Medicine for killing tumor cells

Abstract

The problem of the present invention is to provide a medicine for killing tumor cells, said medicine having few side effects. The present invention provides a medicine for killing tumor cells, said medicine containing: a conjugate of a substance capable of binding to a target substance on the surface of tumor cells and a cytotoxin; and talaporfin sodium, porfimer sodium, or verteporfin. The talaporfin sodium, porfimer sodium, or verteporfin is administered 1-4 days after administrating the conjugate of a substance capable of binding to a target substance on the surface of tumor cells and a cytotoxin, and irradiation is carried out, at a wavelength effective for activating the talaporfin sodium, porfimer sodium, or verteporfin, 1-4 hours after the talaporfin sodium, porfimer sodium, or verteporfin is administered.

Description

Drugs for killing tumor cells

[0001] The present invention relates to a conjugate of a cytotoxin with a substance that binds to a target substance on the surface of tumor cells, and a pharmaceutical agent for killing tumor cells, comprising talaporfin sodium, porfimer sodium, or verteporfin.

[0002] In Japan, 370,000 people die from cancer each year, and it has been the leading cause of death since 1981. To date, many cancer treatment methods have been developed both in Japan and overseas, but an effective drug has yet to be developed.

[0003] So-called small molecule anticancer drugs (cancer chemotherapy) have been developed, but not only are they not necessarily effective, but they also have strong side effects that cause significant pain to patients, making them undesirable medicines. Antibody drugs, with their strong specificity to cancer, can reduce the strong side effects seen with small molecule anticancer drugs and are becoming more widely used, but there are still very few antibody drugs that are effective against solid cancers. ADCs (antibody drug conjugates) have been developed to enhance drug efficacy, but they are not yet satisfactory due to issues such as toxicity.

[0004] Furthermore, immunotherapeutic antibodies (checkpoint inhibitors), which are new antibody drugs, have a novel mechanism that makes them highly effective against a wide range of cancer types, but it has been found that they do not necessarily work for many patients, and in some cases can cause severe side effects that can be fatal.

[0005] Meanwhile, photodynamic therapy (PDT) has been developed with the aim of limiting the treatment site and reducing side effects. PDT is a treatment method in which the affected area is irradiated with light of a wavelength that activates a photosensitizing dye that has accumulated at the tumor site, and although it has shown some effectiveness in lung cancer and other cancers, it cannot be said that it has achieved satisfactory efficacy.

[0006] Under these circumstances, the present inventors felt the need to develop a pharmaceutical agent with few side effects and strong efficacy, and have therefore developed the present invention. An object of the present invention is to provide a pharmaceutical agent for killing tumor cells with few side effects and a method for administering the same.

[0007] PDT is a method of destroying tumor cells by accumulating a sensitizing dye in tumor tissue and irradiating it with light. Known sensitizing dyes used in PDT are highly water-soluble and have high tumor accumulation, such as talaporfin sodium, porfimer sodium, and verteporfin, all of which are already used in the treatment of lung cancer and other diseases. While PDT is a minimally invasive treatment, it has the drawback of not always providing satisfactory efficacy.

[0008] Photochemical internalization (PCI) is a method of disrupting the endosomal membrane by accumulating a photosensitizer in the membrane and then irradiating it with light. This is thought to release anticancer drugs or immunotoxins encapsulated in the endosomal membrane into the cytoplasm, destroying tumor cells. Unlike PDT, PCI dyes are used because they accumulate in the endosomal membrane, and amphiphilic photosensitizers such as sulfonated tetraphenylchlorin (TPCS2a) or aluminum phthalocyanine (AlPcS2a) are used.

[0009] However, amphiphilic sulfonated tetraphenylchlorin (TPCS2a) and aluminum phthalocyanine (AlPcS2a) have drawbacks such as (1) concerns about neurotoxicity, (2) accumulation in cell membranes other than endosomal membranes, resulting in cytotoxicity, and (3) low tumor accumulation, resulting in nonspecific side effects.

[0010] As a result of our intensive efforts to solve these problems, we have discovered that highly water-soluble talaporfin sodium, porfimer sodium, or verteporfin has the unexpected effect of increasing endosomal membrane permeability at low concentrations. Furthermore, we have found that combining talaporfin sodium, porfimer sodium, or verteporfin with a conjugate of a cytotoxin and a substance that binds to a target substance on the surface of tumor cells can significantly enhance cytotoxicity and tumor specificity.

