Radiation therapy conjugates for treating cancer

Abstract

This disclosure relates to a method for treating cancer, which includes administering to a patient an agent containing a targeted component conjugated to a cancer treatment component.

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims priority to U.S. Provisional Patent Application No. 63 / 495,642, filed on 12 April 2023, the contents of which are incorporated herein by reference in their entirety.

[0002] Sequence listing reference The contents of the electronic sequence listing (filename: CNTH_007_01WO_SeqList_ST26.xml, size: 38,665 bytes, and creation date: April 9, 2024) are incorporated herein by reference in their entirety. [Background technology]

[0003] background Prostate cancer (PC) is a significant health burden, with 180,890 new cases diagnosed and 26,120 deaths in the United States in 2016. Despite advances in diagnostic techniques and treatment strategies, up to 40% of patients treated with first-line therapy for therapeutic purposes will experience disease progression. Death from PC is usually a consequence of metastatic castration-resistant prostate cancer (mCRPC), and historically, the median survival for men with mCRPC has been less than two years. Metastatic castration-resistant prostate cancer (mCRPC) presents specific clinical challenges requiring additional therapeutic approaches beyond conventional androgen deprivation therapy. These include autologous immunotherapy using the chemotherapy compounds docetaxel and cabazitaxel, the androgen receptor signaling inhibitor enzalutamide, the CYP-17 inhibitor abiraterone, cypleucel-T, and bone-accumulating α-emitters. 223 Ra has shown improved overall survival (OS), and has largely demonstrated quality of life benefits as well. However, although these drugs are being tested in multiple pathologies of CRPC to determine whether or when patients may benefit from each treatment, in all cases these currently established therapies lose their effectiveness in controlling tumor progression over time.

[0004] Prostate-specific membrane antigen (PSMA) is a cell surface marker that may be overexpressed in malignant prostate tissue compared to other organs in the human body, such as the kidneys, proximal small intestine, and salivary glands. It is present and concentrated in 75–95% of metastatic castration-resistant prostate cancer (mCRPC). PSMA is also expressed in neovascular structures within many non-prostate solid tumors, including lung cancer, colon cancer, breast cancer, kidney cancer, liver cancer, pancreatic cancer, thyroid cancer, transitional cell carcinoma of the bladder, neuroendocrine carcinoma, glioblastoma multiforme, melanoma, and non-soft tissue sarcoma, but not in normal vascular structures.

[0005] There is an urgent need for new therapies to treat cancers, including PSMA-expressing cancers such as prostate cancer.

[0006] This invention relates to overcoming these and other defects in the art. [Overview of the project]

[0007] overview In one embodiment, the disclosure relates to a method for treating cancer by administering to a subject with cancer an agent containing a targeted component conjugated to a cancer treatment component.

[0008] In one embodiment, a method for treating cancer is provided herein by administering an agent containing a targeted component bound to a cancer treatment component. The targeted component is huJ591, and the cancer treatment component is Ac 225 It is a radioactive nuclide, The patient was PSMA I&T-Lu 177 Or PSMA617-Lu 177 The patient had received prior treatment with PSMA radioligands such as [list of other devices]. In another specific embodiment, the cancer was recurrent and / or refractory, or PSMA I&T-Lu 177 Alternatively, PSMA617-Lu 177 It is resistant to PSMA radioactive ligands such as the above. In an embodiment, a method for treating or improving prostate cancer in a patient in need thereof, This includes administering to a patient a drug containing a targeted component bound to a cancer treatment component, The targeted component is huJ591, and the cancer treatment component is Ac 225 It is a radioactive nuclide, Patients have not undergone or do not require a pre-treatment PSMA PET scan. A method is provided herein.

[0009] In embodiments, the present disclosure is a method for treating cancer in patients who need it, This includes administering to a patient an initial dose and subsequent doses of a drug containing a targeted component bound to a cancer treatment component. The targeted component is huJ591, and the cancer treatment component is Ac 225 It is a radioactive nuclide. The cumulative amount of the drug administered in the initial and subsequent doses is within the range of approximately 90 KBq / Kg to approximately 130 KBq / Kg. Provide a method. [Brief explanation of the drawing]

[0010] [Figure 1] This shows the best PSA response (best percentage change in PSA) per subject after a divided dose regimen at 45 KBq / Kg, 50 KBq / Kg, 55 KBq / Kg, 60 KBq / Kg, or 65 KBq / Kg dose levels. [Figure 2] This indicates the best PSA response (best percentage change in PSA) per subject after frequent dose regimens at 45 KBq / Kg, 55 KBq / Kg, or 65 KBq / Kg dose levels. [Modes for carrying out the invention]

[0011] definition The following are definitions of various terms used herein and in the claims to illustrate this disclosure. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this disclosure belongs.

[0012] Throughout this specification, the terms “about” and / or “approximately” may be used in conjunction with numbers and / or ranges. The term “about” is understood to mean values ​​that are close to the listed values. Furthermore, the phrases “less than [value]” or “greater than [value]” should be understood in consideration of the definition of the term “about” provided herein. The terms “about” and “approximately” may be used alternately.

[0013] Throughout this specification, numerical ranges are provided for specific quantities. It will be understood that these ranges include all subranges within them. Thus, the range "50-80" includes all possible ranges within it (e.g., 51-79, 52-78, 53-77, 54-76, 55-75, 60-70, etc.). Furthermore, all values ​​within a given range may be endpoints of the range it encompasses (e.g., the range 50-80 includes ranges with endpoints such as 55-80, 50-75, etc.).

[0014] As used herein, the verb “includes” and its conjugations are used in its non-restrictive sense to mean that the item following the word is included, but items not specifically mentioned are not excluded. The present invention may appropriately “include,” “consist of,” or “essentially consist of” the steps, elements, and / or reagents described in the claims.

[0015] It should be further noted that the claims may be drafted to exclude any optional element. Therefore, this statement is intended to serve as a precedent for the use of exclusive terminology such as “solely” or “only,” or for the use of “negative” restrictions, with respect to the enumeration of elements of the claims.

