoclonal antibodies. Designated as “1.62.3-u1-IgG1K” , “1.62.3-u1-3-IgG1K” , “1.7.10-u1-IgG1K” , “1.134.9-u1-IgG1L” , “1.186.19-u1-IgG1K” and “1.214.23-u1-IgG1K” , respectively.
- Nucleic acids of the disclosure can be obtained using standard molecular biology techniques.
- cDNAs encoding the light and heavy chains of the antibody made by the hybridoma can be obtained by standard PCR amplification or cDNA cloning techniques.
- antibodies obtained from an immunoglobulin gene library e.g., using phage display techniques
- a nucleic acid encoding such antibodies can be recovered from the gene library.
- the isolated nucleic acid encoding the VH region can be converted to a full-length heavy chain gene by operatively linking the VH-encoding nucleic acid to another DNA molecule encoding heavy chain constant regions (CH1, CH2, and CH3) .
- heavy chain constant regions CH1, CH2, and CH3 .
- the sequences of human heavy chain constant region genes are known in the art (see e.g., Kabat et al. (1991) , supra) and DNA fragments encompassing these regions can be obtained by standard PCR amplification.
- the heavy chain constant region can be an IgG1, IgG2, IgG3, IgG4, IgA, IgE, IgM, or IgD constant region, but more preferably is an IgG1 or IgG4 constant region.
- the isolated nucleic acid encoding the VL region can be converted to a full-length light chain gene (as well as a Fab light chain gene) by operatively linking the VL-encoding DNA to another DNA molecule encoding the light chain constant region, CL.
- the sequences of human light chain constant region genes are known in the art (see e.g., Kabat et al., supra) and DNA fragments encompassing these regions can be obtained by standard PCR amplification.
- the light chain constant region can be a kappa or lambda constant region.
- VH and VL segments are obtained, these DNA fragments can be further manipulated by standard recombinant DNA techniques, for example to convert the variable region genes to full-length antibody chain genes, to Fab fragment genes or to a scFv gene.
- a VL-or VH-encoding DNA fragment is operatively linked to another DNA fragment encoding another protein, such as an antibody constant region or a flexible linker.
- the term “operatively linked” is intended to mean that the two DNA fragments are joined such that the amino acid sequences encoded by the two DNA fragments remain in-frame.
- PI3K are believed to be one of the key therapeutic targets for cancer treatment based on the observation that hyperactivity of PI3K signaling is significantly correlated with human tumor progression, increased tumor micro-vessel density and enhanced chemotaxis and invasive potential of cancer cells.
- PI3K signaling pathway is believed to be deregulated in a wide spectrum of human cancers making it an attractive target to target. Mutations of the kinases and/or decreased expression of PTEN lead to neoplastic transformation, underscoring its central role in human carcinogenesis.
- PI3K pathway is deregulated through a variety of mechanisms, including loss or inactivation of the tumor suppressor PTEN, mutation or amplification of PI3K, as well as activation of tyrosine kinase growth factor receptors or oncogenes upstream of PI3K.
- compositions that comprise inhibitors against a phosphoinositide 3-kinase (PI3K) .
- PI3K phosphoinositide 3-kinase
- Provided inhibitors can be direct or indirect inhibitors of PI3K.
- provided inhibitors can directly target any number of factors in the PI3K pathway.
- a provided inhibitor can indirectly target a factor in the PI3K pathway.
- inhibitors can target factors associated with aberrations involved in PI3K signaling as is further described herein.
- PI3K is a group of plasma membrane-associated lipid kinases, comprising three subunits: p85 regulatory subunit, p55 regulatory subunit, and p110 catalytic subunit. According to their different structures and specific substrates, PI3K is divided into 3 classes: classes I, II, and III. Class I PI3Ks comprised of class IA and class IB PI3Ks. Class IA PI3K, a heterodimer of p58 regulatory subunit and p110 catalytic subunit, is the type most clearly implicated in human cancer.
- Class IA PI3K contains p110 ⁇ , p110 ⁇ and p110 ⁇ catalytic subunits produced from different genes (PIK3CA, PIK3CB, and PIK3CD, respectively) , while p110 ⁇ produced by PIK3CG represents the only catalytic subunit in class IB PI3K.
- the p85 regulatory subunit is composed of p85a (p85a, p55a and p50a splice variants) , p85b and p55g, which are encoded by the genes PIK3R1, PIK3R2 and PIK3R3, respectively.
- p85 regulatory subunit binds and integrates signals from various transmembrane and intracellular proteins, including tyrosine kinase-linked receptors, protein kinase C (PKC) , Src homology 2 domain-containing protein tyrosine phosphatase 1 (SHP1) , Rac, Rho, hormonal receptors, Src, as well as mutated Ras.
- PKC protein kinase C
- SHP1 Src homology 2 domain-containing protein tyrosine phosphatase 1
- Rho protein tyrosine phosphatase 1
- a provided PI3K inhibitor is: a PI3K/mTOR inhibitor, pan-PI3K inhibitor, isoform-specific inhibitor, or any combination thereof.
- a PI3K inhibitor is a dual PI3K/mTOR inhibitor.
- Exemplary dual PI3K/mTOR inhibitors are selected from the group that comprises: BGT-226, DS-7423, PF-04691502, PKI-179, GSK458/Omipalisib, P7170, SB2343/VS-5584, BEZ235/Dactolisib, GDC-0084, GDC-0980/Apitolisib, LY3023414, PQR309/Bimiralisib, XL765/Voxtalisib, SF-1126, PF-05212384/gedatolisib/PKI-587, or combinations thereof.
- a PI3K inhibitor is a pan-PI3K inhibitor.
- Exemplary pan-PI3K inhibitors are selected from the group that comprises: GDC-0941/Pictilisib, PX-866, TG100–115, CH5132799, XL147/Pilaralisib, ZSTK474, BKM-120/Buparlisib, BAY80–6946/Copanlisib, WX-037, AZD8186, KA2237, CAL-120, ME401, AMG319, GSK2636771, INCB050465, INK-1117, TGR-1202, RP6530, GDC-0032, BYL719, IPI-145, CAL-101, or combinations thereof.
- a PI3K inhibitor is an isoform-specific inhibitor.
- Exemplary isoform-specific inhibitors are selected from the group that comprises: AZD8835 ⁇ / ⁇ , WX-037 ⁇ , AZD8186 ⁇ / ⁇ , KA2237 ⁇ / ⁇ , GS-9820/CAL-120 ⁇ / ⁇ , ME401/PWT-143 ⁇ , AMG 319 ⁇ , GSK2636771 ⁇ , INCB050465/Parsaclisib ⁇ , Serabelisib/INK-1117 ⁇ , Umbralisib/TGR-1202 ⁇ , RP6530/Tenalisib ⁇ / ⁇ , GDC-0032/Taselisib ⁇ / ⁇ / ⁇ (Taselisib) , BYL719/Alpelisib ⁇ , Duvelisib/IPI-145 ⁇ / ⁇ , CAL-101/idelalisib ⁇ , or combinations thereof.
- PI3K inhibitors include but are not limited to: CUDC-907/Fimepinostat and Rigosertib/ON-01910.
- a PI3K inhibitor is against one or more members selected from the group consisting of class 1 catalytic PI3K (e.g., PI3K alpha, PI3K beta, PI3K delta, PI3K gamma) , class 1 regulatory PI3K (e.g., PIK3R1, PIK3R2, PIK3R3, PIK3R4, PIK3R5, PIK3R6) , class 2 PI3K (e.g., PIK3C2A, PIK3C2B, PIK3C2G) , and class 3 PI3K (e.g., PIK3C3) .
- class 1 catalytic PI3K e.g., PI3K alpha, PI3K beta, PI3K delta, PI3K gamma
- class 1 regulatory PI3K e.g., PIK3R1, PIK3R2, PIK3R3, PI
- a PI3K inhibitor can be against one or more members selected from the group consisting of PI3K alpha, PI3K beta, PI3K delta, and PI3K gamma. In some cases, a PI3K inhibitor can be against one or more members selected from the group consisting of PI3K delta and PI3K gamma. In some examples, a PI3K inhibitor can be against both PI3K delta and PI3K gamma.
- a PI3K inhibitor is selected from the group that consists of: Wortmannin, LY294002, hibiscone C, Idelalisib, Copanlisib, Duvelisib, Alpelisib, Taselisib, Perifosine, Buparlisib, Umbralisib, PX-866, Dactolisib, CUDC-907, Voxtalisib, CUDC-907, ME-401, IPI-549, SF1126, Tenalisib (RP6530) , INK1117, pictilisib, XL147, Palomid 529, GSK1059615, ZSTK474, PWT33597, IC87114, TG100–115, CAL263, RP6503, PI-103, GNE-477, and AEZS-136.
- Wortmannin LY294002
- hibiscone C Idelalisib, Copanlisib
- a PI3K inhibitor is selected from the group consisting of: Idelalisib, Copanlisib, Duvelisib, Alpelisib, Taselisib, Perifosine, Buparlisib, Umbralisib, and Tenalisib.
- the PI3K inhibitor comprises Tenalisib.
- inhibitors that indirectly target pathologic signaling through the PI3K pathway.
- pathologic signaling through this pathway can also occur in other ways, including tyrosine kinase growth factor receptors (e.g. human epidermal growth factor receptor 2 and insulin-like growth factor -1 receptor) , cell adhesion molecules (e.g. integrins, GPCR) , and oncogenes (e.g. RAS) all of which can be targeted to resolve aberrant PI3K signaling.
- tyrosine kinase growth factor receptors e.g. human epidermal growth factor receptor 2 and insulin-like growth factor -1 receptor
- cell adhesion molecules e.g. integrins, GPCR
- oncogenes e.g. RAS
- compositions provided herein that comprise antigen binding moieties and inhibitors can be utilized for treatment and prevention of disease.
- Provided compositions can be utilized in combination therapies to combat cancer and to reduce and/or eliminate primary and/or secondary resistance to immunotherapy.
- a method for treating a subject in need thereof comprises: (a) administering to the subject a polypeptide comprising an antigen binding moiety exhibiting binding specificity to OX40.
- the antigen binding moiety comprises at least one heavy chain CDR (CDRH) selected from the group consisting of (i) - (iii) and at least one light chain CDR (CDRL) selected from the group consisting of (iv) - (vi) , wherein: (i) a CDRH1 having at least 80% sequence identity to a sequence selected from the group consisting of SEQ ID NOs: 1, 7, 13, 15, 21 and 27; (ii) a CDRH2 having at least 80% sequence identity to a sequence selected from the group consisting of SEQ ID NOs: 3, 9, 17, 23 and 29; (iii) a CDRH3 having at least 80% sequence identity to a sequence selected from the group consisting of SEQ ID NOs: 5, 11, 19, 25 and 31; (iv) a CDRL1 having at least one heavy chain
- a method comprises treating a subject in need thereof, comprising: (a) administering to the subject a polypeptide comprising an antigen binding moiety exhibiting binding specificity to OX40; and (b) administering to the subject an inhibitor against PI3K.
- the inhibitor is a PI3K/mTOR inhibitor, pan-PI3K inhibitor, isoform-specific inhibitor, or any combination thereof.
- an inhibitor is the isoform-specific inhibitor.
- the inhibitor comprises one or more members selected from the group consisting of Wortmannin, LY294002, hibiscone C, Idelalisib, Copanlisib, Duvelisib, Alpelisib, Taselisib, Perifosine, Buparlisib, Umbralisib, PX-866, Dactolisib, CUDC-907, Voxtalisib, CUDC-907, ME-401, IPI-549, SF1126, RP6530, INK1117, pictilisib, XL147, Palomid 529, GSK1059615, ZSTK474, PWT33597, IC87114, TG100–115, CAL263, RP6503, PI-103, GNE-477, and AEZS-136.
- Wortmannin LY294002
- hibiscone C Idelalisib, Copanlisib, Duvelisib, Alpelis
- the inhibitor comprises one or more members selected from the group consisting of Idelalisib, Copanlisib, Duvelisib, Alpelisib, Taselisib, Perifosine, Buparlisib, and Umbralisib.
- the inhibitor comprises Tenalisib.
- the reduction in tumor size can be at least about or at most about: 1-fold, 5-fold, 10- fold, 15-fold, 20-fold, 40-fold, 60-fold, 80-fold, 100-fold, or up to about 200-fold. In an embodiment, the reduction in tumor size is elimination of the tumor.
- the disclosure also provides a method of enhancing (for example, stimulating) an immune response in a subject comprising administering a subject polypeptide and/or a subject inhibitor to the subject such that an immune response in the subject is enhanced.
- the enhancement is greater than a comparable method lacking the combination or the polypeptide or inhibitor.
- the subject is a mammal.
- the subject is a human.
- the enhancement is greater than a comparable method lacking the combination or the polypeptide or inhibitor by at least about or at most about 1 fold, 2 fold, 3 fold, 4 fold, 10 fold, 20 fold, 30 fold, 40 fold, 60 fold, 100 fold, 200 fold, 300 fold, or 500 fold.
- the subject is a mammal.
- the subject is a human.
- enhancing an immune response or its grammatical variations means stimulating, evoking, increasing, improving, or augmenting any response of a mammal’s immune system.
- the immune response may be a cellular response (i.e. cell-mediated, such as cytotoxic T lymphocyte mediated) or a humoral response (i.e. antibody mediated response) , and may be a primary or secondary immune response.
- Examples of enhancement of immune response include increased CD4 + helper T cell activity and generation of cytolytic T cells.
- the enhancement of immune response can be assessed using a number of in vitro or in vivo measurements known to those skilled in the art, including, but not limited to, cytotoxic T lymphocyte assays, release of cytokines (for example IL-2 production or IFN- ⁇ production) , regression of tumors, survival of tumor bearing animals, antibody production, immune cell proliferation, expression of cell surface markers, and cytotoxicity.
- cytotoxic T lymphocyte assays release of cytokines (for example IL-2 production or IFN- ⁇ production) , regression of tumors, survival of tumor bearing animals, antibody production, immune cell proliferation, expression of cell surface markers, and cytotoxicity.
- methods of the disclosure enhance the immune response by a mammal when compared to the immune response by an untreated mammal or a mammal not treated using the methods as disclosed herein.
- the polypeptide and/or inhibitor is used to enhance the immune response of a human to a subject target.
- the method enhances a cellular immune response, particularly a cytotoxic T cell response.
- the cellular immune response is a T helper cell response.
- the immune response is a cytokine production, particularly IFN- ⁇ production or IL-2 production.
- compositions and methods disclosed herein can be utilized to treat a target cell, a target tissue, a target condition, or a target disease of a subject.
- a target disease can be a viral, bacterial, and/or parasitic infection; inflammatory and/or autoimmune disease; or neoplasm such as a cancer and/or tumor.
- a target cell can be a diseased cell.
- a diseased cell can have altered metabolic, gene expression, and/or morphologic features.
- a diseased cell can be a cancer cell, a diabetic cell, and an apoptotic cell.
- a diseased cell can be a cell from a diseased subject. Exemplary diseases can include blood disorders, cancers, metabolic disorders, eye disorders, organ disorders, musculoskeletal disorders, cardiac disease, and the like.
- a variety of target cells can be killed using any one of the methods or compositions disclosed herein.
- a target cell can include a wide variety of cell types.
- a target cell can be in vitro.
- a target cell can be in vivo.
- a target cell can be ex vivo.
- a target cell can be an isolated cell.
- a target cell can be a cell inside of an organism.
- a target cell can be an organism.
- a target cell can be a cell in a cell culture.
- a target cell can be one of a collection of cells.
- a target cell can be a mammalian cell or derived from a mammalian cell.
- a target cell can be a rodent cell or derived from a rodent cell.
- a target cell can be a human cell or derived from a human cell.
- a target cell can be a prokaryotic cell or derived from a prokaryotic cell.
- a target cell can be a bacterial cell or can be derived from a bacterial cell.
- a target cell can be an archaeal cell or derived from an archaeal cell.
- a target cell can be a eukaryotic cell or derived from a eukaryotic cell.
- a target cell can be a pluripotent stem cell.
- a target cell can be a plant cell or derived from a plant cell.
- a target cell can be an animal cell or derived from an animal cell.
- a target cell can be an invertebrate cell or derived from an invertebrate cell.
- a target cell can be a vertebrate cell or derived from a vertebrate cell.
- a target cell can be a microbe cell or derived from a microbe cell.
- a target cell can be a fungi cell or derived from a fungi cell.
- a target cell can be a stem cell or progenitor cell.
- Target cells can include stem cells (e.g., adult stem cells, embryonic stem cells, induced pluripotent stem (iPS) cells) and progenitor cells (e.g., cardiac progenitor cells, neural progenitor cells, etc. ) .
- Target cells can include mammalian stem cells and progenitor cells, including rodent stem cells, rodent progenitor cells, human stem cells, human progenitor cells, etc.
- Clonal cells can comprise the progeny of a cell.
- a target cell can comprise a target nucleic acid.
- a target cell can be in a living organism.
- a target cell can be a genetically modified cell.
- a target cell can be a host cell.
- a target cell can be a totipotent stem cell, however, in some embodiments of this disclosure, the term “cell” may be used but may not refer to a totipotent stem cell.
- a target cell can be a plant cell, but in some embodiments of this disclosure, the term “cell” may be used but may not refer to a plant cell.
- a target cell can be a pluripotent cell.
- a target cell can be a pluripotent hematopoietic cell that can differentiate into other cells in the hematopoietic cell lineage but may not be able to differentiate into any other non-hematopoietic cell.
- a target cell may be able to develop into a whole organism.
- a target cell may or may not be able to develop into a whole organism.
- a target cell may be a whole organism.
- a target cell can be a primary cell.
- cultures of primary cells can be passaged 0 times, 1 time, 2 times, 4 times, 5 times, 10 times, 15 times or more.
- Cells can be unicellular organisms. Cells can be grown in culture.
- a target cell can be a diseased cell.
- a diseased cell can have altered metabolic, gene expression, and/or morphologic features.
- a diseased cell can be a cancer cell, a diabetic cell, and an apoptotic cell.
- a diseased cell can be a cell from a diseased subject. Exemplary diseases can include blood disorders, cancers, metabolic disorders, eye disorders, organ disorders, musculoskeletal disorders, cardiac disease, and the like.
- the target cells may be harvested from an individual by any method.
- leukocytes may be harvested by apheresis, leukocytapheresis, density gradient separation, etc.
- Cells from tissues such as skin, muscle, bone marrow, spleen, liver, pancreas, lung, intestine, stomach, etc. can be harvested by biopsy.
- An appropriate solution may be used for dispersion or suspension of the harvested cells.
- Such solution can generally be a balanced salt solution, (e.g. normal saline, phosphate-buffered saline (PBS) , Hank's balanced salt solution, etc.
- PBS phosphate-buffered saline
- Buffers can include HEPES, phosphate buffers, lactate buffers, etc.
- Cells may be used immediately, or they may be stored (e.g., by freezing) . Frozen cells can be thawed and can be capable of being reused. Cells can be frozen in a DMSO, serum, medium buffer (e.g., 10% DMSO, 50% serum, 40% buffered medium) , and/or some other such common solution used to preserve cells at freezing temperatures.
- Non-limiting examples of cells which can be target cells include, but are not limited to, lymphoid cells, such as B cell, T cell (Cytotoxic T cell, Natural Killer T cell, Regulatory T cell, T helper cell) , Natural killer cell, cytokine induced killer (CIK) cells (see e.g.
- myeloid cells such as granulocytes (Basophil granulocyte, Eosinophil granulocyte, Neutrophil granulocyte/Hypersegmented neutrophil) , Monocyte/Macrophage, Red blood cell (Reticulocyte) , Mast cell, Thrombocyte/Megakaryocyte, Dendritic cell; cells from the endocrine system, including thyroid (Thyroid epithelial cell, Parafollicular cell) , parathyroid (Parathyroid chief cell, Oxyphil cell) , adrenal (Chromaffin cell) , pineal (Pinealocyte) cells; cells of the nervous system, including glial cells (Astrocyte, Microglia) , Magnocellular neurosecretory cell, Stellate cell, Boettcher cell, and pituitary (Gonadotrope, Corticotrope, Thyrotrope, Somatotrope, Lactotroph) ; cells of the Respiratory system, including Pneumocyte (Type I pneumocyte, granulocyte,
- Apocrine sweat gland cell odoriferous secretion, sex-hormone sensitive
- Gland of Moll cell in eyelid specialized sweat gland
- Sebaceous gland cell lipid-rich sebum secretion
- Bowman's gland cell in nose washes olfactory epithelium
- Brunner's gland cell in duodenum enzymes and alkaline mucus
- Seminal vesicle cell secretes seminal fluid components, including fructose for swimming sperm
- Prostate gland cell secretes seminal fluid components
- Bulbourethral gland cell massbourethral gland cell
- Bartholin's gland cell vaginal lubricant secretion
- Gland of Littre cell Gland of Littre cell
- Uterus endometrium cell (carbohydrate secretion)
- Isolated goblet cell of respiratory and digestive tracts micus secretion
- Duct cell (of seminal vesicle, prostate gland, etc. ) , Epithelial cells lining closed internal body cavities, Ciliated cells with propulsive function, Extracellular matrix secretion cells, Contractile cells; Skeletal muscle cells, stem cell, Heart muscle cells, Blood and immune system cells, Erythrocyte (red blood cell) , Megakaryocyte (platelet precursor) , Monocyte, Connective tissue macrophage (various types) , Epidermal Langerhans cell, Osteoclast (in bone) , Dendritic cell (in lymphoid tissues) , Microglial cell (in central nervous system) , Neutrophil granulocyte, Eosinophil granulocyte, Basophil granulocyte, Mast cell, Helper T cell, Suppressor T cell, Cytotoxic T cell, Natural Killer T cell, B cell, Natural killer cell, Reticulocyte, Stem cells and committed progenitors for the blood and immune system (various types) ,
- the target cell is a cancer cell.
- cancer cells include cells of cancers including Acanthoma, Acinic cell carcinoma, Acoustic neuroma, Acral lentiginous melanoma, Acrospiroma, Acute eosinophilic leukemia, Acute lymphoblastic leukemia, Acute megakaryoblastic leukemia, Acute monocytic leukemia, Acute myeloblastic leukemia with maturation, Acute myeloid dendritic cell leukemia, Acute myeloid leukemia, Acute promyelocytic leukemia, Adamantinoma, Adenocarcinoma, Adenoid cystic carcinoma, Adenoma, Adenomatoid odontogenic tumor, Adrenocortical carcinoma, Adult T-cell leukemia, Aggressive NK-cell leukemia, AIDS-Related Cancers, AIDS-related lymphoma, Alveolar soft part sarcoma
- the targeted cancer cell represents a subpopulation within a cancer cell population, such as a cancer stem cell.
- the cancer is of a hematopoietic lineage, such as a lymphoma.
- the antigen can be a tumor associated antigen.
- an autoimmune disease can include acute disseminated encephalomyelitis (ADEM) , acute necrotizing hemorrhagic leukoencephalitis, Addison's disease, agammaglobulinemia, allergic asthma, allergic rhinitis, alopecia areata, amyloidosis, ankylosing spondylitis, antibody-mediated transplantation rejection, anti-GBM/Anti-TBM nephritis, antiphospholipid syndrome (APS) , autoimmune angioedema, autoimmune aplastic anemia, autoimmune dysautonomia, autoimmune hepatitis, autoimmune hyperlipidemia, autoimmune immunodeficiency, autoimmune inner ear disease (AIED) , autoimmune myocarditis, autoimmune pancreatitis, autoimmune retinopathy, autoimmune thrombocytopenic purpura (ATP) , autoimmune thyroid disease, autoimmune ur
- ADAM acute disseminated encephalomyelitis
- the autoimmune disease comprises one or more members selected from the group comprising rheumatoid arthritis, type 1 diabetes, systemic lupus erythematosus (lupus or SLE) , myasthenia gravis, multiple sclerosis, scleroderma, Addison's Disease, bullous pemphigoid, pemphigus vulgaris, Guillain-Barré syndrome, Sjogren syndrome, dermatomyositis, thrombotic thrombocytopenic purpura, hypergammaglobulinemia, monoclonal gammopathy of undetermined significance (MGUS) , Waldenstrom's macroglobulinemia (WM) , chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) , Hashimoto's Encephalopathy (HE) , Hashimoto's Thyroiditis, Graves' Disease, Wegener's Granulomatosis, and antibody-mediated transplantation rejection (e.g., for tissue transplant
- the target cells form a tumor (i.e., a solid tumor) .
- a tumor treated with the methods herein can result in stabilized tumor growth (e.g., one or more tumors do not increase more than 1%, 5%, 10%, 15%, or 20% in size, and/or do not metastasize) .
- a tumor is stabilized for at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or more weeks.
- a tumor is stabilized for at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or more months.
- a tumor is stabilized for at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more years.
- the size of a tumor or the number of tumor cells is reduced by at least about 5%, 10%, 15%, 20%, 25, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or more.
- the tumor is completely eliminated, or reduced below a level of detection.
- a subject remains tumor free (e.g. in remission) for at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or more weeks following treatment.
- a subject remains tumor free for at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or more months following treatment.
- a subject remains tumor free for at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more years after treatment.
- the present disclosure provides a method of treating cancer in a mammal, comprising administering to the mammal a therapeutically effective amount of a polypeptide and/or antigen binding moiety provided by the disclosure.
- an administration may treat a subject by reduction or inhibition of further growth or spread of cancer cells, death of cancer cells, inhibition of reoccurrence of cancer, reduction of pain associated with the cancer, or improved survival of the animal.
- Inhibition of reoccurrence of cancer contemplates cancer sites and surrounding tissue which have previously been treated by radiation, chemotherapy, surgery, or other techniques. The effect can be either subjective or objective. For example, if the animal is human, the human may note improved vigor or vitality or decreased pain as subjective symptoms of improvement or response to therapy.
- the clinician may notice a decrease in tumor size or tumor burden based on physical exam, laboratory parameters, tumor markers or radiographic findings.
- Some laboratory signs that the clinician may observe for response to treatment include normalization of tests, such as white blood cell count, red blood cell count, platelet count, erythrocyte sedimentation rate, and various enzyme levels. Additionally, the clinician may observe a decrease in a detectable tumor marker. Alternatively, other tests can be used to evaluate objective improvement, such as sonograms, nuclear magnetic resonance testing and positron emissions testing.
- the polypeptide comprises an OX40 antibody or a binding moiety fragment thereof provided by the disclosure.
- the polypeptide and/or antigen binding moiety is one provided in Table 1 or Table 2.
- the mammal is a human.
- compositions comprising at least: (a) anti-OX40 antibody as disclosed herein; and (b) a pharmaceutically acceptable excipient.
- the subject polypeptides or antigen-binding moieties may be administered alone as monotherapy, or administered in combination with one or more additional therapeutic agents or therapies.
- the present disclosure provides a combination therapy, which comprises a binding moiety or polypeptide provided by the disclosure in combination with one or more additional therapies or therapeutic agents.
- combination therapies and/or therapeutic regimens that comprise administering pharmaceutical compositions that comprise an anti-OX40 antibody and a PI3K inhibitor.
- the anti-OX40 antibody targets human OX40 and the PI3K inhibitor is Tenalisib.
- compositions that comprise any of the aforementioned polypeptides that comprise antigen binding moieties and/or anti-PI3K inhibitors.
- the pharmaceutical composition may optionally contain one or more additional pharmaceutically active ingredients, such as another antibody or a drug.
- additional pharmaceutically active ingredients such as another antibody or a drug.
- the pharmaceutical compositions of the invention also can be administered in a combination therapy with, for example, another immune-stimulatory agent, anti-cancer agent, an antiviral agent, or a vaccine, such that the anti-OX40 antibody enhances the immune response against the vaccine.
