US2021401985A1PendingUtilityA1
Compositions, combinations and related methods for photoimmunotherapy
Est. expiryAug 18, 2035(~9.1 yrs left)· nominal 20-yr term from priority
Inventors:Merrill BielLewis R. MakingsRoger HeimMiguel Garcia-GuzmanEileen Sun ChinDeepak YadavJerry Fong
A61P 35/00A61K 41/0071A61K 47/6803A61K 47/6849A61K 47/6851A61K 2039/505A61K 38/18A61K 2300/00Y02A50/30A61K 41/0057
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Claims
Abstract
Provided herein are conjugates, compositions and methods for use in photoimmunotherapy, such as photoimmunotherapy induced by activation of a phthalocyanine dye conjugated to a targeting molecule that binds a protein on cell, for example, an IR700-antibody conjugate. In some embodiments, the phthalocyanine-dye conjugate can be activated by irradiation with near-infrared light. Features of the conjugates, compositions and methods, including the dose of the conjugate, provide various advantages, such as lower toxicity and/or improved efficacy. In some embodiments, also provided is a dual label phthalocyanine-dye conjugate in which the targeting molecule is conjugated to an additional fluorescent dye, which can be used for photoimmunotherapy while, for example, also exhibiting improved performance for imaging or detection. Also provided are therapeutic methods using the conjugates and compositions for treatment of diseases and conditions, including tumors or cancers.
Claims
exact text as granted — not AI-modified1 . A method of treating a disease or condition in a subject, comprising:
a) administering to a subject having a disease or condition a conjugate comprising a phthalocyanine dye linked to a targeting molecule that binds to a protein on the surface of a cell present in the microenvironment of a lesion associated with the disease or condition, wherein the conjugate is administered to effect a systemic exposure that is no more than 75% of the therapeutically effective systemic exposure of the antibody or antigen-binding antibody fragment that is not so conjugated for treating the same disease or condition; and b) after administering the conjugate, irradiating the lesion at a wavelength of 500 nm to 900 nm at a dose of at least 1 J cm −2 or 1 J/cm of fiber length, thereby treating the disease in the subject.
2 . The method of claim 1 , wherein the wavelength is 600 nm to 850 nm.
3 . The method of claim 1 or claim 2 , wherein the wavelength is 660 nm to 740 nm.
4 . The method of any of claims 1 - 3 , wherein the conjugate is administered in a dosing schedule in which:
the administration of the conjugate is performed only one time as a single injection or infusion; or the dosing schedule does not comprise a subsequent dose of the conjugate; or the dosing schedule does not comprise a subsequent dose of the macromolecule that is not so conjugated.
5 . The method of any of claims 1 - 4 , wherein the conjugate is administered systemically.
6 . The method of any of claims 1 - 5 , wherein the conjugate is administered intravenously.
7 . The method of any of claims 1 - 6 , wherein the conjugate is administered to effect a systemic exposure (AUC) that is no more than 60%, no more than 50%, no more than 40% or no more than 30% of the therapeutically effective systemic exposure of the antibody or antigen-binding antibody fragment that is not so conjugated for treating the same disease or condition.
8 . The method of any of claims 1 - 7 , wherein the disease or condition is a tumor, whereby the antibody or an antigen-binding antibody fragment binds to a molecule on the surface of a cell present in the tumor microenvironment and the tumor is irradiated.
9 . The method of any of claims 1 - 8 , wherein:
the systemic exposure as measured by the average area under the plasma conjugate concentration-time curve from time 0 to infinity (AUC[0-inf]) for a patient population after administration of the conjugate is between or between about 250 μg/mL*h and 100,000 μg/mL*h, between or between about 500 μg/mL*h and 50,000 μg/mL*h, between or between about 500 μs/mL*h and 18,000 μg/mL*h; between or between about 500 μg/mL*h and 10,000 μs/mL*h; or the systemic exposure as measured by the average area under the plasma conjugate concentration-time curve from time 0 to infinity (AUC[0-inf]) for a patient population after administration of the conjugate is no more than 100,000 μg/mL*h, no more than 75,000 μg/mL*h, no more than 50,000 μg/mL*h, no more than 40,000 μg/mL*h, no more than 30,000 μg/mL*h, no more than 20,000 μg/mL*h, no more than 10,000 μg/mL*h, no more than 5,000 μg/mL*h, no more than 2,500 μg/mL*h.
10 . The method of any of claims 1 - 9 , wherein:
the systemic exposure as measured by the average area under the plasma conjugate concentration-time curve from time 0 to 24 hours (AUC[0-24]) for a patient population after administration of the conjugate is between or between about 100 μg/mL*h and 25,000 μg/mL*h, between or between about 200 μg/mL*h and 10,000 μg/mL*h, between or between about 500 μs/mL*h and 5,000 μg/mL*h; or the systemic exposure as measured by the average area under the plasma conjugate concentration-time curve from time 0 to 24 hours (AUC[0-24]) for a patient population after administration of the conjugate is no more than 25,000 μg/mL*h, no more than 15,000 μg/mL*h, no more than 10,000 μg/mL*h, no more than 5,000 μg/mL*h, no more than 2,500 μg/mL*h, no more than 1,000 μg/mL*h, or no more than 500 μg/mL*h.
11 . The method of any of claims 1 - 10 , wherein the conjugate is administered in a dosage range that is at least about 10 mg/m 2 (body surface area of the subject), at least about 50 mg/m 2 or at least about 75 mg/m 2 and is no more than 5000 mg/m 2 , no more than 2000 mg/m 2 , no more than 1000 mg/m 2 , no more than 500 mg/m 2 , no more than 250 mg/m 2 or no more than 200 mg/m 2 .
12 . The method of any of claims 1 - 11 , wherein the conjugate is administered at a dosage that is between or between about 100 mg/m 2 and 1500 mg/m 2 or 150 mg/m 2 and 750 mg/m 2 .
13 . The method of any of claims 1 - 12 , wherein the conjugate is administered at a dosage that is or is about 160 mg/m 2 , 320 mg/m 2 , 640 mg/m 2 or 1280 mg/m 2 .
14 . The method of any of claims 1 - 13 , wherein the targeting molecule is an antibody or an antigen-binding antibody fragment.
15 . The method of claim 14 , wherein the antibody is an antigen-binding antibody fragment that is a Fab, single VH domain, a single chain variable fragment (scFv), a multivalent scFv, a bispecific scFv or an scFv-CH3 dimer.
16 . The method of any of claims 1 - 15 , wherein the irradiation is carried out between or between about 30 minutes and 96 hours after administering the conjugate.
17 . The method of any of claims 1 - 16 , wherein the lesion is irradiated at a wavelength of 690±50 nm or at a wavelength of or about 690±20 nm.
18 . The method of any of claims 1 - 17 , wherein the lesion is irradiated at a dose of from or from about 2 J cm −2 to about 400 J cm −2 or from or from about 2 J/cm fiber length to about 500 J/cm fiber length.
19 . The method of any of claims 1 - 18 , wherein:
the lesion is irradiated at a dose of at least or at least about 2 J cm −2 , 5 J cm −2 , 10 J cm −2 , 25 J cm −2 , 50 J cm −2 , 75 J cm −2 , 100 J cm −2 , 150 J cm −2 , 200 J cm −2 , 300 J cm −2 , 400 J cm −2 , or 500 J cm −2 ; or the lesion is irradiated at a dose of at least or at least about 2 J/cm fiber length, 5 J/cm fiber length, 10 J/cm fiber length, 25 J/cm fiber length, 50 J/cm fiber length, 75 J/cm fiber length, 100 J/cm fiber length, 150 J/cm fiber length, 200 J/cm fiber length, 250 J/cm fiber length, 300 J/cm fiber length, 400 J/cm fiber length or 500 J/cm fiber length.
20 . The method of any of claims 1 - 19 , wherein the phthalocyanine dye has a maximum absorption wavelength from or from about 600 nm to about 850 nm.
21 . The method of any of claims 1 - 20 , wherein the phthalocyanine dye is linked directly or indirectly to the targeting molecule.
22 . The method of any of claims 1 - 21 , wherein the phthalocyanine dye comprises the formula:
wherein:
L is a linker;
Q is a reactive group for attachment of the dye to the targeting molecule;
R 2 , R 3 , R 7 , and R 8 are each independently selected from optionally substituted alkyl and optionally substituted aryl;
R 4 , R 5 , R 6 , R 9 , R 10 , and R 11 are each independently selected from hydrogen, optionally substituted alkyl, optionally substituted alkanoyl, optionally substituted alkoxycarbonyl, optionally substituted alkylcarbamoyl, and a chelating ligand, wherein at least one of R 4 , R 5 , R 6 , R 9 , R 10 , and R 11 comprises a water soluble group;
R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 and R 23 are each independently selected from hydrogen, halogen, optionally substituted alkylthio, optionally substituted alkylamino and optionally substituted alkoxy; and
X 2 and X 3 are each independently C 1 -C 10 alkylene, optionally interrupted by a heteroatom.