[0016] As used herein, the term “to treat” means to alleviate, reduce, delay, decrease, improve, or control at least one symptom of a disease in the subject. The term “to treat” may also mean to stop, delay the onset (i.e., the period before the clinical symptoms of the disease appear), or reduce the risk of developing or worsening the disease.

[0017] "Effective dose" means the amount of the formulation according to the present invention that, when administered to a patient to treat a condition, disorder, or disease, has a sufficient effect to have such a therapeutic effect. The "effective dose" varies depending on the active ingredient, the condition, disorder, or disease being treated and its severity, and the age, weight, health status, and responsiveness of the mammal being treated.

[0018] The term “therapeutic” as applied to dosage or quantity refers to a sufficient amount of a compound or pharmaceutical preparation to produce the desired clinical effect after administration to a patient in need.

[0019] The term "recurrent" refers to the recurrence of cancer cells in patients who have achieved remission after treatment.

[0020] The term "refractory or resistant" refers to a situation where a patient has residual cancer cells in their body even after treatment.

[0021] As used herein, the term “cancer” includes all types of cancerous tumors or carcinogenic processes, metastatic tissues, or malignantly transformed cells, tissues, or organs, regardless of histopathological type or stage of invasiveness.

[0022] As used herein, “targeting component” is a component that binds to, or otherwise can associate with, molecular targets such as membrane components, cell surface receptors, prostate-specific membrane antigens (folate hydrolase 1, glutamate carboxypeptidase II, and PSMA, also known as NAALADase). Agents containing a targeting component may localize to specific targeted sites, such as tumors, disease sites, tissues, organs, or certain types of cells. Thus, an agent may be “target-specific.” In some cases, a therapeutic agent may exert its anticancer effect without needing to be released from the targeting component. In other cases, the therapeutic component may be released from the agent and may be able to interact locally with specific targeted sites.

[0023] As used herein, “cancer therapeutic component” is an agent or combination of agents that, upon contact with cells, tissues, or subjects, treats cells, tissues, or subjects having a disease requiring treatment. The first and second cancer therapeutic components may be the same or different, and may, for example, be therapeutic radionuclides, chemotherapeutic agents, hormones, hormone antagonists, receptor antagonists, enzymes or proenzymes activated by another agent, biologics, autocrine substances, or cytokines. Toxins may also be used in the methods of the present invention. Other therapeutic agents useful in the present invention include anti-DNA, anti-RNA, radiolabeled oligonucleotides, e.g., antisense oligodeoxyribonucleotides, antiproteins, and antichromatin cytotoxic agents or antibacterial agents. Other therapeutic agents are known to those skilled in the art, and the use of such other therapeutic agents according to the present invention is specifically contemplated.

[0024] As used herein, the term "PSMA" or "prostate-specific membrane antigen" protein refers to mammalian PSMA, preferably human PSMA protein. The long transcript of PSMA encodes a protein product with a molecular weight of about 100-120 kDa, has sequence homology with the transferrin receptor, and is characterized as a type II transmembrane receptor with NAALADase activity (Carter et al., "Prostate-Specific Membrane Antigen is a Hydrolase With Substrate and Pharmacologic Characteristics of a Neuropeptidase", Proc. Natl. Acad Sci. USA 93:749-753 (1996), which is incorporated herein by reference in its entirety). (UniProtKB-Q04609 (FOLH1_HUMAN), Isoform I, as described in SEQ ID NO:1).

[0025] As used herein, "radioligand" is a radiochemical or biochemical species such as a ligand radiolabeled with (e.g., 177 lutetium) that can be used for diagnostic or therapeutic purposes. A radioligand can bind to a specific target or antigen. For example, a "PSMA radioligand" refers to a radiolabeled ligand that binds to PSMA or has a high affinity for PSMA. Ligands can be radiolabeled by methods known in the art, including the use of various linkers and chelating agents that bind to a specific radioisotope.

[0026] The term "antibody" is intended to refer to an immunoglobulin molecule, a fragment of an immunoglobulin molecule, or a derivative thereof that has the ability to specifically bind to an antigen under typical physiological conditions. As used herein, the term includes intact polyclonal or monoclonal antibodies and antigen-binding fragments thereof.

[0027] As used herein, the terms “subject” or “patient” refer to humans, as well as other primates, including chimpanzees and other apes and monkey species.

[0028] The following description contains information that may be useful in understanding the present invention. It is not an endorsement that any information provided herein constitutes prior art or relates to the claimed invention, or that any publication specifically or implicitly referenced constitutes prior art.

[0029] Throughout this disclosure, various patents, patent applications, and publications are referenced. These patents, patent applications, and publications are incorporated into this disclosure as a whole, by reference, for all purposes, to more fully describe the current state of the art as known to those skilled in the art as of the date of this disclosure. In the event of any inconsistency between the cited patents, patent applications, and publications and this disclosure, this disclosure shall prevail.

[0030] Treatment drugs In embodiments, the agent used in the method disclosed herein is an agent comprising a targeted component (as described herein) conjugated to a cancer treatment component (as described herein). In one embodiment, the agent is an antibody conjugated to a radionuclide. In one embodiment, the antibody is a PSMA-targeted antibody. In a particular embodiment, the PSMA-targeted antibody is huJ591, including SEQ ID NOs. 38 and 39. In embodiments, the radionuclide is 177 Lu or 225 It is Ac. In one embodiment, the agent is 225 This is Ac-DOTA-huJ591mAb. In certain embodiments, huJ591 is as described in U.S. Patent No. 7,045,605 and PCT Application Publication WO2018 / 204477, which are incorporated herein by reference as a whole.

[0031] targeting component In one embodiment, the targeting component is independently selected from the group consisting of an antibody or its binding fragment.

[0032] Antibodies against molecular targets on tumors are known. For example, antibodies and antibody fragments that are produced by tumors or that specifically bind to tumor-related markers are disclosed, in particular, in Hansen's U.S. Patent No. 3,927,193, and Goldenberg's U.S. Patents No. 4,331,647, 4,348,376, 4,361,544, 4,468,457, 4,444,744, 4,818,709, and 4,624,846, all of which are incorporated herein by reference. Antibodies against antigens, such as tumors of the gastrointestinal tract, lung, breast, prostate, ovarian, testicular, brain, or lymphoid system, sarcomas, or melanomas, are particularly advantageous. Antibodies against cancer-related antigens are well known to those skilled in the art.