[0011] The above-mentioned method is effective when a conjugate of a photosensitizer, a substance that binds to a tumor cell surface target, such as an immunotoxin, and a cytotoxin simultaneously accumulates in endosomes upon light irradiation. However, although photosensitizing dyes with fast metabolic rates are effective in reducing side effects, it is difficult to simultaneously accumulate a conjugate of a substance that binds to a tumor cell surface target, such as an immunotoxin, and a cytotoxin. Therefore, we felt that a different administration method was necessary. As a result of our extensive efforts to find such conditions, we discovered a method in which a substance that binds to a tumor cell surface target, such as an immunotoxin, is administered, left for several days to allow accumulation in the tumor, and then a photosensitizer is administered, followed by light irradiation several hours later, thereby completing the present invention.

[0012] The present invention provides the following: <1> A pharmaceutical for killing tumor cells, comprising: a conjugate of a cytotoxin and a substance that binds to a target substance on the surface of tumor cells; and talaporfin sodium, porfimer sodium, or verteporfin; wherein talaporfin sodium, porfimer sodium, or verteporfin is administered 1 to 4 days after administration of the conjugate of a cytotoxin and a substance that binds to a target substance on the surface of tumor cells, and talaporfin sodium, porfimer sodium, or verteporfin is irradiated with light of a wavelength effective for activating talaporfin sodium, porfimer sodium, or verteporfin 1 to 4 hours after administration of talaporfin sodium, porfimer sodium, or verteporfin. <2> The pharmaceutical according to <1>, wherein the substance that binds to a target substance on the surface of tumor cells is an antibody, an antibody fragment, a ligand, or a peptide. <3> The pharmaceutical according to <1> or <2>, wherein the cytotoxin is saporin, gelonin, or Pseudomonas aeruginosa exotoxin. <4> The pharmaceutical according to any one of <1> to <3>, wherein the tumor cells are cells expressing epidermal growth factor receptors (EGFR, ERBB1, ERBB2, ERBB3, ERBB4), mesothelin, ephrin type-A receptor 2 (EphA2), glypican 3 (GPC3), cadherin 17 (CDH17), or roundabout homolog 1 (Robo1) on the cell surface. <5> The pharmaceutical according to any one of <1> to <4>, wherein the tumor cells are cancer cells of any of head and neck cancer, lung cancer, liver cancer, colorectal cancer, skin cancer, esophageal cancer, gastric cancer, cervical cancer, endometrial cancer, mesothelioma, brain tumor, malignant melanoma, breast cancer, bile duct cancer, pancreatic cancer, ovarian cancer, kidney cancer, bladder cancer, prostate cancer, malignant lymphoma, and osteosarcoma. <6> The medicine according to any one of <1> to <5>, wherein the wavelength effective for activating talaporfin sodium, porfimer sodium, or verteporfin is 600 to 800 nm.

[0013] A method for killing tumor cells, comprising: (1) contacting tumor cells with a conjugate of a cytotoxin and a substance that binds to a target substance on the surface of the tumor cells; (2) 1 to 4 days after performing step (1), contacting the tumor cells with talaporfin sodium, porfimer sodium, or verteporfin; and (3) 1 to 4 hours after performing step (2), killing the tumor cells by irradiating the tumor cells with light of a wavelength effective to activate talaporfin sodium, porfimer sodium, or verteporfin.

[0014] According to the present invention, a drug for killing tumor cells with few side effects can be provided.

[0015] FIG. 1 shows the results of confirming the tumor shrinkage effect in cancer-bearing mice.

[0016] The following describes in detail the embodiments of the present invention. <Summary of the present invention> After studying tumor treatment methods with strong efficacy and few side effects, the inventors concluded that PDT and PCI, which locally enhance drug efficacy using light, hold promise. However, PDT has the drawback of being weakly effective, and PCI is unsatisfactory in terms of both efficacy and toxicity.

[0017] Therefore, as a result of extensive efforts, the present inventors have discovered for the first time that the water-soluble sensitizing dyes talaporphyrin, porfimer sodium, or verteporfin improve endosomal permeability upon light irradiation. By combining this "dye," "a conjugate of a cytotoxin and a substance that binds to a target substance on the surface of tumor cells," and "light irradiation of tumors," they have discovered a treatment method with strong medicinal effects and minimal risk of side effects, and have completed the present invention.