23 . The method of any of claims 1 - 22 , wherein the phthalocyanine dye comprises the formula:
wherein:
X 1 and X 4 are each independently a C 1 -C 10 alkylene optionally interrupted by a heteroatom;
R 2 , R 3 , R 7 , and R 8 are each independently selected from optionally substituted alkyl and optionally substituted aryl;
R 4 , R 5 , R 6 , R 9 , R 10 , and R 11 are each independently selected from hydrogen, optionally substituted alkyl, optionally substituted alkanoyl, optionally substituted alkoxycarbonyl, optionally substituted alkylcarbamoyl, and a chelating ligand, wherein at least one of R 4 , R 5 , R 6 , R 9 , R 10 , and R 11 comprises a water soluble group; and
R 16 , R 17 , R 18 and R 19 are each independently selected from hydrogen, halogen, optionally substituted alkylthio, optionally substituted alkylamino and optionally substituted alkoxy.
24 . The method of any of claims 1 - 23 , wherein the phthalocyanine dye comprises IRDye 700DX (IR700).
25 . The method of any of claims 1 - 24 , wherein the cell surface protein is selected from among ACTHR, endothelial cell Anxa-1, aminopetidase N, anti-IL-6R, alpha-4-integrin, alpha-5-beta-3 integrin, alpha-5-beta-5 integrin, alpha-fetoprotein (AFP), ANPA, ANPB, APA, APN, APP, 1AR, 2AR, AT1, B1, B2, BAGE1, BAGE2, B-cell receptor BB1, BB2, BB4, calcitonin receptor, cancer antigen 125 (CA 125), CCK1, CCK2, CD5, CD10, CD11a, CD13, CD14, CD19, CD20, CD22, CD25, CD30, CD33, CD38, CD45, CD52, CD56, CD68, CD90, CD133, CD7, CD15, CD34, CD44, CD206, CD271, CEA (CarcinoEmbryonic Antigen), CGRP, chemokine receptors, cell-surface annexin-1, cell-surface plectin-1, Cripto-1, CRLR, CXCR2, CXCR4, DCC, DLL3, E2 glycoprotein, EGFR, EGFRvIII, EMR1, Endosialin, EP2, EP4, EpCAM, EphA2, ET receptors, Fibronectin, Fibronectin ED-B, FGFR, frizzled receptors, GAGE1, GAGE2, GAGE3, GAGE4, GAGE5, GAGE6, GLP-1 receptor, G-protein coupled receptors of the Family A (Rhodopsin-like), G-protein coupled receptors of the Family B (Secretin receptor-like) like), G-protein coupled receptors of the Family C (Metabotropic Glutamate Receptor-like), GD2, GP100, GP120, Glypican-3, hemagglutinin, Heparin sulfates, HER1, HER2, HER3, HER4, HMFG, HPV 16/18 and E6/E7 antigens, hTERT, IL11-R, IL-13R, ITGAM, Kalikrien-9, Lewis Y, LH receptor, LHRH-R, LPA1, MAC-1, MAGE 1, MAGE 2, MAGE 3, MAGE 4, MART 1, MC1R, Mesothelin, MUC1, MUC16, Neu (cell-surface Nucleolin), Neprilysin, Neuropilin-1, Neuropilin-2, NG2, NK1, NK2, NK3, NMB-R, Notch-1, NY-ESO-1, OT-R, mutant p53, p97 melanoma antigen, NTR2, NTR3, p32 (p32/gClq-R/HABP1), p′75, PAC1, PAR1, Patched (PTCH), PDGFR, PDFG receptors, PDT, Protease-cleaved collagen IV, proteinase 3, prohibitin, protein tyrosine kinase 7, PSA, PSMA, purinergic P2X family (e.g., P2X1-5), mutant Ras, RAMP1, RAMP2, RAMP3 patched, RET receptor, plexins, smoothened, sst1, sst2A, sst2B, sst3, sst4, sst5, substance P, TEMs, T-cell CD3 Receptor, TAG72, TGFBR1, TGFBR2, Tie-1, Tie-2, Trk-A, Trk-B, Trk-C, TR1, TRPA, TRPC, TRPV, TRPM, TRPML, TRPP (e.g., TRPV1-6, TRPA1, TRPC1-7, TRPM1-8, TRPP1-5, TRPML1-3), TSH receptor, VEGF receptors (VEGFR1 or Flt-1, VEGFR2 or FLK-1/KDR, and VEGF-3 or FLT-4), voltage-gated ion channels, VPAC1, VPAC2, Wilms tumor 1, Y1, Y2, Y4, and Y5.
26 . The method of any of claims 1 - 25 , wherein the cell surface protein is selected from among HER1/EGFR, HER2/ERBB2, CD20, CD25 (IL-2Ra receptor), CD33, CD52, CD133, CD206, CEA, CEACAM1, CEACAM3, CEACAM5, CEACAM6, cancer antigen 125 (CA125), alpha-fetoprotein (AFP), Lewis Y, TAG72, Caprin-1, mesothelin, PDGF receptor, PD-1, PD-L1, CTLA-4, IL-2 receptor, vascular endothelial growth factor (VEGF), CD30, EpCAM, EphA2, Glypican-3, gpA33, mucins, CAIX, PSMA, folate-binding protein, gangliosides (such as GD2, GD3, GM1 and GM2), VEGF receptor (VEGFR), integrin αVβ3, integrin α5β1, ERBB3, MET, IGF1R, EPHA3, TRAILR1, TRAILR2, RANKL, FAP, tenascin, AFP, BCR complex, CD3, CD18, CD44, CTLA-4, gp72, HLA-DR 10 (3, HLA-DR antigen, IgE, MUC-1, nuC242, PEM antigen, metalloproteinases, Ephrin receptor, Ephrin ligands, HGF receptor, CXCR4, CXCR4, Bombesin receptor, and SK-1 antigen.
27 . The method of any of claims 1 - 26 , wherein the cell surface protein is selected from among CD25, PD-1 (CD279), PD-L1 (CD274, B7-H1), PD-L2 (CD273, B7-DC), CTLA-4, LAG3 (CD223), TIM3 (HAVCR2), 4-1BB (CD137, TNFRSF9), CXCR2, CXCR4 (CD184), CD27, CEACAM1, Galectin 9, BTLA, CD160, VISTA (PD1 homologue), B7-H4 (VCTN1), CD80 (B7-1), CD86 (B7-2), CD28, HHLA2 (B7-H7), CD28H, CD155, CD226, TIGIT, CD96, Galectin 3, CD40, CD40L, CD70, LIGHT (TNFSF14), HVEM (TNFRSF14), B7-H3 (CD276), Ox40L (TNFSF4), CD137L (TNFSF9, GITRL), B7RP1, ICOS (CD278), ICOSL, KIR, GALS, NKG2A (CD94), GARP, TL1A, TNFRSF25, TMIGD2, BTNL2, Butyrophilin family, CD48, CD244, Siglec family, CD30, CSF1R, MICA (MEW class I polypeptide-related sequence A), MICB (MHC class I polypeptide-related sequence B), NKG2D, KIR family (Killer-cell immunoglobulin-like receptor, LILR family (Leukocyte immunoglobulin-like receptors, CD85, ILTs, LIRs), SIRPA (Signal regulatory protein alpha), CD47 (IAP), Neuropilin 1 (NRP-1), a VEGFR, and VEGF.
28 . The method of any of claims 1 - 27 , wherein the antibody or an antigen-binding antibody fragment is selected from among cetuximab, panitumumab, zalutumumab, nimotuzumab, Tositumomab (Bexxar®), Rituximab (Rituxan, Mabthera), Ibritumomab tiuxetan (Zevalin), Daclizumab (Zenapax), Gemtuzumab (Mylotarg), Alemtuzumab, CEA-scan Fab fragment, OC125 monoclonal antibody, ab75705, B72.3, Bevacizumab (Avastin®), Basiliximab, nivolumab, pembrolizumab, pidilizumab, MK-3475, BMS-936559, MPDL3280A, ipilimumab, tremelimumab, IMP321, BMS-986016, LAG525, urelumab, PF-05082566, TRX518, MK-4166, dacetuzumab, lucatumumab, SEA-CD40, CP-870, CP-893, MED16469, MEDI6383, MEDI4736, MOXR0916, AMP-224, PDR001, MSB0010718C, rHIgM12B7, Ulocuplumab, BKT140, Varlilumab (CDX-1127), ARGX-110, MGA271, lirilumab (BMS-986015, IPH2101), IPH2201, AGX-115, Emactuzumab, CC-90002 and MNRP1685A or is an antigen-binding antibody fragment thereof.