[0033] The antibodies of the present invention may exist in various forms, including, for example, polyclonal antibodies, monoclonal antibodies, intracellular antibodies ("intrabodies"), antibody fragments (e.g., Fv, Fab, and F(ab)2), semiantibodies, hybrid derivatives, and single-chain antibodies (scFv), chimeric antibodies, and humanized antibodies (each of which is incorporated herein by reference as a whole; Ed Harlow and David Lane, USING ANTIBODIES: A LABORATORY MANUAL (Cold Spring Harbor Laboratory Press, 1999); Houston et al., "Protein Engineering of Antibody Binding Sites: Recovery of Specific Activity in an Anti-Digoxin Single-Chain Fv Analogue Produced in Escherichia coli," Proc. Natl. Acad Sci. USA 85:5879-5883 (1988); Bird et al., "Single-Chain Antigen-Binding Proteins," Science 242:423-426 (1988).

[0034] The antibody of the present invention may be a synthetic antibody. A synthetic antibody is an antibody produced using recombinant DNA technology, such as an antibody expressed by a bacteriophage. Alternatively, a synthetic antibody may be produced by synthesizing a DNA molecule that encodes and expresses the antibody of the present invention, or by synthesizing an amino acid sequence that identifies the antibody, where the DNA or amino acid sequence is obtained using synthetic DNA or amino acid sequence techniques that are available and well known in the art.

[0035] Methods for producing monoclonal antibodies are described herein or can be carried out using techniques well known in the art (as incorporated herein by reference in whole, MONOCLONAL ANTIBODIES PRODUCTION, ENGINEERING AND CLINICAL APPLICATIONS (Mary A. Ritter and Heather M. Ladyman eds., 1995)). Generally, this process involves obtaining immune cells (lymphocytes) from the spleen of a mammal pre-immunized with the antigen of interest, either in vivo or in vitro.

[0036] Alternatively, monoclonal antibodies can be produced using the recombinant DNA method described in U.S. Patent No. 4,816,567 of Cabilly et al., which is incorporated herein by reference in its entirety. The polynucleotides encoding the monoclonal antibody are isolated from mature B cells or hybridoma cells by RT-PCR using oligonucleotide primers that specifically amplify, for example, the genes encoding the heavy and light chains of the antibody. The isolated polynucleotides encoding the heavy and light chains are then cloned into a suitable expression vector and transfected into host cells such as Escherichia coli (E. coli) cells, monkey COS cells, Chinese hamster ovary (CHO) cells, or myeloma cells that do not otherwise produce immunoglobulin proteins, at which point the monoclonal antibody is produced by the host cells. Furthermore, recombinant monoclonal antibodies or fragments of the desired species can be isolated from phage display libraries (incorporated herein by reference as a whole: McCafferty et al., "Phage Antibodies: Filamentous Phage Displaying Antibody Variable Domains," Nature 348:552-554 (1990), Clackson et al., "Making Antibody Fragments using Phage Display Libraries," Nature 352:624-628 (1991), and Marks et al., "By-Passing Immunization. Human Antibodies from V-Gene Libraries Displayed on Phage," J Mal. Biol. 222:581-597 (1991)).

[0037] The polynucleotide(s) encoding a monoclonal antibody can be further modified using recombinant DNA technology to generate alternative antibodies. For example, the constant domains of the light and heavy chains of a mouse monoclonal antibody can be replaced with those regions of a human antibody to generate a chimeric antibody. Alternatively, the constant domains of the light and heavy chains of a mouse monoclonal antibody can be replaced with non-immunoglobulin polypeptides to generate a fusion antibody. In other embodiments, the constant region can be shortened or removed to generate a desired antibody fragment of the monoclonal antibody. Furthermore, site-directed mutagenesis or high-density mutagenesis of the variable region can be used to optimize the specificity and affinity of the monoclonal antibody.

[0038] The monoclonal antibody of the present invention may be a humanized antibody. A humanized antibody is an antibody that contains a minimal sequence from a non-human (e.g., mouse) antibody within its variable region. Such antibodies are used therapeutically to reduce antigenicity and the human anti-mouse antibody response when administered to human subjects. In practice, a humanized antibody is typically a human antibody that contains minimal or no non-human sequence. A human antibody is an antibody produced by a human, or an antibody that has an amino acid sequence corresponding to an antibody produced by a human.

[0039] In addition to the entire antibody, the present invention also encompasses binding portions of such antibodies. Such binding portions include monovalent Fab fragments, Fv fragments (e.g., single-chain antibodies, scFv), single variable VH and VL domains, and bivalent F(ab')2 fragments, Bis-scFv, diabodies, triabodies, minibodies, and the like. These antibody fragments can be prepared by conventional procedures, such as proteolytic fragmentation procedures, or by other methods known in the art, as described in James Goding, MONOCLONAL ANTIBODIES: PRINCIPLES AND PRACTICE 98-118 (Academic Press, 1983) and Ed Harlow and David Lane, ANTIBODIES: A LABORATORY MANUAL (Cold Spring Harbor Laboratory, 1988), which are incorporated herein by reference as a whole.

[0040] In particular, with antibody fragments, it may be even more desirable to modify the antibody to extend its serum half-life. This can be achieved, for example, by incorporating a salvage receptor-binding epitope into the antibody fragment through mutations in the appropriate region of the antibody fragment, or by incorporating the epitope into a peptide tag and then fusing it to the antibody fragment at either end or in the middle (e.g., by DNA or peptide synthesis).

[0041] Antibody mimics are also suitable for use in accordance with the present invention. This includes monobodies derived from the 10th human fibronectin type III domain (10Fn3) (each incorporated herein as a whole by reference: Koide et al., "The Fibronectin Type III Domain as a Scaffold for Novel Binding Proteins", J Mal. Biol. 284:1141-1151 (1998), Koide et al., "Probing Protein Conformational Changes in Living Cells by Using Designer Binding Proteins: Application to the Estrogen Receptor", Proc. Natl. Acad Sci. USA 99:1253-1258 (2002)) and affibodies derived from the stable alpha-helical bacterial receptor domain Z of Staphylococcus protein A (each incorporated herein as a whole by reference: Nord et al., "Binding Proteins Selected from Combinatorial Libraries of an alpha-helical Bacterial Receptor Domain", Nature). Several antibody mimics are known in the art, including, but not limited to, those described in Biotechnol. 15(8):772-777 (1997).