[0018] In other words, in the present invention, a conjugate of a substance that binds to a target substance on the surface of tumor cells and a cytotoxin binds to the tumor and is then encapsulated in endosomes. It is believed that by irradiating light onto talaporfin sodium, porfimer sodium, or verteporfin, which are added separately (or simultaneously), the immunotoxin (or its degradation products) in the endosomes is released into the cytoplasm, thereby killing tumor cells.

[0019] Talaporfin sodium, porfimer sodium, and verteporfin are water-soluble and have the advantage of being less susceptible to side effects when localized in membranes than amphiphilic sulfonated tetraphenylchlorin (TPCS2a) and aluminum phthalocyanine (AlPcS2a). Furthermore, their absorption wavelength of 664 nm does not overlap with the absorption wavelength of hemoglobin, allowing for greater penetration depth. Effective wavelengths for activating talaporfin sodium, porfimer sodium, and verteporfin are preferably 600 to 800 nm, more preferably 600 to 750 nm, even more preferably 600 to 700 nm, and particularly preferably 650 to 680 nm.

[0020] <Method for killing cells> In the present invention, (1) a conjugate of a cytotoxin and a substance that binds to a target substance on the surface of tumor cells is administered, followed by (2) administration of talaporfin sodium, porfimer sodium, or verteporfin, and then (3) irradiation with light of a wavelength that activates talaporfin sodium, porfimer sodium, or verteporfin.

[0021] The interval between the administration of the substance that binds to a target substance on the surface of tumor cells and the administration of talaporfin sodium, porfimer sodium, or verteporfin is 1 to 4 days, preferably 1 to 3 days, for example, 2 days. The interval between the administration of talaporfin sodium, porfimer sodium, or verteporfin and the administration of light is 1 to 4 hours, preferably 1 to 3 hours, for example, 2 hours.

[0022] <Photosensitizing dye> In the present invention, talaporphyrin sodium, porfimer sodium, or verteporfin is used as a sensitizer. Talaporphyrin sodium is also known as laserphyrin, NPe6, or monoaspartyl chlorin e6, and is a sensitizing dye used in PDT.

[0023] Another form of the sensitizing dye is porfimer sodium, also known as photophylin, a PDT dye. Another form of the sensitizing dye is verteporfin, also known as visudyne, a PDT dye.

[0024] <Substances that bind to target substances on the surface of tumor cells> Substances that bind to target substances on the surface of tumor cells include, but are not limited to, antibodies, antibody fragments, ligands, peptides, and the like.

[0025] When an antibody is used as a substance that binds to a target substance on the surface of tumor cells, an antibody that specifically binds to the target substance on the surface of tumor cells (e.g., proteins such as epidermal growth factor receptor (EGFR, ERBB1, ERBB2, ERBB3, ERBB4), mesothelin, ephrin type-A receptor 2 (EphA2), glypican 3 (GPC3), cadhelin 17 (CDH17), cadherin 3 (CDH3), and roundabout homolog 1 (Robo1)) can be used.

[0026] The type of antibody used in the present invention is not particularly limited, and may be any of mouse, human, rat, rabbit, sheep, camel, and avian antibodies, as well as recombinant antibodies artificially modified to reduce heterologous antigenicity against humans, such as chimeric and humanized antibodies. Recombinant antibodies can be produced using known methods. Chimeric antibodies are antibodies consisting of the heavy and light chain variable regions of a non-human mammal, such as a mouse, and the heavy and light chain constant regions of a human antibody. They can be obtained by linking DNA encoding the variable region of a mouse antibody to DNA encoding the constant region of a human antibody, incorporating this into an expression vector, and introducing it into a host for production. Humanized antibodies are antibodies in which the complementarity-determining regions (CDRs) of a non-human mammal, such as a mouse, have been grafted onto the complementarity-determining regions of a human antibody, and common recombinant techniques for producing them are known. Specifically, a DNA sequence designed to link the CDRs of a mouse antibody with the framework regions (FRs) of a human antibody is synthesized by PCR from several oligonucleotides designed to have overlapping ends. The resulting DNA is ligated to DNA encoding the constant regions of a human antibody, then incorporated into an expression vector, which is then introduced into a host for production (see, for example, EP 239400 and WO96 / 02576).