29 . The method of any of claims 1 - 28 , wherein the conjugate is selected from among cetuximab-IR700, panitumumab-IR700, zalutumumab-IR700, nimotuzumab-IR700, Tositumomab-IR700, Rituximab-IR700, Ibritumomab tiuxetan-IR700, Daclizumab-IR700, Gemtuzumab-IR700, Alemtuzumab-IR700, CEA-scan Fab fragment-IR700, OC125-IR700, ab75705-IR700, B72.3-IR700, Bevacizumab-IR700, Basiliximab-IR700, nivolumab-IR700, pembrolizumab-IR700, pidilizumab-IR700, MK-3475-IR700, BMS-936559-IR700, MPDL3280A-IR700, ipilimumab-IR700, tremelimumab-IR700, IMP321-IR700, BMS-986016-IR700, LAG525-IR700, urelumab-IR700, PF-05082566-IR700, TRX518-IR700, MK-4166-IR700, dacetuzumab-IR700, lucatumumab-IR700, SEA-CD40-IR700, CP-870-IR700, CP-893-IR700, MED16469-IR700, MEDI6383-IR700, MEDI4736-IR700, MOXR0916-IR700, AMP-224-IR700, PDR001-IR700, MSB0010718C-IR700, rHIgM12B7-IR700, Ulocuplumab-IR700, BKT140-IR700, Varlilumab-IR700, ARGX-110-IR700, MGA271-IR700, lirilumab-IR700, IPH2201-IR700, AGX-115-IR700, Emactuzumab-IR700, CC-90002-IR700 and MNRP1685A-IR700.
30 . The method of claim 29 , wherein the targeting molecule is an antibody that is cetuximab or is an antigen-binding antibody fragment thereof or the conjugate is cetuximab-IR700.
31 . The method of claim 30 , wherein the average area under the plasma conjugate concentration-time curve from time 0 to infinity (AUC[0-inf]) for a patient population after administration of the conjugate is between or between about 500 μg/mL*h and 18,000 μg/mL*h, between or between about 500 μg/mL*h and 10,000 μg/mL*h, between or between about 500 μg/mL*h and 5,000 μg/mL*h, or between or between about 500 μg/mL*h and 2,500 μg/mL*h.
32 . The method of claim 30 , wherein the average area under the plasma conjugate concentration-time curve from time 0 to 24 hours hours (AUC[0-24]) for a patient population after administration of the conjugate is between or between about 500 μg/mL*h and 8,000 μg/mL*h, between or between about 500 μg/mL*h and 5,000 μg/mL*h, between or between about 500 μg/mL*h and 2,000 μg/mL*h or between or between about 1000 μg/mL*h and 4,000 μg/mL*h.
33 . The method of any of claims 30 - 32 , wherein:
the conjugate is administered in a dosage range that between or between about 75 mg/m 2 (body surface area of the subject) and 1500 mg/m 2 , between or between about 75 mg/m 2 and 1000 mg/m 2 , between or between about 75 mg/m 2 and 500 mg/m 2 or between or between about 75 mg/m 2 and 225 mg/m 2 ′; or is at least about or is about 160 mg/m 2 , 320 mg/m 2 , 640 mg/m 2 or 1280 mg/m 2 .
34 . A method of treating a disease lesion in a subject, comprising:
a) intravenously administering to a subject having a lesion associated with a disease or condition a cetuximab-IR700 conjugate, wherein the conjugate is administered in an amount that is or is about 640 mg/m 2 ; and b) after administering the conjugate, irradiating the lesion at a wavelength of 690±20 nm at a dose of at least or about at least or about 50 J cm −2 or 100 J/cm of fiber length, thereby treating the disease or condition in the subject.
35 . The method of claim 34 , wherein the conjugate is administered in a dosing schedule in which:
the administration of the conjugate is performed only one time as a single injection or infusion; or the dosing schedule does not comprise a subsequent dose of the conjugate; or the dosing schedule does not comprise a subsequent dose of the macromolecule that is not so conjugated.
36 . The method of any of claims 1 - 35 , wherein the irradiation is carried out 24 hours±3 hours after administering the conjugate.
37 . The method of any of claims 34 - 36 , wherein the lesion is a tumor and the disease or condition is a tumor or a cancer.
38 . The method of any of claims 1 - 37 , wherein the lesion is a tumor that is a superficial tumor.
39 . The method of claim 38 , wherein the tumor is less than 10 mm thick.
40 . The method of claim 38 or claim 39 , wherein irradiation is carried out using a microlens-tipped fiber for surface illumination.
41 . The method of any of claims 1 - 40 , wherein the light irradiation dose is from or from about 5 J/cm 2 to about 200 J/cm 2 .
42 . A method for treating a superficial tumor with photoimmunotherapy, comprising illuminating an superficial tumor in a subject with a microlens-tipped fiber for surface illumination with a light dose of from or from about 5 J/cm 2 to about 200 J/cm 2 , wherein the tumor is associated with a phototoxic agent comprising a targeting molecule bound to a cell surface molecule of the tumor.
43 . The method claim 41 or claim 42 , wherein the light irradiation dose is or is about 50 J/cm 2 .
44 . The method of any of claims 1 - 40 , wherein the lesion is a tumor that is an interstitial tumor.
45 . The method of claim 44 , wherein the tumor is greater than 10 mm deep or is a subcutaneous tumor.
46 . The method of claim 44 or claim 45 , wherein irradiation is carried out using cylindrical diffusing fibers comprising a diffuser length of 0.5 cm to 10 cm and spaced 1.8±0.2 cm apart.
47 . The method of any of claims 1 - 37 and 44 - 46 , wherein the light irradiation dose is from or from about 20 J/cm fiber length to about 500 J/cm fiber length.
48 . A method for treating an interstitial tumor with photommunotherapy, comprising illuminating an interstitial tumor in a subject with cylindrical diffusing fibers comprising a diffuser length of 0.5 cm to 10 cm and spaced 1.8±0.2 cm apart with a light dose of or about 100 J/cm fiber length or with a fluence rate of or about 400 mW/cm, wherein the tumor is associated with a phototoxic agent comprising a targeting molecule bound to a cell surface molecule of the tumor.
49 . The method of claim 47 or claim 48 , wherein the light irradiation dose is from or from about 50 J/cm fiber length to about 300 J/cm fiber length.
50 . The method of any of claims 47 - 49 , wherein the light irradiation dose is or is about 100 J/cm fiber length.
51 . The method of any of claims 48 - 50 , wherein the tumor is greater than 10 mm deep or is a subcutaneous tumor.
52 . The method of any of claims 47 - 51 , wherein the cylindrical diffusing fibers are placed in a catheter positioned in the tumor 1.8±0.2 cm apart.
53 . The method of claim 52 , wherein the catheter is optically transparent.
54 . The method of any of claims 42 , 43 and 48 - 53 , wherein greater than 6 hours prior to illuminating the tumor, the subject has been administered the phototoxic agent comprising the targeting molecule, wherein the phototoxic agent associates with the tumor.
55 . The method of claim 54 , wherein the phototoxic agent has been previously administered to the subject greater than or greater than about 12 hours, 24 hours, 26 hours, 48 hours, 72 hours or 96 hours prior to illuminating the tumor.
56 . The method of any of claims 42 , 43 and 48 - 55 , wherein the phototoxic agent is a phthalocyanine dye-targeting molecule conjugate.
57 . The method of claim 56 , wherein the phthalocyanine dye is IR700.
58 . The method of any of claims 1 - 41 , 44 - 47 , 49 , 50 and 52 - 54 , wherein the dosing schedule is repeated, whereby steps (a) and (b) are repeated.
59 . The method of claim 58 , wherein the dosing schedule is repeated if residual lesion remains after a prior treatment with the conjugate.
60 . The method of claim 58 or claim 59 , comprising assessing the subject for the presence of a residual lesion and if residual lesion remains repeating the dosing schedule.
61 . The method of any of claims 58 - 60 , wherein the dosing schedule is repeated if a residual lesion remains at a time that is more than or about or 1 week, 2 weeks, 3 weeks, 4 weeks, 2 months, 6 months or 1 year after initiation of the prior administration of the conjugate.
62 . The method of any of claims 58 - 61 , wherein the dosing schedule is repeated if a residual lesion remains at or about 4 weeks after initiation of the prior administration of the conjugate.