- a pharmaceutically acceptable carrier can include, for example, a pharmaceutically acceptable liquid, gel or solid carriers, an aqueous medium, a non-aqueous medium, an anti-microbial agent, isotonic agents, buffers, antioxidants, anesthetics, suspending/dispersing agent, a chelating agent, a diluent, adjuvant, excipient or a nontoxic auxiliary substance, other known in the art various combinations of components or more
- polypeptides as disclosed herein may be provided in a pharmaceutical composition together with one or more pharmaceutically acceptable carriers or excipients.
- pharmaceutically acceptable carrier includes, but is not limited to, any carrier that does not interfere with the effectiveness of the biological activity of the ingredients and that is not toxic to the patient to whom it is administered.
- suitable pharmaceutical carriers include phosphate buffered saline solutions, water, emulsions, such as oil/water emulsions, various types of wetting agents, sterile solutions etc.
- Such carriers can be formulated by conventional methods and can be administered to the subject at a suitable dose.
- the compositions are sterile.
- These compositions may also contain adjuvants such as preservative, emulsifying agents and dispersing agents. Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents.
- the pharmaceutical composition may be in any suitable form, (depending upon the desired method of administration) . It may be provided in unit dosage form, may be provided in a sealed container and may be provided as part of a kit. Such a kit may include instructions for use. It may include a plurality of said unit dosage forms.
- composition of the invention may be administered in vivo, to a subject in need thereof, by various routes, including, but not limited to, oral, intravenous, intra-arterial, subcutaneous, parenteral, intranasal, intramuscular, intracranial, intracardiac, intraventricular, intratracheal, buccal, rectal, intraperitoneal, intradermal, topical, transdermal, and intrathecal, or otherwise by implantation or inhalation.
- compositions may be formulated into preparations in solid, semi-solid, liquid, or gaseous forms; including, but not limited to, tablets, capsules, powders, granules, ointments, solutions, suppositories, enemas, injections, inhalants, and aerosols.
- the appropriate formulation and route of administration may be selected according to the intended application and therapeutic regimen
- Dosages of the substances of the present disclosure can vary between wide limits, depending upon the disease or disorder to be treated, the age and condition of the individual to be treated, etc. and a physician will ultimately determine appropriate dosages to be used.
- Frequency of administration may be determined and adjusted over the course of therapy, and is based on reducing the number of target cells such as proliferative or tumorigenic cells, maintaining the reduction of such neoplastic cells, reducing the proliferation of neoplastic cells, or delaying the development of metastasis.
- the dosage administered may be adjusted or attenuated to manage potential side effects and/or toxicity.
- sustained continuous release formulations of a subject therapeutic composition may be appropriate.
- appropriate dosages can vary from patient to patient. Determining the optimal dosage will generally involve the balancing of the level of therapeutic benefit against any risk or deleterious side effects.
- the selected dosage level will depend on a variety of factors including, but not limited to, the activity of the particular compound, the route of administration, the time of administration, the rate of excretion of the compound, the duration of the treatment, other drugs, compounds, and/or materials used in combination, the severity of the condition, and the species, sex, age, weight, condition, general health, and prior medical history of the patient.
- the amount of compound and route of administration will ultimately be at the discretion of the physician, veterinarian, or clinician, although generally the dosage will be selected to achieve local concentrations at the site of action that achieve the desired effect without causing substantial harmful or deleterious side-effects.
- the polypeptide that comprises a subject antigen binding moiety may be administered in various ranges. These include about 5 ⁇ g/kg body weight to about 100 mg/kg body weight per dose; about 50 ⁇ g/kg body weight to about 5 mg/kg body weight per dose; about 100 ⁇ g/kg body weight to about 10 mg/kg body weight per dose. Other ranges include about 100 ⁇ g/kg body weight to about 20 mg/kg body weight per dose and about 0.5 mg/kg body weight to about 20 mg/kg body weight per dose.
- the dosage is at least about 100 ⁇ g/kg body weight, at least about 250 ⁇ g/kg body weight, at least about 750 ⁇ g/kg body weight, at least about 3 mg/kg body weight, at least about 5 mg/kg body weight, at least about 10 mg/kg body weight.
- polypeptides further comprise a detectable label, a therapeutic agent, or a pharmacokinetic modifying moiety.
- the detectable label comprises a fluorescent label, a radiolabel, an enzyme, a nucleic acid probe, or a contrast agent.
- Compatible formulations for parenteral administration will comprise the polypeptide that comprises a subject antigen binding moiety as disclosed herein in concentrations of from about 10 ⁇ g/ml to about 100 mg/ml.
- the concentrations of the polypeptide or antigen binding moiety will comprise 20 ⁇ g/ml, 40 ⁇ g/ml, 60 ⁇ g/ml, 80 ⁇ g/ml, 100 ⁇ g/ml, 200 ⁇ g/ml, 300, ⁇ g/ml, 400 ⁇ g/ml, 500 ⁇ g/ml, 600 ⁇ g/ml, 700 ⁇ g/ml, 800 ⁇ g/ml, 900 ⁇ g/ml or 1 mg/ml.
- ADC concentrations will comprise 2 mg/ml, 3 mg/ml, 4 mg/ml, 5 mg/ml, 6 mg/ml, 8 mg/ml, 10 mg/ml, 12 mg/ml, 14 mg/ml, 16 mg/ml, 18 mg/ml, 20 mg/ml, 25 mg/ml, 30 mg/ml, 35 mg/ml, 40 mg/ml, 45 mg/ml, 50 mg/ml, 60 mg/ml, 70 mg/ml, 80 mg/ml, 90 mg/ml or 100 mg/ml.
- the concentration of the inhibitor is 1mg, 4mg, 7mg, 10mg, 13mg, 16mg, 19mg, 22mg, 25mg, 28mg, 31mg, 34mg, 37mg, 40mg, 43mg, 46mg, 49mg, 52mg, 55mg, 58mg, 61mg, 64mg, 67mg, 70mg, 73mg, 76mg, 79mg, 82mg, 85mg, 88mg, 91mg, 94mg, 97mg, or 100mg.
- the inhibit is Tenalisib and it is administered at a dose of 4 mg. In an embodiment, the Tenalisib is administered as two tablets of 2 mg.
- a subject polypeptide and the inhibitor against PI3K are prepared in a same unit dose. In an aspect, the polypeptide and the inhibitor against PI3K are prepared in different unit doses. In an aspect, the polypeptide and the inhibitor are administered concurrently, sequentially, or both concurrently and sequentially.
- a subject can be further administered a co-therapeutic agent.
- Non-limiting examples of a co-therapeutic agent can include cytotoxic agents, chemotherapeutic agents, growth inhibitory agents, agents used in radiation therapy, anti-angiogenesis agents, apoptotic agents, anti-tubulin agents, and other agents to treat cancer, for example, anti-CD20 antibodies, anti-PD1 antibodies (e.g., Pembrolizumab) platelet derived growth factor inhibitors (e.g., GLEEVEC TM (imatinib mesylate) ) , a COX-2 inhibitor (e.g., celecoxib) , interferons, cytokines, antagonists (e.g., neutralizing antibodies) that bind to one or more of the following targets PDGFR- ⁇ , BlyS, APRIL, BCMA receptor (s) , TRAIL/Apo2, other bioactive and organic chemical agents, and the like.
- anti-CD20 antibodies e.g., Pembrolizumab
- platelet derived growth factor inhibitors e.g
- Non-limiting examples of a co-therapeutic agent can include alkylating agents such as thiotepa and cyclosphosphamide; alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelamines including altretamine, triethylenemelamine, trietylenephosphoramide, triethiylenethiophosphoramide and trimethylolomelamine; acetogenins (especially bullatacin and bullatacinone) ; delta-9-tetrahydrocannabinol (dronabinol, ) ; beta-lapachone; lapachol; colchicines; betulinic acid; a camptothecin (including the synthetic analogue topotecan CPT-11 (irinotecan,
- ABRAXANE Cremophor-free, albumin-engineered nanoparticle formulation of paclitaxel (American Pharmaceutical Partners, Schaumberg, Ill. ) , and docetaxel ( Rorer, Antony, France) ; chloranbucil; gemcitabine 6-thioguanine; mercaptopurine; methotrexate; platinum analogs such as cisplatin and carboplatin; vinblastine platinum; etoposide (VP-16) ; ifosfamide; mitoxantrone; vincristine oxaliplatin; leucovovin; vinorelbine novantrone; edatrexate; daunomycin; aminopterin; ibandronate; topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO) ; retinoids such as retinoic acid; capecitabine pharmaceutically acceptable salts, acids or derivatives of any of the above; as well as combinations of
- a co-therapeutic agent can be an anti-hormonal agent or endocrine therapeutic that act to regulate, reduce, block, or inhibit the effects of hormones that can promote the growth of cancer, and are often in the form of systemic, or whole-body treatment. They may be hormones themselves.
- Examples include anti-estrogens and selective estrogen receptor modulators (SERMs) , including, for example, tamoxifen (including tamoxifen) , raloxifene, droloxifene, 4-hydroxytamoxifen, trioxifene, keoxifene, LY117018, onapristone, and toremifene; anti-progesterones; estrogen receptor down-regulators (ERDs) ; agents that function to suppress or shut down the ovaries, for example, leutinizing hormone-releasing hormone (LHRH) agonists such as and ELIGARD) leuprolide acetate, goserelin acetate, buserelin acetate and tripterelin; other anti-androgens such as flutamide, nilutamide and bicalutamide; and aromatase inhibitors that inhibit the enzyme aromatase, which regulates estrogen production in the adrenal glands, such as, for example,
- chemotherapeutic agents includes bisphosphonates such as clodronate (for example, or ) , etidronate, NE-58095, zoledronic acid/zoledronate, alendronate, pamidronate, tiludronate, or risedronate; as well as troxacitabine (a 1, 3-dioxolane nucleoside cytosine analog) ; antisense oligonucleotides, particularly those that inhibit expression of genes in signaling pathways implicated in abherant cell proliferation, such as, for example, PKC-alpha, Raf, H-Ras, and epidermal growth factor receptor (EGFR) ; vaccines such as vaccine and gene therapy vaccines, for example, vaccine, vaccine, and vaccine; topoisomerase 1 inhibitor; rmRH; lapatinib ditosylate (an ErbB-2 and EGFR dual tyrosine kinase small-molecule inhibitor also known as GW572016)
- a co-therapeutic agent can also include antibodies such as alemtuzumab (Campath) , bevacizumab ( Genentech) ; cetuximab ( Imclone) ; panitumumab ( Amgen) , rituximab ( Genentech/Biogen Idec) , pertuzumab ( 2C4, Genentech) , trastuzumab ( Genentech) , tositumomab (Bexxar, Corixia) , and the antibody drug conjugate, gemtuzumab ozogamicin ( Wyeth) .
- antibodies such as alemtuzumab (Campath) , bevacizumab ( Genentech) ; cetuximab ( Imclone) ; panitumumab ( Amgen) , rituximab ( Genentech/Biogen Idec) , pertuzumab ( 2C4, Genentech) , trastu
- Additional humanized monoclonal antibodies with therapeutic potential as agents in combination with the compounds of the invention include: apolizumab, aselizumab, atlizumab, bapineuzumab, bivatuzumab mertansine, cantuzumab mertansine, cedelizumab, certolizumab pegol, cidfusituzumab, cidtuzumab, daclizumab, eculizumab, efalizumab, epratuzumab, erlizumab, feMzumab, fontolizumab, gemtuzumab ozogamicin, inotuzumab ozogamicin, ipilimumab, labetuzumab, lintuzumab, matuzumab, mepolizumab, motavizumab, motovizumab, natalizumab, nimotuzumab, nolov
- a co-therapeutic agent can be a tyrosine kinase inhibitor such as an EGFR-targeting agent (e.g., small molecule, antibody, etc. ) ; small molecule HER2 tyrosine kinase inhibitor such as TAK165 available from Takeda; CP-724, 714, an oral selective inhibitor of the ErbB2 receptor tyrosine kinase (Pfizer and OSI) ; dual-HER inhibitors such as EKB-569 (available from Wyeth) which preferentially binds EGFR but inhibits both HER2 and EGFR-overexpressing cells; lapatinib (GSK572016; available from Glaxo-SmithKline) , an oral HER2 and EGFR tyrosine kinase inhibitor; PKI-166 (available from Novartis) ; pan-HER inhibitors such as canertinib (CI-1033; Pharmacia) ; Raf-1 inhibitors such as antisense
- a co-therapeutic agent can also include a growth inhibitory agent such as a compound or composition which inhibits growth and/or proliferation of a cell (e.g., a cell whose growth is dependent on PD-L1 expression) either in vitro or in vivo.
- the growth inhibitory agent may be one which significantly reduces the percentage of cells in S phase.
- growth inhibitory agents include agents that block cell cycle progression (at a place other than S phase) , such as agents that induce G1 arrest and M-phase arrest.
- Classical M-phase blockers include the vincas (vincristine and vinblastine) , taxanes, and topoisomerase II inhibitors such as the anthracycline antibiotic doxorubicin ( (8S-cis) -10- [ (3-amino-2, 3, 6-trideoxy- ⁇ -L-lyxo hexapyranosyl) oxy] -7, 8, 9, 10-tetrahydro-6, 8, 11-trihydroxy-8- (hydroxyacetyl) -1-methoxy-5, 12-naphthacenedione) , epirubicin, daunorubicin, etoposide, and bleomycin.
- doxorubicin (8S-cis) -10- [ (3-amino-2, 3, 6-trideoxy- ⁇ -L-lyxo hexapyranosyl) oxy] -7, 8, 9, 10-tetrahydro-6, 8, 11-trihydroxy-8- (hydroxyacetyl) -1-methoxy-5
- Those agents that arrest G1 also spill over into S-phase arrest, for example, DNA alkylating agents such as tamoxifen, prednisone, dacarbazine, mechlorethamine, cisplatin, methotrexate, 5-fluorouracil, and ara-C.
- DNA alkylating agents such as tamoxifen, prednisone, dacarbazine, mechlorethamine, cisplatin, methotrexate, 5-fluorouracil, and ara-C.
- the taxanes are anticancer drugs both derived from the yew tree.
- Docetaxel Rhone-Poulenc Rorer
- Rhone-Poulenc Rorer derived from the European yew, is a semisynthetic analogue of paclitaxel ( Bristol-Myers Squibb) .
- a co-therapeutic agent can also include dexamethasone, interferons, colchicine, metoprine, cyclosporine, amphotericin, metronidazole, alemtuzumab, alitretinoin, allopurinol, amifostine, arsenic trioxide, asparaginase, BCG live, bevacuzimab, bexarotene, cladribine, clofarabine, darbepoetin alfa, denileukin, dexrazoxane, epoetin alfa, elotinib, filgrastim, histrelin acetate, ibritumomab, interferon alfa-2a, interferon al
- a co-therapeutic agent can also include hydrocortisone, hydrocortisone acetate, cortisone acetate, tixocortol pivalate, triamcinolone acetonide, triamcinolone alcohol, mometasone, amcinonide, budesonide, desonide, fluocinonide, fluocinolone acetonide, betamethasone, betamethasone sodium phosphate, dexamethasone, dexamethasone sodium phosphate, fluocortolone, hydrocortisone-17-butyrate, hydrocortisone-17-valerate, aclometasone dipropionate, betamethasone valerate, betamethasone dipropionate, prednicarbate, clobetasone-17- butyrate, clobetasol-17-propionate, fluocortolone caproate, fluocortolone pivalate and fluprednidene acetate: immune
- the combination therapy for treating cancer also encompasses the combination of a polypeptide provided by the disclosure with surgery to remove a tumor.
- the polypeptide and/or combination therapy comprising the polypeptide may be administered to the mammal before, during, or after the surgery.
- the combination therapy for treating cancer also encompasses combination of a binding molecule provided by the disclosure with radiation therapy, such as ionizing (electromagnetic) radiotherapy (e.g., X-rays or gamma rays) and particle beam radiation therapy (e.g., high linear energy radiation) .
- radiation therapy such as ionizing (electromagnetic) radiotherapy (e.g., X-rays or gamma rays) and particle beam radiation therapy (e.g., high linear energy radiation) .
- the source of radiation can be external or internal to the mammal.
- the binding molecule may be administered to the mammal before, during, or after the radiation therapy.
- an article of manufacture containing materials useful for the treatment, prevention and/or diagnosis of the disorders described above comprises a container and a label or package insert on or associated with the container.
- Suitable containers include, for example, bottles, vials, syringes, IV solution bags, etc.
- the containers may be formed from a variety of materials such as glass or plastic.
- the container holds a composition which is by itself or combined with another composition effective for treating, preventing and/or diagnosing the condition and may have a sterile access port (for example the container may be an intravenous solution bag or a vial having a stopper that is pierceable by a hypodermic injection needle) .
- At least one active agent in the composition is anti-OX40 antibody as defined herein before.
- the label or package insert indicates that the composition is used for treating the condition of choice.
- the article of manufacture may comprise (a) a first container with a composition contained therein, wherein the composition comprises the antibody of the disclosure; and (b) a second container with a composition contained therein, wherein the composition comprises a PI3K inhibitor.
- the article of manufacture in this embodiment of the invention may further comprise a package insert indicating that the compositions can be used to treat a particular condition.
- the article of manufacture may further comprise a second (or third) container comprising a pharmaceutically-acceptable buffer, such as bacteriostatic water for injection (BWFI) , phosphate-buffered saline, Ringer's solution and dextrose solution. It may further include other materials desirable from a commercial and user standpoint, including other buffers, diluents, filters, needles, and syringes.
- a pharmaceutically-acceptable buffer such as bacteriostatic water for injection (BWFI) , phosphate-buffered saline, Ringer's solution and dextrose solution.
- Example 1 CN401 in combination with OX86 ( ⁇ -mOX40 mAb) and ⁇ -mPD1 mAb in MC38 syngeneic model
- CN401 Tenalisib
- CN1 anti-huOX40, clone 1.134.9-u1-IgG1L
- OX86 anti-mouse OX40, from BioXcell
- RMP1-14 anti-PD-1 antibody
- C57bl/6 mice (20–25 g) were purchased from Shanghai Super -B&K laboratory animal Corp. Ltd. and inoculated with MC38 cells (0.5million cells per mouse) by subcutaneous inoculation into the right flank of mouse. The treatments started when the tumors were palpable (approximately 70 mm 3 ) .
- Anti-OX40 mAb was administered by i.p. twice a week at 100 ⁇ g/mouse for 3 weeks.
- CN401 was oral gavage twice per day at 15 mg/kg or 50mg/kg or 150mg/kg for 3 weeks.
- Anti-PD-1 mAb was administered by i.p. twice a week at 60 ⁇ g/mouse for 3 weeks.
- the control group received a vehicle (0.5%MC and PBS) without the active product.
- the tumor size and body weight were measured thrice a week.
- the animal experiments were performed according to AAALAC and were approved by the IACUC for Animal Experimentation of the Super -B&K laboratory animal Center.
- FIG. 1A-FIG. 1B and FIG. 2A-FIG. 2G Antitumor activity of CN401 in combination with ⁇ -mOX40 mAb and anti-mPD1 mAb in MC38 syngeneic model is provided in FIG. 1A-FIG. 1B and FIG. 2A-FIG. 2G.
- Table 5 Antitumor activity of CN401 in combination with ⁇ -mOX40 mAb and anti-mPD1 mAb in MC38 syngeneic model: The TGI and p value on day 20 as compared with vehicle group.
- Example 2 Tenalisib (CN401) in combination with OX86 ( ⁇ -mOX40mAb) and ⁇ -mPD1 mAb in A20 syngeneic model
- Balb/c mice Six- to eight-weeks-old Balb/c mice (20–25 g) were purchased from Shanghai Super -B&K laboratory animal Corp. Ltd. and inoculated with A20 cells (0.5 million cells per mouse) by subcutaneous inoculation into the right flank of mouse. The treatments started when the tumors were palpable (approximately 70 mm 3 ) .
- Anti-OX40 mAb was administered by i.p. twice a week at 100 ⁇ g/mouse for 3 weeks.
- CN401 was oral gavage twice per day at 150 mg/kg or 300mg/kg for 3 weeks.
- the control group was received a vehicle (0.5% MC and PBS) without the active product.
- Anti-PD-1 mAb was administered by i.p.
- Table 7 Antitumor activity of CN401 in combination with ⁇ -OX40 mAb and anti-PD1 mAb in A20 syngeneic model: the TGI and p value on day 17 as compared with vehicle group. Data for vehicle group is not shown.
- mice administered CN401 in combination with ⁇ -OX40 mAb and anti-PD1 mAb in A20 syngeneic model is provided in FIG 4A-FIG 4H.
- mice in groups 4-7 achieved complete responses (tumor-free) .
- Example 3 CN401 in combination with CN1 (anti-huOX40) in A20 humanized transgenic mice
- mice Six- to eight-weeks-old Balb/c-hPD1/hOX40 transgenic mice (20–25 g) were purchased from GemPharmatech and inoculated with A20 (0.5 million cells per mouse) by subcutaneous inoculation into the right flank of mouse. The treatments started when the tumors were palpable (approximately 70 mm 3 ) .
- CN1 was administered by i.p. twice a week at 1mg/kg for 3 weeks.
- CN401 was oral gavage twice per day at 150 mg/kg for 3 weeks.
- the control groups received a vehicle (0.5% MC and PBS) without the active product.
- the tumor size and body weight were measured thrice a week.
- the animal experiments were performed according to AAALAC and were approved by the IACUC for Animal Experimentation of the Super -B&K laboratory animal Center.
- Group Animal Regimen 1 8 vehicle (PBS i.p. biw * 3 + 0.5%MC p.o. bid *3weeks) 2 8 CN1 1mg/kg, i.p., biw*3weeks 3 8 CN401 150mg/kg, po, bid *3weeks 4 8 CN1 1mg/kg, i.p., biw*3w+ CN401 150mg/kg, po, bid *3w
- Table 9 Antitumor activity of CN401 in combination with CN1 Ab in A20 humanized transgenic mice: the TGI and p value on day 19 as compared with vehicle group.
- Example 4 CN401 in combination with CN1 in A20 humanized Ox40 transgenic mouse syngeneic model
- mice Six- to eight-weeks-old Balb/c-hPD1/hOX40 transgenic mice (20–25 g) were purchased from GemPharmatech and inoculated with A20 (0.5 million cells per mouse) by subcutaneous inoculation into the right flank of mouse. The treatments started when the tumors were palpable (approximately 70 mm 3 ) .
- CN1 was administered by i.p. twice a week at 1mg/kg for 3 weeks.
- CN401 was oral gavage twice per day at 150 mg/kg for 3 weeks.
- the control groups received a vehicle (0.5% MC and PBS) without the active product.
- the tumor size and body weight were measured thrice a week.
- the animal experiments were performed according to AAALAC and were approved by the IACUC for Animal Experimentation of the Super -B&K laboratory animal Center.
- FIG. 6A-FIG. 6D Antitumor activity of CN401 in combination with CN1 in A20 humanized Ox40 transgenic mouse syngeneic model is shown in FIG. 6A-FIG. 6D. Of note is that treated mice in Groups 14-16 achieved complete responses (tumor free) .
- Example 5 Antitumor activity of Tenalisb (CN401) or Duvelishib in various tumor cell lines in vitro
- MC38 cell line was obtained from Wuxi Biology company, other 10 cell lines were obtained from the American Type Culture Collection (ATCC) . All the cell lines were maintained in the specific medium according to ATCC culture method supplemented with 10% heat-inactivated fetal bovine serum (FBS) and 100 units/ml penicillin and 100ug/ml streptomycin. All the cell cultures were maintained at 37°C in a humidified atmosphere of 5% CO2.
- FBS heat-inactivated fetal bovine serum
- All eleven tumor cell lines were seeded in 96 well white opaque plate (Corning, costar#3917) at density of 5000 cell in 100 ⁇ l media per well. On the next day all cell lines were treated with varying concentrations of Tenalisib or Duvelisib (ranging between 0.002 ⁇ M and 10 ⁇ M ) . At 72-hour post treatment, 100 ⁇ l of CTG assay reagents were added to the well and the Relative luminescence Units (RLU) were read by Envision 2105 (PerkinElmar) multimode plate reader. IC50 reported as proliferation inhibition were analyzed by Graphpad Prism8.0 software normalized with RLU (Relative Luminescence Unit) of DMSO treated wells.
- RLU Relative luminescence Unit
- Tenalisib was active in 2 out of 11 cell lines showing max inhibition of proliferation greater than 50%.
- the IC50s of Tenalisib in MV-4-11 cell line was 1.652 ⁇ M and was 5.49 ⁇ M in A20 cell line.
- Tenalisib sand Duvelishib selectively inhibited cell proliferation in MV-4-11 and A20. Eleven tumor cell lines were treated with Tenalisib (A) or Duvelisib (B) for 72 hr. The range of compound concentration was from 0.002 ⁇ M 10 ⁇ M to with 3 fold serial dilution. The cell viability was evaluated with Luminescent Cell Viability Assay Kit (Promega, #G7572) , see FIG. 7A- FIG. 7D.
- Example 6 Tenalisib (CN401) & Duvelisib in combination with OX86 ( ⁇ -mOX40 mAb) and ⁇ -mPD1 mAb in MC38 syngeneic model
- C57bl/6 mice (20–25 g) were purchased from Shanghai Super -B&K laboratory animal Corp. Ltd. and inoculated with MC38 cells (0.5million cells per mouse) by subcutaneous inoculation into the right flank of mouse. The treatments started when the tumors were palpable (approximately 70 mm 3 ) .
- Anti-OX40 mAb was administered by i.p. twice a week at 100 ⁇ g/mouse for 3 weeks.
- CN401 was oral gavage twice per day at 15 mg/kg or 50mg/kg or 150mg/kg for 3 weeks.
- Anti-PD-1 mAb was administered by i.p. twice a week at 60 ⁇ g/mouse for 3 weeks.
- Duvelisib was oral gavage twice per day at 50mg/kg for 3 weeks.
- the control group received a vehicle (0.5%MC and PBS) without the active product.
- the tumor size and body weight were measured thrice a week.
- the animal experiments were performed according to AAALAC and were approved by the IACUC for Animal Experimentation of the Super -B&K laboratory animal Center.
- Table 11 Antitumor activity of Tenalisib (CN401) & duvelisib in combination with ⁇ -OX40 mAb and anti-PD1 mAb in MC38 syngeneic model: TGI and p value on day 20 as compared with vehicle group.
- FIG. 9A – FIG. 9H show the individual tumor growth curve of tumors from groups in Table 11.
- Example 7 Tenalisib (CN401) and duvelisib in combination with OX86 ( ⁇ -mOX40mAb) and ⁇ -mPD1 mAb in A20 syngeneic model
- Balb/c mice Six- to eight-weeks-old Balb/c mice (20–25 g) were purchased from Shanghai Super -B&K laboratory animal Corp. Ltd. and inoculated with A20 cells (0.5 million cells per mouse) by subcutaneous inoculation into the right flank of mouse. The treatments started when the tumors were palpable (approximately 70 mm 3 ) .
- Anti-OX40 mAb was administered by i.p. twice a week at 100 ⁇ g/mouse for 3 weeks.
- CN401 was oral gavage twice per day at 150 mg/kg or 300mg/kg for 3 weeks.
- Anti-PD-1 mAb was administered by i.p. twice a week at 60 ⁇ g/mouse for 3 weeks.
- Duvelisib was oral gavage twice per day at 50 mg/kg for 3 weeks.
- the control group was received a vehicle (0.5% MC and PBS) without the active product.