[0027] Methods for obtaining human antibodies are also known. For example, human lymphocytes can be sensitized in vitro with a desired antigen or cells expressing the desired antigen, and the sensitized lymphocytes can be fused with human myeloma cells, such as U266, to obtain a desired human antibody with antigen-binding activity (see Japanese Patent Publication No. 1-59878). Alternatively, a desired human antibody can be obtained by immunizing a transgenic animal carrying a full repertoire of human antibody genes with the desired antigen (see WO93 / 12227, WO92 / 03918, WO94 / 02602, WO94 / 25585, WO96 / 34096, and WO96 / 33735). Furthermore, a technique for obtaining human antibodies by panning using a human antibody library is also known. For example, the variable regions of human antibodies can be expressed on the surface of phages as single-chain fragments (scFvs) using phage display, and phages that bind to the antigen can be selected. By analyzing the genes of the selected phages, the DNA sequence encoding the variable region of the human antibody that binds to the antigen can be determined. Once the DNA sequence of the scFv that binds to the antigen is known, the sequence can be used to construct an appropriate expression vector to obtain a human antibody. These methods are already well known, and reference can be made to WO92 / 01047, WO92 / 20791, WO93 / 06213, WO93 / 11236, W93 / 19172, WO95 / 01438, and WO95 / 15388.

[0028] Antibodies that bind to tumor cells are preferably, but not limited to, humanized or human antibodies.

[0029] Furthermore, these antibodies may be minibodies such as antibody fragments or modified antibodies, as long as they retain the ability to recognize the full length or a portion of the protein encoded by the antigen gene on the surface of tumor cells. An antibody fragment is a portion of an antibody that retains its ability to bind to ROBO1. Specific examples of antibody fragments include Fab, Fab', F(ab')2, Fv, diabody, and single-chain antibody fragment (scFv). Such antibody fragments can be obtained by constructing genes encoding these antibody fragments, introducing them into an expression vector, and then expressing them in appropriate host cells. Antibodies conjugated with various molecules such as polyethylene glycol (PEG) can also be used as modified antibodies.

[0030] DNA encoding a monoclonal antibody can be readily isolated and sequenced by conventional methods (e.g., using oligonucleotide probes capable of binding specifically to genes encoding the heavy and light chains of the monoclonal antibody). Hybridoma cells are a preferred starting source for such DNA. Once isolated, the DNA can be inserted into an expression vector and recombined into host cells such as E. coli cells, COS cells, CHO cells, or myeloma cells that do not produce immunoglobulins unless transformed, and the monoclonal antibody can be produced from the recombinant host cells.

[0031] Ligands can be used as substances that bind to target substances on the surface of tumor cells. When the target substance on the surface of tumor cells is a receptor such as epidermal growth factor receptor (EGFR, ERBB1, ERBB2, ERBB3, ERBB4), mesothelin, or ephrin type A receptor 2 (EphA2), ligands for the receptors can be used.

[0032] Peptides can also be used as substances that bind to target substances on the surface of tumor cells. Those skilled in the art can design and produce peptides that bind to target substances on the surface of tumor cells.

[0033] <Cytotoxin> The cytotoxin is preferably a cytotoxic protein, but is not limited thereto, and may be a synthetic or natural compound with anticancer activity, such as bleomycin, or a compound used in ADC. Preferred cytotoxic proteins include saporin, gelonin, Pseudomonas aeruginosa exotoxin, ricin A chain, deglycosylated ricin A chain, ribosome-inactivating protein, alpha-sarcin, aspergillin, restrictocin, ribonuclease, epodophyllotoxin, diphtheria toxin, ciguatoxin, and mutants and recombinant forms thereof.

[0034] <Conjugates of a substance that binds to a target substance on the surface of tumor cells and a cytotoxin> The substance that binds to a target substance on the surface of tumor cells and the cytotoxin must be directly or indirectly conjugated. When an antibody or its fragment is used as the substance that binds to a target substance on the surface of tumor cells, the method for directly chemically conjugating it to a cytotoxin can be the conjugation method used in known ADCs (Antibody Drug Conjugates). In addition, when the cytotoxin is a protein, a bifunctional crosslinker can also be used.