[0042] In this embodiment, the targeted component is a PSMA receptor antibody.

[0043] In embodiments, the targeted component may bind to a receptor (e.g., PSMA). A PSMA receptor antibody is an antibody that interacts with (e.g., binds to) PSMA, preferably the human PSMA protein. Preferably, the PSMA receptor antibody interacts with, for example, the extracellular domain of PSMA, e.g., the extracellular domain of human PSMA located at approximately amino acids 44-750 of human PSMA (the amino acid residues correspond to the human PSMA sequence disclosed in U.S. Patent No. 5,538,866, which is incorporated herein by reference in whole). PSMA receptor antibodies are known in the art (Goldsmith et al., "Targeted Radionuclide Therapy for Prostate Cancer," in Therapeutic Nuclear Medicine 617-628 (R. Baum ed. 2014), which is incorporated herein by reference in whole). Exemplary PSMA receptor antibodies include, but are not limited to, J591, J415, J533, and E99 (SEQ ID NOs: 2-13).

[0044] In some embodiments, the PSMA receptor antibody includes a CDR in any of the disclosed antibodies. In some embodiments, the CDR is illustrated by any numbering system known in the art, including AbM, Kabat, Chothia, and IMGT. In some embodiments, the PSMA receptor antibody includes a CDR disclosed in SEQ ID NOs. 14-37. In some embodiments, the PSMA receptor antibody includes a CDR disclosed in SEQ ID NOs. 14-19. In some embodiments, the PSMA receptor antibody includes a CDR disclosed in SEQ ID NOs. 20-25. In some embodiments, the PSMA receptor antibody includes a CDR disclosed in SEQ ID NOs. 26-31. In some embodiments, the PSMA receptor antibody includes a CDR disclosed in SEQ ID NOs. 32-37.

[0045] In some embodiments, the PSMA receptor antibody comprises a variable heavy chain sequence that is at least 90%, at least 92%, at least 94%, at least 96%, at least 98%, or 100% similar to SEQ ID NO: 2 or 10, and consists of CDR1 containing SEQ ID NO: 14, CDR2 containing SEQ ID NO: 15, and CDR3 containing SEQ ID NO: 16. In some embodiments, the variable heavy chain of the PSMA receptor antibody consists of SEQ ID NO: 2 or 10. In some embodiments, the PSMA receptor antibody comprises a variable light chain sequence that is at least 90%, at least 92%, at least 94%, at least 96%, at least 98%, or 100% similar to SEQ ID NO: 3 or 11, and consists of CDR1 containing SEQ ID NO: 17, CDR2 containing SEQ ID NO: 18, and CDR3 containing SEQ ID NO: 19. In some embodiments, the variable light chain of the PSMA receptor antibody consists of SEQ ID NO: 3 or 11.

[0046] In some embodiments, the PSMA receptor antibody comprises a variable heavy chain sequence that is at least 90%, at least 92%, at least 94%, at least 96%, at least 98%, or 100% similar to SEQ ID NO: 4 or 12, and consists of CDR1 containing SEQ ID NO: 20, CDR2 containing SEQ ID NO: 21, and CDR3 containing SEQ ID NO: 22. In some embodiments, the variable heavy chain of the PSMA receptor antibody consists of SEQ ID NO: 4 or 12. In some embodiments, the PSMA receptor antibody comprises a variable light chain sequence that is at least 90%, at least 92%, at least 94%, at least 96%, at least 98%, or 100% similar to SEQ ID NO: 5 or 13, and consists of CDR1 containing SEQ ID NO: 23, CDR2 containing SEQ ID NO: 24, and CDR3 containing SEQ ID NO: 25. In some embodiments, the variable light chain of the PSMA receptor antibody consists of SEQ ID NO: 5 or 13.

[0047] In some embodiments, the PSMA receptor antibody comprises a variable heavy chain sequence that is at least 90%, at least 92%, at least 94%, at least 96%, at least 98%, or 100% similar to SEQ ID NO: 6, and consists of CDR1 containing SEQ ID NO: 26, CDR2 containing SEQ ID NO: 27, and CDR3 containing SEQ ID NO: 28. In some embodiments, the variable heavy chain of the PSMA receptor antibody consists of SEQ ID NO: 6. In some embodiments, the PSMA receptor antibody comprises a variable light chain sequence that is at least 90%, at least 92%, at least 94%, at least 96%, at least 98%, or 100% similar to SEQ ID NO: 7, and consists of CDR1 containing SEQ ID NO: 29, CDR2 containing SEQ ID NO: 30, and CDR3 containing SEQ ID NO: 31. In some embodiments, the variable light chain of the PSMA receptor antibody consists of SEQ ID NO: 7.

[0048] In some embodiments, the PSMA receptor antibody comprises a variable heavy chain sequence that is at least 90%, at least 92%, at least 94%, at least 96%, at least 98%, or 100% similar to SEQ ID NO: 8, and consists of CDR1 containing SEQ ID NO: 32, CDR2 containing SEQ ID NO: 33, and CDR3 containing SEQ ID NO: 34. In some embodiments, the variable heavy chain of the PSMA receptor antibody consists of SEQ ID NO: 8. In some embodiments, the PSMA receptor antibody comprises a variable light chain sequence that is at least 90%, at least 92%, at least 94%, at least 96%, at least 98%, or 100% similar to SEQ ID NO: 9, and consists of CDR1 containing SEQ ID NO: 35, CDR2 containing SEQ ID NO: 36, and CDR3 containing SEQ ID NO: 37. In some embodiments, the variable light chain of the PSMA receptor antibody consists of SEQ ID NO: 9.

[0049] In one embodiment, the PSMA receptor antibody is selected from the group consisting of J591, J415, J533, and E99.