- the tumor size and body weight were measured thrice a week.
- the animal experiments were performed according to AAALAC and were approved by the IACUC for Animal Experimentation of the Super -B&K laboratory animal Center.
- Table 13 shows antitumor activity of Tenalisib (CN401) and duvelisib in combination with ⁇ -OX40 mAb and anti-PD1 mAb in A20 syngeneic model: TGI and p value on day 17 as compared with vehicle group. There was synergistic effect between CN401/duvelisib and ⁇ -OX40 mAb in A20 syngeneic model.
- FIG. 10A and FIG. 10B show average tumor volume and average body weight of mice treated with Tenalisib (CN401) and duvelisib in combination with ⁇ -OX40 mAb and anti-PD1 mAb.
- FIG. 11A – FIG. 11J show individual tumor growth curves of mice from groups in Table 13 as compared to vehicle control.
- Example 8 Tenalisib (CN401) in combination with CN1 and in A20 humanized transgenic mice
- mice Six- to eight-weeks-old Balb/c-hPD1/hOX40 transgenic mice (20–25 g) were purchased from GemPharmatech and inoculated with A20 (0.5 million cells per mouse) by subcutaneous inoculation into the right flank of mouse. The treatments started when the tumors were palpable (approximately 70 mm 3 ) .
- CN1 was administered by i.p. twice a week at 1mg/kg for 3 weeks.
- CN401 was oral gavage twice per day at 150 mg/kg for 3 weeks.
- the control groups received a vehicle (0.5% MC and PBS) without the active product.
- the tumor size and body weight was measured thrice a week.
- the animal experiments were performed according to AAALAC and were approved by the IACUC for Animal Experimentation of the Super -B&K laboratory animal Center.
- Group Animal Regimen 1 8 Vehicle (pbs control i.p. biw * 3w + 0.5% MC p.o. bid *3w) 2 8 CN1 1mg/kg, i.p., biw*3w 3 8 CN401 150mg/kg, po, bid *3w 4 8 CN1 1mg/kg i.p. biw*3w+CN401 150mg/kg, p.o. bid*3w
- Table 15 shows antitumor activity of Tenalisib (CN401) in combination with CN1 and in A20 humanized transgenic mice: The TGI and p value on day 19 as compared with vehicle group.
- Results show that CN-1/ ⁇ -huOX40 antibody and PI3K inhibitors combination showed synergistic anti-tumor activity in A20 tumor model and that CN-1/ ⁇ -huOX40 antibody and PI3K inhibitors combination could induce tumor regression in A20 syngeneic model.
- Example 9 Duvelisib in combination with OX86 ( ⁇ -mOX40 mAb) in MC38 syngeneic model
- C57bl/6 mice (20–25 g) were purchased from Shanghai Super -B&K laboratory animal Corp. Ltd. and inoculated with MC38 cells (0.5million cells per mouse) by subcutaneous inoculation into the right flank of mouse. The treatments started when the tumors were palpable (approximately 70 mm 3 ) .
- Anti-OX40 mAb was administered by i.p. twice a week at 100 ⁇ g/mouse for 3 weeks.
- Duvelisib was oral gavage twice per day at 50mg/kg for 3 weeks.
- the control group received a vehicle (0.5%MC and PBS) without the active product.
- the tumor size and body weight were measured thrice a week.
- the animal experiments were performed according to AAALAC and were approved by the IACUC for Animal Experimentation of the Super -B&K laboratory animal Center.
- Group Animal Regimen 1 8 Vehicle (PBS i.p. biw * 3 + PO bid *3 weeks 2 8 duvelisib, 50mg/kg, p.o. bid*3 weeks 3 8 ⁇ -OX40 mAb 100ug/mouse, i.p. biw*3 weeks
- FIG. 14A and FIG. 14B show antitumor activity of duvelisib in combination with ⁇ -OX40 mAb in MC38 syngeneic model.
- the TGI and p value on day 20 as compared with vehicle group is provided in Table 16.
- Table 17 Antitumor activity of duvelisib in combination with ⁇ -OX40 mAb in MC38 syngeneic model. The TGI and p value on day 20 as compared with vehicle group is shown.
- FIG. 15A-FIG. 15D show antitumor activity of duvelisib in combination with ⁇ -OX40 mAb in the MC38 syngeneic model of groups treated as described in Table 17 as compared to control.
- Example 10 Duvelisib in combination with OX86 ( ⁇ -OX40mAb) in A20 syngeneic model
- Balb/c mice (20–25 g) were purchased from Shanghai Super -B&K laboratory animal Corp. Ltd. and inoculated with A20 cells (0.5 million cells per mouse) by subcutaneous inoculation into the right flank of mouse. The treatments started when the tumors were palpable (approximately 70 mm 3 ) .
- Anti-OX40 mAb was administered by i.p. twice a week at 100 ⁇ g/mouse for 3 weeks.
- Duvelisib was oral gavage twice per day at 50 mg/kg for 3 weeks.
- the control group was received a vehicle (0.5% MC and PBS) without the active product.
- the tumor size and body weight were measured thrice a week.
- the animal experiments were performed according to AAALAC and were approved by the IACUC for Animal Experimentation of the Super -B&K laboratory animal Center.
- FIG. 16A and FIG. 16B show antitumor activity of duvelisib in combination with ⁇ -OX40 mAb in A20 syngeneic model.
- Table 19 shows the TGI and p value on day 17 as compared with vehicle group. There was synergistic effect between duvelisib and ⁇ -OX40 mAb in A20 syngeneic model.
- Table 19 Antitumor activity of duvelisib in combination with ⁇ -OX40 mAb in A20 syngeneic model: TGI and p value on day 17 as compared with vehicle group.
- FIG. 17A- FIG. 17D shows individual tumor growth curve of tumor from mice treated according to Table 19 as compared to control.
- Example 11 CN401 in combination with CN1 in humanized CT26. WT murine colon carcinoma model
- Group Animal Regimen 1 8 vehicle (PBS i.p. biw * 3weeks + 0.5% MC p.o. bid *3 weeks) 2 8 CN1 5mg/kg, i.p., biw *3weeks 3 8 CN401 150mg/kg, po, bid *3weeks 4 8 CN1 5mg/kg, i.p., biw *3weeks + CN401 150mg/kg, po, bid *3weeks
- WT tumor model is provided in FIG. 18A-FIG. 18B and FIG. 19A-FIG. 19D.
- Table 21 Antitumor activity of CN401 in combination with CN1 in humanized CT26.
- WT tumor model The TGI and p value on day 17 as compared with vehicle group.
- Example 12 CN401 in combination with CN1 in humanized B16-F10 murine melanoma tumor model
- Group Animal Regimen 1 8 vehicle (PBS i.p. biw * 2weeks + 0.5% MC p.o. bid *2 weeks) 2 8 CN1 10mg/kg, i.p., biw *2weeks 3 8 CN401 150mg/kg, po, bid *2weeks 4 8 CN1 10mg/kg, i.p., biw *2weeks + CN401 150mg/kg, po, bid *2weeks
- FIG. 20A-FIG. 20B and FIG. 21A-FIG. 21D Antitumor activity of CN401 in combination with CN1 in humanized B16-F10 tumor model is provided in FIG. 20A-FIG. 20B and FIG. 21A-FIG. 21D.
- Table 23 Antitumor activity of CN401 in combination with CN1 (anti-huOX40 Ab) in humanized B16-F10 tumor model: The TGI and p value on day 14 as compared with vehicle group.
Abstract
Provided herein are compositions and methods that comprise anti-OX40 polypeptides and fragment thereof and inhibitors for use in combination therapy. Also provided are methods of using the anti-OX40 polypeptides in combination therapies for the treatment of diseases and conditions.
Description
CROSS REFERENCE BY INCORPORATION
The present application claims the priority to international Patent Application No. PCT/CN2020/128453, titled " COMBINATION THERAPY AND METHODS UTILIZING THE SAME " , filed on November 12, 2020 with the China National Intellectual Property Administration, which is incorporated herein by reference in entirety.
Immune checkpoint blockade with antagonistic monoclonal antibodies (mAbs) targeting B7 immunoglobulin superfamily molecules (CTLA-4, PD-1, and PD-L1) generate long lasting anti-tumor immune responses translating into clinical benefit across many cancer types. However, many patients are primarily resistant to immune checkpoint blockade–based monotherapy and many others will eventually relapse.
SUMMARY
In some aspects, the present disclosure provides novel compositions and methods thereof for overcoming primary and secondary resistance to immunotherapy across numerous cancer types. New immunostimulatory targets, such as the tumor necrosis factor receptor superfamily comprising many other immune checkpoints, can be used as the next generation immunomodulators. In some embodiments, OX40 (CD134) , a co-stimulatory molecule that can be expressed by activated immune cells, can be utilized as a new immunostimulatory target.
In one aspect, the present disclosure provides a method for treating a subject in need thereof, comprising: (a) administering to the subject a polypeptide comprising an antigen binding moiety exhibiting binding specificity to OX40, wherein the antigen binding moiety comprises at least one heavy chain CDR (CDRH) selected from the group consisting of (i) - (iii) and at least one light chain CDR (CDRL) selected from the group consisting of (iv) - (vi) , wherein: (i) a CDRH1 having at least 80% sequence identity to a sequence selected from the group consisting of SEQ ID NOs: 1, 7, 13, 15, 21 and 27; (ii) a CDRH2 having at least 80% sequence identity to a sequence selected from the group consisting of SEQ ID NOs: 3, 9, 17, 23 and 29; (iii) a CDRH3 having at least 80% sequence identity to a sequence selected from the group consisting of SEQ ID NOs: 5, 11, 19, 25 and 31; (iv) a CDRL1 having at least 80% sequence identity to a sequence selected from the group consisting of SEQ ID NOs: 2, 8, 14, 16, 22 and 28; (v) a CDRL2 having at least 80%sequence identity to a sequence selected from the group consisting of SEQ ID NOs: 4, 10, 18, 24 and 30; and (vi) a CDRL3 having at least 80% sequence identity to a sequence selected from the group consisting of SEQ ID NOs: 6, 12, 20, 26 and 32; and (b) administering to the subject an inhibitor against PI3K.
In some embodiments, wherein the antigen binding moiety comprises: (1) a heavy chain variable region (VH) having at least 80% sequence identity to a sequence selected from the group consisting of SEQ ID NOs: 33, 35, 37, 39, 41 and 43; and (2) a light chain variable region (VL) having at least 80% sequence identity to a sequence selected from the group consisting of SEQ ID NOs: 34, 36, 38, 40, 42 and 44.
In some embodiments of any one of the methods disclosed herein, the antigen binding moiety comprises (1) a VH having at least 80% sequence identity to SEQ ID NO: 39 and (2) a VL having at least 80% sequence identity to SEQ ID NO: 40.
In some embodiments of any one of the methods disclosed herein, the inhibitor against PI3K comprises one or more small molecule inhibitors against PI3K alpha, PI3K beta, PI3K delta, or PI3K gamma. In some embodiments of any one of the methods disclosed herein, the inhibitor against PI3K comprises one or more small molecule inhibitors against PI3K delta or PI3K gamma.
In one aspect, the present disclosure provides a method comprising treating a subject in need thereof, comprising: (a) administering to the subject a polypeptide comprising an antigen binding moiety exhibiting binding specificity to OX40; and (b) administering to the subject an inhibitor against PI3K comprising one or more members selected from the group consisting of Wortmannin, LY294002, hibiscone C, Idelalisib, Copanlisib, Duvelisib, Alpelisib, Taselisib, Perifosine, Buparlisib, Umbralisib, PX-866, Dactolisib, CUDC-907, Voxtalisib, CUDC-907, ME-401, IPI-549, SF1126, Tenalisib, INK1117, pictilisib, XL147, Palomid 529, GSK1059615, ZSTK474, PWT33597, IC87114, TG100–115, CAL263, RP6503, PI-103, GNE-477, AEZS-136, modifications thereof, and combinations thereof.
In some embodiments, the inhibitor against PI3K comprises one or more members selected from the group consisting of Idelalisib, Copanlisib, Duvelisib, Alpelisib, Taselisib, Perifosine, Buparlisib, Umbralisib, Tenalisib, modifications thereof, and combinations thereof. In some embodiments, the inhibitor against PI3K comprises Tenalisib.
In some embodiments of any one of the methods disclosed herein, the polypeptide comprises an antibody, a fragment thereof, or a functional variant thereof.
In some embodiments of any one of the methods disclosed herein, administration of the polypeptide occurs prior to, simultaneously with, or subsequent to administration of the inhibitor against PI3K.
In some embodiments of any one of the methods disclosed herein, the polypeptide and the inhibitor against PI3K are administered in a same unit dose. Alternatively or in addition to, in some embodiments of any one of the methods disclosed herein, the polypeptide and the inhibitor against PI3K are administered in different unit doses.
In some embodiments of any one of the methods disclosed herein, administration of the polypeptide and the inhibitor against PI3K synergistically yields one or more characteristics selected from the group consisting of: (A) a greater degree of toxicity against a diseased cell as compared to either of the polypeptide or the inhibitor against PI3K; and (B) a reduction in tumor size as compared to either of the polypeptide or the inhibitor against PI3K.
In some embodiments of any one of the methods disclosed herein, administration of the polypeptide and the inhibitor against PI3K synergistically yields one or more characteristics selected from the group consisting of: (A) a degree of toxicity against a diseased cell that is at least about 20%, at least about 40%, at least about 60%, at least about 80%, at least about 100%, or at least about 200% greater than that that of either of the polypeptide or the inhibitor against PI3K; and (B) a reduction in tumor size by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, or at least about 60% as compared to that of either the polypeptide or the inhibitor against PI3K.
In some embodiments of any one of the methods disclosed herein, the diseased cell comprises a tumor cell or a cancer cell. In some embodiments of any one of the methods disclosed herein, the diseased cell comprises a colorectal cancer cell. In some embodiments of any one of the methods disclosed herein, the diseased cell comprises a lymphoma cell.
In some embodiments of any one of the methods disclosed herein, the method further comprises administering to the subject a co-therapeutic agent.
In some embodiments of any one of the methods disclosed herein, the subject has or is suspected of having a disease.
In some embodiments of any one of the methods disclosed herein, the disease comprises tumor or cancer. In some embodiments of any one of the methods disclosed herein, the disease comprises colorectal cancer. In some embodiments of any one of the methods disclosed herein, the disease comprises lymphoma. In some embodiments of any one of the methods disclosed herein, the disease comprises B cell lymphoma.
In one aspect, the present disclosure provides a composition comprising: (a) a polypeptide comprising an antigen binding moiety exhibiting binding specificity to OX40, wherein the antigen binding moiety comprises at least one heavy chain CDR (CDRH) selected from the group consisting of (i) - (iii) and at least one light chain CDR (CDRL) selected from the group consisting of (iv) - (vi) , wherein: (i) a CDRH1 having at least 80% sequence identity to a sequence selected from the group consisting of SEQ ID NOs: 1, 7, 13, 15, 21 and 27; (ii) a CDRH2 having at least 80% sequence identity to a sequence selected from the group consisting of SEQ ID NOs: 3, 9, 17, 23 and 29; (iii) a CDRH3 having at least 80% sequence identity to a sequence selected from the group consisting of SEQ ID NOs: 5, 11, 19, 25 and 31; (iv) a CDRL1 having at least 80% sequence identity to a sequence selected from the group consisting of SEQ ID NOs: 2, 8, 14, 16, 22 and 28; (v) a CDRL2 having at least 80% sequence identity to a sequence selected from the group consisting of SEQ ID NOs: 4, 10, 18, 24 and 30; and (vi) a CDRL3 having at least 80% sequence identity to a sequence selected from the group consisting of SEQ ID NOs: 6, 12, 20, 26 and 32; and (b) an inhibitor against PI3K.
In some embodiments, the antigen binding moiety comprises: (1) a heavy chain variable region (VH) having at least 80% sequence identity to a sequence selected from the group consisting of SEQ ID NOs: 33, 35, 37, 39, 41 and 43; and (2) a light chain variable region (VL) having at least 80% sequence identity to a sequence selected from the group consisting of SEQ ID NOs: 34, 36, 38, 40, 42 and 44.
In some embodiments of any one of the compositions disclosed herein, the antigen binding moiety comprises (1) a VH having at least 80% sequence identity to SEQ ID NO: 39 and (2) a VL having at least 80% sequence identity to SEQ ID NO: 40.
In some embodiments of any one of the compositions disclosed herein, the inhibitor against PI3K comprises one or more small molecule inhibitors against PI3K alpha, PI3K beta, PI3K delta, or PI3K gamma. In some embodiments of any one of the compositions disclosed herein, the inhibitor against PI3K comprises one or more small molecule inhibitors against PI3K delta or PI3K gamma.
In one aspect, the present disclosure provides a composition comprising: (a) a polypeptide comprising an antigen binding moiety exhibiting binding specificity to OX40; and (b) an inhibitor against PI3K comprising one or more members selected from the group consisting of Wortmannin, LY294002, hibiscone C, Idelalisib, Copanlisib, Duvelisib, Alpelisib, Taselisib, Perifosine, Buparlisib, Umbralisib, PX-866, Dactolisib, CUDC-907, Voxtalisib, CUDC-907, ME-401, IPI-549, SF1126, Tenalisib, INK1117, pictilisib, XL147, Palomid 529, GSK1059615, ZSTK474, PWT33597, IC87114, TG100–115, CAL263, RP6503, PI-103, GNE-477, AEZS-136, modifications thereof, and combinations thereof.
In some embodiments, the inhibitor against PI3K comprises one or more members selected from the group consisting of Idelalisib, Copanlisib, Duvelisib, Alpelisib, Taselisib, Perifosine, Buparlisib, Umbralisib, Tenalisib, modifications thereof, and combinations thereof. In some embodiments, the inhibitor against PI3K comprises Tenalisib.
In some embodiments of any one of the compositions disclosed herein, the polypeptide comprises an antibody, a fragment thereof, or a functional variant thereof.
In some embodiments of any one of the compositions disclosed herein, the polypeptide and the inhibitor against PI3K are prepared in a same unit dose. In some embodiments of any one of the compositions disclosed herein, the polypeptide and the inhibitor against PI3K are prepared in different unit doses.
In some embodiments of any one of the compositions disclosed herein, the composition further comprises a co-therapeutic agent.
Additional aspects and advantages of the present disclosure will become readily apparent to those skilled in this art from the following detailed description, wherein only illustrative embodiments of the present disclosure are shown and described. As will be realized, the present disclosure is capable of other and different embodiments, and its several details are capable of modifications in various obvious respects, all without departing from the disclosure. Accordingly, the drawings and description are to be regarded as illustrative in nature, and not as restrictive.
INCORPORATION BY REFERENCE
All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.
The novel features of the invention are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present invention will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the invention are utilized, and the accompanying drawings of which:
FIG. 1A Antitumor activity of Tenalisib (CN401) in combination with α-mOX40 mAb and anti-mPD1 mAb in MC38 syngeneic model. The panel shows tumor growth curve as measured by average tumor size (n=8) of mice, Red arrows indicated days of dosing. MC38 cells (0.5million/mouse) were injected into the right flank of c57bl/6 mice. 6 days after cell implantation, when average tumor size reached about 70 mm
3, mice were administered vehicle, CN401 (15mg/kg, 50mg/kg and 150mg/kg p.o. BID) , α-OX40 mAb (100ug/mouse I.p. BIW) , α-PD-1 mAb (60ug/mouse i.p. BIW) and their combination. FIG. 1B shows body weight growth of each group, mouse body weight was measured thrice a week.
FIG. 2A shows antitumor activity of Tenalisib (CN401) in combination with α-mOX40 mAb and anti-mPD1 mAb in MC38 syngeneic model. In particular the panel shows individual tumor growth curve of tumor from vehicle treated mice. FIG. 2B shows the individual tumor growth curve for CN401 (150mg/kg) treated mice. FIG. 2C shows the individual tumor growth curve for α-OX40 mAb (100ug/kg) treated mice. FIG. 2D shows individual tumor growth curve of α-OX40 mAb (100ug/kg) +CN410 (150mg/kg) treated mice. FIG. 2E shows individual tumor growth curve of α-OX40 mAb (100ug/kg) + CN401 (50mg/kg) treated mice. FIG. 2F shows individual tumor growth curve of α-OX40 mAb (100ug/kg) +CN410 (15mg/kg) treated mice. FIG. 2G shows individual tumor growth curve of α-OX40 mAb (100ug/kg) +CN410 (150mg/kg) + -PD1 mAb (3mg/kg) treated mice.
FIG. 3A shows antitumor activity of Tenalisib (CN401) in combination with α-OX40 mAb and anti-PD1 mAb in A20 syngeneic model. A20 cells (0.5million/mouse) were injected into right flank of balb/c mice. 11 days after cell implantation, when average tumor size reached about 70 mm
3, mice were administered vehicle, CN401 (150mg/kg and 300mg/kg p.o. BID) , α-OX40 mAb (100ug/mouse I.p. BIW) , α-PD-1 mAb (60ug/mouse i.p. BIW) and their combination. In particular, the panel shows a tumor growth curve as measured by average tumor size (n=6) of mice, Red arrows indicated days of dosing. FIG. 3B shows body weight growth of each group, mouse body weight was measured thrice a week.
FIG. 4A shows antitumor activity of Tenalisib (CN401) in combination with α-OX40 mAb and anti-PD1 mAb in A20 syngeneic model. In particular, the panel shows the individual tumor growth curve of tumor from vehicle treated mice. FIG. 4B shows the individual tumor growth curve of tumor from CN401 (300mg/kg) treated mice. FIG. 4C shows the individual tumor growth curve of tumor from CN401 (150mg/kg) treated mice. FIG. 4D shows the individual tumor growth curve of tumor from α-OX40 mAb (100ug/kg) treated mice. FIG. 4E shows the individual tumor growth curve of tumor from α-OX40 mAb treated mice. Of note, 3/6 mice achieved complete responses (tumor-free) . FIG. 4F shows the individual tumor growth curve of tumor from α-OX40 mAb (100ug/kg) +CN410 (150mg/kg) treated mice. Of note, 1/6 mice achieved complete responses. FIG. 4G shows the individual tumor growth curve of tumors from α-OX40 mAb (100ug/kg) + α-PD1 mAb (60ug/mouse) treated mice. Of note, are that 3/6 mice achieved complete responses. FIG. 4H shows individual tumor growth curve of tumor from α-OX40 mAb (100ug/kg) +CN410 (150mg/kg) + -PD1 mAb (60ug/mouse) treated mice. Of note, are that 4/6 mice achieved complete responses.
FIG. 5A shows antitumor activity of Tenalisib (CN401) in combination with CN1 Ab in A20 humanized transgenic mice. A20 cells (0.5million/mouse) were injected into right flank of balb/c mice. 9 days after cell implantation, when average tumor size reached about 70 mm
3, mice were administered vehicle, CN401 (150mg/kg p.o. BID) , CN1 (1mg/kg i.p. BIW and their combination. FIG. 5B shows the body weight growth of each group, mouse body weight was measured thrice a week.
FIG. 6A shows antitumor activity of Tenalisib (CN401) in combination with CN1 in A20 humanized Ox40 transgenic mouse syngeneic model. In particular, the panel shows the individual tumor growth curve of tumor from vehicle treated mice. FIG. 6B shows individual tumor growth curve of tumor from CN401 (1mg/kg) treated mice. Of note is that 4/8 treated mice achieved complete responses. FIG. 6C shows individual tumor growth curve of tumor from CN401 (150mg/kg) treated mice. Of note is that 1/8 treated mice achieved complete responses. FIG. 6D shows individual growth curve from CN1 (1mg/kg) +CN401 (150mg/kg) treated mice. Of note is that 5/8 treated mice achieved complete responses.
FIG. 7A shows results of different tumor cell lines treated with 10μM Tenalisib for 72 hr. and the effects on cell proliferation were measured as percentage of control. Two cell lines (MV-4-11, human leukemia cells; A20, mouse B cell lymphoma) showed inhibition greater than 50%. FIG. 7B shows a chemical structure of Tenalisib (RP6530) . FIG. 7C shows results of different tumor cell lines treated with Duvelishib (The range of compound concentration was from 0.002 μM 10 μM to with 3 fold serial dilution ) for 72 hours and the effects on cell proliferation were measured as percentage of control. FIG. 7D shows a chemical structure of Duvelishib.
FIG. 8A shows antitumor activity of Tenalisib (CN401) and duvelisib in combination with α-OX40 mAb and anti-PD1 mAb in MC38 syngeneic model. MC38 cells (0.5million/mouse) were injected into right flank of c57bl/6 mice. 6 days after cell implantation, when average tumor size reached about 70 mm
3, mice were administered vehicle, CN401 (15mg/kg, 50mg/kg and 150mg/kg p.o. BID) , α-OX40 mAb (100ug/mouse I.p. BIW) , α-PD-1 mAb (60ug/mouse i.p. BIW) , Duvelisib (50mg/kg p.o. BID) and their combination. In particular the panel shows tumor growth curve as measured by average tumor size (n=8) of mice, Red arrows indicated days of dosing. FIG. 8B shows body weight growth of each group, mouse body weight was measured thrice a week.
FIG. 9A shows antitumor activity of Tenalisib (CN401) & duvelisib in combination with α-OX40 mAb and anti-PD1 mAb in MC38 syngeneic model. In particular, the panel shows the individual tumor growth curve of tumor from vehicle treated mice. FIG. 9B shows the individual tumor growth curve of tumor from CN401 (150mg/kg) treated mice. FIG. 9C shows the individual tumor growth curve of tumor from α-OX40 mAb (100ug/mouse) treated mice. FIG. 9D shows the individual tumor growth curve of tumor from duvelisib (50mg/kg) treat mice. FIG. 9E shows the individual tumor growth curve of tumor from α-OX40 mAb (100ug/mouse) +CN410 (150mg/kg) treated mice. FIG. 9F shows the individual tumor growth curve of tumor from α-OX40 mAb (100ug/mouse) + CN401 (50mg/kg) treated mice. FIG. 9G shows the individual tumor growth curve of tumor from α-OX40 mAb (100ug/mouse) +CN410 (15mg/kg) treated mice. FIG. 9H shows the individual tumor growth curve of tumor from α-OX40 mAb (100ug/mouse) +duvelisib (50mg/kg) treated mice; (i) α-OX40 mAb (100ug/mouse) +CN410 (150mg/kg) + -PD1 mAb (60ug/mouse) treated mice.
FIG. 10A shows antitumor activity of Tenalisib (CN401) and duvelisib in combination with α-OX40 mAb and anti-PD1 mAb in A20 syngeneic model. A20 cells (0.5million/mouse) were injected into right flank of balb/c mice. 11 days after cell implantation, when average tumor size reached about 70 mm
3, mice were administered vehicle, CN401 (150mg/kg and 300mg/kg p.o. BID) , duvelisib (50mg/kg p.o. BID) , α-OX40 mAb (100ug/mouse I.p. BIW) , α-PD-1 mAb (60ug/mouse i.p. BIW) and their combination. In particular, the panel shows tumor growth curve as measured by average tumor size (n=6) of mice, Red arrows indicated days of dosing. FIG. 10B shows the body weight growth of each group, mouse body weight was measured thrice a week.