[0035] Furthermore, when the cytotoxin is a protein, an immunotoxin can be prepared by genetically fusing a toxin with an antibody or its fragment to form a fusion protein. Alternatively, a technique can be used in which an antibody or its fragment is indirectly bound to a cytotoxin using a second binding pair. Examples of the second binding pair that can be used include avidin-biotin and antibody-hapten.

[0036] In addition, in the present invention, instead of an immunotoxin in which an antibody is bound to a toxin, it is also possible to use a conjugate of a toxin and a peptide or ligand that binds to a target substance on the surface of tumor cells.

[0037] <Administration Method and Dosage> The administration method when administering the pharmaceutical of the present invention to a subject having a tumor (e.g., cancer) is not particularly limited. A conjugate of a cytotoxin and a substance that binds to a target substance on the surface of tumor cells can be administered, for example, by intravenous administration, arterial administration, intramuscular administration, subcutaneous administration, intradermal administration, intraperitoneal administration, or oral administration. Administration to tumor tissue and its surroundings can also be performed by local injection, application, spraying, or other methods. Talaporfin sodium, porfimer sodium, or verteporfin can be administered, for example, by intravenous administration, arterial administration, intramuscular administration, subcutaneous administration, intradermal administration, intraperitoneal administration, or oral administration. Administration to tumor tissue and its surroundings can also be performed by local injection, application, spraying, or other methods.

[0038] The dosage of the conjugate of the substance that binds to a target substance on the surface of tumor cells and the cytotoxin is not particularly limited, but can be, for example, 1 μg / kg body weight to 100 mg / kg body weight, preferably 10 μg / kg body weight to 10 mg / kg body weight. The dosage of talaporfin sodium, porfimer sodium, or verteporfin is not particularly limited, but can be, for example, 1 μg / kg body weight to 100 mg / kg body weight, preferably 10 μg / kg body weight to 10 mg / kg body weight.

[0039] The number of administrations is not particularly limited, and can be one or more times (1 to 20 times, preferably 1 to 10 times), for example, every 2 to 4 weeks or every 1 to 2 months. The number of light irradiations is also not particularly limited, and can be one or more times.

[0040] <Target cells and diseases> Tumors to which the pharmaceutical agent of the present invention is administered are tumors that express epidermal growth factor receptors (EGFR, ERBB1, ERBB2, ERBB3, ERBB4), mesothelin, ephrin type-A receptor 2 (EphA2), glypican 3 (GPC3), cadhelin 17 (CDH17), cadhelin 3 (CDH3), roundabout homolog 1 (Robo1), or the like on their surface.

[0041] Specific examples include head and neck cancer, lung cancer, liver cancer, colon cancer, skin cancer, esophageal cancer, stomach cancer, cervical cancer, endometrial cancer, mesothelioma, brain tumor, malignant melanoma, breast cancer, bile duct cancer, pancreatic cancer, ovarian cancer, kidney cancer, bladder cancer, prostate cancer, malignant lymphoma, osteosarcoma, etc. In addition to treating diseases in humans, the present invention can also be used to treat non-human animals such as dogs, cats, and horses.

[0042] Example: Confirmation of tumor regression effect in tumor-bearing mice by iTAP treatment using IT-Cetuximab and Laserphyrin. <Material acquisition> As an EGFR-expressing cell line, A549 (human lung cancer cells) was obtained from KAC Co., Ltd. (Kyoto, Japan). As an anti-EGFR antibody, cetuximab was obtained from Selleck Biotech Co., Ltd. (Tokyo, Japan). Laserphyrin was obtained from Meiji Seika Pharma Co., Ltd. (Tokyo, Japan).

[0043] <Immunotoxin preparation> Cetuximab dissolved in PBS(-) was mixed with EZ-LINK Sulfo-NHS-LC-Biotinylation Reagent (Thermo Fisher Scientific, Massachusetts) dissolved in ultrapure water at a molar ratio of 1:40, and the mixture was purified using a PD SpinTrap G-25 (GE Healthcare Life Sciences, England). The resulting biotinylated cetuximab was mixed with equal amounts of streptavidin-saporin (Biotin-Z Internalization Kit [KIT-27-Z], Advanced Targeting Systems, California) and incubated at room temperature for 30 minutes to yield saporin-conjugated cetuximab (IT-Cetuximab).