63 . The method of any of claims 1 - 62 , wherein the conjugate comprises 1 to 100, 1 to 10 or 2 to 5 phthalocyanine dye molecules per macromolecule.
64 . The method of any of claims 1 - 63 , wherein the method does not comprise administration of an additional therapeutic agent or anti-cancer treatment.
65 . The method of any of claims 1 - 63 , wherein the method comprises administration of an additional therapeutic agent or anti-cancer treatment.
66 . The method of claim 65 , wherein the anti-cancer treatment comprises radiation therapy.
67 . The method of claim 66 , wherein the additional therapeutic agent is an anti-cancer agent or an immune modulating agent.
68 . The method of claim 67 , wherein the additional therapeutic agent is an immune modulating agent that is an immune checkpoint inhibitor.
69 . The method of claim 68 , wherein the immune checkpoint inhibitor specifically binds a molecule selected from among CD25, PD-1, PD-L1, PD-L2, CTLA-4, LAG-3, TIM-3, 4-1BB, GITR, CD40, CD40L, OX40, OX40L, CXCR2, B7-H3, B7-H4, BTLA, HVEM, CD28 and VISTA.
70 . The method of claim 68 or claim 69 , wherein the immune checkpoint inhibitor is and antibody or antigen-binding fragment, a small molecule or a polypeptide.
71 . The method of any of claims 68 - 70 , wherein the immune checkpoint inhibitor is selected from among nivolumab, pembrolizumab, pidilizumab, MK-3475, BMS-936559, MPDL3280A, ipilimumab, tremelimumab, IMP31, BMS-986016, urelumab, TRX518, dacetuzumab, lucatumumab, SEQ-CD40, CP-870, CP-893, MED16469, MEDI4736, MOXR0916, AMP-224, and MSB001078C, or is an antigen-binding fragment thereof.
72 . The method of any of claims 67 - 71 , wherein the additional therapeutic agent is administered prior to irradiating the lesion or tumor.
73 . The method of claim 72 , wherein the additional therapeutic agent is administered greater than or greater than about 30 minutes, 1 hour, 2 hours, 6 hours, 12 hours, 24 hours, 48 hours, 96 hours, one week, two weeks, three weeks or one month prior to irradiating the tumor.
74 . The method of any of claims 67 - 73 , comprising continued administration of the additional therapeutic agent subsequent to the irradiation three times a week, two times a week, once every week, once every two weeks, once every three weeks or once a month.
75 . A method of treating a tumor in a subject comprising:
a) administering to a subject an immune modulating agent; b) administering to the subject a therapeutically effective amount of a conjugate comprising a phthalocyanine dye linked to a targeting molecule capable of binding to a molecule on the surface of a cell present in the microenvironment of a tumor; and c) greater than 12 hours after administering the immune modulating agent, irradiating the tumor at a wavelength that renders the conjugate cytotoxic, thereby treating the tumor.
76 . The method of claim 75 , wherein the immune modulating agent is administered greater than or greater than about 24 hours, 48 hours, 96 hours, one week, two weeks, three weeks or one month prior to irradiating the tumor.
77 . The method of claim 75 or claim 76 , wherein the conjugate binds to a protein on the surface of a cell present in the microenvironment of the tumor.
78 . The method of any of claims 75 - 77 , wherein step c) of irradiating the tumor is carried out either i) after administration of the immune modulating agent and after administration of the conjugate or ii) only after administration of the conjugate.
79 . The method of any of claims 67 - 78 , wherein the conjugate is administered prior to, simultaneously or subsequently to administration of the immune-modulating agent.
80 . The method of any of claims 67 - 79 , wherein the conjugate is administered after administering the immune modulating agent but prior to irradiating the tumor.
81 . The method of any of claims 67 - 80 , wherein the conjugate is administered from or from about 12 hours to 48 hours prior to irradiating the tumor and the immune modulating agent is administered from or from about 12 hours to about 1 month prior to irradiating the tumor.
82 . The method of any of claims 75 - 81 , wherein the immune modulating agent is an immune checkpoint inhibitor.
83 . The method of claim 82 , wherein the immune checkpoint inhibitor specifically binds a molecule selected from among CD25, PD-1, PD-L1, PD-L2, CTLA-4, LAG-3, TIM-3, 4-1BB, GITR, CD40, CD40L, OX40, OX40L, CXCR2, B7-H3, B7-H4, BTLA, HVEM, CD28 and VISTA.
84 . The method of claim 82 or claim 83 , wherein the immune checkpoint inhibitor is and antibody or antigen-binding fragment, a small molecule or a polypeptide.
85 . The method of any of claims 82 - 84 , wherein the immune checkpoint inhibitor is selected from among nivolumab, pembrolizumab, pidilizumab, MK-3475, BMS-936559, MPDL3280A, ipilimumab, tremelimumab, IMP31, BMS-986016, urelumab, TRX518, dacetuzumab, lucatumumab, SEQ-CD40, CP-870, CP-893, MED16469, MEDI4736, MOXR0916, AMP-224, and MSB001078C, or is an antigen-binding fragment thereof of any of the foregoing.
86 . The method of any of claims 75 - 81 , wherein the immune modulating agent that is a demethylating agent that upregulates expression of a tumor associated antigen (TAA) or is a cytokine.
87 . The method of any of claims 75 - 86 , comprising continued administration of the immune modulating agent subsequent to the irradiation three times a week, two times a week, once every week, once every two weeks, once every three weeks or once a month.
88 . A method of treating a tumor in a subject comprising:
a) administering to a subject an immune modulating agent that enhances the expression of a molecule on the surface of a cell present in the microenvironment of the tumor; b) administering to the subject a therapeutically effective amount of a conjugate comprising a phthalocyanine dye linked to a targeting molecule that is capable of binding to the cell surface molecule; and c) greater than 5 minutes after administering the conjugate, irradiating the tumor at a wavelength that renders the conjugate cytotoxic, thereby treating the tumor.
89 . The method of claim 88 , wherein the immune modulating agent is a cytokine or is an agent that induces increased expression of a cytokine in the tumor microenvironment.
90 . The method of claim 88 or claim 89 , wherein the cytokine is interferon gamma.
91 . The method of any of claims 88 - 90 , wherein the molecule on the surface of the cells is selected from CD25, PD-1, PD-L1, PD-L2, CTLA-4, LAG-3, TIM-3, 4-1BB, GITR, CD40, CD40L, OX40, OX40L, CXCR2, B7-H3, B7-H4, BTLA, HVEM, CD28 and VISTA.
92 . The method of any of claims 88 - 91 , wherein the molecule on the surface of the cell is PD-L1.
93 . The method of any of claims 88 - 92 , wherein the targeting molecule is an immune checkpoint inhibitor.
94 . The method of any of claims 88 - 93 , wherein the targeting molecule is an antibody or antibody fragment, a small molecule or a polypeptide.
95 . The method of any of claims 88 - 94 , wherein the targeting molecule is selected from among nivolumab, pembrolizumab, pidilizumab, MK-3475, BMS-936559, MPDL3280A, ipilimumab, tremelimumab, IMP31, BMS-986016, urelumab, TRX518, dacetuzumab, lucatumumab, SEQ-CD40, CP-870, CP-893, MED16469, MED14736, MOXR0916, AMP-224, and MSB001078C, or is an antigen-binding fragment thereof of any of the foregoing.
96 . A method of treating a tumor in a subject comprising:
a) administering to a subject a conjugate comprising a phthalocyanine dye linked to a targeting molecule capable of binding a cell surface molecule on a cell in the microenvironment of the tumor; b) greater than 5 minutes after administering the conjugate, irradiating the tumor at a wavelength that renders the conjugate cytotoxic, wherein the treatment of the tumor with the conjugate followed by light irradiation increases the presence of immunosuppressive cells in the tumor or increases the expression of immunosuppressive markers at the tumor; and c) administering to the subject a therapeutically effective amount of an immune modulating agent capable of reducing the amount or activity of immunosuppressive cells in the tumor or capable of blocking the activity of the immunosuppressive marker.
97 . The method of claim 96 , wherein the phthalocyanine dye is a first dye and the immune modulating agent comprises a conjugate comprising a second phthalocyanine dye conjugated to an immune modulating agent capable of binding to the immunosuppressive cell.
98 . The method of claim 97 , wherein the first and second phthalocyanine dye is the same or different.
99 . The method of any of claims 96 - 98 , wherein the immune modulating agent is an immune checkpoint inhibitor.
100 . The method of any of claims 96 - 99 , wherein the immune modulating agent specifically binds a molecule selected from among CD25, PD-1, PD-L1, PD-L2, CTLA-4, LAG-3, TIM-3, 4-1BB, GITR, CD40, CD40L, OX40, OX40L, CXCR2, B7-H3, B7-H4, BTLA, HVEM, CD28 and VISTA.