FIG. 11A shows antitumor activity of CN401 and duvelisib in combination with α-OX40 mAb and anti-PD1 mAb in A20 syngeneic model. In particular the panel shows the individual tumor growth curve of tumor from vehicle treated mice. FIG. 11B shows the individual tumor growth curve of tumor from CN401 (300mg/kg) treated mice. FIG. 11C shows the individual tumor growth curve of tumor from CN401 (150mg/kg) treated mice. FIG. 11D shows the individual tumor growth curve of tumor from duvelisib (50mg/kg) treat mice. FIG. 11E shows the individual tumor growth curve of tumor from α-OX40 mAb (100ug/mouse) treated mice. FIG. 11F shows the individual tumor growth curve of tumor from α-OX40 mAb (100ug/kg) + CN401 (300mg/kg) treated mice. FIG. 11G shows the individual tumor growth curve of tumor from α-OX40 mAb (100ug/kg) +CN410 (150mg/kg) treated mice. FIG. 11H shows the individual tumor growth curve of tumor from α-OX40 mAb (100ug/kg) +duvelisib (50mg/kg) treated mice. FIG. 11I shows the individual tumor growth curve of tumor from α-OX40 mAb (100ug/kg) + α- PD1 mAb (60ug/mouse) treated mice. FIG. 11J shows the individual tumor growth curve of tumor from α-OX40 mAb (100ug/mouse) +CN410 (150mg/kg) + -PD1 mAb (60ug/mouse) treated mice.
FIG. 12A shows antitumor activity of Tenalisib (CN401) in combination with CN1 and anti-PD1 Ab in A20 humanized transgenic mice. A20 cells (0.5million/mouse) were injected into right flank of balb/c mice. 9 days after cell implantation, when average tumor size reached about 70 mm
3, mice were administered vehicle, CN401 (150mg/kg p.o. BID) , CN1 (1mg/kg i.p. BIW and their combination. In particular the panel shows tumor growth curve as measured by average tumor size (n=8) of mice, Black arrows indicated days of dosing. FIG. 12B shows the body weight growth of each group, mouse body weight was measured thrice a week.
FIG. 13A shows the antitumor activity of Tenalisib (CN401) in combination with CN1 in A20 humanized Ox40 transgenic mouse syngeneic model. In particular, the panel shows the individual tumor growth curve of tumor from vehicle treated mice. FIG. 13B shows individual tumor growth curve of tumor from CN401 (1mg/kg) treated mice. Of note is that 4/8 mice achieved complete responses. FIG. 13C shows individual tumor growth curve of tumor from CN401 (150mg/kg) treated mice. Of note is that 1/8 mice achieved complete responses. FIG. 13D shows individual tumor growth curve of tumor from CN1 (1mg/kg) +CN401 (150mg/kg) treated mice. Of note, 5/8 mice achieved complete responses.
FIG. 14A shows antitumor activity of duvelisib in combination with α-OX40 mAb in MC38 syngeneic model. MC38 cells (0.5million/mouse) were injected into right flank of C57 mice. 6 days after cell implantation, when average tumor size reached about 70 mm
3, mice were administered vehicle, α-OX40 mAb (100ug/mouse I.p. BIW) , Duvelisib (50mg/kg p.o. BID) and their combination. In particular the panel shows tumor growth curve as measured by average tumor size (n=8) of mice, Red arrows indicated days of dosing. FIG. 14B shows the body weight growth of each group, mouse body weight was measured thrice a week. (C) The TGI and p value on day 20 as compared with vehicle group.
FIG. 15A shows antitumor activity of duvelisib in combination with α-OX40 mAb in MC38 syngeneic model. The panel specifically shows the individual tumor growth curve of tumor from vehicle treated mice. FIG. 15B shows the individual tumor growth curve of tumor from α-OX40 mAb (100ug/mouse) treated mice. FIG. 15C shows the individual tumor growth curve of tumor from duvelisib (50mg/kg) treated mice. FIG. 15D shows the individual tumor growth curve of tumor from α-OX40 mAb (100ug/mouse) +duvelisib (50mg/kg) treated mice.
FIG. 16A shows antitumor activity of duvelisib in combination with α-OX40 mAb in A20 syngeneic model. A20 cells (0.5million/mouse) were injected into right flank of balb/c mice. 11 days after cell implantation, when average tumor size reached about 70 mm
3, mice were administered vehicle, duvelisib (50mg/kg p.o. BID) , α-OX40 mAb (100ug/mouse I.p. BIW) and their combination. In particular, the panel shows tumor growth curve as measured by average tumor size (n=6) of mice, Red arrows indicated days of dosing. FIG. 16B shows the body weight growth of each group, mouse body weight was measured thrice a week.
FIG. 17A shows antitumor activity of duvelisib in combination with α-OX40 mAb in A20 syngeneic model. The individual tumor growth curve of tumor from vehicle treated mice is shown. FIG. 17B shows individual tumor growth curve of tumor from duvelisib (50mg/kg) treated mice. FIG. 17C shows individual tumor growth curve of tumor from α-OX40 mAb (100ug/mouse) treated mice. FIG. 17D shows individual tumor growth curve of tumor from α-OX40 mAb (100ug/mouse) +duvelisib (50mg/kg) treated mice.
FIG. 18A shows antitumor activity of CN401 in combination with CN1 in humanized CT26. WT murine colon carcinoma model. CT26. WT cells (0.1 million/mouse) were injected into right flank of mice. 9 days after cell implantation, when average tumor size reached about 70 mm
3, mice were administered vehicle, CN401 (150mg/kg p.o. BID) , CN1 (5mg/kg mouse i.p. BIW) and their combination. In particular, the panel shows tumor growth curve as measured by average tumor size (n=-8) of mice. FIG. 18B shows the body weight growth of each group, mouse body weight was measured thrice a week.
FIG. 19A shows antitumor activity of CN401 in combination with CN1 in CT26. WT murine colon carcinoma model. The individual tumor growth curve of tumor from vehicle treated mice is shown. FIG. 19B shows individual tumor growth curve of tumor from CN401 (150mg/kg) treated mice. FIG. 19C shows individual tumor growth curve of tumor from CN1 (5mg/kg) treated mice. FIG. 19D shows individual tumor growth curve of tumor from CN1 (5mg/kg) +CN401 (150mg/kg) treated mice.
FIG. 20A shows antitumor activity of CN401 in combination with CN1 in humanized B16-F10 murine melanoma tumor model. B16-F10 cells (0.1 million/mouse) were injected into right flank of mice. 9 days after cell implantation, when average tumor size reached about 40 mm
3 , mice were administered vehicle, CN401 (150mg/kg p.o. BID) , CN1 (10mg/kg i.p. BIW) and their combination. In particular, the panel shows tumor growth curve as measured by average tumor size (n=-8 ) of mice. FIG. 20B shows the body weight growth of each group, mouse body weight was measured thrice a week.
FIG. 21A shows antitumor activity of CN401 in combination with CN1 in B16-F10 melanoma model. The individual tumor growth curve of tumor from vehicle treated mice is shown. FIG. 20B shows individual tumor growth curve of tumor from CN401 (150mg/kg) treat mice. FIG. 20C shows individual tumor growth curve of tumor from CN1 (10mg/kg) treated mice. FIG. 20D shows individual tumor growth curve of tumor from CN1 (10mg/kg) +CN401 (150mg/kg) treated mice.
While various embodiments of the invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions may occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed.
As used in the specification and claims, the singular forms “a, ” “an, ” and “the” include plural references unless the context clearly dictates otherwise.
The term “about” or “approximately” generally means within an acceptable error range for the particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, i.e., the limitations of the measurement system. For example, “about” can mean within 1 or more than 1 standard deviation, per the practice in the art. Alternatively, “about” can mean a range of up to 20%, up to 10%, up to 5%, or up to 1% of a given value. Alternatively, particularly with respect to biological systems or processes, the term can mean within an order of magnitude, preferably within 5-fold, and more preferably within 2- fold, of a value. Where particular values are described in the application and claims, unless otherwise stated, the term “about” meaning within an acceptable error range for the particular value should be assumed.
The use of the alternative (e.g., “or” ) should be understood to mean either one, both, or any combination thereof of the alternatives. The term “and/or” should be understood to mean either one, or both of the alternatives.
The term “cell” generally refers to a biological cell. A cell can be the basic structural, functional and/or biological unit of a living organism. A cell can originate from any organism having one or more cells. Some non-limiting examples include: a prokaryotic cell, eukaryotic cell, a bacterial cell, an archaeal cell, a cell of a single-cell eukaryotic organism, a protozoa cell, a cell from a plant (e.g. cells from plant crops, fruits, vegetables, grains, soy bean, corn, maize, wheat, seeds, tomatoes, rice, cassava, sugarcane, pumpkin, hay, potatoes, cotton, cannabis, tobacco, flowering plants, conifers, gymnosperms, ferns, clubmosses, hornworts, liverworts, mosses) , an algal cell, (e.g., Botryococcus braunii, Chlamydomonas reinhardtii, Nannochloropsis gaditana, Chlorella pyrenoidosa, Sargassum patens C. Agardh, and the like) , seaweeds (e.g. kelp) , a fungal cell (e.g., a yeast cell, a cell from a mushroom) , an animal cell, a cell from an invertebrate animal (e.g. fruit fly, cnidarian, echinoderm, nematode, etc. ) , a cell from a vertebrate animal (e.g., fish, amphibian, reptile, bird, mammal) , a cell from a mammal (e.g., a pig, a cow, a goat, a sheep, a rodent, a rat, a mouse, a non-human primate, a human, etc. ) , and etcetera. Sometimes a cell is not originating from a natural organism (e.g. a cell can be a synthetically made, sometimes termed an artificial cell) .
The term “nucleotide, ” as used herein, generally refers to a base-sugar-phosphate combination. A nucleotide can comprise a synthetic nucleotide. A nucleotide can comprise a synthetic nucleotide analog. Nucleotides can be monomeric units of a nucleic acid sequence (e.g. deoxyribonucleic acid (DNA) and ribonucleic acid (RNA) ) . The term nucleotide can include ribonucleoside triphosphates adenosine triphosphate (ATP) , uridine triphosphate (UTP) , cytosine triphosphate (CTP) , guanosine triphosphate (GTP) and deoxyribonucleoside triphosphates such as dATP, dCTP, dITP, dUTP, dGTP, dTTP, or derivatives thereof. Such derivatives can include, for example, [αS] dATP, 7-deaza-dGTP and 7-deaza-dATP, and nucleotide derivatives that confer nuclease resistance on the nucleic acid molecule containing them. The term nucleotide as used herein can refer to dideoxyribonucleoside triphosphates (ddNTPs) and their derivatives. Illustrative examples of dideoxyribonucleoside triphosphates can include, but are not limited to, ddATP, ddCTP, ddGTP, ddITP, and ddTTP. A nucleotide may be unlabeled or detectably labeled by well-known techniques. Labeling can also be carried out with quantum dots. Detectable labels can include, for example, radioactive isotopes, fluorescent labels, chemiluminescent labels, bioluminescent labels and enzyme labels. Fluorescent labels of nucleotides may include but are not limited fluorescein, 5-carboxyfluorescein (FAM) , 2′7′-dimethoxy-4′5-dichloro-6-carboxyfluorescein (JOE) , rhodamine, 6-carboxyrhodamine (R6G) , N, N, N′, N′-tetramethyl-6-carboxyrhodamine (TAMRA) , 6-carboxy-X-rhodamine (ROX) , 4- (4′dimethylaminophenylazo) benzoic acid (DABCYL) , Cascade Blue, Oregon Green, Texas Red, Cyanine and 5- (2′-aminoethyl) aminonaphthalene-1-sulfonic acid (EDANS) . Specific examples of fluorescently labeled nucleotides can include [R6G] dUTP, [TAMRA] dUTP, [R110] dCTP, [R6G] dCTP, [TAMRA] dCTP, [JOE] ddATP, [R6G] ddATP, [FAM] ddCTP, [R110] ddCTP, [TAMRA] ddGTP, [ROX] ddTTP, [dR6G] ddATP, [dR110] ddCTP, [dTAMRA] ddGTP, and [dROX] ddTTP available from Perkin Elmer, Foster City, Calif. FluoroLink DeoxyNucleotides, FluoroLink Cy3-dCTP, FluoroLink Cy5-dCTP, FluoroLink Fluor X-dCTP, FluoroLink Cy3-dUTP, and FluoroLink Cy5-dUTP available from Amersham, Arlington Heights, Ill.; Fluorescein-15-dATP, Fluorescein-12-dUTP, Tetramethyl-rodamine-6-dUTP, IR770-9-dATP, Fluorescein-12-ddUTP, Fluorescein-12-UTP, and Fluorescein-15-2′-dATP available from Boehringer Mannheim, Indianapolis, Ind.; and Chromosome Labeled Nucleotides, BODIPY-FL-14-UTP, BODIPY-FL-4-UTP, BODIPY-TMR-14-UTP, BODIPY-TMR-14-dUTP, BODIPY-TR-14-UTP, BODIPY-TR-14-dUTP, Cascade Blue-7-UTP, Cascade Blue-7-dUTP, fluorescein-12-UTP, fluorescein-12-dUTP, Oregon Green 488-5-dUTP, Rhodamine Green-5-UTP, Rhodamine Green-5-dUTP, tetramethylrhodamine-6-UTP, tetramethylrhodamine-6-dUTP, Texas Red-5-UTP, Texas Red-5-dUTP, and Texas Red-12-dUTP available from Molecular Probes, Eugene, Oreg. Nucleotides can also be labeled or marked by chemical modification. A chemically-modified single nucleotide can be biotin-dNTP. Some non-limiting examples of biotinylated dNTPs can include, biotin-dATP (e.g., bio-N6-ddATP, biotin-14-dATP) , biotin-dCTP (e.g., biotin-11-dCTP, biotin-14-dCTP) , and biotin-dUTP (e.g. biotin-11-dUTP, biotin-16-dUTP, biotin-20-dUTP) .
The term “polynucleotide, ” “oligonucleotide, ” or “nucleic acid, ” as used interchangeably herein, generally refers to a polymeric form of nucleotides of any length, either deoxyribonucleotides or ribonucleotides, or analogs thereof, either in single-, double-, or multi-stranded form. A polynucleotide can be exogenous or endogenous to a cell. A polynucleotide can exist in a cell-free environment. A polynucleotide can be a gene or fragment thereof. A polynucleotide can be DNA. A polynucleotide can be RNA. A polynucleotide can have any three dimensional structure, and can perform any function, known or unknown. A polynucleotide can comprise one or more analogs (e.g. altered backbone, sugar, or nucleobase) . If present, modifications to the nucleotide structure can be imparted before or after assembly of the polymer. Some non-limiting examples of analogs include: 5-bromouracil, peptide nucleic acid, xeno nucleic acid, morpholinos, locked nucleic acids, glycol nucleic acids, threose nucleic acids, dideoxynucleotides, cordycepin, 7-deaza-GTP, florophores (e.g. rhodamine or flurescein linked to the sugar) , thiol containing nucleotides, biotin linked nucleotides, fluorescent base analogs, CpG islands, methyl-7-guanosine, methylated nucleotides, inosine, thiouridine, pseudourdine, dihydrouridine, queuosine, and wyosine. Non-limiting examples of polynucleotides include coding or non-coding regions of a gene or gene fragment, loci (locus) defined from linkage analysis, exons, introns, messenger RNA (mRNA) , transfer RNA (tRNA) , ribosomal RNA (rRNA) , short interfering RNA (siRNA) , short-hairpin RNA (shRNA) , micro-RNA (miRNA) , ribozymes, cDNA, recombinant polynucleotides, branched polynucleotides, plasmids, vectors, isolated DNA of any sequence, isolated RNA of any sequence, cell-free polynucleotides including cell-free DNA (cfDNA) and cell-free RNA (cfRNA) , nucleic acid probes, and primers. The sequence of nucleotides can be interrupted by non-nucleotide components.
The term “peptide, ” “polypeptide, ” or “protein, ” as used interchangeably herein, generally refers to a polymer of at least two amino acid residues joined by peptide bond (s) . This term does not connote a specific length of polymer, nor is it intended to imply or distinguish whether the peptide is produced using recombinant techniques, chemical or enzymatic synthesis, or is naturally occurring. The terms apply to naturally occurring amino acid polymers as well as amino acid polymers comprising at least one modified amino acid. In some cases, the polymer can be interrupted by non-amino acids. The terms include amino acid chains of any length, including full length proteins, and proteins with or without secondary and/or tertiary structure (e.g., domains) . The terms also encompass an amino acid polymer that has been modified, for example, by disulfide bond formation, glycosylation, lipidation, acetylation, phosphorylation, oxidation, and any other manipulation such as conjugation with a labeling component. The terms “amino acid” and “amino acids, ” as used herein, generally refer to natural and non-natural amino acids, including, but not limited to, modified amino acids and amino acid analogues. Modified amino acids can include natural amino acids and non-natural amino acids, which have been chemically modified to include a group or a chemical moiety not naturally present on the amino acid. Amino acid analogues can refer to amino acid derivatives. The term “amino acid” includes both D-amino acids and L-amino acids.
The term “derivative, ” “variant, ” or “fragment, ” as used herein with reference to a polypeptide, generally refers to a polypeptide related to a wild type polypeptide, for example either by amino acid sequence, structure (e.g., secondary and/or tertiary) , activity (e.g., enzymatic activity) and/or function. Derivatives, variants and fragments of a polypeptide can comprise one or more amino acid variations (e.g., mutations, insertions, and deletions) , truncations, modifications, or combinations thereof compared to a wild type polypeptide.
The term “antibody” generally refers to a proteinaceous binding molecule with immunoglobulin-like functions. The term antibody includes antibodies (e.g., monoclonal and polyclonal antibodies) , as well as derivatives, variants, and fragments thereof. Antibodies include, but are not limited to, immunoglobulins (Ig's) of different classes (i.e. IgA, IgG, IgM, IgD and IgE) and subclasses (such as IgG1, IgG2, etc. ) . A derivative, variant or fragment thereof can refer to a functional derivative or fragment which retains the binding specificity (e.g., complete and/or partial) of the corresponding antibody. Antigen-binding fragments include Fab, Fab′, F (ab′) 2, variable fragment (Fv) , single chain variable fragment (scFv) , minibodies, diabodies, and single-domain antibodies ( “sdAb” or “nanobodies” or “camelids” ) . The term antibody includes antibodies and antigen-binding fragments of antibodies that have been optimized, engineered or chemically conjugated. Examples of antibodies that have been optimized include affinity-matured antibodies. Examples of antibodies that have been engineered include Fc optimized antibodies (e.g., antibodies optimized in the fragment crystallizable region) and multispecific antibodies (e.g., bispecific antibodies) .
The term “antigen binding moiety” or “antigen binding domain, ” as used interchangeably herein, generally refers to a construct exhibiting preferential binding to a specific target antigen. An antigen binding domain can be a polypeptide construct, such as an antibody, modification thereof, fragment thereof, or a combination thereof. The antigen binding domain can be any antibody as disclosed herein, or a functional variant thereof. Non-limiting examples of an antigen binding domain can include a murine antibody, a human antibody, a humanized antibody, a camel Ig, a shark heavy-chain-only antibody (VNAR) , Ig NAR, a chimeric antibody, a recombinant antibody, or antibody fragment thereof. Non-limiting examples of antibody fragment include Fab, Fab′, F (ab) ′2, F (ab) ′3, Fv, single chain antigen binding fragment (scFv) , (scFv) 2, disulfide stabilized Fv (dsFv) , minibody, diabody, triabody, tetrabody, single-domain antigen binding fragments (sdAb, Nanobody) , recombinant heavy-chain-only antibody (VHH) , and other antibody fragments that maintain the binding specificity of the whole antibody.
The term “enhanced activity, ” “increased activity, ” or “upregulated activity” generally refers to activity of a moiety of interest (e.g., a polynucleotide or a polypeptide) that is modified to a level that is above a normal level of activity of the moiety of interest in a host strain (e.g., a host cell) . The normal level of activity can be substantially zero (or null) or higher than zero. The moiety of interest can comprise a polypeptide construct of the host strain. The moiety of interest can comprise a heterologous polypeptide construct that is introduced to or into the host strain. For example, a heterologous gene encoding a polypeptide of interest can be knocked-in (KI) to a genome of the host strain for enhanced activity of the polypeptide of interest in the host strain.
The term “reduced activity, ” “decreased activity, ” or “downregulated activity” generally refers to activity of a moiety of interest (e.g., a polynucleotide or a polypeptide) that is modified to a level that is below a normal level of activity of the moiety of interest in a host strain (e.g., a host cell) . The normal level of activity is higher than zero. The moiety of interest can comprise an endogenous gene or polypeptide construct of the host strain. In some cases, the moiety of interest can be knocked-out or knocked-down in the host strain. In some examples, reduced activity of the moiety of interest can include a complete inhibition of such activity in the host strain.
The term “subject, ” “individual, ” or “patient, ” as used interchangeably herein, generally refers to a vertebrate, preferably a mammal such as a human. Mammals include, but are not limited to, murines, simians, humans, farm animals, sport animals, and pets. Tissues, cells and their progeny of a biological entity obtained in vivo or cultured in vitro are also encompassed.
The term “treatment” or “treating” generally refers to an approach for obtaining beneficial or desired results including but not limited to a therapeutic benefit and/or a prophylactic benefit. For example, a treatment can comprise administering a system or cell population disclosed herein. By therapeutic benefit is meant any therapeutically relevant improvement in or effect on one or more diseases, conditions, or symptoms under treatment. For prophylactic benefit, a composition can be administered to a subject at risk of developing a particular disease, condition, or symptom, or to a subject reporting one or more of the physiological symptoms of a disease, even though the disease, condition, or symptom may not have yet been manifested.
The term “effective amount” or “therapeutically effective amount” generally refers to the quantity of a composition, for example a composition (e.g., one or more unit doses) as disclosed herein, that is sufficient to result in a desired activity upon administration to a subject in need thereof. Within the context of the present disclosure, the term “therapeutically effective” generally refers to that quantity of a composition that is sufficient to delay the manifestation, arrest the progression, relieve or alleviate at least one symptom of a disorder treated by the methods of the present disclosure.
The terms “Tenalisib, ” “CN401, ” and “RP6530” are used interchangeably herein.
Provided herein are compositions that comprise antibodies, such an anti-OX40 and/or anti-PD-1 antibodies, and PI3K inhibitors and methods of using the same to treat or prevent cancer. Also provided are therapeutic regimens that comprise administrations of antibodies and PI3K inhibitors. Combination therapies can confer increased anti-tumor effects as compared to single-therapy treatments due to synergistic effects associated with the combination therapies.
Provided herein are compositions that comprise antigen binding moieties. Provided herein is also a method for treating a subject in need thereof, comprising (a) administering to the subject a polypeptide comprising an antigen binding moiety exhibiting binding specificity to OX40.
OX40 is a type 1 transmembrane glycoprotein, is predominantly expressed by T cells (constitutively by regulatory T phenotypes and, after activation, by effector T cells) . OX40 induces expression of proteins with anti-apoptotic (Bcl-2, Bcl-xl and Bfl-1) and cell-cycle progression (Survivin) properties. OX40 counterbalance the inhibition of immune cells (including T lymphocytes CD4 +and CD8+, NK cells and B lymphocytes) while directly stimulating effector T cells.
Given the biological rationale to use co-stimulatory receptors as target therapy for enhancing immune response against tumors and based on in vitro results, many drugs that stimulate OX40 signaling have been developed. OX40 signaling can be triggered by OX40-specific agonistic antibodies, OX40L-Fc fusion proteins, transfection of DC with OX40L mRNA and tumor cells engineered to express OX40L on the surface, and any combination thereof.
In an aspect, provided herein is an antigen binding moiety that binds OX40 or a fragment thereof. In an aspect, an antigen binding moiety provided herein comprises an antibody or functional fragment there. An antibody may include polyclonal antibodies, multiclonal antibodies, monoclonal antibodies, chimeric antibodies, humanized and primatized antibodies, CDR grafted antibodies, human antibodies, recombinantly produced antibodies, intrabodies, multispecific antibodies, bispecific antibodies, monovalent antibodies, multivalent antibodies, anti-idiotypic antibodies, synthetic antibodies, including muteins and variants thereof, ; and derivatives thereof including Fc fusions and other modifications, and any other immunoreactive molecule so long as it exhibits preferential association or binding with a OX40 protein. Moreover, unless dictated otherwise by contextual constraints the term further comprises all classes of antibodies (i.e. IgA, IgD, IgE, IgG, and IgM) and all subclasses (i.e., IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2) . In a preferred embodiment, the antibody is a monoclonal antibody. In a more preferred embodiment, the antibody is a human monoclonal antibody. In a more preferred embodiment, the antibody is a human anti-OX40 monoclonal antibody.
In an aspect, an antigen binding moiety provided herein comprises an anti-OX40 monoclonal antibody. In an embodiment, exemplary polypeptides, antigen binding moieties, and combinations thereof can be provided in: WO2019214624, US7960515, US9695246, US9475880, US9040048, and sequences adapted therefrom, all of which are incorporated by reference herein.
Suitable antigen binding moieties and functional fragments thereof, are provided in Table 1 and Table 2. Polynucleotides that encode the antigen binding moieties and functional fragments thereof of Table 1 and Table 2 are provided in Table 3. In an embodiment, an antigen binding moiety comprises at least about 70%, 72%, 74%, 76%, 78%, 80%, 82%, 84%, 86%, 88%, 90%, 92%, 94%, 96%, 98%, or up to about 100% sequence identity to a CDR sequence of Table 1 or a variable polypeptide sequence of Table 2. In an embodiment, an antigen binding moiety is encoded by a polynucleotide sequence that comprises at least about 70%, 72%, 74%, 76%, 78%, 80%, 82%, 84%, 86%, 88%, 90%, 92%, 94%, 96%, 98%, or up to about 100% sequence identity to a sequence of Table 3.
In an embodiment, the antigen binding moiety comprises at least one heavy chain CDR (CDRH) selected from the group consisting of (i) - (iii) and at least one light chain CDR (CDRL) selected from the group consisting of (iv) - (vi) , wherein: (i) a CDRH1 having at least 80% sequence identity to a sequence selected from the group consisting of SEQ ID NOs: 1, 7, 13, 15, 21 and 27; (ii) a CDRH2 having at least 80% sequence identity to a sequence selected from the group consisting of SEQ ID NOs: 3, 9, 17, 23 and 29; (iii) a CDRH3 having at least 80% sequence identity to a sequence selected from the group consisting of SEQ ID NOs: 5, 11, 19, 25 and 31; (iv) a CDRL1 having at least 80% sequence identity to a sequence selected from the group consisting of SEQ ID NOs: 2, 8, 14, 16, 22 and 28; (v) a CDRL2 having at least 80% sequence identity to a sequence selected from the group consisting of SEQ ID NOs: 4, 10, 18, 24 and 30; and (vi) a CDRL3 having at least 80%sequence identity to a sequence selected from the group consisting of SEQ ID NOs: 6, 12, 20, 26 and 32.
Table 1: CDR amino acid sequences of fully human anti-OX40 monoclonal antibodies. Designated as “1.62.3-u1-IgG1K” , “1.62.3-u1-3-IgG1K” , “1.7.10-u1-IgG1K” , “1.134.9-u1-IgG1L” , “1.186.19-u1-IgG1K” and “1.214.23-u1-IgG1K” , respectively.
In an aspect, an antigen binding moiety provided herein comprises an anti-OX40 monoclonal antibody that comprises variable region sequence selected from a polypeptide in Table 2 or any combination thereof.