[0050] In one embodiment, the variable chain of the PSMA receptor antibody includes sequences selected from the group consisting of J591 (SEQ ID NOs: 2 and 3), immunogenicity-reduced J591 (also referred to herein as "huJ591") (SEQ ID NOs: 10 and 11), J415 (SEQ ID NOs: 4 and 5), immunogenicity-reduced J415 (SEQ ID NOs: 12 and 13), J533 (SEQ ID NOs: 6 and 7), and E99 (SEQ ID NOs: 8 and 9).

[0051] In one embodiment, the PSMA receptor antibody is J591, which includes SEQ ID NOs: 2 and 3. In one embodiment, the PSMA receptor antibody is J415, which includes SEQ ID NOs: 4 and 5. In one embodiment, the PSMA receptor antibody is J533, which includes SEQ ID NOs: 6 and 7. In one embodiment, the PSMA receptor antibody is E99, which includes SEQ ID NOs: 8 and 9. In one embodiment, the PSMA receptor antibody is immunogenicity reduced J591, which includes SEQ ID NOs: 10 and 11. In one embodiment, the PSMA receptor antibody is immunogenicity reduced J451, which includes SEQ ID NOs: 12 and 13. In some embodiments, the PSMA receptor antibody is incorporated herein in its entirety and disclosed in US2010 / 0278726.

[0052] In some embodiments, the PSMA receptor antibody contains a variable heavy chain sequence that is at least 90%, at least 92%, at least 94%, at least 96%, at least 98%, or 100% similar to SEQ ID NO: 38. In some embodiments, the variable heavy chain of the PSMA receptor antibody consists of SEQ ID NO: 38. In some embodiments, the PSMA receptor antibody contains a variable light chain sequence that is at least 90%, at least 92%, at least 94%, at least 96%, at least 98%, or 100% similar to SEQ ID NO: 39. In some embodiments, the variable light chain of the PSMA receptor antibody consists of SEQ ID NO: 39. In some embodiments, the variable light chain of the PSMA receptor antibody contains or consists of SEQ ID NO: 38 and 39. In some embodiments, the PSMA receptor antibody contains or consists of SEQ ID NO: 39. TIFF2026514046000002.tif59165

[0053] For example, a PSMA receptor antibody, as described in Bander's U.S. Patent No. 7,045,605, incorporated herein by reference as a whole, is conjugated with 1,4,7,10-tetraazacyclododecane-N,N',N",N'"-tetraacetic acid (DOTA), 111 indium, 90 yttrium, or 177 It can be radiolabeled with lutetium.

[0054] Cancer treatment components In some embodiments, the cancer treatment component may include a chemotherapeutic agent or a radionuclide. In some embodiments, the cancer treatment component may include a chemotherapeutic agent. In some embodiments, the cancer treatment component may include a radionuclide.

[0055] In one embodiment, the cancer treatment component is 186 Re, 90 Y, 67 Cu, 169 Er, 121 Sn, 127 Te, 142 Pr, 198 Au, 199 Au, 161 Tb, 109 Pd, 188 Rh, 166 Dy, 166 Ho, 149 PM, 151 PM, 153 Sm, 159 Gd, 172 Tm, 169 Yb, 175 Yb, 177 Lu, 105 Rh, 111 Ag, 131 I, 117m Sn, 225 Ac, 227 Th, 211 At, 212 It is a radioactive nuclide selected from the group consisting of Pb and combinations thereof.

[0056] Procedures for labeling agents with radioisotopes are generally known in the art. For example, there is a broad range of components that can function as chelate ligands and be derivatized to the targeted components of the present invention. For example, chelate ligands may be derivatives of 1,4,7,10-tetraazacyclododecanetetraacetic acid (DOTA), ethylenediaminetetraacetic acid (EDTA), diethylenetriaminepentaacetic acid (DTPA), and 1-p-isothiocyanato-benzyl-methyl-diethylenetriaminepentaacetic acid (ITC-MX). These chelating agents typically have a group on their side chain, which can be used to attach the chelating agent to the targeted components of the present invention. Such groups include, for example, benzyl isothiocyanates, which can bond DOTA, DTPA, or EDTA to, for example, an amine group of the targeted component. Procedures for iodinating biological agents such as antibodies, their binding sites, probes, or ligands are incorporated herein by reference as a whole, as described in Hunter and Greenwood, "Preparation of Iodine-131 Labelled Human Growth Hormone of High Specific Activity," Nature 144:496-496 (1962), David et al., "Protein Iodination With Solid State Lactoperoxidase," Biochemistry 13:1014-1021 (1974), and U.S. Patent No. 3,867,517 by Ling and Patent No. 4,376,110 by David.Other procedures for iodizing biological agents are described by Greenwood et al., “The Preparation of I-131-Labelled Human Growth Hormone of High Specific Radioactivity”, Biochem.J 89:114-123 (1963), Marchalonis, “An Enzymic Method for the Trace Iodination of Immunoglobulins and Other Proteins”, Biochem.J.113:299-305 (1969), and Morrison et al., “Use of Lactoperoxidase Catalyzed Iodination in Immunochemical Studies”, Immunochemistry 8:289-297 (1971), which are incorporated herein by reference as a whole. The procedure for 99mTC labeling is described in Rhodes, B. et al. in Burchiel, S. et al. (eds.), Tumor Imaging: The Radioimmunochemical Detection of Cancer, New York: Masson 111-123 (1982), and the references cited herein, and is incorporated herein by reference in its entirety.Procedures suitable for 111In-labeled biological agents are described herein by reference in their entirety in Hnatowich et al., "The Preparation of DTPA-coupled Antibodies Radiolabeled With Metallic Radionuclides: An Improved Method," J Immul. Methods 65:147-157 (1983), Hnatowich et al., "Coupling Antibody With DTPA: An Alternative to the Cyclic Anhydride," Int. J Applied Radiation 35:554-557 (1984), and Buckley et al., "An Efficient Method For Labelling Antibodies With 111In," FEBS 166:202-204 (1984).