101 . The method of any of claims 96 - 100 , wherein the immune modulating agent is an antibody or antibody fragment, a small molecule or a polypeptide.
102 . The method of any of claims 96 - 101 , wherein the immune modulating agent is not an anti-CTLA4 antibody.
103 . The method of any of claims 96 - 102 , wherein the immune modulating agent is selected from among nivolumab, pembrolizumab, pidilizumab, MK-3475, BMS-936559, MPDL3280A, ipilimumab, tremelimumab, IMP31, BMS-986016, urelumab, TRX518, dacetuzumab, lucatumumab, SEQ-CD40, CP-870, CP-893, MED16469, MED14736, MOXR0916, AMP-224, and MSB001078C, or is an antigen-binding fragment thereof of any of the foregoing.
104 . A method of treating a tumor in a subject comprising:
a) administering to a subject a conjugate comprising a phthalocyanine dye linked to a targeting macromolecule capable of binding to a molecule on the surface of a cell present in the microenvironment of the tumor; b) greater than 5 minutes after administering the conjugate, irradiating the tumor at a wavelength that renders the conjugate cytotoxic, wherein the treatment of the tumor with the conjugate followed by light irradiation primes activation of immune cells; and c) administering to the subject a therapeutically effective amount of an immune modulating agent capable of increasing the activity of the immune cell.
105 . The method of claim 104 , wherein the immune cell is an antigen presenting cell.
106 . The method of claim 105 , wherein the immune cell is a dendritic cell.
107 . The method of any of claims 104 - 106 , wherein the immune modulating agent is selected from among GM-CSF, CpG-ODN (CpG oligodeoxynucleotides), lipopolysaccharide (LPS), monophosphoryl lipid A (MPL), alum, recombinant Leishmania polyprotein, imiquimod, MF59, poly I:C, poly A:U, type 1 IFN, Pam3Cys, Pam2Cys, complete freund's adjuvant (CFA), alpha-galactosylceramide, RC-529, MDF2β, Loxoribine, anti-CD40 agonist, SIRPa antagonist, AS04, AS03, Flagellin, Resiquimod, DAP (diaminopimelic acid), MDP (muramyl dipeptide) CAF01 (cationic adjuvant formulation-01), antrhacyclins (doxorubicin, mitoxantron), BK channel agonists, bortezomib, botrtezomib plus mitocycin C plus hTert-Ad, Cardiac glycosides plus non-Immunogenic cell death inducers, cyclophosphamide, GADD34/PP1 inhibitors plus mitomycin, LV-tSMAC, and oxaliplatin.
108 . The method of any of claims 104 - 107 , wherein the immune modulating agent is a Toll-like receptor (TLR) agonist, an adjuvant or a cytokine.
109 . The method of claim 108 , wherein the immune modulating agent is a TLR agonist and the TLR agonist is TLR agonist is a TLR4 agonist, a TLR7 agonist, a TLR8 agonist, or a TLR9 agonist.
110 . The method of claim 108 or claim 109 , wherein the TLR agonist is selected from among triacylated lipoprotein, diacylated lipopeptide, lipoteichoic acid, peptidoglycan, zymosan, Pam3CSK4, dsRNA, polyI:C, Poly G10, Poly G3, CpG, 3M003, flagellin, lipopolysaccharide (LPS) Leishmania homolog of eukaryotic ribosomal elongation and initiation factor 4a (LeIF), MEDI9197, SD-101, and imidazoquinoline TLR agonists.
111 . The method of any of claims 104 - 107 , wherein the immune modulating agent is a cytokine and the cytokine is IL-4, TNF-α, GM-CSF or IL-2.
112 . The method of any of claims 96 - 111 , wherein the immune modulating agent is administered prior to, simultaneously with or after the irradiation.
113 . The method of claim 112 , wherein the immune modulating agent is administered no more than 5 minutes, 30 minutes, 60 minutes, 2 hours, 6 hours, 12 hours or 24 hours after the irradiation.
114 . The method of any of claims 75 - 113 , wherein the targeting molecule binds to molecule or protein directly or indirectly.
115 . The method of claim 114 , wherein the targeting molecule is a second binding molecule that binds to a first binding molecule, said first binding molecule being capable of binding to the molecule or protein.
116 . The method of claim 114 or claim 115 , wherein the targeting molecule is a secondary antibody.
117 . The method of any of claims 75 - 116 , wherein the phthalocyanine dye has a maximum absorption wavelength from or from about 600 nm to about 850 nm.
118 . The method of any of claims 75 - 117 , wherein the phthalocyanine dye is covalently or non-covalently linked to the targeting molecule.
119 . The method of any of claims 75 - 118 , wherein the phthalocyanine dye comprises a linker comprising a reactive group for attachment of the dye to the targeting molecule.
120 . The method of claim 119 , wherein the phthalocyanine dye comprises the formula:
wherein:
L is a linker;
Q is a reactive group for attachment of the dye to the targeting molecule;
R 2 , R 3 , R 7 , and R 8 are each independently selected from optionally substituted alkyl and optionally substituted aryl;
R 4 , R 5 , R 6 , R 9 , R 10 , and R 11 are each independently selected from hydrogen, optionally substituted alkyl, optionally substituted alkanoyl, optionally substituted alkoxycarbonyl, optionally substituted alkylcarbamoyl, and a chelating ligand, wherein at least one of R 4 , R 5 , R 6 , R 9 , R 10 , and R 11 comprises a water soluble group;
R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 and R 23 are each independently selected from hydrogen, halogen, optionally substituted alkylthio, optionally substituted alkylamino and optionally substituted alkoxy; and
X 2 and X 3 are each independently C 1 -C 10 alkylene, optionally interrupted by a heteroatom.
121 . The method of claim 119 or claim 120 , wherein the phthalocyanine dye comprises the formula:
wherein:
X 1 and X 4 are each independently a C 1 -C 10 alkylene optionally interrupted by a heteroatom;
R 2 , R 3 , R 7 , and R 8 are each independently selected from optionally substituted alkyl and optionally substituted aryl;
R 4 , R 5 , R 6 , R 9 , R 10 , and R 11 are each independently selected from hydrogen, optionally substituted alkyl, optionally substituted alkanoyl, optionally substituted alkoxycarbonyl, optionally substituted alkylcarbamoyl, and a chelating ligand, wherein at least one of R 4 , R 5 , R 6 , R 9 , R 10 , and R 11 comprises a water soluble group; and
R 16 , R 17 , R 18 and R 19 are each independently selected from hydrogen, halogen, optionally substituted alkylthio, optionally substituted alkylamino and optionally substituted alkoxy.
122 . The method of any of claims 75 - 121 , wherein the phthalocyanine dye comprises IRDye 700DX (IR700).
123 . The method of any of claims 75 - 122 , wherein the conjugate is administered at a dose from or from about 50 mg/m 2 to about 5000 mg/m 2 , from about 250 mg/m 2 to about 2500 mg/m 2 , from about 750 mg/m 2 to about 1250 mg/m 2 or from about 100 mg/m 2 to about 1000 mg/m 2 .
124 . The method of any of claims 8 - 33 and 37 - 123 , wherein the tumor is a cancer.
125 . The method of claim 124 , wherein the cancer is a cancer located at the head and neck, breast, liver, colon, ovary, prostate, pancreas, brain, cervix, bone, skin, eye, bladder, stomach, esophagus, peritoneum, or lung.
126 . The method of any of claims 8 - 33 and 37 - 125 , wherein the tumor is a sarcoma or carcinoma.
127 . The method of claim 126 , wherein the tumor is a carcinoma that is a squamous cell carcinoma, basal cell carcinoma or adenocarcinoma.
128 . The method of claim 127 , wherein the tumor is a carcinoma that is a carcinoma of the bladder, pancreas, colon, ovary, lung, breast, stomach, prostate, cervix, esophagus or head and neck.
129 . The method of any of claims 75 - 128 , wherein the tumor is irradiated at a wavelength of 600 nm to 850 nm at a dose of at least 1 J cm −2 or at least 1 J/cm fiber length.
130 . The method of any of claims 75 - 129 , wherein the tumor is irradiated at a wavelength of 690 nm±50 nm or at a wavelength of or about 690±20 nm.
131 . The method of any of claims 1 - 130 , wherein the method reduces the size or volume of the tumor by at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80% at least 90% or more within one month of the irradiation compared to the size or volume of the tumor prior to the administration and irradiation.