In an embodiment, an antigen binding moiety provided herein comprises (1) a heavy chain variable region (VH) having at least 70%, 72%, 74%, 76%, 78%, 80%, 82%, 84%, 86%, 88%, 90%, 92%, 94%, 96%, 98%, or up to about 100% sequence identity to a sequence selected from the group consisting of SEQ ID NOs: 33, 35, 37, 39, 41 and 43; and/or (2) a light chain variable region (VL) having at least 70%, 72%, 74%, 76%, 78%, 80%, 82%, 84%, 86%, 88%, 90%, 92%, 94%, 96%, 98%, or up to about 100% sequence identity to a sequence selected from the group consisting of SEQ ID NOs: 34, 36, 38, 40, 42 and 44. In an embodiment, the antigen binding moiety comprises (1) a VH having at least 70%, 72%, 74%, 76%, 78%, 80%, 82%, 84%, 86%, 88%, 90%, 92%, 94%, 96%, 98%, or up to about 100% sequence identity to SEQ ID NO: 39 and (2) a VL having at least 70%, 72%, 74%, 76%, 78%, 80%, 82%, 84%, 86%, 88%, 90%, 92%, 94%, 96%, 98%, or up to about 100% sequence identity to SEQ ID NO: 40.
Table 2: Variable region amino acid sequences of fully human anti-OX40 monoclonal antibodies. Designated as “1.62.3-u1-IgG1K” , “1.62.3-u1-3-IgG1K” , “1.7.10-u1-IgG1K” , “1.134.9-u1-IgG1L” , “1.186.19-u1-IgG1K” and “1.214.23-u1-IgG1K” , respectively.
In some aspects, the disclosure is directed to an isolated nucleic acid molecule, comprising a nucleic acid sequence encoding the heavy chain variable region and/or the light chain variable region of an antigen binding moiety as disclosed herein. An exemplary isolated nucleic acid molecule is provided in Table 3.
Table 3: Variable region nucleotide sequences of fully human anti-OX40 monoclonal antibodies. Designated as “1.62.3-u1-IgG1K” , “1.62.3-u1-3-IgG1K” , “1.7.10-u1-IgG1K” , “1.134.9-u1-IgG1L” , “1.186.19-u1-IgG1K” and “1.214.23-u1-IgG1K” , respectively.
Nucleic acids of the disclosure can be obtained using standard molecular biology techniques. For antibodies expressed by hybridomas (e.g., hybridomas prepared from transgenic mice carrying human immunoglobulin genes as described further below) , cDNAs encoding the light and heavy chains of the antibody made by the hybridoma can be obtained by standard PCR amplification or cDNA cloning techniques. For antibodies obtained from an immunoglobulin gene library (e.g., using phage display techniques) , a nucleic acid encoding such antibodies can be recovered from the gene library. The isolated nucleic acid encoding the VH region can be converted to a full-length heavy chain gene by operatively linking the VH-encoding nucleic acid to another DNA molecule encoding heavy chain constant regions (CH1, CH2, and CH3) . The sequences of human heavy chain constant region genes are known in the art (see e.g., Kabat et al. (1991) , supra) and DNA fragments encompassing these regions can be obtained by standard PCR amplification. The heavy chain constant region can be an IgG1, IgG2, IgG3, IgG4, IgA, IgE, IgM, or IgD constant region, but more preferably is an IgG1 or IgG4 constant region. The isolated nucleic acid encoding the VL region can be converted to a full-length light chain gene (as well as a Fab light chain gene) by operatively linking the VL-encoding DNA to another DNA molecule encoding the light chain constant region, CL. The sequences of human light chain constant region genes are known in the art (see e.g., Kabat et al., supra) and DNA fragments encompassing these regions can be obtained by standard PCR amplification. In preferred embodiments, the light chain constant region can be a kappa or lambda constant region.
Once DNA fragments encoding VH and VL segments are obtained, these DNA fragments can be further manipulated by standard recombinant DNA techniques, for example to convert the variable region genes to full-length antibody chain genes, to Fab fragment genes or to a scFv gene. In these manipulations, a VL-or VH-encoding DNA fragment is operatively linked to another DNA fragment encoding another protein, such as an antibody constant region or a flexible linker. The term “operatively linked” , as used in this context, is intended to mean that the two DNA fragments are joined such that the amino acid sequences encoded by the two DNA fragments remain in-frame.
PI3K are believed to be one of the key therapeutic targets for cancer treatment based on the observation that hyperactivity of PI3K signaling is significantly correlated with human tumor progression, increased tumor micro-vessel density and enhanced chemotaxis and invasive potential of cancer cells. PI3K signaling pathway is believed to be deregulated in a wide spectrum of human cancers making it an attractive target to target. Mutations of the kinases and/or decreased expression of PTEN lead to neoplastic transformation, underscoring its central role in human carcinogenesis. PI3K pathway is deregulated through a variety of mechanisms, including loss or inactivation of the tumor suppressor PTEN, mutation or amplification of PI3K, as well as activation of tyrosine kinase growth factor receptors or oncogenes upstream of PI3K.
Provided herein are compositions that comprise inhibitors against a phosphoinositide 3-kinase (PI3K) . Provided inhibitors can be direct or indirect inhibitors of PI3K. In an aspect, provided inhibitors can directly target any number of factors in the PI3K pathway. In another aspect, a provided inhibitor can indirectly target a factor in the PI3K pathway. In embodiments of the disclosure, inhibitors can target factors associated with aberrations involved in PI3K signaling as is further described herein.
PI3K is a group of plasma membrane-associated lipid kinases, comprising three subunits: p85 regulatory subunit, p55 regulatory subunit, and p110 catalytic subunit. According to their different structures and specific substrates, PI3K is divided into 3 classes: classes I, II, and III. Class I PI3Ks comprised of class IA and class IB PI3Ks. Class IA PI3K, a heterodimer of p58 regulatory subunit and p110 catalytic subunit, is the type most clearly implicated in human cancer. Class IA PI3K contains p110α, p110β and p110δ catalytic subunits produced from different genes (PIK3CA, PIK3CB, and PIK3CD, respectively) , while p110γ produced by PIK3CG represents the only catalytic subunit in class IB PI3K. The p85 regulatory subunit is composed of p85a (p85a, p55a and p50a splice variants) , p85b and p55g, which are encoded by the genes PIK3R1, PIK3R2 and PIK3R3, respectively. As an integration point for p110 activation and downstream molecular, p85 regulatory subunit binds and integrates signals from various transmembrane and intracellular proteins, including tyrosine kinase-linked receptors, protein kinase C (PKC) , Src homology 2 domain-containing protein tyrosine phosphatase 1 (SHP1) , Rac, Rho, hormonal receptors, Src, as well as mutated Ras.
In an aspect, a provided PI3K inhibitor is: a PI3K/mTOR inhibitor, pan-PI3K inhibitor, isoform-specific inhibitor, or any combination thereof.
In an aspect, a PI3K inhibitor is a dual PI3K/mTOR inhibitor. Exemplary dual PI3K/mTOR inhibitors are selected from the group that comprises: BGT-226, DS-7423, PF-04691502, PKI-179, GSK458/Omipalisib, P7170, SB2343/VS-5584, BEZ235/Dactolisib, GDC-0084, GDC-0980/Apitolisib, LY3023414, PQR309/Bimiralisib, XL765/Voxtalisib, SF-1126, PF-05212384/gedatolisib/PKI-587, or combinations thereof.
In an aspect, a PI3K inhibitor is a pan-PI3K inhibitor. Exemplary pan-PI3K inhibitors are selected from the group that comprises: GDC-0941/Pictilisib, PX-866, TG100–115, CH5132799, XL147/Pilaralisib, ZSTK474, BKM-120/Buparlisib, BAY80–6946/Copanlisib, WX-037, AZD8186, KA2237, CAL-120, ME401, AMG319, GSK2636771, INCB050465, INK-1117, TGR-1202, RP6530, GDC-0032, BYL719, IPI-145, CAL-101, or combinations thereof.
In an aspect, a PI3K inhibitor is an isoform-specific inhibitor. Exemplary isoform-specific inhibitors are selected from the group that comprises: AZD8835 δ/α, WX-037 α, AZD8186 β/δ, KA2237 β/δ, GS-9820/CAL-120 β/δ, ME401/PWT-143 δ, AMG 319 δ, GSK2636771 β, INCB050465/Parsaclisib δ, Serabelisib/INK-1117 α, Umbralisib/TGR-1202 δ, RP6530/Tenalisib δ/γ, GDC-0032/Taselisib α/δ/γ (Taselisib) , BYL719/Alpelisib α, Duvelisib/IPI-145 δ/γ, CAL-101/idelalisib δ, or combinations thereof. In an embodiment, a PI3K inhibitor is an isoform-specific inhibitor. In an embodiment, a PI3K inhibitor is the isoform-specific inhibitor and is Taselisib.
Other suitable PI3K inhibitors include but are not limited to: CUDC-907/Fimepinostat and Rigosertib/ON-01910.
In an embodiment, a PI3K inhibitor is against one or more members selected from the group consisting of class 1 catalytic PI3K (e.g., PI3K alpha, PI3K beta, PI3K delta, PI3K gamma) , class 1 regulatory PI3K (e.g., PIK3R1, PIK3R2, PIK3R3, PIK3R4, PIK3R5, PIK3R6) , class 2 PI3K (e.g., PIK3C2A, PIK3C2B, PIK3C2G) , and class 3 PI3K (e.g., PIK3C3) . In some cases, a PI3K inhibitor can be against one or more members selected from the group consisting of PI3K alpha, PI3K beta, PI3K delta, and PI3K gamma. In some cases, a PI3K inhibitor can be against one or more members selected from the group consisting of PI3K delta and PI3K gamma. In some examples, a PI3K inhibitor can be against both PI3K delta and PI3K gamma.
In an embodiment, a PI3K inhibitor is selected from the group that consists of: Wortmannin, LY294002, hibiscone C, Idelalisib, Copanlisib, Duvelisib, Alpelisib, Taselisib, Perifosine, Buparlisib, Umbralisib, PX-866, Dactolisib, CUDC-907, Voxtalisib, CUDC-907, ME-401, IPI-549, SF1126, Tenalisib (RP6530) , INK1117, pictilisib, XL147, Palomid 529, GSK1059615, ZSTK474, PWT33597, IC87114, TG100–115, CAL263, RP6503, PI-103, GNE-477, and AEZS-136. In an embodiment, a PI3K inhibitor is selected from the group consisting of: Idelalisib, Copanlisib, Duvelisib, Alpelisib, Taselisib, Perifosine, Buparlisib, Umbralisib, and Tenalisib. In an embodiment, the PI3K inhibitor comprises Tenalisib.
In another aspect, provided are inhibitors that indirectly target pathologic signaling through the PI3K pathway. In addition to inherent aberrations in members of the PI3K pathway, pathologic signaling through this pathway can also occur in other ways, including tyrosine kinase growth factor receptors (e.g. human epidermal growth factor receptor 2 and insulin-like growth factor -1 receptor) , cell adhesion molecules (e.g. integrins, GPCR) , and oncogenes (e.g. RAS) all of which can be targeted to resolve aberrant PI3K signaling.
In an aspect, compositions provided herein that comprise antigen binding moieties and inhibitors can be utilized for treatment and prevention of disease. Provided compositions can be utilized in combination therapies to combat cancer and to reduce and/or eliminate primary and/or secondary resistance to immunotherapy.
In an aspect, a method for treating a subject in need thereof comprises: (a) administering to the subject a polypeptide comprising an antigen binding moiety exhibiting binding specificity to OX40. In an embodiment, the antigen binding moiety comprises at least one heavy chain CDR (CDRH) selected from the group consisting of (i) - (iii) and at least one light chain CDR (CDRL) selected from the group consisting of (iv) - (vi) , wherein: (i) a CDRH1 having at least 80% sequence identity to a sequence selected from the group consisting of SEQ ID NOs: 1, 7, 13, 15, 21 and 27; (ii) a CDRH2 having at least 80% sequence identity to a sequence selected from the group consisting of SEQ ID NOs: 3, 9, 17, 23 and 29; (iii) a CDRH3 having at least 80% sequence identity to a sequence selected from the group consisting of SEQ ID NOs: 5, 11, 19, 25 and 31; (iv) a CDRL1 having at least 80% sequence identity to a sequence selected from the group consisting of SEQ ID NOs: 2, 8, 14, 16, 22 and 28; (v) a CDRL2 having at least 80%sequence identity to a sequence selected from the group consisting of SEQ ID NOs: 4, 10, 18, 24 and 30; and (vi) a CDRL3 having at least 80% sequence identity to a sequence selected from the group consisting of SEQ ID NOs: 6, 12, 20, 26 and 32; and (b) administering to the subject an inhibitor against PI3K.
In an aspect, a method comprises treating a subject in need thereof, comprising: (a) administering to the subject a polypeptide comprising an antigen binding moiety exhibiting binding specificity to OX40; and (b) administering to the subject an inhibitor against PI3K. In an embodiment, the inhibitor is a PI3K/mTOR inhibitor, pan-PI3K inhibitor, isoform-specific inhibitor, or any combination thereof. In an embodiment an inhibitor is the isoform-specific inhibitor. In an embodiment the inhibitor comprises one or more members selected from the group consisting of Wortmannin, LY294002, hibiscone C, Idelalisib, Copanlisib, Duvelisib, Alpelisib, Taselisib, Perifosine, Buparlisib, Umbralisib, PX-866, Dactolisib, CUDC-907, Voxtalisib, CUDC-907, ME-401, IPI-549, SF1126, RP6530, INK1117, pictilisib, XL147, Palomid 529, GSK1059615, ZSTK474, PWT33597, IC87114, TG100–115, CAL263, RP6503, PI-103, GNE-477, and AEZS-136. In an embodiment, the inhibitor comprises one or more members selected from the group consisting of Idelalisib, Copanlisib, Duvelisib, Alpelisib, Taselisib, Perifosine, Buparlisib, and Umbralisib. In an aspect, the inhibitor comprises Tenalisib.
In an aspect, administration of the polypeptide and the inhibitor against PI3K synergistically yield one or more characteristics selected from the group consisting of: (A) a greater degree of toxicity against a diseased cell as compared to either of the polypeptide or the inhibitor against PI3K; and (B) a reduction in tumor size as compared to either of the polypeptide or the inhibitor against PI3K. In an embodiment, the administration of the polypeptide and the inhibitor against PI3K synergistically yields one or more characteristics selected from the group consisting of: (A) a degree of toxicity against a diseased cell that is at least about 20%, at least about 40%, at least about 60%, at least about 80%, at least about 100%, or at least about 200% greater than that that of either of the polypeptide or the inhibitor against PI3K and/or (B) a reduction in tumor size by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, or at least about 60% as compared to that of either the polypeptide or the inhibitor against PI3K. In an embodiment, the reduction in tumor size can be at least about or at most about: 1-fold, 5-fold, 10- fold, 15-fold, 20-fold, 40-fold, 60-fold, 80-fold, 100-fold, or up to about 200-fold. In an embodiment, the reduction in tumor size is elimination of the tumor.
In some aspects, the disclosure also provides a method of enhancing (for example, stimulating) an immune response in a subject comprising administering a subject polypeptide and/or a subject inhibitor to the subject such that an immune response in the subject is enhanced. In an aspect, the enhancement is greater than a comparable method lacking the combination or the polypeptide or inhibitor. For example, the subject is a mammal. In a specific embodiment, the subject is a human. In an aspect, the enhancement is greater than a comparable method lacking the combination or the polypeptide or inhibitor by at least about or at most about 1 fold, 2 fold, 3 fold, 4 fold, 10 fold, 20 fold, 30 fold, 40 fold, 60 fold, 100 fold, 200 fold, 300 fold, or 500 fold. For example, the subject is a mammal. In a specific embodiment, the subject is a human.
In an aspect, enhancing an immune response or its grammatical variations, means stimulating, evoking, increasing, improving, or augmenting any response of a mammal’s immune system. The immune response may be a cellular response (i.e. cell-mediated, such as cytotoxic T lymphocyte mediated) or a humoral response (i.e. antibody mediated response) , and may be a primary or secondary immune response. Examples of enhancement of immune response include increased CD4 + helper T cell activity and generation of cytolytic T cells. The enhancement of immune response can be assessed using a number of in vitro or in vivo measurements known to those skilled in the art, including, but not limited to, cytotoxic T lymphocyte assays, release of cytokines (for example IL-2 production or IFN-γ production) , regression of tumors, survival of tumor bearing animals, antibody production, immune cell proliferation, expression of cell surface markers, and cytotoxicity. Typically, methods of the disclosure enhance the immune response by a mammal when compared to the immune response by an untreated mammal or a mammal not treated using the methods as disclosed herein. In one embodiment, the polypeptide and/or inhibitor is used to enhance the immune response of a human to a subject target. In one embodiment, the method enhances a cellular immune response, particularly a cytotoxic T cell response. In another embodiment, the cellular immune response is a T helper cell response. In still another embodiment, the immune response is a cytokine production, particularly IFN-γ production or IL-2 production.
Any one of the compositions and methods disclosed herein can be utilized to treat a target cell, a target tissue, a target condition, or a target disease of a subject.
A target disease can be a viral, bacterial, and/or parasitic infection; inflammatory and/or autoimmune disease; or neoplasm such as a cancer and/or tumor.
A target cell can be a diseased cell. A diseased cell can have altered metabolic, gene expression, and/or morphologic features. A diseased cell can be a cancer cell, a diabetic cell, and an apoptotic cell. A diseased cell can be a cell from a diseased subject. Exemplary diseases can include blood disorders, cancers, metabolic disorders, eye disorders, organ disorders, musculoskeletal disorders, cardiac disease, and the like.
A variety of target cells can be killed using any one of the methods or compositions disclosed herein. A target cell can include a wide variety of cell types. A target cell can be in vitro. A target cell can be in vivo. A target cell can be ex vivo. A target cell can be an isolated cell. A target cell can be a cell inside of an organism. A target cell can be an organism. A target cell can be a cell in a cell culture. A target cell can be one of a collection of cells. A target cell can be a mammalian cell or derived from a mammalian cell. A target cell can be a rodent cell or derived from a rodent cell. A target cell can be a human cell or derived from a human cell. A target cell can be a prokaryotic cell or derived from a prokaryotic cell. A target cell can be a bacterial cell or can be derived from a bacterial cell. A target cell can be an archaeal cell or derived from an archaeal cell. A target cell can be a eukaryotic cell or derived from a eukaryotic cell. A target cell can be a pluripotent stem cell. A target cell can be a plant cell or derived from a plant cell. A target cell can be an animal cell or derived from an animal cell. A target cell can be an invertebrate cell or derived from an invertebrate cell. A target cell can be a vertebrate cell or derived from a vertebrate cell. A target cell can be a microbe cell or derived from a microbe cell. A target cell can be a fungi cell or derived from a fungi cell. A target cell can be from a specific organ or tissue.
A target cell can be a stem cell or progenitor cell. Target cells can include stem cells (e.g., adult stem cells, embryonic stem cells, induced pluripotent stem (iPS) cells) and progenitor cells (e.g., cardiac progenitor cells, neural progenitor cells, etc. ) . Target cells can include mammalian stem cells and progenitor cells, including rodent stem cells, rodent progenitor cells, human stem cells, human progenitor cells, etc. Clonal cells can comprise the progeny of a cell. A target cell can comprise a target nucleic acid. A target cell can be in a living organism. A target cell can be a genetically modified cell. A target cell can be a host cell.
A target cell can be a totipotent stem cell, however, in some embodiments of this disclosure, the term “cell” may be used but may not refer to a totipotent stem cell. A target cell can be a plant cell, but in some embodiments of this disclosure, the term “cell” may be used but may not refer to a plant cell. A target cell can be a pluripotent cell. For example, a target cell can be a pluripotent hematopoietic cell that can differentiate into other cells in the hematopoietic cell lineage but may not be able to differentiate into any other non-hematopoietic cell. A target cell may be able to develop into a whole organism. A target cell may or may not be able to develop into a whole organism. A target cell may be a whole organism.
A target cell can be a primary cell. For example, cultures of primary cells can be passaged 0 times, 1 time, 2 times, 4 times, 5 times, 10 times, 15 times or more. Cells can be unicellular organisms. Cells can be grown in culture.
A target cell can be a diseased cell. A diseased cell can have altered metabolic, gene expression, and/or morphologic features. A diseased cell can be a cancer cell, a diabetic cell, and an apoptotic cell. A diseased cell can be a cell from a diseased subject. Exemplary diseases can include blood disorders, cancers, metabolic disorders, eye disorders, organ disorders, musculoskeletal disorders, cardiac disease, and the like.
If the target cells are primary cells, they may be harvested from an individual by any method. For example, leukocytes may be harvested by apheresis, leukocytapheresis, density gradient separation, etc. Cells from tissues such as skin, muscle, bone marrow, spleen, liver, pancreas, lung, intestine, stomach, etc. can be harvested by biopsy. An appropriate solution may be used for dispersion or suspension of the harvested cells. Such solution can generally be a balanced salt solution, (e.g. normal saline, phosphate-buffered saline (PBS) , Hank's balanced salt solution, etc. ) , conveniently supplemented with fetal calf serum or other naturally occurring factors, in conjunction with an acceptable buffer at low concentration. Buffers can include HEPES, phosphate buffers, lactate buffers, etc. Cells may be used immediately, or they may be stored (e.g., by freezing) . Frozen cells can be thawed and can be capable of being reused. Cells can be frozen in a DMSO, serum, medium buffer (e.g., 10% DMSO, 50% serum, 40% buffered medium) , and/or some other such common solution used to preserve cells at freezing temperatures.
Non-limiting examples of cells which can be target cells include, but are not limited to, lymphoid cells, such as B cell, T cell (Cytotoxic T cell, Natural Killer T cell, Regulatory T cell, T helper cell) , Natural killer cell, cytokine induced killer (CIK) cells (see e.g. US20080241194) ; myeloid cells, such as granulocytes (Basophil granulocyte, Eosinophil granulocyte, Neutrophil granulocyte/Hypersegmented neutrophil) , Monocyte/Macrophage, Red blood cell (Reticulocyte) , Mast cell, Thrombocyte/Megakaryocyte, Dendritic cell; cells from the endocrine system, including thyroid (Thyroid epithelial cell, Parafollicular cell) , parathyroid (Parathyroid chief cell, Oxyphil cell) , adrenal (Chromaffin cell) , pineal (Pinealocyte) cells; cells of the nervous system, including glial cells (Astrocyte, Microglia) , Magnocellular neurosecretory cell, Stellate cell, Boettcher cell, and pituitary (Gonadotrope, Corticotrope, Thyrotrope, Somatotrope, Lactotroph) ; cells of the Respiratory system, including Pneumocyte (Type I pneumocyte, Type II pneumocyte) , Clara cell, Goblet cell, Dust cell; cells of the circulatory system, including Myocardiocyte, Pericyte; cells of the digestive system, including stomach (Gastric chief cell, Parietal cell) , Goblet cell, Paneth cell, G cells, D cells, ECL cells, I cells, K cells, S cells; enteroendocrine cells, including enterochromaffm cell, APUD cell, liver (Hepatocyte, Kupffer cell) , Cartilage/bone/muscle; bone cells, including Osteoblast, Osteocyte, Osteoclast, teeth (Cementoblast, Ameloblast) ; cartilage cells, including Chondroblast, Chondrocyte; skin cells, including Trichocyte, Keratinocyte, Melanocyte (Nevus cell) ; muscle cells, including Myocyte; urinary system cells, including Podocyte, Juxtaglomerular cell, Intraglomerular mesangial cell/Extraglomerular mesangial cell, Kidney proximal tubule brush border cell, Macula densa cell; reproductive system cells, including Spermatozoon, Sertoli cell, Leydig cell, Ovum; and other cells, including Adipocyte, Fibroblast, Tendon cell, Epidermal keratinocyte (differentiating epidermal cell) , Epidermal basal cell (stem cell) , Keratinocyte of fingernails and toenails, Nail bed basal cell (stem cell) , Medullary hair shaft cell, Cortical hair shaft cell, Cuticular hair shaft cell, Cuticular hair root sheath cell, Hair root sheath cell of Huxley's layer, Hair root sheath cell of Henle's layer, External hair root sheath cell, Hair matrix cell (stem cell) , Wet stratified barrier epithelial cells, Surface epithelial cell of stratified squamous epithelium of cornea, tongue, oral cavity, esophagus, anal canal, distal urethra and vagina, basal cell (stem cell) of epithelia of cornea, tongue, oral cavity, esophagus, anal canal, distal urethra and vagina, Urinary epithelium cell (lining urinary bladder and urinary ducts) , Exocrine secretory epithelial cells, Salivary gland mucous cell (polysaccharide-rich secretion) , Salivary gland serous cell (glycoprotein enzyme-rich secretion) , Von Ebner's gland cell in tongue (washes taste buds) , Mammary gland cell (milk secretion) , Lacrimal gland cell (tear secretion) , Ceruminous gland cell in ear (wax secretion) , Eccrine sweat gland dark cell (glycoprotein secretion) , Eccrine sweat gland clear cell (small molecule secretion) . Apocrine sweat gland cell (odoriferous secretion, sex-hormone sensitive) , Gland of Moll cell in eyelid (specialized sweat gland) , Sebaceous gland cell (lipid-rich sebum secretion) , Bowman's gland cell in nose (washes olfactory epithelium) , Brunner's gland cell in duodenum (enzymes and alkaline mucus) , Seminal vesicle cell (secretes seminal fluid components, including fructose for swimming sperm) , Prostate gland cell (secretes seminal fluid components) , Bulbourethral gland cell (mucus secretion) , Bartholin's gland cell (vaginal lubricant secretion) , Gland of Littre cell (mucus secretion) , Uterus endometrium cell (carbohydrate secretion) , Isolated goblet cell of respiratory and digestive tracts (mucus secretion) , Stomach lining mucous cell (mucus secretion) , Gastric gland zymogenic cell (pepsinogen secretion) , Gastric gland oxyntic cell (hydrochloric acid secretion) , Pancreatic acinar cell (bicarbonate and digestive enzyme secretion) , Paneth cell of small intestine (lysozyme secretion) , Type II pneumocyte of lung (surfactant secretion) , Clara cell of lung, Hormone secreting cells, Anterior pituitary cells, Somatotropes, Lactotropes, Thyrotropes, Gonadotropes, Corticotropes, Intermediate pituitary cell, Magnocellular neurosecretory cells, Gut and respiratory tract cells, Thyroid gland cells, thyroid epithelial cell, parafollicular cell, Parathyroid gland cells, Parathyroid chief cell, Oxyphil cell, Adrenal gland cells, chromaffin cells, Ley dig cell of testes, Theca interna cell of ovarian follicle, Corpus luteum cell of ruptured ovarian follicle, Granulosa lutein cells, Theca lutein cells, Juxtaglomerular cell (renin secretion) , Macula densa cell of kidney, Metabolism and storage cells, Barrier function cells (Lung, Gut, Exocrine Glands and Urogenital Tract) , Kidney, Type I pneumocyte (lining air space of lung) , Pancreatic duct cell (centroacinar cell) , Nonstriated duct cell (of sweat gland, salivary gland, mammary gland, etc. ) , Duct cell (of seminal vesicle, prostate gland, etc. ) , Epithelial cells lining closed internal body cavities, Ciliated cells with propulsive function, Extracellular matrix secretion cells, Contractile cells; Skeletal muscle cells, stem cell, Heart muscle cells, Blood and immune system cells, Erythrocyte (red blood cell) , Megakaryocyte (platelet precursor) , Monocyte, Connective tissue macrophage (various types) , Epidermal Langerhans cell, Osteoclast (in bone) , Dendritic cell (in lymphoid tissues) , Microglial cell (in central nervous system) , Neutrophil granulocyte, Eosinophil granulocyte, Basophil granulocyte, Mast cell, Helper T cell, Suppressor T cell, Cytotoxic T cell, Natural Killer T cell, B cell, Natural killer cell, Reticulocyte, Stem cells and committed progenitors for the blood and immune system (various types) , Pluripotent stem cells, Totipotent stem cells, Induced pluripotent stem cells, adult stem cells, Sensory transducer cells, Autonomic neuron cells, Sense organ and peripheral neuron supporting cells, Central nervous system neurons and glial cells, Lens cells, Pigment cells, Melanocyte, Retinal pigmented epithelial cell, Germ cells, Oogonium/Oocyte, Spermatid, Spermatocyte, Spermatogonium cell (stem cell for spermatocyte) , Spermatozoon, Nurse cells, Ovarian follicle cell, Sertoli cell (in testis) , Thymus epithelial cell, Interstitial cells, and Interstitial kidney cells.