[0044] <Cell Culture> A549 was cultured in a high glucose-containing Dulbecco's Modified Eagle Medium (DMEM) medium supplemented with 10% fetal bovine serum at 37°C and a CO2 concentration of 5%.

[0045] <A549 cell line xenograft mouse production> Separately cultured A549 cells were cultured at 1 × 10 ７ The cells were adjusted to cells / 100 μL and administered subcutaneously (SC) to the right thigh of 7-week-old male BALB / c Slc-nu / nu mice to generate xenograft mice (tumor-bearing mice). Tumor size was calculated using the following formula: Tumor volume (mm3) = major axis (mm) × minor axis (mm) × minor axis (mm) × 0.5

[0046] <Study of the tumor shrinkage effect in cancer-bearing mice by iTAP treatment using IT-Cetuximab and Laserphyrin> 1. Administration and irradiation The average tumor size of the mice was approximately 150 mm ３ When this was reached, the subjects were randomly divided into the following groups (n=3).

[0047] Condition (1) Control group (no administration) Condition (2) Laserphyrin (5 mg / kg) administration and 664 nm laser light (30 J / cm2) irradiation group Condition (3) IT-Cetuximab (3 mg / kg) administration group Condition (4) Laserphyrin (5 mg / kg), IT-Cetuximab (3 mg / kg) administration and 664 nm laser light (30 J / cm2) irradiation group

[0048] Mice were administered IT-Cetuximab intraperitoneally, followed two days later by administration of Laserphyrin via the tail vein, and then 2 hours after administration, the tumor site was locally irradiated with 664 nm laser light.

[0049] 2. Observation: Tumor size was measured every 3 to 5 days after administration.

[0050] <Results> The results of measuring tumor size after administration are shown in Figure 1. In the (4) IT-Cetuximab + Laserphyrin combination group, significant suppression of tumor growth was observed compared to the (1) control group, (2) Laserphyrin alone group, or (3) IT-Cetuximab alone group.

[0051] Furthermore, while tumor growth was confirmed macroscopically in the (1) control group, (2) Laserphyrin alone group, and (3) IT-Cetuximab alone group, in the (4) IT-Cetuximab + Laserphyrin combination group, a scab formed at the irradiated site several days after laser irradiation, and the tumor subsequently shrank as the scab fell off. These results demonstrate the remarkable tumor-suppressing effect of this method.

Claims

1. A conjugate of a substance that binds to a target substance on the surface of tumor cells and a cytotoxin; and Sodium talaporfin, sodium porfimer, or verteporfin; A pharmaceutical for killing tumor cells, comprising: Sodium talaporfin, sodium porfimer, or verteporfin is administered 1 to 4 days after administration of the conjugate of a substance that binds to a target substance on the surface of tumor cells and a cytotoxin, and 1 to 4 hours after administration of sodium talaporfin, sodium porfimer, or verteporfin, irradiated with a wavelength effective for activating sodium talaporfin, sodium porfimer, or verteporfin. A pharmaceutical.

2. The pharmaceutical according to claim 1, wherein the substance that binds to the target substance on the surface of tumor cells is an antibody, an antibody fragment, a ligand, or a peptide.

3. The pharmaceutical according to claim 1 or 2, wherein the cytotoxin is saporin, gelonin, or Pseudomonas aeruginosa exotoxin.

4. The pharmaceutical according to claim 1 or 2, wherein the tumor cells are cells expressing Epidermal Growth Factor Receptor (EGFR, ERBB1, ERBB2, ERBB3, ERBB4), Mesothelin, Ephrin type-A receptor 2 (EphA2), Glypican3 (GPC3), Cadherin17 (CDH17), or Roundabout homolog 1 (Robo1) on the cell surface.

5. The pharmaceutical according to claim 1 or 2, wherein the tumor cells are cancer cells of any one of head and neck cancer, lung cancer, liver cancer, colorectal cancer, skin cancer, esophageal cancer, gastric cancer, cervical cancer, endometrial cancer, mesothelioma, brain tumor, malignant melanoma, breast cancer, cholangiocarcinoma, pancreatic cancer, ovarian cancer, kidney cancer, bladder cancer, prostate cancer, or malignant lymphoma, osteosarcoma.

6. The pharmaceutical according to claim 1 or 2, wherein the wavelength effective for activating sodium talaporfin, sodium porfimer, or verteporfin is 600 to 800 nm.