132 . The method of any of claims 1 - 131 , which, in a population of treated subjects, effects an improvement of a disorder- or cancer-related parameter compared to a similarly situated population of subjects treated with the antibody or antigen-binding antibody fragment that is not conjugated, wherein the parameter is selected from one or more of: a) objective response rate (ORR); b) progression free survival (PFS); c) overall survival (OS); d) reduction in toxicity; e) tumor response; of f) quality of life.
133 . The method of claim 132 , wherein the parameter is improved by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 100% or more.
134 . The method of any of claims 1 - 133 , which, in a population of treated subjects, effects an objective response rate (ORR) of at least 15%, at least 25%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or more.
135 . The method of any of claims 1 - 133 , wherein the phthalocyanine dye is a first dye and the conjugate further comprises a second fluorescent dye linked to the macromolecule that is different than the first dye.
136 . The method of claim 135 , wherein irradiating the lesion or tumor emits a fluorescence signal from the second fluorescent dye to effect detection of the presence of the conjugate at the lesion or tumor in the subject.
137 . The method of claim 135 or claim 136 , further comprising imaging the lesion or tumor in the subject by irradiating or illuminating the tumor at a wavelength capable of being absorbed by the second dye.
138 . The method of any of claims 135 - 137 , wherein the second fluorescent dye exhibits one or more spectral properties selected from among fluorescent quantum yield in water, extinction coefficient, Stokes shift, absorption and emission at long wavelength and photostability that is greater compared to the corresponding spectral property of the first dye.
139 . The method of any of claims 135 - 138 , wherein the first dye is IR700.
140 . The method of any of claims 135 - 139 , wherein the second dye is not IR700.
141 . The method of any of claims 135 - 140 , wherein the second dye is selected from among hydroxycoumarin, Cascade Blue, Dylight 405, Pacific Orange, Alexa Fluor 430, Fluorescein, Oregon Green, Alexa Fluor 488, BODIPY 493, 2.7-Diochlorofluorescien, ATTO 488, Chromeo 488, Dylight 488, HiLyte 488, Alexa Fluor 555, ATTO 550, BODIPY TMR-X, CF 555, Chromeo 546, Cy3, TMR, TRITC, Dy547, Dy548, Dy549, HiLyte 555, Dylight 550, BODIPY 564, Alexa Fluor 568, Alexa Fluor 594, Rhodamine, Texas Red, Alexa Fluor 610, Alexa Fluor 633, Dylight 633, Alexa Fluor 647, APC, ATTO 655, CF633, CF640R, Chromeo642, Cy5, Dylight 650, Alexa Fluor 680, IRDye 680, Alexa Fluor 700, Cy 5.5, ICG, Alexa Fluor 750, Dylight 755, IRDye 750, Cy7.5, Alexa Fluor 790, Dylight 800, IRDye 800, Qdot® 525, Qdot® 565, Qdot® 605, Qdot® 655, Qdot® 705 and Qdot® 800.
142 . The method of any of claims 135 - 141 , wherein the first dye is IR700 and the conjugate comprises 1 to 10 or 1 to 5 second dye molecules per macromolecule.
143 . The method of any of claims 135 - 142 , wherein the second dye exhibits a Stokes shift that is greater than 15 nm, greater than 20 nm, greater than 30 nm, greater than 40 nm, greater than 50 nm, greater than 60 nm, greater than 70 nm, greater than 80 nm, greater than 90 nm or greater than 100 nm.
144 . The method of any of claims 135 - 143 , wherein the second dye has a quantum yield in water that is greater than 10%, greater than 15%, greater than 20% or greater than 25%, greater than 30%, greater than 40%, greater than 50% or greater.
145 . The method of any of claims 135 - 144 , wherein the second dye has an absorption and emission wavelength in the spectrum between or between about 650 nm and 950 nm, between or between about 700 nm and 1000 nm, or between or between about 1000 nm and 1700 nm.
146 . The method of any of claims 135 - 145 , wherein the first dye and second dye do not exhibit an overlapping emission and absorption spectra.
147 . The method of any of claims 135 - 146 , wherein the second dye is selected from among ICG, IRDye 680, Alexa Fluor 750, Dylight 755, IRDye 750, Cy7.5, Alexa Fluor 790, Dylight 800 and IRDye 800.
148 . The method of any of claims 135 - 147 , wherein the second dye is Alexa Fluor 488, IRDye 680, IRDye 800 or Dylight 755.
149 . The method of any of claims 1 - 148 , wherein the irradiating or illuminating is performed with a device selected from among a hand-held ultraviolet lamp, a mercury lamp, a xenon lamp, a laser, a laser diode or an LED imaging device.
150 . The method of claim 149 , wherein the imaging device comprises a near-infrared (NIR) diode.
151 . A composition, comprising a conjugate comprising a phthalocyanine dye linked to an antibody or antigen-binding antibody fragment that binds to a molecule on the surface of a cell present in the microenvironment of a lesion, wherein the composition is formulated for single dosage administration of the conjugate in an amount that is between or between about 100 mg and 2000 mg.
152 . The composition of claim 151 , wherein the composition is formulated for single dosage administration of an amount between or between about 100 mg and 500 mg, between or between about 200 mg and 400 mg.
153 . The composition of claim 151 or claim 152 , wherein the composition is formulated for single dosage administration of an amount between or between about 500 mg and 1500 mg, 800 mg and 1200 mg, or 1000 mg and 1500 mg.
154 . The composition of any of claims 151 - 153 , wherein:
the volume of the composition is between or between about 10 mL and 1000 mL, or 50 mL and 500 mL; or the volume of the composition is at least 10 mL, 20 mL, 30 mL, 40 mL, 50 mL, 75 mL, 100 mL, 150 mL, 200 mL, 250 mL, 300 mL, 400 mL, 500 mL or 1000 mL.
155 . An article of manufacture, comprising:
a plurality of sealable containers, each individually comprising a fraction of a single administration dose of a composition comprising a conjugate comprising a phthalocyanine dye linked to an antibody or antigen-binding antibody fragment that binds to a molecule on the surface of a cell present in the microenvironment of a lesion, wherein the combined amount of the conjugate in the plurality of sealable containers is between or between about 100 mg and 1500 mg; packaging material; and a label or package insert comprising instructions for combining the contents of the plurality of vials to prepare a single dosage formulation of the composition.
156 . The article of manufacture of claim 155 , wherein the combined amount of the conjugate in the plurality of sealable containers is between or between about 100 mg and 1200 mg.
157 . The article of manufacture of claim 155 or claim 156 , wherein the combined amount of the conjugate in the plurality of sealable container is between or between about 100 mg and 500 mg, between or between about 200 mg and 400 mg, between or between about 500 mg and 1500 mg, between or between about 800 mg and 1200 mg or between or between about 1000 mg and 1500 mg.
158 . The composition of any of claims 151 - 154 or the article of manufacture of any of claims 155 - 157 , wherein the lesion is a tumor.
159 . A conjugate, comprising a phthalocyanine dye linked to an antibody or antigen-binding fragment that is an immune modulating agent.
160 . The conjugate of claim 159 , wherein the immune modulating agent is an immune checkpoint inhibitor.
161 . The conjugate of claim 159 or claim 160 , wherein the immune modulating agent is an antibody or antigen binding fragment that binds to the surface of a tumor, tumor cell or cancer cell.
162 . The conjugate of any of claims 159 - 161 , wherein the immune modulating agent specifically binds a molecule selected from among CD25, PD-1, PD-L1, PD-L2, CTLA-4, LAG-3, TIM-3, 4-1BB, GITR, CD40, CD40L, OX40, OX40L, CXCR2, B7-H3, B7-H4, BTLA, HVEM, CD28 and VISTA.
163 . The conjugate of any of claims 159 - 162 , wherein the immune modulating agent is selected from among nivolumab, pembrolizumab, pidilizumab, MK-3475, BMS-936559, MPDL3280A, ipilimumab, tremelimumab, IMP31, BMS-986016, urelumab, TRX518, dacetuzumab, lucatumumab, SEQ-CD40, CP-870, CP-893, MED16469, MED14736, MOXR0916, AMP-224, and MSB001078C, or is an antigen-binding fragment thereof of any of the foregoing.
164 . The conjugate of any of claims 159 - 163 , wherein the immune modulating agent is an antibody or antibody fragment that binds to PD-L1.
165 . The conjugate of claim 164 , wherein the immune modulating agent is an antibody selected from BMS-935559, MEDI4736, MPDL3280A and MSB0010718C, or an antigen-binding fragment thereof.
166 . A conjugate, comprising a targeting molecule linked to at least a first and second fluorescent dye, wherein the first fluorescent dye is a phthalocyanine dye capable of exhibiting phototoxicity.