Of particular interest are cancer cells. In some embodiments, the target cell is a cancer cell. Non-limiting examples of cancer cells include cells of cancers including Acanthoma, Acinic cell carcinoma, Acoustic neuroma, Acral lentiginous melanoma, Acrospiroma, Acute eosinophilic leukemia, Acute lymphoblastic leukemia, Acute megakaryoblastic leukemia, Acute monocytic leukemia, Acute myeloblastic leukemia with maturation, Acute myeloid dendritic cell leukemia, Acute myeloid leukemia, Acute promyelocytic leukemia, Adamantinoma, Adenocarcinoma, Adenoid cystic carcinoma, Adenoma, Adenomatoid odontogenic tumor, Adrenocortical carcinoma, Adult T-cell leukemia, Aggressive NK-cell leukemia, AIDS-Related Cancers, AIDS-related lymphoma, Alveolar soft part sarcoma, Ameloblastic fibroma, Anal cancer, Anaplastic large cell lymphoma, Anaplastic thyroid cancer, Angioimmunoblastic T-cell lymphoma, Angiomyolipoma, Angiosarcoma, Appendix cancer, Astrocytoma, Atypical teratoid rhabdoid tumor, Basal cell carcinoma, Basal-like carcinoma, B-cell leukemia, B-cell lymphoma, Bellini duct carcinoma, Biliary tract cancer, Bladder cancer, Blastoma, Bone Cancer, Bone tumor, Brain Stem Glioma, Brain Tumor, Breast Cancer, Brenner tumor, Bronchial Tumor, Bronchioloalveolar carcinoma, Brown tumor, Burkitt's lymphoma, Cancer of Unknown Primary Site, Carcinoid Tumor, Carcinoma, Carcinoma in situ, Carcinoma of the penis, Carcinoma of Unknown Primary Site, Carcinosarcoma, Castleman's Disease, Central Nervous System Embryonal Tumor, Cerebellar Astrocytoma, Cerebral Astrocytoma, Cervical Cancer, Cholangiocarcinoma, Chondroma, Chondrosarcoma, Chordoma, Choriocarcinoma, Choroid plexus papilloma, Chronic Lymphocytic Leukemia, Chronic monocytic leukemia, Chronic myelogenous leukemia, Chronic Myeloproliferative Disorder, Chronic neutrophilic leukemia, Clear-cell tumor, Colon Cancer, Colorectal cancer, Craniopharyngioma, Cutaneous T-cell lymphoma, Degos disease, Dermatofibrosarcoma protuberans, Dermoid cyst, Desmoplastic small round cell tumor, Diffuse large B cell lymphoma, Dysembryoplastic neuroepithelial tumor, Embryonal carcinoma, Endodermal sinus tumor, Endometrial cancer, Endometrial Uterine Cancer, Endometrioid tumor, Enteropathy-associated T-cell lymphoma, Ependymoblastoma, Ependymoma, Epithelioid sarcoma, Erythroleukemia, Esophageal cancer, Esthesioneuroblastoma, Ewing Family of Tumor, Ewing Family Sarcoma, Ewing's sarcoma, Extracranial Germ Cell Tumor, Extragonadal Germ Cell Tumor, Extrahepatic Bile Duct Cancer, Extramammary Paget's disease, Fallopian tube cancer, Fetus in fetu, Fibroma, Fibrosarcoma, Follicular lymphoma, Follicular thyroid cancer, Gallbladder Cancer, Gallbladder cancer, Ganglioglioma, Ganglioneuroma, Gastric Cancer, Gastric lymphoma, Gastrointestinal cancer, Gastrointestinal Carcinoid Tumor, Gastrointestinal Stromal Tumor, Gastrointestinal stromal tumor, Germ cell tumor, Germinoma, Gestational choriocarcinoma, Gestational Trophoblastic Tumor, Giant cell tumor of bone, Glioblastoma multiforme, Glioma, Gliomatosis cerebri, Glomus tumor, Glucagonoma, Gonadoblastoma, Granulosa cell tumor, Hairy Cell Leukemia, Hairy cell leukemia, Head and Neck Cancer, Head and neck cancer, Heart cancer, Hemangioblastoma, Hemangiopericytoma, Hemangiosarcoma, Hematological malignancy, Hepatocellular carcinoma, Hepatosplenic T-cell lymphoma, Hereditary breast-ovarian cancer syndrome, Hodgkin Lymphoma, Hodgkin's lymphoma, Hypopharyngeal Cancer, Hypothalamic Glioma, Inflammatory breast cancer, Intraocular Melanoma, Islet cell carcinoma, Islet Cell Tumor, Juvenile myelomonocytic leukemia, Kaposi Sarcoma, Kaposi's sarcoma, Kidney Cancer, Klatskin tumor, Krukenberg tumor, Laryngeal Cancer, Laryngeal cancer, Lentigo maligna melanoma, Leukemia, Leukemia, Lip and Oral Cavity Cancer, Liposarcoma, Lung cancer, Luteoma, Lymphangioma, Lymphangiosarcoma, Lymphoepithelioma, Lymphoid leukemia, Lymphoma, Macroglobulinemia, Malignant Fibrous Histiocytoma, Malignant fibrous histiocytoma, Malignant Fibrous Histiocytoma of Bone, Malignant Glioma, Malignant Mesothelioma, Malignant peripheral nerve sheath tumor, Malignant rhabdoid tumor, Malignant triton tumor, MALT lymphoma, Mantle cell lymphoma, Mast cell leukemia, Mediastinal germ cell tumor, Mediastinal tumor, Medullary thyroid cancer, Medulloblastoma, Medulloblastoma, Medulloepithelioma, Melanoma, Melanoma, Meningioma, Merkel Cell Carcinoma, Mesothelioma, Mesothelioma, Metastatic Squamous Neck Cancer with Occult Primary, Metastatic urothelial carcinoma, Mixed Mullerian tumor, Monocytic leukemia, Mouth Cancer, Mucinous tumor, Multiple Endocrine Neoplasia Syndrome, Multiple Myeloma, Multiple myeloma, Mycosis Fungoides, Mycosis fungoides, Myelodysplastic Disease, Myelodysplastic Syndromes, Myeloid leukemia, Myeloid sarcoma, Myeloproliferative Disease, Myxoma, Nasal Cavity Cancer, Nasopharyngeal Cancer, Nasopharyngeal carcinoma, Neoplasm, Neurinoma, Neuroblastoma, Neuroblastoma, Neurofibroma, Neuroma, Nodular melanoma, Non-Hodgkin Lymphoma, Non-Hodgkin lymphoma, Nonmelanoma Skin Cancer, Non-Small Cell Lung Cancer, Ocular oncology, Oligoastrocytoma, Oligodendroglioma, Oncocytoma, Optic nerve sheath meningioma, Oral Cancer, Oral cancer, Oropharyngeal Cancer, Osteosarcoma, Osteosarcoma, Ovarian Cancer, Ovarian cancer, Ovarian Epithelial Cancer, Ovarian Germ Cell Tumor, Ovarian Low Malignant Potential Tumor, Paget's disease of the breast, Pancoast tumor, Pancreatic Cancer, Pancreatic cancer, Papillary thyroid cancer, Papillomatosis, Paraganglioma, Paranasal Sinus Cancer, Parathyroid Cancer, Penile Cancer, Perivascular epithelioid cell tumor, Pharyngeal Cancer, Pheochromocytoma, Pineal Parenchymal Tumor of Intermediate Differentiation, Pineoblastoma, Pituicytoma, Pituitary adenoma, Pituitary tumor, Plasma Cell Neoplasm, Pleuropulmonary blastoma, Polyembryoma, Precursor T-lymphoblastic lymphoma, Primary central nervous system lymphoma, Primary effusion lymphoma, Primary Hepatocellular Cancer, Primary Liver Cancer, Primary peritoneal cancer, Primitive neuroectodermal tumor, Prostate cancer, Pseudomyxoma peritonei, Rectal Cancer, Renal cell carcinoma, Respiratory Tract Carcinoma Involving the NUT Gene on Chromosome 15, Retinoblastoma, Rhabdomyoma, Rhabdomyosarcoma, Richter's transformation, Sacrococcygeal teratoma, Salivary Gland Cancer, Sarcoma, Schwannomatosis, Sebaceous gland carcinoma, Secondary neoplasm, Seminoma, Serous tumor, Sertoli-Leydig cell tumor, Sex cord-stromal tumor, Sezary Syndrome, Signet ring cell carcinoma, Skin Cancer, Small blue round cell tumor, Small cell carcinoma, Small Cell Lung Cancer, Small cell lymphoma, Small intestine cancer, Soft tissue sarcoma, Somatostatinoma, Soot wart, Spinal Cord Tumor, Spinal tumor, Splenic marginal zone lymphoma, Squamous cell carcinoma, Stomach cancer, Superficial spreading melanoma, Supratentorial Primitive Neuroectodermal Tumor, Surface epithelial-stromal tumor, Synovial sarcoma, T-cell acute lymphoblastic leukemia, T-cell large granular lymphocyte leukemia, T-cell leukemia, T-cell lymphoma, T-cell prolymphocytic leukemia, Teratoma, Terminal lymphatic cancer, Testicular cancer, Thecoma, Throat Cancer, Thymic Carcinoma, Thymoma, Thyroid cancer, Transitional Cell Cancer of Renal Pelvis and Ureter, Transitional cell carcinoma, Urachal cancer, Urethral cancer, Urogenital neoplasm, Uterine sarcoma, Uveal melanoma, Vaginal Cancer, Verner Morrison syndrome, Verrucous carcinoma, Visual Pathway Glioma, Vulvar Cancer, Waldenstrom's macroglobulinemia, Warthin's tumor, Wilms' tumor, and combinations thereof. In some embodiments, the targeted cancer cell represents a subpopulation within a cancer cell population, such as a cancer stem cell. In some embodiments, the cancer is of a hematopoietic lineage, such as a lymphoma. The antigen can be a tumor associated antigen.
In some cases, the subject can have or can be suspected of having an autoimmune disease. Non-limiting examples of an autoimmune disease can include acute disseminated encephalomyelitis (ADEM) , acute necrotizing hemorrhagic leukoencephalitis, Addison's disease, agammaglobulinemia, allergic asthma, allergic rhinitis, alopecia areata, amyloidosis, ankylosing spondylitis, antibody-mediated transplantation rejection, anti-GBM/Anti-TBM nephritis, antiphospholipid syndrome (APS) , autoimmune angioedema, autoimmune aplastic anemia, autoimmune dysautonomia, autoimmune hepatitis, autoimmune hyperlipidemia, autoimmune immunodeficiency, autoimmune inner ear disease (AIED) , autoimmune myocarditis, autoimmune pancreatitis, autoimmune retinopathy, autoimmune thrombocytopenic purpura (ATP) , autoimmune thyroid disease, autoimmune urticaria, axonal & neuronal neuropathies, Balo disease, Behcet's disease, bullous pemphigoid, cardiomyopathy, Castleman disease, celiac disease, Chagas disease, chronic fatigue syndrome, chronic inflammatory demyelinating polyneuropathy (CIDP) , chronic recurrent multifocal ostomyelitis (CRMO) , Churg-Strauss syndrome, cicatricial pemphigoid/benign mucosal pemphigoid, Crohn's disease, Cogans syndrome, cold agglutinin disease, congenital heart block, coxsackie myocarditis, CREST disease, essential mixed cryoglobulinemia, demyelinating neuropathies, dermatitis herpetiformis, dermatomyositis, Devic's disease (neuromyelitis optica) , discoid lupus, Dressler's syndrome, endometriosis, eosinophilic fasciitis, erythema nodosum, experimental allergic encephalomyelitis, Evans syndrome, fibromyalgia, fibrosing alveolitis, giant cell arteritis (temporal arteritis) , glomerulonephritis, goodpasture's syndrome, granulomatosis with polyangiitis (GPA) , Graves' disease, Guillain-Barre syndrome, Hashimoto's encephalitis, Hashimoto's thyroiditis, hemolytic anemia, Henoch-Schonlein purpura, herpes gestationis, hypogammaglobulinemia, hypergammaglobulinemia, idiopathic thrombocytopenic purpura (ITP) , IgA nephropathy, IgG4-related sclerosing disease, immunoregulatory lipoproteins, inclusion body myositis, inflammatory bowel disease, insulin-dependent diabetes (type 1) , interstitial cystitis, juvenile arthritis, juvenile diabetes, Kawasaki syndrome, Lambert-Eaton syndrome, leukocytoclastic vasculitis, lichen planus, lichen sclerosus, ligneous conjunctivitis, linear IgA disease (LAD) , lupus (SLE) , lyme disease, Meniere's disease, microscopic polyangiitis, mixed connective tissue disease (MCTD) , monoclonal gammopathy of undetermined significance (MGUS) , Mooren's ulcer, Mucha-Habermann disease, multiple sclerosis, myasthenia gravis, myositis, narcolepsy, neuromyelitis optica (Devic's) , neutropenia, ocular cicatricial pemphigoid, optic neuritis, palindromic rheumatism, PANDAS (Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcus) , paraneoplastic cerebellar degeneration, paroxysmal nocturnal hemoglobinuria (PNH) , Parry Romberg syndrome, Parsonnage-Turner syndrome, pars planitis (peripheral uveitis) , pemphigus, peripheral neuropathy, perivenous encephalomyelitis, pernicious anemia, POEMS syndrome, polyarteritis nodosa, type I, II, & III autoimmune polyglandular syndromes, polymyalgia rheumatic, polymyositis, postmyocardial infarction syndrome, postpericardiotomy syndrome, progesterone dermatitis, primary biliary cirrhosis, primary sclerosing cholangitis, psoriasis, psoriatic arthritis, idiopathic pulmonary fibrosis, pyoderma gangrenosum, pure red cell aplasia, Raynauds phenomenon, reflex sympathetic dystrophy, Reiter's syndrome, relapsing polychondritis, restless legs syndrome, retroperitoneal fibrosis, rheumatic fever, rheumatoid arthritis, sarcoidosis, Schmidt syndrome, scleritis, scleroderma, Sjogren's syndrome, sperm & testicular autoimmunity, stiff person syndrome, subacute bacterial endocarditis (SBE) , Susac's syndrome, sympathetic ophthalmia, Takayasu's arteritis, temporal arteritis/Giant cell arteritis, thrombocytopenic purpura (TTP) , Tolosa-Hunt syndrome, transverse myelitis, ulcerative colitis, undifferentiated connective tissue disease (UCTD) , uveitis, vasculitis, vesiculobullous dermatosis, vitiligo, Waldenstrom's macroglobulinemia (WM) , and Wegener's granulomatosis (Granulomatosis with Polyangiitis (GPA) ) .
In some cases, the autoimmune disease comprises one or more members selected from the group comprising rheumatoid arthritis, type 1 diabetes, systemic lupus erythematosus (lupus or SLE) , myasthenia gravis, multiple sclerosis, scleroderma, Addison's Disease, bullous pemphigoid, pemphigus vulgaris, Guillain-Barré syndrome, Sjogren syndrome, dermatomyositis, thrombotic thrombocytopenic purpura, hypergammaglobulinemia, monoclonal gammopathy of undetermined significance (MGUS) , Waldenstrom's macroglobulinemia (WM) , chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) , Hashimoto's Encephalopathy (HE) , Hashimoto's Thyroiditis, Graves' Disease, Wegener's Granulomatosis, and antibody-mediated transplantation rejection (e.g., for tissue transplants such as renal transplant) . In examples, the autoimmune disease can be type 1 diabetes, lupus, or rheumatoid arthritis.
In some cases, the target cells form a tumor (i.e., a solid tumor) . A tumor treated with the methods herein can result in stabilized tumor growth (e.g., one or more tumors do not increase more than 1%, 5%, 10%, 15%, or 20% in size, and/or do not metastasize) . In some cases, a tumor is stabilized for at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or more weeks. In some cases, a tumor is stabilized for at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or more months. In some cases, a tumor is stabilized for at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more years. In some cases, the size of a tumor or the number of tumor cells is reduced by at least about 5%, 10%, 15%, 20%, 25, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or more. In some cases, the tumor is completely eliminated, or reduced below a level of detection. In some cases, a subject remains tumor free (e.g. in remission) for at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or more weeks following treatment. In some cases, a subject remains tumor free for at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or more months following treatment. In some cases, a subject remains tumor free for at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more years after treatment.
In another particular aspect, the present disclosure provides a method of treating cancer in a mammal, comprising administering to the mammal a therapeutically effective amount of a polypeptide and/or antigen binding moiety provided by the disclosure. In an aspect, an administration may treat a subject by reduction or inhibition of further growth or spread of cancer cells, death of cancer cells, inhibition of reoccurrence of cancer, reduction of pain associated with the cancer, or improved survival of the animal. Inhibition of reoccurrence of cancer contemplates cancer sites and surrounding tissue which have previously been treated by radiation, chemotherapy, surgery, or other techniques. The effect can be either subjective or objective. For example, if the animal is human, the human may note improved vigor or vitality or decreased pain as subjective symptoms of improvement or response to therapy. Alternatively, the clinician may notice a decrease in tumor size or tumor burden based on physical exam, laboratory parameters, tumor markers or radiographic findings. Some laboratory signs that the clinician may observe for response to treatment include normalization of tests, such as white blood cell count, red blood cell count, platelet count, erythrocyte sedimentation rate, and various enzyme levels. Additionally, the clinician may observe a decrease in a detectable tumor marker. Alternatively, other tests can be used to evaluate objective improvement, such as sonograms, nuclear magnetic resonance testing and positron emissions testing. In some embodiments, the polypeptide comprises an OX40 antibody or a binding moiety fragment thereof provided by the disclosure. In a further embodiment the polypeptide and/or antigen binding moiety is one provided in Table 1 or Table 2. In a further embodiment, the mammal is a human.
Disclosed herein, in some embodiments, are pharmaceutical compositions comprising at least: (a) anti-OX40 antibody as disclosed herein; and (b) a pharmaceutically acceptable excipient. In practicing the therapeutic methods, the subject polypeptides or antigen-binding moieties may be administered alone as monotherapy, or administered in combination with one or more additional therapeutic agents or therapies. Thus, in another aspect, the present disclosure provides a combination therapy, which comprises a binding moiety or polypeptide provided by the disclosure in combination with one or more additional therapies or therapeutic agents.
Also provided are combination therapies and/or therapeutic regimens that comprise administering pharmaceutical compositions that comprise an anti-OX40 antibody and a PI3K inhibitor. In an embodiment, the anti-OX40 antibody targets human OX40 and the PI3K inhibitor is Tenalisib.
Provided herein are also pharmaceutical compositions that comprise any of the aforementioned polypeptides that comprise antigen binding moieties and/or anti-PI3K inhibitors.
The pharmaceutical composition may optionally contain one or more additional pharmaceutically active ingredients, such as another antibody or a drug. The pharmaceutical compositions of the invention also can be administered in a combination therapy with, for example, another immune-stimulatory agent, anti-cancer agent, an antiviral agent, or a vaccine, such that the anti-OX40 antibody enhances the immune response against the vaccine. A pharmaceutically acceptable carrier can include, for example, a pharmaceutically acceptable liquid, gel or solid carriers, an aqueous medium, a non-aqueous medium, an anti-microbial agent, isotonic agents, buffers, antioxidants, anesthetics, suspending/dispersing agent, a chelating agent, a diluent, adjuvant, excipient or a nontoxic auxiliary substance, other known in the art various combinations of components or more
For administration to a subject, polypeptides as disclosed herein, may be provided in a pharmaceutical composition together with one or more pharmaceutically acceptable carriers or excipients. The term "pharmaceutically acceptable carrier" includes, but is not limited to, any carrier that does not interfere with the effectiveness of the biological activity of the ingredients and that is not toxic to the patient to whom it is administered. Examples of suitable pharmaceutical carriers are well known in the art and include phosphate buffered saline solutions, water, emulsions, such as oil/water emulsions, various types of wetting agents, sterile solutions etc. Such carriers can be formulated by conventional methods and can be administered to the subject at a suitable dose. Preferably, the compositions are sterile. These compositions may also contain adjuvants such as preservative, emulsifying agents and dispersing agents. Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents.
The pharmaceutical composition may be in any suitable form, (depending upon the desired method of administration) . It may be provided in unit dosage form, may be provided in a sealed container and may be provided as part of a kit. Such a kit may include instructions for use. It may include a plurality of said unit dosage forms.
The pharmaceutical composition of the invention may be administered in vivo, to a subject in need thereof, by various routes, including, but not limited to, oral, intravenous, intra-arterial, subcutaneous, parenteral, intranasal, intramuscular, intracranial, intracardiac, intraventricular, intratracheal, buccal, rectal, intraperitoneal, intradermal, topical, transdermal, and intrathecal, or otherwise by implantation or inhalation. The subject compositions may be formulated into preparations in solid, semi-solid, liquid, or gaseous forms; including, but not limited to, tablets, capsules, powders, granules, ointments, solutions, suppositories, enemas, injections, inhalants, and aerosols. The appropriate formulation and route of administration may be selected according to the intended application and therapeutic regimen
Dosages of the substances of the present disclosure can vary between wide limits, depending upon the disease or disorder to be treated, the age and condition of the individual to be treated, etc. and a physician will ultimately determine appropriate dosages to be used.
Frequency of administration may be determined and adjusted over the course of therapy, and is based on reducing the number of target cells such as proliferative or tumorigenic cells, maintaining the reduction of such neoplastic cells, reducing the proliferation of neoplastic cells, or delaying the development of metastasis. In some embodiments, the dosage administered may be adjusted or attenuated to manage potential side effects and/or toxicity. Alternatively, sustained continuous release formulations of a subject therapeutic composition may be appropriate.
It will be appreciated by one of skill in the art that appropriate dosages can vary from patient to patient. Determining the optimal dosage will generally involve the balancing of the level of therapeutic benefit against any risk or deleterious side effects. The selected dosage level will depend on a variety of factors including, but not limited to, the activity of the particular compound, the route of administration, the time of administration, the rate of excretion of the compound, the duration of the treatment, other drugs, compounds, and/or materials used in combination, the severity of the condition, and the species, sex, age, weight, condition, general health, and prior medical history of the patient. The amount of compound and route of administration will ultimately be at the discretion of the physician, veterinarian, or clinician, although generally the dosage will be selected to achieve local concentrations at the site of action that achieve the desired effect without causing substantial harmful or deleterious side-effects.
In general, the polypeptide that comprises a subject antigen binding moiety may be administered in various ranges. These include about 5 μg/kg body weight to about 100 mg/kg body weight per dose; about 50 μg/kg body weight to about 5 mg/kg body weight per dose; about 100 μg/kg body weight to about 10 mg/kg body weight per dose. Other ranges include about 100 μg/kg body weight to about 20 mg/kg body weight per dose and about 0.5 mg/kg body weight to about 20 mg/kg body weight per dose. In certain embodiments, the dosage is at least about 100 μg/kg body weight, at least about 250 μg/kg body weight, at least about 750 μg/kg body weight, at least about 3 mg/kg body weight, at least about 5 mg/kg body weight, at least about 10 mg/kg body weight.
In some embodiments, polypeptides further comprise a detectable label, a therapeutic agent, or a pharmacokinetic modifying moiety. In some embodiments, the detectable label comprises a fluorescent label, a radiolabel, an enzyme, a nucleic acid probe, or a contrast agent.
Compatible formulations for parenteral administration (e.g., intravenous injection) will comprise the polypeptide that comprises a subject antigen binding moiety as disclosed herein in concentrations of from about 10 μg/ml to about 100 mg/ml. In certain selected embodiments, the concentrations of the polypeptide or antigen binding moiety will comprise 20 μg/ml, 40 μg/ml, 60 μg/ml, 80 μg/ml, 100 μg/ml, 200 μg/ml, 300, μg/ml, 400 μg/ml, 500 μg/ml, 600 μg/ml, 700 μg/ml, 800 μg/ml, 900 μg/ml or 1 mg/ml. In other preferred embodiments ADC concentrations will comprise 2 mg/ml, 3 mg/ml, 4 mg/ml, 5 mg/ml, 6 mg/ml, 8 mg/ml, 10 mg/ml, 12 mg/ml, 14 mg/ml, 16 mg/ml, 18 mg/ml, 20 mg/ml, 25 mg/ml, 30 mg/ml, 35 mg/ml, 40 mg/ml, 45 mg/ml, 50 mg/ml, 60 mg/ml, 70 mg/ml, 80 mg/ml, 90 mg/ml or 100 mg/ml.
In an embodiment, the concentration of the inhibitor is 1mg, 4mg, 7mg, 10mg, 13mg, 16mg, 19mg, 22mg, 25mg, 28mg, 31mg, 34mg, 37mg, 40mg, 43mg, 46mg, 49mg, 52mg, 55mg, 58mg, 61mg, 64mg, 67mg, 70mg, 73mg, 76mg, 79mg, 82mg, 85mg, 88mg, 91mg, 94mg, 97mg, or 100mg. In an embodiment, the inhibit is Tenalisib and it is administered at a dose of 4 mg. In an embodiment, the Tenalisib is administered as two tablets of 2 mg.
In an aspect, a subject polypeptide and the inhibitor against PI3K are prepared in a same unit dose. In an aspect, the polypeptide and the inhibitor against PI3K are prepared in different unit doses. In an aspect, the polypeptide and the inhibitor are administered concurrently, sequentially, or both concurrently and sequentially.
In an aspect, a subject can be further administered a co-therapeutic agent.
Non-limiting examples of a co-therapeutic agent can include cytotoxic agents, chemotherapeutic agents, growth inhibitory agents, agents used in radiation therapy, anti-angiogenesis agents, apoptotic agents, anti-tubulin agents, and other agents to treat cancer, for example, anti-CD20 antibodies, anti-PD1 antibodies (e.g., Pembrolizumab) platelet derived growth factor inhibitors (e.g., GLEEVEC
TM (imatinib mesylate) ) , a COX-2 inhibitor (e.g., celecoxib) , interferons, cytokines, antagonists (e.g., neutralizing antibodies) that bind to one or more of the following targets PDGFR-β, BlyS, APRIL, BCMA receptor (s) , TRAIL/Apo2, other bioactive and organic chemical agents, and the like.