[0057] In another embodiment, the cancer treatment components include busulfan, cisplatin, carboplatin, chlorambucil, cyclophosphamide, ifosfamide, dacarbazine (DTIC), mechloretamine (nitrogen mustard), melphalancarmustine (BCNU), lomustine (CCNU), 5-fluorouracil (5-FU), capecitabine, methotrexate, gemcitabine, cytarabine (ara-C), fludarabine, dactinomycin, daunorubicin, doxorubicin (adriamycin), idarubicin, mitoxantrone, paclitaxel, docetaxel, etoposide (VP-16), vinblastine, vincristine, and vinorelbine. The chemotherapeutic agent is independently selected from the group consisting of prednisone, dexamethasone, tamoxifen, fulvestrant, anastrozole, letrozole, megestrol acetate, bicalutamide, flutamide, leuprolide, goserelin, L-asparaginase, tretinoin, meitansine, auristatin, pyrrolobenzodiazepine, duocalmycin, and combinations thereof.

[0058] Procedures for conjugating biological agents with chemotherapeutic agents are well known in the art. Most chemotherapeutic agents currently used in cancer treatment have functional groups that readily crosslink directly with the amine or carboxyl groups of the targeting components of the present invention. For example, free amino groups are available in methotrexate, doxorubicin, daunorubicin, cytosine arabinoside, cisplatin, vindesine, mitomycin, and bleomycin, while free carboxylic acid groups are available in methotrexate, melphalan, and chlorambucil. These functional groups, free amino acids and carboxylic acids, are targets for a variety of homobifunctional and heterobifunctional chemical crosslinkers that can directly crosslink these drugs with the free amino groups of the targeting components. Specific procedures for conjugating the targeting components with chemotherapeutic agents have been described and are known in the art. For example, the conjugation of chlorambucil with antibodies is described by Flechner, "The Cure and Concomitant Immunization of Mice Bearing Ehrlich Ascites Tumors by Treatment With an Antibody-Alkylating Agent Complex," European Journal of Cancer 9:741-745 (1973), which is incorporated herein by reference as a whole; Ghose et al., "Immunochemotherapy of Cancer with Chlorambucil-Carrying Antibody," British Medical Journal 3:495-499 (1972); and Szekerke et al., "The Use of Macromolecules as Carriers of Cytotoxic Groups (part II) Nitrogen Mustard-Protein Complexes," Neoplasma 19:211-215 (1972).Procedures for conjugating daunomycin and adriamycin to antibodies are described in Hurwitz et al., "The Covalent Binding of Daunomycin and Adriamycin to Antibodies, With Retention of Both Drug and Antibody Activities," Cancer Research 35:1175-1181 (1975) and Arnon et al., Cancer Surveys 1:429-449 (1982), which are incorporated herein by reference in their entirety. The conjugation procedure is also described in EP8630916.2, which is incorporated herein by reference in its entirety.

[0059] A pharmaceutical composition comprising an agent for use in the method of the present invention may include a pharmaceutically acceptable carrier, one or more activators, and a suitable delivery vehicle, as described below.

[0060] The agent of the present invention may be administered orally, for example, with an inert diluent or an assimilated food carrier, or encapsulated in a hard-shell or soft-shell capsule, or compressed into a tablet, or directly mixed with therapeutic food. The agent of the present invention may be incorporated into a device such as a sustained-release capsule or nanotube for sustained-release administration. Such a device provides flexibility in terms of time and dosage. For oral therapeutic administration, the agent of the present invention may be incorporated with excipients and used in the form of tablets, capsules, elixirs, suspensions, syrups, etc. Such compositions and preparations should contain at least 0.1% of the agent, although lower concentrations may be effective and may actually be optimal. The proportion of the agent in these compositions may, of course, vary, and for convenience, may be about 2% to about 60% by weight of its unit. The amount of the agent of the present invention in such therapeutically useful compositions is such that an appropriate dosage is obtained.

[0061] When administering the agent of the present invention parenterally, a solution or suspension of the agent can be prepared in water and, in some cases, may be appropriately mixed with a surfactant such as hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycol, and mixtures thereof in oil. Exemplary oils are petroleum, animal oil, vegetable oil, or synthetically derived oils, such as peanut oil, soybean oil, or mineral oil. Generally, water, physiological saline, dextrose aqueous solutions, and related sugar solutions, as well as glycols such as propylene glycol or polyethylene glycol, are preferred liquid carriers, especially for injection solutions. These superorganic materials may contain preservatives to prevent microbial growth under normal storage and use conditions.

[0062] Pharmaceutical formulations suitable for injection include sterile aqueous solutions or sterile dispersions, and sterile powders for the immediate preparation of sterile injection solutions or sterile injection dispersions. In all cases, the form must be sterile and fluid enough to pass easily through a needle. The form must be stable under manufacturing and storage conditions and protected from contamination by microorganisms such as bacteria and fungi. The carrier may be a solvent or dispersion medium containing, for example, water, ethanol, polyols (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.

[0063] If systemic delivery of the agent of the present invention is desired, the agent may be formulated for parenteral administration by injection, for example, bolus injection or continuous infusion. The formulation for injection may be provided in unit dosage forms, for example in ampoules, or in multi-dose containers with preservatives added. The composition may take the form of a suspension, solution, or emulsion in an oily or aqueous vehicle, and may contain agents such as suspending agents, stabilizers, and / or dispersants.

[0064] The agents of the present invention can also be administered intraperitoneally or intrathecally using an infusion pump device. Such a device allows for continuous infusion of the desired compound while avoiding multiple infusions and operations.

[0065] In addition to the formulations described above, this drug can also be formulated as a depot preparation. Such long-acting formulations can be formulated as suitable polymer or hydrophobic materials (e.g., as an emulsion in an acceptable oil), or as an ion exchange resin, or as a sparingly soluble derivative, for example, as a sparingly soluble salt.

[0066] therapeutic use In one embodiment, a method for treating cancer is provided herein by administering an agent comprising a targeted component (as described herein) conjugated to a cancer treatment component (as described herein).