167 . The conjugate of claim 166 , comprising the formula:
[D 1 -(L 1 ) n ] p -A-[(L 2 ) n -D 2 ] o , wherein: A is a targeting molecule that can bind to a molecule on the surface of a cell; L 1 and L 2 are each an independently selected linker, which can be the same or different; n and m are independently 1 or 2; D 1 is a first dye that is the phthalocyanine dye capable of exhibiting phototoxicity; D 2 is a second dye that is a fluorescent dye, wherein D 2 is different than D 1 ; p is 1 to 10; and o is 1 to 10.
168 . The conjugate of claim 166 or claim 167 , wherein the targeting molecule is an antibody or an antigen-binding antibody fragment.
169 . The conjugate of any of claims 166 - 168 , wherein the cell surface molecule comprises an antigen, a polypeptide, a lipid, or a carbohydrate or a combination of these molecules.
170 . The conjugate of any of claims 166 - 169 , wherein the cell surface molecule is selected from among ACTHR, endothelial cell Anxa-1, aminopetidase N, anti-IL-6R, alpha-4-integrin, alpha-5-beta-3 integrin, alpha-5-beta-5 integrin, alpha-fetoprotein (AFP), ANPA, ANPB, APA, APN, APP, 1AR, 2AR, AT1, B1, B2, BAGE1, BAGE2, B-cell receptor BB1, BB2, BB4, calcitonin receptor, cancer antigen 125 (CA 125), CCK1, CCK2, CD5, CD10, CD11a, CD13, CD14, CD19, CD20, CD22, CD25, CD30, CD33, CD38, CD45, CD52, CD56, CD68, CD90, CD133, CD7, CD15, CD34, CD44, CD206, CD271, CEA (CarcinoEmbryonic Antigen), CGRP, chemokine receptors, cell-surface annexin-1, cell-surface plectin-1, Cripto-1, CRLR, CXCR2, CXCR4, DCC, DLL3, E2 glycoprotein, EGFR, EGFRvIII, EMR1, Endosialin, EP2, EP4, EpCAM, EphA2, ET receptors, Fibronectin, Fibronectin ED-B, FGFR, frizzled receptors, GAGE1, GAGE2, GAGE3, GAGE4, GAGE5, GAGE6, GLP-1 receptor, G-protein coupled receptors of the Family A (Rhodopsin-like), G-protein coupled receptors of the Family B (Secretin receptor-like) like), G-protein coupled receptors of the Family C (Metabotropic Glutamate Receptor-like), GD2, GP100, GP120, Glypican-3, hemagglutinin, Heparin sulfates, HER1, HER2, HER3, HER4, HMFG, HPV 16/18 and E6/E7 antigens, hTERT, IL11-R, IL-13R, ITGAM, Kalikrien-9, Lewis Y, LH receptor, LHRH-R, LPA1, MAC-1, MAGE 1, MAGE 2, MAGE 3, MAGE 4, MART 1, MC1R, Mesothelin, MUC1, MUC16, Neu (cell-surface Nucleolin), Neprilysin, Neuropilin-1, Neuropilin-2, NG2, NK1, NK2, NK3, NMB-R, Notch-1, NY-ESO-1, OT-R, mutant p53, p97 melanoma antigen, NTR2, NTR3, p32 (p32/gClq-R/HABP1), p′75, PAC1, PAR1, Patched (PTCH), PDGFR, PDFG receptors, PDT, Protease-cleaved collagen IV, proteinase 3, prohibitin, protein tyrosine kinase 7, PSA, PSMA, purinergic P2X family (e.g., P2X1-5), mutant Ras, RAMP1, RAMP2, RAMP3 patched, RET receptor, plexins, smoothened, sst1, sst2A, sst2B, sst3, sst4, sst5, substance P, TEMs, T-cell CD3 Receptor, TAG72, TGFBR1, TGFBR2, Tie-1, Tie-2, Trk-A, Trk-B, Trk-C, TR1, TRPA, TRPC, TRPV, TRPM, TRPML, TRPP (e.g., TRPV1-6, TRPA1, TRPC1-7, TRPM1-8, TRPP1-5, TRPML1-3), TSH receptor, VEGF receptors (VEGFR1 or Flt-1, VEGFR2 or FLK-1/KDR, and VEGF-3 or FLT-4), voltage-gated ion channels, VPAC1, VPAC2, Wilms tumor 1, Y1, Y2, Y4, and Y5.
171 . The conjugate of any of claims 166 - 170 , wherein the cell surface molecule is selected from among HER1/EGFR, HER2/ERBB2, CD20, CD25 (IL-2Ra receptor), CD33, CD52, CD133, CD206, CEA, CEACAM1, CEACAM3, CEACAM5, CEACAM6, cancer antigen 125 (CA125), alpha-fetoprotein (AFP), Lewis Y, TAG72, Caprin-1, mesothelin, PDGF receptor, PD-1, PD-L1, CTLA-4, IL-2 receptor, vascular endothelial growth factor (VEGF), CD30, EpCAM, EphA2, Glypican-3, gpA33, mucins, CAIX, PSMA, folate-binding protein, gangliosides (such as GD2, GD3, GM1 and GM2), VEGF receptor (VEGFR), integrin αVβ3, integrin α5β1, ERBB3, MET, IGF1R, EPHA3, TRAILR1, TRAILR2, RANKL, FAP, tenascin, AFP, BCR complex, CD3, CD18, CD44, CTLA-4, gp72, HLA-DR 10 (3, HLA-DR antigen, IgE, MUC-1, nuC242, PEM antigen, metalloproteinases, Ephrin receptor, Ephrin ligands, HGF receptor, CXCR4, CXCR4, Bombesin receptor, and SK-1 antigen.
172 . The conjugate of any of claims 166 - 171 , wherein the cell surface molecule is selected from among CD25, PD-1 (CD279), PD-L1 (CD274, B7-H1), PD-L2 (CD273, B7-DC), CTLA-4, LAG3 (CD223), TIM3 (HAVCR2), 4-1BB (CD137, TNFRSF9), CXCR2, CXCR4 (CD184), CD27, CEACAM1, Galectin 9, BTLA, CD160, VISTA (PD1 homologue), B7-H4 (VCTN1), CD80 (B7-1), CD86 (B7-2), CD28, HHLA2 (B7-H7), CD28H, CD155, CD226, TIGIT, CD96, Galectin 3, CD40, CD40L, CD70, LIGHT (TNFSF14), HVEM (TNFRSF14), B7-H3 (CD276), Ox40L (TNFSF4), CD137L (TNFSF9, GITRL), B7RP1, ICOS (CD278), ICOSL, KIR, GALS, NKG2A (CD94), GARP, TL1A, TNFRSF25, TMIGD2, BTNL2, Butyrophilin family, CD48, CD244, Siglec family, CD30, CSF1R, MICA (MEW class I polypeptide-related sequence A), MICB (MEW class I polypeptide-related sequence B), NKG2D, KIR family (Killer-cell immunoglobulin-like receptor, LILR family (Leukocyte immunoglobulin-like receptors, CD85, ILTs, LIRs), SIRPA (Signal regulatory protein alpha), CD47 (IAP), Neuropilin 1 (NRP-1), a VEGFR, and VEGF.
173 . The conjugate of any of claims 166 - 172 , wherein the macromolecule is an antibody or an antigen-binding antibody fragment that is selected from among cetuximab, panitumumab, zalutumumab, nimotuzumab, Tositumomab (Bexxar®), Rituximab (Rituxan, Mabthera), Ibritumomab tiuxetan (Zevalin), Daclizumab (Zenapax), Gemtuzumab (Mylotarg), Alemtuzumab, CEA-scan Fab fragment, OC125 monoclonal antibody, ab75705, B72.3, Bevacizumab (Avastin®), Basiliximab, nivolumab, pembrolizumab, pidilizumab, MK-3475, BMS-936559, MPDL3280A, ipilimumab, tremelimumab, IMP321, BMS-986016, LAG525, urelumab, PF-05082566, TRX518, MK-4166, dacetuzumab, lucatumumab, SEA-CD40, CP-870, CP-893, MED16469, MEDI6383, MEDI4736, MOXR0916, AMP-224, PDR001, MSB0010718C, rHIgM12B7, Ulocuplumab, BKT140, Varlilumab (CDX-1127), ARGX-110, MGA271, lirilumab (BMS-986015, IPH2101), IPH2201, AGX-115, Emactuzumab, CC-90002 and MNRP1685A or is an antigen-binding antibody fragment thereof.
174 . The conjugate of any of claims 166 - 173 , wherein the targeting molecule is not or does not comprise a nanocarrier.
175 . The conjugate of any of claims 166 - 174 , wherein the targeting molecule is not or does not comprise a virus-like particle, a nanoparticle, a liposome, a quantum dot, or a combination thereof.