Non-limiting examples of a co-therapeutic agent, such as a chemotherapeutic agent can include alkylating agents such as thiotepa and
cyclosphosphamide; alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelamines including altretamine, triethylenemelamine, trietylenephosphoramide, triethiylenethiophosphoramide and trimethylolomelamine; acetogenins (especially bullatacin and bullatacinone) ; delta-9-tetrahydrocannabinol (dronabinol,
) ; beta-lapachone; lapachol; colchicines; betulinic acid; a camptothecin (including the synthetic analogue topotecan
CPT-11 (irinotecan,
) , acetylcamptothecin, scopolectin, and 9-aminocamptothecin) ; bryostatin; callystatin; CC-1065 (including its adozelesin, carzelesin and bizelesin synthetic analogues) ; podophyllotoxin; podophyllinic acid; teniposide; cryptophycins (particularly cryptophycin 1 and cryptophycin 8) ; dolastatin; duocarmycin (including the synthetic analogues, KW-2189 and CB1-TM1) ; eleutherobin; pancratistatin; a sarcodictyin; spongistatin; nitrogen mustards such as chlorambucil, chlomaphazine, cholophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimnustine; antibiotics such as the enediyne antibiotics; dynemicin, including dynemicin A; an esperamicin; as well as neocarzinostatin chromophore and related chromoprotein enediyne antiobiotic chromophores) , aclacinomysins, actinomycin, authramycin, azaserine, bleomycins, cactinomycin, carabicin, carminomycin, carzinophilin, chromomycinis, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine,
doxorubicin (including morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin and deoxydoxorubicin) , epirubicin, esorubicin, idarubicin, marcellomycin, mitomycins such as mitomycin C, mycophenolic acid, nogalamycin, olivomycins, peplomycin, potfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; anti-metabolites such as methotrexate and 5-fluorouracil (5-FU) ; folic acid analogues such as denopterin, methotrexate, pteropterin, trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine; androgens such as calusterone, dromostanolone propionate, epitiostanol, mepitiostane, testolactone; anti-adrenals such as aminoglutethimide, mitotane, trilostane; folic acid replenisher such as frolinic acid; aceglatone; aidophosphamide glycoside; aminolevulinic acid; eniluracil; amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elfornithine; elliptinium acetate; an epothilone; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidainine; maytansinoids such as maytansine and ansamitocins; mitoguazone; mitoxantrone; mopidanmol; nitraerine; pentostatin; phenamet; pirarubicin; losoxantrone; 2-ethylhydrazide; procarbazine;
polysaccharide complex (JHS Natural Products, Eugene, Oreg. ) ; razoxane; rhizoxin; sizofiran; spirogermanium; tenuazonic acid; triaziquone; 2, 2′, 2″-trichlorotriethylamine; trichothecenes (especially T-2 toxin, verracurin A, roridin A and anguidine) ; urethan; vindesine
dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside ( “Ara-C” ) ; thiotepa; taxoids, for example taxanes including
paclitaxel (Bristol-Myers Squibb Oncology, Princeton, N.J. ) , ABRAXANE
TM Cremophor-free, albumin-engineered nanoparticle formulation of paclitaxel (American Pharmaceutical Partners, Schaumberg, Ill. ) , and
docetaxel (
Rorer, Antony, France) ; chloranbucil; gemcitabine
6-thioguanine; mercaptopurine; methotrexate; platinum analogs such as cisplatin and carboplatin; vinblastine
platinum; etoposide (VP-16) ; ifosfamide; mitoxantrone; vincristine
oxaliplatin; leucovovin; vinorelbine
novantrone; edatrexate; daunomycin; aminopterin; ibandronate; topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO) ; retinoids such as retinoic acid; capecitabine
pharmaceutically acceptable salts, acids or derivatives of any of the above; as well as combinations of two or more of the above such as CHOP, an abbreviation for a combined therapy of cyclophosphamide, doxorubicin, vincristine, and prednisolone, and FOLFOX, an abbreviation for a treatment regimen with oxaliplatin (ELOXATIN
TM) combined with 5-FU and leucovorin. Additional chemotherapeutic agents include the cytotoxic agents useful as antibody drug conjugates, such as maytansinoids (DM1, for example) and the auristatins MMAE and MMAF, for example.
In an aspect, a co-therapeutic agent can be an anti-hormonal agent or endocrine therapeutic that act to regulate, reduce, block, or inhibit the effects of hormones that can promote the growth of cancer, and are often in the form of systemic, or whole-body treatment. They may be hormones themselves. Examples include anti-estrogens and selective estrogen receptor modulators (SERMs) , including, for example, tamoxifen (including
tamoxifen) ,
raloxifene, droloxifene, 4-hydroxytamoxifen, trioxifene, keoxifene, LY117018, onapristone, and
toremifene; anti-progesterones; estrogen receptor down-regulators (ERDs) ; agents that function to suppress or shut down the ovaries, for example, leutinizing hormone-releasing hormone (LHRH) agonists such as
and ELIGARD) leuprolide acetate, goserelin acetate, buserelin acetate and tripterelin; other anti-androgens such as flutamide, nilutamide and bicalutamide; and aromatase inhibitors that inhibit the enzyme aromatase, which regulates estrogen production in the adrenal glands, such as, for example, 4 (5) -imidazoles, aminoglutethimide,
megestrol acetate,
exemestane, formestanie, fadrozole,
vorozole,
letrozole, and
anastrozole. In addition, such definition of chemotherapeutic agents includes bisphosphonates such as clodronate (for example,
or
) ,
etidronate, NE-58095,
zoledronic acid/zoledronate,
alendronate,
pamidronate,
tiludronate, or
risedronate; as well as troxacitabine (a 1, 3-dioxolane nucleoside cytosine analog) ; antisense oligonucleotides, particularly those that inhibit expression of genes in signaling pathways implicated in abherant cell proliferation, such as, for example, PKC-alpha, Raf, H-Ras, and epidermal growth factor receptor (EGFR) ; vaccines such as
vaccine and gene therapy vaccines, for example,
vaccine,
vaccine, and
vaccine;
topoisomerase 1 inhibitor;
rmRH; lapatinib ditosylate (an ErbB-2 and EGFR dual tyrosine kinase small-molecule inhibitor also known as GW572016) ; and pharmaceutically acceptable salts, acids or derivatives of any of the above.
In an embodiment, a co-therapeutic agent can also include antibodies such as alemtuzumab (Campath) , bevacizumab (
Genentech) ; cetuximab (
Imclone) ; panitumumab (
Amgen) , rituximab (
Genentech/Biogen Idec) , pertuzumab (
2C4, Genentech) , trastuzumab (
Genentech) , tositumomab (Bexxar, Corixia) , and the antibody drug conjugate, gemtuzumab ozogamicin (
Wyeth) . Additional humanized monoclonal antibodies with therapeutic potential as agents in combination with the compounds of the invention include: apolizumab, aselizumab, atlizumab, bapineuzumab, bivatuzumab mertansine, cantuzumab mertansine, cedelizumab, certolizumab pegol, cidfusituzumab, cidtuzumab, daclizumab, eculizumab, efalizumab, epratuzumab, erlizumab, feMzumab, fontolizumab, gemtuzumab ozogamicin, inotuzumab ozogamicin, ipilimumab, labetuzumab, lintuzumab, matuzumab, mepolizumab, motavizumab, motovizumab, natalizumab, nimotuzumab, nolovizumab, numavizumab, ocrelizumab, omalizumab, palivizumab, pascolizumab, pecfusituzumab, pectuzumab, pexelizumab, ralivizumab, ranibizumab, reslivizumab, reslizumab, resyvizumab, rovelizumab, ruplizumab, sibrotuzumab, siplizumab, sontuzumab, tacatuzumab tetraxetan, tadocizumab, talizumab, tefibazumab, tocilizumab, toralizumab, tucotuzumab celmoleukin, tucusituzumab, umavizumab, urtoxazumab, ustekinumab, visilizumab, and the anti-interleukin-12 (ABT-874/J695, Wyeth Research and Abbott Laboratories) which is a recombinant exclusively human-sequence, full-length IgG1λ antibody genetically modified to recognize interleukin-12 p40 protein.
In an embodiment, a co-therapeutic agent can be a tyrosine kinase inhibitor such as an EGFR-targeting agent (e.g., small molecule, antibody, etc. ) ; small molecule HER2 tyrosine kinase inhibitor such as TAK165 available from Takeda; CP-724, 714, an oral selective inhibitor of the ErbB2 receptor tyrosine kinase (Pfizer and OSI) ; dual-HER inhibitors such as EKB-569 (available from Wyeth) which preferentially binds EGFR but inhibits both HER2 and EGFR-overexpressing cells; lapatinib (GSK572016; available from Glaxo-SmithKline) , an oral HER2 and EGFR tyrosine kinase inhibitor; PKI-166 (available from Novartis) ; pan-HER inhibitors such as canertinib (CI-1033; Pharmacia) ; Raf-1 inhibitors such as antisense agent ISIS-5132 available from ISIS Pharmaceuticals which inhibit Raf-1 signaling; non-HER targeted TK inhibitors such as imatinib mesylate (
available from Glaxo SmithKline) ; multi-targeted tyrosine kinase inhibitors such as sunitinib (
available from Pfizer) ; VEGF receptor tyrosine kinase inhibitors such as vatalanib (PTK787/ZK222584, available from Novartis/Schering AG) ; MAPK extracellular regulated kinase I inhibitor CI-1040 (available from Pharmacia) ; quinazolines, such as PD 153035, 4- (3-chloroanilino) quinazoline; pyridopyrimidines; pyrimidopyrimidines; pyrrolopyrimidines, such as CGP 59326, CGP 60261 and CGP 62706; pyrazolopyrimidines, 4- (phenylamino) -7H-pyrrolo [2, 3-d] pyrimidines; curcumin (diferuloyl methane, 4, 5-bis (4-fluoroanilino) phthalimide) ; tyrphostines containing nitrothiophene moieties; PD-0183805 (Warner-Lamber) ; antisense molecules (e.g., those that bind to HER-encoding nucleic acid) ; quinoxalines (U.S. Pat. No. 5,804,396) ; tryphostins (U.S. Pat. No. 5,804,396) ; ZD6474 (Astra Zeneca) ; PTK-787 (Novartis/Schering AG) ; pan-HER inhibitors such as CI-1033 (Pfizer) ; Affinitac (ISIS 3521; Isis/Lilly) ; imatinib mesylate
PKI 166 (Novartis) ; GW2016 (Glaxo SmithKline) ; CI-1033 (Pfizer) ; EKB-569 (Wyeth) ; Semaxinib (Pfizer) ; ZD6474 (AstraZeneca) ; PTK-787 (Novartis/Schering AG) ; INC-1C11 (Imclone) ; and rapamycin (sirolimus,
) .
In an embodiment, a co-therapeutic agent can also include a growth inhibitory agent such as a compound or composition which inhibits growth and/or proliferation of a cell (e.g., a cell whose growth is dependent on PD-L1 expression) either in vitro or in vivo. The growth inhibitory agent may be one which significantly reduces the percentage of cells in S phase. Non-limiting examples of growth inhibitory agents include agents that block cell cycle progression (at a place other than S phase) , such as agents that induce G1 arrest and M-phase arrest. Classical M-phase blockers include the vincas (vincristine and vinblastine) , taxanes, and topoisomerase II inhibitors such as the anthracycline antibiotic doxorubicin ( (8S-cis) -10- [ (3-amino-2, 3, 6-trideoxy-α-L-lyxo hexapyranosyl) oxy] -7, 8, 9, 10-tetrahydro-6, 8, 11-trihydroxy-8- (hydroxyacetyl) -1-methoxy-5, 12-naphthacenedione) , epirubicin, daunorubicin, etoposide, and bleomycin. Those agents that arrest G1 also spill over into S-phase arrest, for example, DNA alkylating agents such as tamoxifen, prednisone, dacarbazine, mechlorethamine, cisplatin, methotrexate, 5-fluorouracil, and ara-C. The taxanes (paclitaxel and docetaxel) are anticancer drugs both derived from the yew tree. Docetaxel (
Rhone-Poulenc Rorer) , derived from the European yew, is a semisynthetic analogue of paclitaxel (
Bristol-Myers Squibb) . Paclitaxel and docetaxel promote the assembly of microtubules from tubulin dimers and stabilize microtubules by preventing depolymerization, which results in the inhibition of mitosis in cells. In an embodiment, a co-therapeutic agent can also include dexamethasone, interferons, colchicine, metoprine, cyclosporine, amphotericin, metronidazole, alemtuzumab, alitretinoin, allopurinol, amifostine, arsenic trioxide, asparaginase, BCG live, bevacuzimab, bexarotene, cladribine, clofarabine, darbepoetin alfa, denileukin, dexrazoxane, epoetin alfa, elotinib, filgrastim, histrelin acetate, ibritumomab, interferon alfa-2a, interferon alfa-2b, lenalidomide, levamisole, mesna, methoxsalen, nandrolone, nelarabine, nofetumomab, oprelvekin, palifermin, pamidronate, pegademase, pegaspargase, pegfilgrastim, pemetrexed disodium, plicamycin, porfimer sodium, quinacrine, rasburicase, sargramostim, temozolomide, VM-26, 6-TG, toremifene, tretinoin, ATRA, valrubicin, zoledronate, and zoledronic acid, and pharmaceutically acceptable salts thereof. A co-therapeutic agent can also include hydrocortisone, hydrocortisone acetate, cortisone acetate, tixocortol pivalate, triamcinolone acetonide, triamcinolone alcohol, mometasone, amcinonide, budesonide, desonide, fluocinonide, fluocinolone acetonide, betamethasone, betamethasone sodium phosphate, dexamethasone, dexamethasone sodium phosphate, fluocortolone, hydrocortisone-17-butyrate, hydrocortisone-17-valerate, aclometasone dipropionate, betamethasone valerate, betamethasone dipropionate, prednicarbate, clobetasone-17- butyrate, clobetasol-17-propionate, fluocortolone caproate, fluocortolone pivalate and fluprednidene acetate: immune selective anti-inflammatory peptides (ImSAIDs) such as phenylalanine-glutamine-glycine (FEG) and its D-isomeric form (feG) (IMULAN BioTherapeutics, LLC) ; anti-rheumatic drugs such as azathioprine, ciclosporin (cyclosporine A) , D-penicillamine, gold salts, hydroxychloroquine, leflunomideminocycline, sulfasalazine, tumor necrosis factor alpha (TNFα) blockers such as etanercept
infliximab
adalimumab
certolizumab pegol
golimumab
Interleukin 1 (IL-1) blockers such as anakinra
T-cell costimulation blockers such as abatacept
Interleukin 6 (IL-6) blockers such as tocilizumab
Interleukin 13 (IL-13) blockers such as lebrikizumab; Interferon alpha (IFN) blockers such as rontalizumab; beta 7 integrin blockers such as rhuMAb Beta7; IgE pathway blockers such as Anti-M1 prime; Secreted homotrimeric LTa3 and membrane bound heterotrimer LTa/β2 blockers such as Anti-lymphotoxin alpha (LTa) ; miscellaneous investigational agents such as thioplatin, PS-341, phenylbutyrate, ET-18-OCH3, or famesyl transferase inhibitors (L-739749, L-744832) ; polyphenols such as quercetin, resveratrol, piceatannol, epigallocatechine gallate, theaflavins, flavanols, procyanidins, betulinic acid and derivatives thereof; autophagy inhibitors such as chloroquine; delta-9-tetrahydrocannabinol (dronabinol,
) ; beta-lapachone; lapachol; colchicines; betulinic acid; acetylcamptothecin, scopolectin, and 9-aminocamptothecin) ; podophyllotoxin; tegafur
bexarotene
bisphosphonates such as clodronate (for example,
or
) , etidronate
NE-58095, zoledronic acid/zoledronate
alendronate
pamidronate
tiludronate
or risedronate
and epidermal growth factor receptor (EGF-R) ; vaccines such as
vaccine; perifosine, COX-2 inhibitor (e.g., celecoxib or etoricoxib) , proteosome inhibitor (e.g., PS341) ; CCI-779; tipifamib (R11577) ; orafenib, ABT510; Bcl-2 inhibitor such as oblimersen sodium
pixantrone; famesyltransferase inhibitors such as lonafamib (SCH 6636, SARASAR
TM) ; and pharmaceutically acceptable salts, acids or derivatives of any of the above; as well as combinations of two or more of the above.
The combination therapy for treating cancer also encompasses the combination of a polypeptide provided by the disclosure with surgery to remove a tumor. The polypeptide and/or combination therapy comprising the polypeptide may be administered to the mammal before, during, or after the surgery.
The combination therapy for treating cancer also encompasses combination of a binding molecule provided by the disclosure with radiation therapy, such as ionizing (electromagnetic) radiotherapy (e.g., X-rays or gamma rays) and particle beam radiation therapy (e.g., high linear energy radiation) . The source of radiation can be external or internal to the mammal. The binding molecule may be administered to the mammal before, during, or after the radiation therapy.
In another aspect of the invention, an article of manufacture containing materials useful for the treatment, prevention and/or diagnosis of the disorders described above is provided. The article of manufacture comprises a container and a label or package insert on or associated with the container. Suitable containers include, for example, bottles, vials, syringes, IV solution bags, etc. The containers may be formed from a variety of materials such as glass or plastic. The container holds a composition which is by itself or combined with another composition effective for treating, preventing and/or diagnosing the condition and may have a sterile access port (for example the container may be an intravenous solution bag or a vial having a stopper that is pierceable by a hypodermic injection needle) . At least one active agent in the composition is anti-OX40 antibody as defined herein before.
The label or package insert indicates that the composition is used for treating the condition of choice. Moreover, the article of manufacture may comprise (a) a first container with a composition contained therein, wherein the composition comprises the antibody of the disclosure; and (b) a second container with a composition contained therein, wherein the composition comprises a PI3K inhibitor. The article of manufacture in this embodiment of the invention may further comprise a package insert indicating that the compositions can be used to treat a particular condition.
Alternatively, or additionally, the article of manufacture may further comprise a second (or third) container comprising a pharmaceutically-acceptable buffer, such as bacteriostatic water for injection (BWFI) , phosphate-buffered saline, Ringer's solution and dextrose solution. It may further include other materials desirable from a commercial and user standpoint, including other buffers, diluents, filters, needles, and syringes.
EXAMPLES
Example 1: CN401 in combination with OX86 (α-mOX40 mAb) and α-mPD1 mAb in MC38 syngeneic model
Study Design: Tumor challenge, drug treatment and tumor growth monitoring
An exemplary study was performed to evaluate safety and tolerability of combination therapies provided herein in a mouse model. The study tested the synergistic effects of administration of Tenalisib (CN401) , CN1 (anti-huOX40, clone 1.134.9-u1-IgG1L) or OX86 (anti-mouse OX40, from BioXcell) antibody and anti-PD-1 antibody (RMP1-14, from BioXcell) in a mouse tumor model. Also evaluated was the antitumor activity of CN401 in various tumor cell lines in vitro.
Six- to eight-weeks-old C57bl/6 mice (20–25 g) were purchased from Shanghai Super -B&K laboratory animal Corp. Ltd. and inoculated with MC38 cells (0.5million cells per mouse) by subcutaneous inoculation into the right flank of mouse. The treatments started when the tumors were palpable (approximately 70 mm
3) . Anti-OX40 mAb was administered by i.p. twice a week at 100μg/mouse for 3 weeks. CN401 was oral gavage twice per day at 15 mg/kg or 50mg/kg or 150mg/kg for 3 weeks. Anti-PD-1 mAb was administered by i.p. twice a week at 60μg/mouse for 3 weeks. The control group received a vehicle (0.5%MC and PBS) without the active product. The tumor size and body weight were measured thrice a week. The animal experiments were performed according to AAALAC and were approved by the IACUC for Animal Experimentation of the Super -B&K laboratory animal Center.
Table 4: Experimental Design
Antitumor activity of CN401 in combination with α-mOX40 mAb and anti-mPD1 mAb in MC38 syngeneic model is provided in FIG. 1A-FIG. 1B and FIG. 2A-FIG. 2G.
Table 5: Antitumor activity of CN401 in combination with α-mOX40 mAb and anti-mPD1 mAb in MC38 syngeneic model: The TGI and p value on day 20 as compared with vehicle group.
Statistical analysis
A one-way ANOVA or student t test was performed to compare the tumor volume and the tumor weight among groups when the data fit the normal distribution, otherwise using Mann-Whitney test. All growth curves were completed by GraphPad Prism 8.0.
Example 2: Tenalisib (CN401) in combination with OX86 (α-mOX40mAb) and α-mPD1 mAb in A20 syngeneic model
Study Design: Tumor challenge, drug treatment and tumor growth monitor
Six- to eight-weeks-old Balb/c mice (20–25 g) were purchased from Shanghai Super -B&K laboratory animal Corp. Ltd. and inoculated with A20 cells (0.5 million cells per mouse) by subcutaneous inoculation into the right flank of mouse. The treatments started when the tumors were palpable (approximately 70 mm
3) . Anti-OX40 mAb was administered by i.p. twice a week at 100μg/mouse for 3 weeks. CN401 was oral gavage twice per day at 150 mg/kg or 300mg/kg for 3 weeks. The control group was received a vehicle (0.5% MC and PBS) without the active product. Anti-PD-1 mAb was administered by i.p. twice a week at 60μg/mouse for 3 weeks. The tumor size and body weight were measured thrice a week. The animal experiments were performed according to AAALAC and were approved by the IACUC for Animal Experimentation of the Super -B&K laboratory animal Center.
Table 6: Experimental Design
As provided in Table 7, there was a synergistic effect between CN401 and α-OX40 mAb in A20 syngeneic model, see FIG. 3A-FIG. 3B.
Table 7: Antitumor activity of CN401 in combination with α-OX40 mAb and anti-PD1 mAb in A20 syngeneic model: the TGI and p value on day 17 as compared with vehicle group. Data for vehicle group is not shown.
Antitumor activity in mice administered CN401 in combination with α-OX40 mAb and anti-PD1 mAb in A20 syngeneic model is provided in FIG 4A-FIG 4H. Of note, are that mice in groups 4-7 achieved complete responses (tumor-free) .
Statistical Analysis
A one-way ANOVA or student t test was performed to compare the tumor volume and the tumor weight among groups when the data fit the normal distribution, otherwise using Mann-Whitney test. All growth curves were completed by GraphPad Prism 8.0
Example 3: CN401 in combination with CN1 (anti-huOX40) in A20 humanized transgenic mice
Study Design: Tumor challenge, drug treatment and tumor growth monitor
Six- to eight-weeks-old Balb/c-hPD1/hOX40 transgenic mice (20–25 g) were purchased from GemPharmatech and inoculated with A20 (0.5 million cells per mouse) by subcutaneous inoculation into the right flank of mouse. The treatments started when the tumors were palpable (approximately 70 mm
3) . CN1 was administered by i.p. twice a week at 1mg/kg for 3 weeks. CN401 was oral gavage twice per day at 150 mg/kg for 3 weeks. The control groups received a vehicle (0.5% MC and PBS) without the active product. The tumor size and body weight were measured thrice a week. The animal experiments were performed according to AAALAC and were approved by the IACUC for Animal Experimentation of the Super -B&K laboratory animal Center.
Table 8: Exemplary Study Design
Group | Animal | Regimen |
1 | 8 | vehicle (PBS i.p. biw * 3 + 0.5%MC p.o. bid *3weeks) |
2 | 8 | CN1 1mg/kg, i.p., biw*3weeks |
3 | 8 | CN401 150mg/kg, po, bid * |
4 | 8 | CN1 1mg/kg, i.p., biw*3w+ CN401 150mg/kg, po, bid *3w |
As provided in Table 9, there was a synergistic effect between CN401 and α-OX40 mAb in A20 humanized transgenic mice, see FIG. 5A-FIG. 5B.
Table 9: Antitumor activity of CN401 in combination with CN1 Ab in A20 humanized transgenic mice: the TGI and p value on day 19 as compared with vehicle group.
Statistical Analysis
A one-way ANOVA or student t test was performed to compare the tumor volume and the tumor weight among groups when the data fit the normal distribution, otherwise using Mann-Whitney test. All growth curves were completed by GraphPad Prism 8.0
Example 4: CN401 in combination with CN1 in A20 humanized Ox40 transgenic mouse syngeneic model
Study Design
Six- to eight-weeks-old Balb/c-hPD1/hOX40 transgenic mice (20–25 g) were purchased from GemPharmatech and inoculated with A20 (0.5 million cells per mouse) by subcutaneous inoculation into the right flank of mouse. The treatments started when the tumors were palpable (approximately 70 mm
3) . CN1 was administered by i.p. twice a week at 1mg/kg for 3 weeks. CN401 was oral gavage twice per day at 150 mg/kg for 3 weeks. The control groups received a vehicle (0.5% MC and PBS) without the active product. The tumor size and body weight were measured thrice a week. The animal experiments were performed according to AAALAC and were approved by the IACUC for Animal Experimentation of the Super -B&K laboratory animal Center.
Antitumor activity of CN401 in combination with CN1 in A20 humanized Ox40 transgenic mouse syngeneic model is shown in FIG. 6A-FIG. 6D. Of note is that treated mice in Groups 14-16 achieved complete responses (tumor free) .
Example 5: Antitumor activity of Tenalisb (CN401) or Duvelishib in various tumor cell lines in vitro
Cell Proliferation Assay
Cell growth inhibitory activity of Tenalisib across the panel of 11 tumor cell lines were evaluated by quantitation of ATP with
Luminescent Cell Viability Assay Kit (Promega, #G7572) after a 72-hour treatment. Except that MC38 cell line was obtained from Wuxi Biology company, other 10 cell lines were obtained from the American Type Culture Collection (ATCC) . All the cell lines were maintained in the specific medium according to ATCC culture method supplemented with 10% heat-inactivated fetal bovine serum (FBS) and 100 units/ml penicillin and 100ug/ml streptomycin. All the cell cultures were maintained at 37℃ in a humidified atmosphere of 5% CO2.
All eleven tumor cell lines were seeded in 96 well white opaque plate (Corning, costar#3917) at density of 5000 cell in 100 μl media per well. On the next day all cell lines were treated with varying concentrations of Tenalisib or Duvelisib (ranging between 0.002 μM and 10 μM ) . At 72-hour post treatment, 100 μl of CTG assay reagents were added to the well and the Relative luminescence Units (RLU) were read by Envision 2105 (PerkinElmar) multimode plate reader. IC50 reported as proliferation inhibition were analyzed by Graphpad Prism8.0 software normalized with RLU (Relative Luminescence Unit) of DMSO treated wells.
Tenalisib was active in 2 out of 11 cell lines showing max inhibition of proliferation greater than 50%. The IC50s of Tenalisib in MV-4-11 cell line was 1.652 μM and was 5.49 μM in A20 cell line.
Tenalisib sand Duvelishib selectively inhibited cell proliferation in MV-4-11 and A20. Eleven tumor cell lines were treated with Tenalisib (A) or Duvelisib (B) for 72 hr. The range of compound concentration was from 0.002 μM 10 μM to with 3 fold serial dilution. The cell viability was evaluated with
Luminescent Cell Viability Assay Kit (Promega, #G7572) , see FIG. 7A- FIG. 7D.
Example 6: Tenalisib (CN401) & Duvelisib in combination with OX86 (α-mOX40 mAb) and α-mPD1 mAb in MC38 syngeneic model
Study Design
Six- to eight-weeks-old C57bl/6 mice (20–25 g) were purchased from Shanghai Super -B&K laboratory animal Corp. Ltd. and inoculated with MC38 cells (0.5million cells per mouse) by subcutaneous inoculation into the right flank of mouse. The treatments started when the tumors were palpable (approximately 70 mm
3) . Anti-OX40 mAb was administered by i.p. twice a week at 100μg/mouse for 3 weeks. CN401 was oral gavage twice per day at 15 mg/kg or 50mg/kg or 150mg/kg for 3 weeks. Anti-PD-1 mAb was administered by i.p. twice a week at 60μg/mouse for 3 weeks. Duvelisib was oral gavage twice per day at 50mg/kg for 3 weeks. The control group received a vehicle (0.5%MC and PBS) without the active product. The tumor size and body weight were measured thrice a week. The animal experiments were performed according to AAALAC and were approved by the IACUC for Animal Experimentation of the Super -B&K laboratory animal Center.