[0067] In one embodiment, a method for treating cancer in a patient who needs it, This includes administering to a patient a drug containing a targeted component bound to a cancer treatment component, The targeting component is huJ591, and the cancer treatment component is a radionuclide. The patient had received prior treatment with at least one PSMA radioligand. A method is provided herein. In a particular embodiment, the PSMA radioligand is PSMA I&T-Lu 177 and / or PSMA617-Lu 177 In certain embodiments, the cancer is recurrent and / or refractory, or resistant to at least one PSMA radioligand. In certain embodiments, the PSMA radioligand is PSMA617-Lu 177 and / or PSMA I&T-Lu 177 That is the case.

[0068] In one embodiment, a method for treating cancer in a patient who needs it, This includes administering to a patient a drug containing a targeted component bound to a cancer treatment component, The targeted component is huJ591, and the cancer treatment component is Ac 225 It is a radioactive nuclide, The cancer is recurrent and / or refractory, or resistant to at least one PSMA radioligand. In certain embodiments, the PSMA radioligand is PSMA I&T-Lu 177 and / or PSMA617-Lu 177 That is, A method is provided herein.

[0069] In embodiments, the present disclosure is a method for treating or improving prostate cancer in patients who need it, This includes administering to a patient a drug containing a targeted component bound to a cancer treatment component, The targeted component is huJ591, and the cancer treatment component is Ac 225 It is a radioactive nuclide, Patients have not undergone or do not require a pre-treatment PSMA PET scan. Provide a method.

[0070] In embodiments, the present disclosure is a method for treating cancer in patients who need it, This involves administering to a patient an initial dose and at least one subsequent dose of a drug containing a targeted component bound to a cancer treatment component. The targeted component is huJ591, and the cancer treatment component is Ac 225 It is a radioactive nuclide, The cumulative amount of the drug administered in the initial and subsequent doses is within the range of approximately 90 KBq / Kg to approximately 130 KBq / Kg or approximately 180 KBq / Kg to approximately 340 KBq / Kg. Provide a method.

[0071] In certain embodiments, the cancer is prostate cancer, neuroendocrine cancer, breast cancer, or non-Hodgkin lymphoma. In some embodiments, the cancer is a primary tumor, and in other embodiments, the cancer is a secondary or metastatic tumor. In embodiments of this disclosure, the cancer is prostate cancer.

[0072] In some embodiments, the cancer is a PSMA-expressing cancer.

[0073] In this embodiment, the cancer is breast cancer, prostate cancer, neuroendocrine cancer, lung cancer, non-Hodgkin lymphoma, colorectal cancer, lung cancer, endometrial cancer and ovarian cancer, gastric cancer, renal cell carcinoma, urothelial carcinoma, hepatocellular carcinoma, oral squamous cell carcinoma, thyroid cancer, glioblastoma, or adenoid cystic carcinoma.

[0074] In this embodiment, the cancer is prostate cancer. In this embodiment, when the cancer is prostate cancer, the targeting component targets the PSMA receptor. In this embodiment, when the cancer is prostate cancer, the targeting component is an antibody against the PSMA receptor.

[0075] In this embodiment, the prostate cancer is metastatic prostate cancer. In this embodiment, when the cancer is metastatic prostate cancer, the targeting component targets the PSMA receptor. In this embodiment, when the cancer is metastatic prostate cancer, the targeting component is a PSMA receptor antibody.

[0076] In some embodiments, the cancer is metastatic castration-resistant prostate cancer (mCRPC). In some embodiments, the cancer is castration-sensitive prostate cancer. In embodiments, when the cancer is mCRPC, the targeting component targets the PSMA receptor. In embodiments, when the cancer is mCRPC, the targeting component is a PSMA receptor antibody.

[0077] In some embodiments, the cancer is prostate-specific membrane antigen (PSMA)-positive metastatic castration-resistant prostate cancer (mCRPC) that has been treated with prior therapies such as androgen receptor (AR) pathway inhibition and / or taxane-based chemotherapy and / or anti-PSMA therapy. In another embodiment, the cancer is castration-sensitive prostate cancer.

[0078] In some embodiments, the cancer is recurrent and / or refractory to prior treatment with a therapeutic agent comprising a second targeted component conjugated to a second cancer therapeutic component (e.g., a cancer therapeutic component described herein). In embodiments, the second targeted component is a PSMA receptor-binding peptide or a PSMA receptor inhibitor. The PSMA receptor inhibitor may include any lipid, carbohydrate, polynucleotide, peptide, polypeptide, or any other biomolecule, organic molecule, or inorganic molecule that conjugates the enzyme active site and inhibits the function of the PSMA receptor. Exemplary PSMA receptor inhibitors are known in the art, including PSMA617, PSMA I&T, 177 This includes, but is not limited to, Lu-J591, DCFBC, DCFPyL, glutamate-urea-lysine analogs, phosphoramidate analogs, and 2-(phosphinylmethyl)pentanedioic acid analogs (which are incorporated herein by reference as a whole: Lutje et al., "PSMA Ligands for Radionuclide Imaging and Therapy of Prostate Cancer: Clinical Status", Theranostics 5(12):1388-1401 (2015), Haberkorn et al., "New Strategies in Prostate Cancer: Prostate-Specific Membrane Antigen (PSMA) Ligands for Diagnosis and Therapy", Clin. Cancer Res. 22(1):9-15 (2016)). In the embodiment, the second targeting component is a peptide selected from the group consisting of PSMA617, PSMA I&T, DCFBC, DCFPyL, glutamate-urea-lysine analog, phosphoramidate analog, 2-(phosphenylmethyl)pentanedioic acid analog, and other PSMA ligands / inhibitors. In the embodiment, cancer is PSMA617- 177 Lu or PSMA I&T- 177 The cancer is relapsed and / or refractory to prior treatment with Lu. In embodiments, the cancer is PSMA617- 177 The condition is relapsed and / or refractory to prior treatment with Lu.

[0079] In some embodiments, the method is PSMA617- 177 Lu and / or PSMA I&T- 177 The regimen includes prior treatment with a therapeutic agent containing a second targeted component conjugated to a second cancer treatment component, such as a PSMA radioligand including Lu. In embodiments, the therapeutic agent used in prior treatment is a small molecule conjugated to a radionuclide and is administered in doses of approximately 200-1,000 mCi total in a two-week cycle, or approximately 300-800 mCi total in a two-week cycle, or approximately 400-700 mCi total in a two-week cycle, or approximately 500-600 mCi total in a two-week cycle. Specific doses may include 200, 225, 250, 300, 325, 350, 375, 400, 425, 450, 475, 500, 525, 550, 575, 600, 625, 650, 675, 700, 725, 750, 775, 800, 825, 850, 875, 900, 925, 950, 975, and 1,000 mCi. In certain embodiments, these amounts represent the total dose over a two-week cycle.