176 . The conjugate of any of claims 166 - 175 , wherein the first dye that is a phthalocyanine dye that has a maximum absorption wavelength from or from about 600 nm to about 850 nm.
177 . The conjugate of any of claims 166 - 176 , wherein the first dye that is a phthalocyanine dye comprises the formula:
wherein:
L is a linker;
Q is a reactive group for attachment of the dye to the targeting molecule;
R 2 , R 3 , R 7 , and R 8 are each independently selected from optionally substituted alkyl and optionally substituted aryl;
R 4 , R 5 , R 6 , R 9 , R 10 , and R 11 are each independently selected from hydrogen, optionally substituted alkyl, optionally substituted alkanoyl, optionally substituted alkoxycarbonyl, optionally substituted alkylcarbamoyl, and a chelating ligand, wherein at least one of R 4 , R 5 , R 6 , R 9 , R 10 , and R 11 comprises a water soluble group;
R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 and R 23 are each independently selected from hydrogen, halogen, optionally substituted alkylthio, optionally substituted alkylamino and optionally substituted alkoxy; and
X 2 and X 3 are each independently C 1 -C 10 alkylene, optionally interrupted by a heteroatom.
178 . The conjugate of any of claims 166 - 177 , wherein the first dye that is a phthalocyanine dye comprises the formula:
wherein:
X 1 and X 4 are each independently a C 1 -C 10 alkylene optionally interrupted by a heteroatom;
R 2 , R 3 , R 7 , and R 8 are each independently selected from optionally substituted alkyl and optionally substituted aryl;
R 4 , R 5 , R 6 , R 9 , R 10 , and R 11 are each independently selected from hydrogen, optionally substituted alkyl, optionally substituted alkanoyl, optionally substituted alkoxycarbonyl, optionally substituted alkylcarbamoyl, and a chelating ligand, wherein at least one of R 4 , R 5 , R 6 , R 9 , R 10 , and R 11 comprises a water soluble group; and
R 16 , R 17 , R 18 and R 19 are each independently selected from hydrogen, halogen, optionally substituted alkylthio, optionally substituted alkylamino and optionally substituted alkoxy.
179 . The conjugate of any of claims 166 - 178 , wherein the first dye that is a phthalocyanine dye comprises IRDye 700DX (IR700).
180 . The conjugate of any of claims 166 - 179 , wherein the second fluorescent dye exhibits one or more spectral properties selected from among fluorescent quantum yield in water, extinction coefficient, Stokes shift, absorption and emission at long wavelength and photostability that is greater compared to the corresponding spectral property of the first dye.
181 . The conjugate of any of claims 166 - 180 , wherein the second dye is not IR700.
182 . The conjugate of any of claims 166 - 181 , wherein the second dye is selected from among hydroxycoumarin, Cascade Blue, Dylight 405, Pacific Orange, Alexa Fluor 430, Fluorescein, Oregon Green, Alexa Fluor 488, BODIPY 493, 2.7-Diochlorofluorescien, ATTO 488, Chromeo 488, Dylight 488, HiLyte 488, Alexa Fluor 555, ATTO 550, BODIPY TMR-X, CF 555, Chromeo 546, Cy3, TMR, TRITC, Dy547, Dy548, Dy549, HiLyte 555, Dylight 550, BODIPY 564, Alexa Fluor 568, Alexa Fluor 594, Rhodamine, Texas Red, Alexa Fluor 610, Alexa Fluor 633, Dylight 633, Alexa Fluor 647, APC, ATTO 655, CF633, CF640R, Chromeo642, Cy5, Dylight 650, Alexa Fluor 680, IRDye 680, Alexa Fluor 700, Cy 5.5, ICG, Alexa Fluor 750, Dylight 755, IRDye 750, Cy7.5, Alexa Fluor 790, Dylight 800, IRDye 800, Qdot® 525, Qdot® 565, Qdot® 605, Qdot® 655, Qdot® 705 and Qdot® 800.
183 . The conjugate of any of claims 166 - 182 , wherein the first dye is IR700 and the conjugate comprises 1 to 10 or 1 to 5 second dye molecules per macromolecule.
184 . The conjugate of any of claims 166 - 183 , wherein the second dye exhibits a Stokes shift that is greater than 15 nm, greater than 20 nm, greater than 30 nm, greater than 40 nm, greater than 50 nm, greater than 60 nm, greater than 70 nm, greater than 80 nm, greater than 90 nm or greater than 100 nm.
185 . The conjugate of any of claims 166 - 184 , wherein the second dye has a quantum yield in water that is greater than 10%, greater than 15%, greater than 20% or greater than 25%, greater than 30%, greater than 40%, greater than 50% or greater.
186 . The conjugate of any of claims 166 - 185 , wherein the second dye has an absorption and emission wavelength in the spectrum between or between about 650 nm and 950 nm, between or between about 700 nm and 1000 nm, between or between about 1000 nm and 1700 nm.
187 . The conjugate of any of claims 166 - 186 , wherein the first dye and second dye do not exhibit an overlapping emission and absorption spectra.
188 . The conjugate of any of claims 166 - 187 , wherein the second dye is selected from among ICG, IRDye 680, Alexa Fluor 750, Dylight 755, IRDye 750, Cy7.5, Alexa Fluor 790, Dylight 800 and IRDye 800.
189 . The conjugate of any of claims 166 - 188 , wherein the second dye is Alexa Fluor 488, IRDye 680, IRDye 800 or Dylight 755.
190 . A composition, comprising the conjugate of any of claims 159 - 189 .
191 . The composition of claim 190 , further comprising a pharmaceutically acceptable excipient.
192 . A method of treating a disease or condition in a subject comprising:
a) administering to the subject a therapeutically effective amount of the conjugate of any of claims 159 - 165 or composition of claim 190 or claim 191 , wherein the conjugate binds to a cell present in the microenvironment of a lesion associated with a disease or condition; and b) after administering the conjugate, irradiating the lesion at one or more wavelengths to induce phototoxic activity of the conjugate, thereby treating the disease or condition.
193 . A method of treating a disease or condition in a subject comprising:
a) administering to the subject a therapeutically effective amount of the conjugate of any of claims 166 - 189 or composition of claim 190 or claim 191 , wherein the conjugate binds to a cell present in the microenvironment of a lesion associated with a disease or condition; and b) after administering the conjugate, irradiating the lesion at one or more wavelengths to induce phototoxic activity of the first dye of the conjugate and a fluorescent signal of the second dye of the conjugate.
194 . The method of claim 192 or claim 193 , comprising irradiating the lesion at a wavelength that is from or from about 400 to about 900 nm at a dose of at least 1 J cm −1 or 1 J/cm of fiber length.
195 . The method of claim 193 or claim 194 , comprising irradiating the lesion with a single wavelength.
196 . The method of claim 193 or claim 195 , comprising irradiating the lesion at two different wavelengths, simultaneously or sequentially, wherein one wavelength induces the phototoxic activity and the other wavelength induces the fluorescent signal.
197 . The method of any of claims 192 - 196 , wherein the disease or condition is a tumor.
198 . The method of claim 197 , comprising irradiating the tumor at a wavelength of 660 nm to 740 nm and at a dose of at least 1 J cm −2 , thereby treating the tumor in the subject.
199 . The method of claim 197 or claim 198 , wherein the tumor is a cancer.
200 . The method of claim 199 , wherein the cancer is a cancer located at the head and neck, breast, liver, colon, ovary, prostate, pancreas, brain, cervix, bone, skin, eye, bladder, stomach, esophagus, peritoneum, or lung.
201 . The method of any of claims 197 - 200 , wherein the tumor is a sarcoma or carcinoma.
202 . The method of claim 201 , wherein the tumor is a carcinoma that is a squamous cell carcinoma, basal cell carcinoma or adenocarcinoma.
203 . The method of claim 202 , wherein the tumor is a carcinoma that is a carcinoma of the bladder, pancreas, colon, ovary, lung, breast, stomach, prostate, cervix, esophagus or head and neck.
204 . The method of any of claims 1 - 150 and 192 - 203 , wherein prior to administration of the conjugate the targeting molecule is administered to the subject.
205 . The method of any of claims 1 - 150 and 192 - 204 , wherein the targeting molecule is administered up to 96 hours prior to administration of the conjugate.
206 . The method of claim 204 or claim 205 , wherein the targeting molecule is administered at a dose within a range from or from about 10 mg/m 2 to about 500 mg/m 2 .
207 . The method of any of claims 1 - 150 and 192 - 206 , wherein the targeting molecule is an antibody or antigen binding fragment.
208 . The method of claim 207 , wherein the antibody is cetuximab.Join the waitlist — get patent alerts
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