Table 10: Exemplary Study Design
Antitumor activity of Tenalisib (CN401) & duvelisib in combination with α-OX40 mAb and anti-PD1 mAb in MC38 syngeneic model, see FIG. 8A and FIG. 8B. There was no synergistic effect between CN401/ duvelisib and α-OX40 mAb in MC38 syngeneic model, see Table 11.
Table 11: Antitumor activity of Tenalisib (CN401) & duvelisib in combination with α-OX40 mAb and anti-PD1 mAb in MC38 syngeneic model: TGI and p value on day 20 as compared with vehicle group.
FIG. 9A – FIG. 9H show the individual tumor growth curve of tumors from groups in Table 11.
Example 7: Tenalisib (CN401) and duvelisib in combination with OX86 (α-mOX40mAb) and α-mPD1 mAb in A20 syngeneic model
Study Design
Six- to eight-weeks-old Balb/c mice (20–25 g) were purchased from Shanghai Super -B&K laboratory animal Corp. Ltd. and inoculated with A20 cells (0.5 million cells per mouse) by subcutaneous inoculation into the right flank of mouse. The treatments started when the tumors were palpable (approximately 70 mm
3) . Anti-OX40 mAb was administered by i.p. twice a week at 100μg/mouse for 3 weeks. CN401 was oral gavage twice per day at 150 mg/kg or 300mg/kg for 3 weeks. Anti-PD-1 mAb was administered by i.p. twice a week at 60μg/mouse for 3 weeks. Duvelisib was oral gavage twice per day at 50 mg/kg for 3 weeks. The control group was received a vehicle (0.5% MC and PBS) without the active product. The tumor size and body weight were measured thrice a week. The animal experiments were performed according to AAALAC and were approved by the IACUC for Animal Experimentation of the Super -B&K laboratory animal Center.
Table 12: Exemplary study design
Table 13 shows antitumor activity of Tenalisib (CN401) and duvelisib in combination with α-OX40 mAb and anti-PD1 mAb in A20 syngeneic model: TGI and p value on day 17 as compared with vehicle group. There was synergistic effect between CN401/duvelisib and α-OX40 mAb in A20 syngeneic model.
FIG. 10A and FIG. 10B show average tumor volume and average body weight of mice treated with Tenalisib (CN401) and duvelisib in combination with α-OX40 mAb and anti-PD1 mAb. FIG. 11A – FIG. 11J show individual tumor growth curves of mice from groups in Table 13 as compared to vehicle control.
Example 8: Tenalisib (CN401) in combination with CN1 and in A20 humanized transgenic mice
Study Design
Six- to eight-weeks-old Balb/c-hPD1/hOX40 transgenic mice (20–25 g) were purchased from GemPharmatech and inoculated with A20 (0.5 million cells per mouse) by subcutaneous inoculation into the right flank of mouse. The treatments started when the tumors were palpable (approximately 70 mm
3) . CN1 was administered by i.p. twice a week at 1mg/kg for 3 weeks. CN401 was oral gavage twice per day at 150 mg/kg for 3 weeks. The control groups received a vehicle (0.5% MC and PBS) without the active product. The tumor size and body weight was measured thrice a week. The animal experiments were performed according to AAALAC and were approved by the IACUC for Animal Experimentation of the Super -B&K laboratory animal Center.
Table 14: Exemplary study design
Group | Animal | Regimen |
1 | 8 | Vehicle (pbs control i.p. biw * 3w + 0.5% MC p.o. bid *3w) |
2 | 8 | CN1 1mg/kg, i.p., biw*3w |
3 | 8 | CN401 150mg/kg, po, bid * |
4 | 8 | CN1 1mg/kg i.p. biw*3w+CN401 150mg/kg, p.o. bid*3w |
Table 15 shows antitumor activity of Tenalisib (CN401) in combination with CN1 and in A20 humanized transgenic mice: The TGI and p value on day 19 as compared with vehicle group.
As shown in Table X and FIG. 12A and FIG. 12B, there was a synergistic effect between CN401 and α-OX40 mAb in A20 humanized transgenic mice. Antitumor activity, as measured by individual tumor growth curves is provided in FIG. 13A -FIG. 13D, of note are complete responses achieved in the 3 treatment groups, 4/8, 1/8 and 5/8 mice accordingly.
Results show that CN-1/ α-huOX40 antibody and PI3K inhibitors combination showed synergistic anti-tumor activity in A20 tumor model and that CN-1/ α-huOX40 antibody and PI3K inhibitors combination could induce tumor regression in A20 syngeneic model.
Example 9: Duvelisib in combination with OX86 (α-mOX40 mAb) in MC38 syngeneic model
Study Design
Six- to eight-weeks-old C57bl/6 mice (20–25 g) were purchased from Shanghai Super -B&K laboratory animal Corp. Ltd. and inoculated with MC38 cells (0.5million cells per mouse) by subcutaneous inoculation into the right flank of mouse. The treatments started when the tumors were palpable (approximately 70 mm
3) . Anti-OX40 mAb was administered by i.p. twice a week at 100μg/mouse for 3 weeks. Duvelisib was oral gavage twice per day at 50mg/kg for 3 weeks. The control group received a vehicle (0.5%MC and PBS) without the active product. The tumor size and body weight were measured thrice a week. The animal experiments were performed according to AAALAC and were approved by the IACUC for Animal Experimentation of the Super -B&K laboratory animal Center.
Table 16: Exemplary study design
Group | Animal | Regimen |
1 | 8 | Vehicle (PBS i.p. biw * 3 + PO bid *3 |
2 | 8 | duvelisib, 50mg/kg, p.o. bid*3 weeks |
3 | 8 | α-OX40 mAb 100ug/mouse, i.p. biw*3 weeks |
4 | 8 | α-OX40 mAb 100ug/mouse i.p. biw*3w+duvelisib 50mg/kg, p.o. bid*2w |
FIG. 14A and FIG. 14B show antitumor activity of duvelisib in combination with α-OX40 mAb in MC38 syngeneic model. The TGI and p value on day 20 as compared with vehicle group is provided in Table 16.
Table 17: Antitumor activity of duvelisib in combination with α-OX40 mAb in MC38 syngeneic model. The TGI and p value on day 20 as compared with vehicle group is shown.
FIG. 15A-FIG. 15D show antitumor activity of duvelisib in combination with α-OX40 mAb in the MC38 syngeneic model of groups treated as described in Table 17 as compared to control.
Example 10: Duvelisib in combination with OX86 (α-OX40mAb) in A20 syngeneic model
Study Design
Six- to eight-weeks-old Balb/c mice (20–25 g) were purchased from Shanghai Super -B&K laboratory animal Corp. Ltd. and inoculated with A20 cells (0.5 million cells per mouse) by subcutaneous inoculation into the right flank of mouse. The treatments started when the tumors were palpable (approximately 70 mm
3) . Anti-OX40 mAb was administered by i.p. twice a week at 100μg/mouse for 3 weeks. Duvelisib was oral gavage twice per day at 50 mg/kg for 3 weeks. The control group was received a vehicle (0.5% MC and PBS) without the active product. The tumor size and body weight were measured thrice a week. The animal experiments were performed according to AAALAC and were approved by the IACUC for Animal Experimentation of the Super -B&K laboratory animal Center.
Table 18: Exemplary study design
Group | Animal | Regimen |
1 | 6 | Vehicle (PBS i.p. biw * 3 + 0.5% MC PO bid *3weeks) |
2 | 6 | Duvelisib 50mg/kg, p.o., bid*3 weeks |
3 | 6 | α-OX40 mAb 100ug/mouse, i.p. biw*3 |
4 | 6 | α-OX40 mAb 100ug/mouse i.p. biw*3w+duvelisib 50mg/kg, p.o. bid*3w |
FIG. 16A and FIG. 16B show antitumor activity of duvelisib in combination with α-OX40 mAb in A20 syngeneic model. Table 19 shows the TGI and p value on day 17 as compared with vehicle group. There was synergistic effect between duvelisib and α-OX40 mAb in A20 syngeneic model.
Table 19: Antitumor activity of duvelisib in combination with α-OX40 mAb in A20 syngeneic model: TGI and p value on day 17 as compared with vehicle group.
FIG. 17A- FIG. 17D shows individual tumor growth curve of tumor from mice treated according to Table 19 as compared to control.
Example 11: CN401 in combination with CN1 in humanized CT26. WT murine colon carcinoma model
Study Design
An exemplary study was performed to evaluate safety and tolerability of combination therapies provided herein in a mouse model. The study tested the synergistic effects of administration of Tenalisib (CN401) and anti-huOX40 (CN1) antibody in a human OX40 transgenic mouse model.
Six- to eight-weeks-old human OX40 transgenic balb/c mice (20–25 g) were purchased from Jiangsu GemPharmatech Co., Ltd. and inoculated with CT26. WT murine colon carcinoma cells (0.1million cells per mouse) by subcutaneous inoculation into the right flank of mouse. The treatments started when the tumors were palpable (approximately 70 mm
3) . CN1 was administered by i.p. twice a week at 5mg/kg for 3 weeks. CN401 was oral gavage twice per day at 150mg/kg for 3 weeks. The control groups received a vehicle (0.5%MC and PBS) without the active product. The tumor size and body weight were measured thrice a week. The animal experiments were performed according to AAALAC and were approved by the IACUC for Animal Experimentation of the Super -B&K laboratory animal Center.
Table 20: Experimental Design
Group | Animal | Regimen |
1 | 8 | vehicle (PBS i.p. biw * 3weeks + 0.5% MC p.o. bid *3 weeks) |
2 | 8 | CN1 5mg/kg, i.p., biw *3weeks |
3 | 8 | CN401 150mg/kg, po, bid * |
4 | 8 | CN1 5mg/kg, i.p., biw *3weeks + CN401 150mg/kg, po, bid *3weeks |
Antitumor activity of CN401 in combination with CN1in humanized CT26. WT tumor model is provided in FIG. 18A-FIG. 18B and FIG. 19A-FIG. 19D.
Table 21: Antitumor activity of CN401 in combination with CN1 in humanized CT26. WT tumor model: The TGI and p value on day 17 as compared with vehicle group.
Example 12: CN401 in combination with CN1 in humanized B16-F10 murine melanoma tumor model
Study Design
An exemplary study was performed to evaluate safety and tolerability of combination therapies provided herein in a mouse model. The study tested the synergistic effects of administration of Tenalisib (CN401) and anti-huOX40 (CN1) antibody in a human OX40 transgenic mouse model.
Six- to eight-weeks-old human OX40 transgenic C57bl/6 mice (20–25 g) were purchased from Biocytogen Pharmaceuticals (Beijing) Co., Ltd. and inoculated with B16-F10 murine melanoma cells (0.1million cells per mouse) by subcutaneous inoculation into the right flank of mouse. The treatments started when the tumors were palpable (approximately 40 mm
3) . CN1 was administered by i.p. twice a week at 10mg/kg for 2 weeks. CN401 was oral gavage twice per day at 150mg/kg for 2 weeks. The control groups received a vehicle (0.5%MC and PBS) without the active product. The tumor size and body weight were measured thrice a week. The animal experiments were performed according to AAALAC and were approved by the IACUC for Animal Experimentation of the Super -B&K laboratory animal Center.
Table 22: Experimental Design
Group | Animal | Regimen |
1 | 8 | vehicle (PBS i.p. biw * 2weeks + 0.5% MC p.o. bid *2 weeks) |
2 | 8 | CN1 10mg/kg, i.p., biw *2weeks |
3 | 8 | CN401 150mg/kg, po, bid * |
4 | 8 | CN1 10mg/kg, i.p., biw *2weeks + CN401 150mg/kg, po, bid *2weeks |
Antitumor activity of CN401 in combination with CN1 in humanized B16-F10 tumor model is provided in FIG. 20A-FIG. 20B and FIG. 21A-FIG. 21D.
Table 23: Antitumor activity of CN401 in combination with CN1 (anti-huOX40 Ab) in humanized B16-F10 tumor model: The TGI and p value on day 14 as compared with vehicle group.
While preferred embodiments of the present invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention. It is intended that the following claims define the scope of the invention and that methods and structures within the scope of these claims and their equivalents be covered thereby.
Claims (53)
- A method for treating a subject in need thereof, comprising:(a) administering to the subject a polypeptide comprising an antigen binding moiety exhibiting binding specificity to OX40, wherein the antigen binding moiety comprises at least one heavy chain CDR (CDRH) selected from the group consisting of (i) - (iii) and/or at least one light chain CDR (CDRL) selected from the group consisting of (iv) - (vi) , wherein:(i) a CDRH1 having at least 80% sequence identity to a sequence selected from the group consisting of SEQ ID NOs: 1, 7, 13, 15, 21 and 27;(ii) a CDRH2 having at least 80% sequence identity to a sequence selected from the group consisting of SEQ ID NOs: 3, 9, 17, 23 and 29;(iii) a CDRH3 having at least 80% sequence identity to a sequence selected from the group consisting of SEQ ID NOs: 5, 11, 19, 25 and 31;(iv) a CDRL1 having at least 80% sequence identity to a sequence selected from the group consisting of SEQ ID NOs: 2, 8, 14, 16, 22 and 28;(v) a CDRL2 having at least 80% sequence identity to a sequence selected from the group consisting of SEQ ID NOs: 4, 10, 18, 24 and 30; and(vi) a CDRL3 having at least 80% sequence identity to a sequence selected from the group consisting of SEQ ID NOs: 6, 12, 20, 26 and 32; and(b) administering to the subject an inhibitor against PI3K.
- The method of claim 1, wherein, the antigen binding moiety exhibiting binding specificity to OX40 comprises at least one heavy chain CDR (CDRH) selected from the group consisting of (i) - (iii) and/or at least one light chain CDR (CDRL) selected from the group consisting of (iv) - (vi) , wherein:(i) a CDRH1 having at least 80% sequence identity to a sequence of SEQ ID NOs: 15;(ii) a CDRH2 having at least 80% sequence identity to a sequence of SEQ ID NOs: 17;(iii) a CDRH3 having at least 80% sequence identity to a sequence of SEQ ID NOs: 19;(iv) a CDRL1 having at least 80% sequence identity to a sequence of SEQ ID NOs: 16;(v) a CDRL2 having at least 80% sequence identity to a sequence of SEQ ID NOs: 18;(vi) a CDRL3 having at least 80% sequence identity to a sequence of SEQ ID NOs: 20.
- The method of claim 1 or 2, wherein the antigen binding moiety comprises:(1) a heavy chain variable region (VH) having at least 80% sequence identity to a sequence selected from the group consisting of SEQ ID NOs: 33, 35, 37, 39, 41 and 43; and/or(2) a light chain variable region (VL) having at least 80% sequence identity to a sequence selected from the group consisting of SEQ ID NOs: 34, 36, 38, 40, 42 and 44.
- The method of any one of the preceding claims, wherein the antigen binding moiety comprises (1) a VH having at least 80% sequence identity to SEQ ID NO: 39 and/or (2) a VL having at least 80%sequence identity to SEQ ID NO: 40.
- The method of any one of the preceding claims, wherein the inhibitor against PI3K comprises one or more small molecule inhibitors against PI3K alpha, PI3K beta, PI3K delta, or PI3K gamma.
- The method of any one of the preceding claims, wherein the inhibitor against PI3K comprises one or more small molecule inhibitors against PI3K delta and/or PI3K gamma.
- The method of any one of the preceding claims, wherein the inhibitor against PI3K is one or more members selected from the group consisting of Wortmannin, LY294002, hibiscone C, Idelalisib, Copanlisib, Duvelisib, Alpelisib, Taselisib, Perifosine, Buparlisib, Umbralisib, PX-866, Dactolisib, CUDC-907, Voxtalisib, CUDC-907, ME-401, IPI-549, SF1126, Tenalisib, INK1117, pictilisib, XL147, Palomid 529, GSK1059615, ZSTK474, PWT33597, IC87114, TG100–115, CAL263, RP6503, PI-103, GNE-477, and AEZS-136.
- The method of any one of the preceding claims, wherein the inhibitor against PI3K is a dual inhibitor against PI3K delta and PI3K gama.
- The method of any one of the preceding claims, wherein the inhibitor against PI3K is Tenalisib.
- A method comprising treating a subject in need thereof, comprising:(a) administering to the subject a polypeptide comprising an antigen binding moiety exhibiting binding specificity to OX40; and(b) administering to the subject an inhibitor against PI3K comprising one or more members selected from the group consisting of Wortmannin, LY294002, hibiscone C, Idelalisib, Copanlisib, Duvelisib, Alpelisib, Taselisib, Perifosine, Buparlisib, Umbralisib, PX-866, Dactolisib, CUDC-907, Voxtalisib, CUDC-907, ME-401, IPI-549, SF1126, Tenalisib, INK1117, pictilisib, XL147, Palomid 529, GSK1059615, ZSTK474, PWT33597, IC87114, TG100–115, CAL263, RP6503, PI-103, GNE-477, and AEZS-136.
- The method of claim 10, wherein the inhibitor against PI3K comprises one or more members selected from the group consisting of Idelalisib, Copanlisib, Duvelisib, Alpelisib, Taselisib, Perifosine, Buparlisib, Umbralisib, and Tenalisib.
- The method of claim 10 or 11, wherein the inhibitor against PI3K comprises Tenalisib.
- The method of any one of the preceding claims, wherein the polypeptide comprises an antibody, a fragment thereof, or a functional variant thereof.
- The method of any one of the preceding claims, wherein administration of the polypeptide occurs prior to, simultaneously with, or subsequent to administration of the inhibitor against PI3K.
- The method of any one of the preceding claims, wherein the polypeptide and the inhibitor against PI3K are administered in a same unit dose.
- The method of any one of the preceding claims, wherein the polypeptide and the inhibitor against PI3K are administered in different unit doses.
- The method of any one of the preceding claims, wherein administration of the polypeptide and the inhibitor against PI3K synergistically yields one or more characteristics selected from the group consisting of:(A) a greater degree of toxicity against a diseased cell as compared to either of the polypeptide or the inhibitor against PI3K; and(B) a reduction in tumor size as compared to either of the polypeptide or the inhibitor against PI3K.
- The method of any one of the preceding claims, wherein administration of the polypeptide and the inhibitor against PI3K synergistically yields one or more characteristics selected from the group consisting of:(A) a degree of toxicity against a diseased cell that is at least about 20%, at least about 40%, at least about 60%, at least about 80%, at least about 100%, or at least about 200% greater than that that of either of the polypeptide or the inhibitor against PI3K; and(B) a reduction in tumor size by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, or at least about 60% as compared to that of either the polypeptide or the inhibitor against PI3K.
- The method of any one of the preceding claims, wherein the diseased cell comprises a tumor cell or a cancer cell.
- The method of any one of the preceding claims, wherein the diseased cell comprises a colorectal cancer cell.
- The method of any one of the preceding claims, wherein the diseased cell comprises a lymphoma cell.
- The method of any one of the preceding claims, further comprising administering to the subject a co-therapeutic agent.
- The method of any one of the preceding claims, further comprising(c) administering to the subject an inhibitor against the binding of PD-1 to PD-L1, particularly a polypeptide comprising an antigen binding moiety exhibiting binding specificity to PD-1 or PD-L1, and more particularly an antibody, a fragment thereof or a functional variant thereof against PD-1 or PD-L1.
- The method of any one of the preceding claims, wherein the administration of the polypeptide specifically binding to OX40, the inhibitor against PI3K and the inhibitor against the binding of PD-1 to PD-L1 occurs simultaneously or concomitantly.
- The method of any one of the preceding claims, wherein the polypeptide specifically binding to OX40, the inhibitor against PI3K and the inhibitor against the binding of PD-1 to PD-L1 are administered in a same unit dose.
- The method of any one of the preceding claims, wherein the polypeptide specifically binding to OX40, the inhibitor against PI3K and the inhibitor against the binding of PD-1 to PD-L1 are administered in different unit doses.
- The method of any one of the preceding claims, wherein the subject has or is suspected of having a disease.
- The method of any one of the preceding claims, wherein the disease comprises tumor or cancer.
- The method of any one of the preceding claims, wherein the disease comprises colorectal cancer.
- The method of any one of the preceding claims, wherein the disease comprises lymphoma.
- The method of any one of the preceding claims, wherein the disease comprises B cell lymphoma.
- A composition comprising:(a) a polypeptide comprising an antigen binding moiety exhibiting binding specificity to OX40, wherein the antigen binding moiety comprises at least one heavy chain CDR (CDRH) selected from the group consisting of (i) - (iii) and/or at least one light chain CDR (CDRL) selected from the group consisting of (iv) - (vi) , wherein:(i) a CDRH1 having at least 80% sequence identity to a sequence selected from the group consisting of SEQ ID NOs: 1, 7, 13, 15, 21 and 27;(ii) a CDRH2 having at least 80% sequence identity to a sequence selected from the group consisting of SEQ ID NOs: 3, 9, 17, 23 and 29;(iii) a CDRH3 having at least 80% sequence identity to a sequence selected from the group consisting of SEQ ID NOs: 5, 11, 19, 25 and 31;(iv) a CDRL1 having at least 80% sequence identity to a sequence selected from the group consisting of SEQ ID NOs: 2, 8, 14, 16, 22 and 28;(v) a CDRL2 having at least 80% sequence identity to a sequence selected from the group consisting of SEQ ID NOs: 4, 10, 18, 24 and 30; and(vi) a CDRL3 having at least 80% sequence identity to a sequence selected from the group consisting of SEQ ID NOs: 6, 12, 20, 26 and 32; and(b) an inhibitor against PI3K.
- The composition of claim 32, wherein the antigen binding moiety comprises:(1) a heavy chain variable region (VH) having at least 80% sequence identity to a sequence selected from the group consisting of SEQ ID NOs: 33, 35, 37, 39, 41 and 43; and/or(2) a light chain variable region (VL) having at least 80% sequence identity to a sequence selected from the group consisting of SEQ ID NOs: 34, 36, 38, 40, 42 and 44.
- The composition of any one of claims 32 to 33, wherein the antigen binding moiety comprises (1) a VH having at least 80% sequence identity to SEQ ID NO: 39 and/or (2) a VL having at least 80%sequence identity to SEQ ID NO: 40.
- The composition of any one of claims 32 to 34, wherein the inhibitor against PI3K comprises one or more small molecule inhibitors against PI3K alpha, PI3K beta, PI3K delta, or PI3K gamma.
- The composition of any one of claims 32 to 35, wherein the inhibitor against PI3K comprises one or more small molecule inhibitors against PI3K delta and/or PI3K gamma.
- The composition of any one of claim 32 to 36, wherein the inhibitor against PI3K is a dual inhibitor of PI3K delta and PI3K gama.
- The composition of any one of claims 32 to 37, wherein the inhibitor against PI3K is selected from Tenalisib.
- A composition comprising:(a) a polypeptide comprising an antigen binding moiety exhibiting binding specificity to OX40; and(b) an inhibitor against PI3K comprising one or more members selected from the group consisting of Wortmannin, LY294002, hibiscone C, Idelalisib, Copanlisib, Duvelisib, Alpelisib, Taselisib, Perifosine, Buparlisib, Umbralisib, PX-866, Dactolisib, CUDC-907, Voxtalisib, CUDC-907, ME-401, IPI-549, SF1126, Tenalisib, INK1117, pictilisib, XL147, Palomid 529, GSK1059615, ZSTK474, PWT33597, IC87114, TG100–115, CAL263, RP6503, PI-103, GNE-477, and AEZS-136.
- The composition of any one of claims 32 to 39, wherein the inhibitor against PI3K comprises one or more members selected from the group consisting of Idelalisib, Copanlisib, Duvelisib, Alpelisib, Taselisib, Perifosine, Buparlisib, Umbralisib, and Tenalisib.
- The composition of any one of claims 32 to 40, wherein the inhibitor against PI3K comprises Tenalisib.
- The composition of any one of claims 32 to 41, wherein the polypeptide comprises an antibody, a fragment thereof, or a functional variant thereof.
- The composition of any one of claims 32 to 42, wherein the polypeptide and the inhibitor against PI3K are prepared in a same unit dose.
- The composition of any one of claims 32 to 43, wherein the polypeptide and the inhibitor against PI3K are prepared in different unit doses.
- The composition of any one of claims 32 to 44, further comprising a co-therapeutic agent.
- The composition of any one of claims 32 to 45, further comprising an inhibitor against the binding of PD-1 to PD-L1, particularly a polypeptide comprising an antigen binding moiety exhibiting binding specificity to PD-1 or PD-L1, and more particularly an antibody, a fragment thereof or a functional variant thereof against PD-1 or PD-L1.
- The composition of any one of claims 39 to 46, wherein the antigen binding moiety exhibiting binding specificity to OX40 comprises at least one heavy chain CDR (CDRH) selected from the group consisting of (i) - (iii) and/or at least one light chain CDR (CDRL) selected from the group consisting of (iv) - (vi) , wherein:(i) a CDRH1 having at least 80% sequence identity to a sequence selected from the group consisting of SEQ ID NOs: 1, 7, 13, 15, 21 and 27;(ii) a CDRH2 having at least 80% sequence identity to a sequence selected from the group consisting of SEQ ID NOs: 3, 9, 17, 23 and 29;(iii) a CDRH3 having at least 80% sequence identity to a sequence selected from the group consisting of SEQ ID NOs: 5, 11, 19, 25 and 31;(iv) a CDRL1 having at least 80% sequence identity to a sequence selected from the group consisting of SEQ ID NOs: 2, 8, 14, 16, 22 and 28;(v) a CDRL2 having at least 80% sequence identity to a sequence selected from the group consisting of SEQ ID NOs: 4, 10, 18, 24 and 30; and(vi) a CDRL3 having at least 80% sequence identity to a sequence selected from the group consisting of SEQ ID NOs: 6, 12, 20, 26 and 32.
- The composition of any one of claims 32 to 47, wherein the antigen binding moiety exhibiting binding specificity to OX40 comprises at least one heavy chain CDR (CDRH) selected from the group consisting of (i) - (iii) and/or at least one light chain CDR (CDRL) selected from the group consisting of (iv) - (vi) , wherein:(i) a CDRH1 having at least 80% sequence identity to a sequence of SEQ ID NOs: 15;(ii) a CDRH2 having at least 80% sequence identity to a sequence of SEQ ID NOs: 17;(iii) a CDRH3 having at least 80% sequence identity to a sequence of SEQ ID NOs: 19;(iv) a CDRL1 having at least 80% sequence identity to a sequence of SEQ ID NOs: 16;(v) a CDRL2 having at least 80% sequence identity to a sequence of SEQ ID NOs: 18;(vi) a CDRL3 having at least 80% sequence identity to a sequence of SEQ ID NOs: 20.
- The composition of any one of claims 39 to 48, wherein the antigen binding moiety exhibiting binding specificity to OX40 comprises:(1) a heavy chain variable region (VH) having at least 80% sequence identity to a sequence selected from the group consisting of SEQ ID NOs: 33, 35, 37, 39, 41 and 43; and/or(2) a light chain variable region (VL) having at least 80% sequence identity to a sequence selected from the group consisting of SEQ ID NOs: 34, 36, 38, 40, 42 and 44.
- The composition of any one of claims 39 to 49, wherein the antigen binding moiety comprises (1) a VH having at least 80% sequence identity to SEQ ID NO: 39 and/or (2) a VL having at least 80%sequence identity to SEQ ID NO: 40.
- The composition of any one of claims 39 to 50, wherein the inhibitor against PI3K comprises one or more small molecule inhibitors against PI3K alpha, PI3K beta, PI3K delta, or PI3K gamma.
- The composition of any one of claim 39 to 51, wherein the inhibitor against PI3K is a dual inhibitor against PI3K delta and PI3K gama.
- The composition of any one of claim 39 to 52, wherein the inhibitor against PI3K is Tenalisib.
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