[0080] In some embodiments, the additional therapeutic agent is a PSMA radioligand. In certain embodiments, the prior treatment is PSMA617- 177 Lu or PSMA I&T- 177 This involves administering Lu in doses of approximately 1 GBq to approximately 12 GBq, or approximately 2 GBq to approximately 20 GBq, or approximately 3 GBq to approximately 9 GBq, or approximately 4 GBq to approximately 8 GBq, or any range in between. In another embodiment, prior treatment is performed with one of the disclosed doses described herein of PSMA617- 177 Lu or PSMA I&T- 177The treatment involves Lu and is administered once a week, every two weeks, every three weeks, every four weeks, every five weeks, every six weeks, every seven weeks, every eight weeks, every nine weeks, every ten weeks, every eleven weeks, or every twelve weeks. In certain embodiments, the total number of cycles or doses is one dose or one cycle, two doses or two cycles, three doses or four doses or four cycles of a cycle, five doses or five cycles, six doses or six cycles, seven doses or seven cycles, or eight doses or eight cycles. In embodiments, the therapeutic agent, which includes a second targeted component conjugated to a second cancer treatment component, is administered intravenously.

[0081] In certain embodiments, the pretreatment is with a therapeutic agent which is a PSMA radioligand. In certain embodiments, the PSMA radioligand is PSMA617- 177 The drug is Lu and includes administering approximately 5.9 GBq (160 mCi) to approximately 7.4 GBq (200 mCi) every 6 to 10 weeks. In embodiments, the therapeutic agent, PSMA617- 177 Prior treatment with Lu involves administering approximately 1 GBq to approximately 12 GBq, or approximately 2 GBq to approximately 20 GBq, or approximately 3 GBq to approximately 9 GBq, or approximately 4 GBq to approximately 8 GBq, or any range in between. In certain embodiments, PSMA617- 177 Lu is administered once a week, every two weeks, every three weeks, every four weeks, every five weeks, every six weeks, every seven weeks, every eight weeks, every nine weeks, every ten weeks, every eleven weeks, or every twelve weeks. In certain embodiments, the total number of cycles or doses is one dose or one cycle, two doses or two cycles, three doses per cycle, four doses or four cycles, five doses or five cycles, six doses or six cycles, seven doses or seven cycles, or eight doses or eight cycles. In several embodiments, the therapeutic agent PSMA617- 177 Prior treatment with Lu involves administering approximately 7.4 GBq (200 mCi) every 6 weeks for up to 6 doses. In another specific embodiment, PSMA617- 177Lu is administered in a dose of 8.5 GBq. In another specific embodiment, the subsequent dose decreases. In a specific embodiment, the subsequent dose can be administered at approximately 8.5 GBq. In another embodiment, the next dose is approximately 8.0 GBq to 8.5 GBq. In another embodiment, the next dose is approximately 7.5 GBq to 8.0 GBq. In another embodiment, the next dose is approximately 7.0 GBq to 7.5 GBq. In another embodiment, the next dose is approximately 6.5 GBq to 7.0 GBq.

[0082] In the embodiment, the therapeutic agent, PSMA I&T- 177 Prior treatment with Lu involves administering approximately 1 GBq to approximately 12 GBq, or approximately 2 GBq to approximately 20 GBq, or approximately 3 GBq to approximately 9 GBq, or approximately 4 GBq to approximately 8 GBq, or any range in between. In certain embodiments, PSMA I&T- 177 Lu is administered once a week, every two weeks, every three weeks, every four weeks, every five weeks, every six weeks, every seven weeks, every eight weeks, every nine weeks, every ten weeks, every eleven weeks, or every twelve weeks. In certain embodiments, the total number of cycles or doses may be one dose or one cycle, two doses or two cycles, three doses per cycle, four doses or four cycles, five doses or five cycles, six doses or six cycles, seven doses or seven cycles, or eight doses or eight cycles.

[0083] 225 Medication of Ac-huJ591 In embodiments, the agent provided herein includes a targeted component conjugated to a cancer treatment component, i.e., 225The total daily dose of Ac-huJ591 may be in the range of approximately 10 KBq / Kg to approximately 130 KBq / Kg, for example, approximately 10 KBq / Kg, approximately 15 KBq / Kg, approximately 20 KBq / Kg, approximately 25 KBq / Kg, approximately 30 KBq / Kg, approximately 35 KBq / Kg, approximately 40 KBq / Kg, approximately 45 KBq / Kg, approximately 50 KBq / Kg, approximately 55 KBq / Kg, approximately 60 KBq / Kg, approximately 65 The values ​​include KBq / Kg, approximately 70KBq / Kg, approximately 75KBq / Kg, approximately 80KBq / Kg, approximately 85KBq / Kg, approximately 90KBq / Kg, approximately 95KBq / Kg, approximately 100KBq / Kg, approximately 105KBq / Kg, approximately 110KBq / Kg, approximately 115KBq / Kg, approximately 120KBq / Kg, and between approximately 125KBq / Kg and 130KBq / Kg (including all values ​​and partial ranges between them). In embodiments, the total daily dose of the agent administered in the method provided herein may be in the range of approximately 13.3KBq / Kg to approximately 93.3KBq / Kg. In embodiments, the total daily dose of the agent administered in the method provided herein may be in the range of approximately 45KBq / Kg to approximately 65KBq / Kg. In embodiments, the total daily dose of the agent administered in the method provided herein may be a dose of about 40 KBq / Kg, 45 KBq / Kg, about 55 KBq / Kg, about 60 KBq / Kg, about 65 KBq / Kg, about 70 KBq / Kg, about 75 KBq / Kg, about 80 KBq / Kg, or about 85 KBq / Kg. In embodiments, the total daily dose is about 45 KBq / Kg. In embodiments, the total daily dose is about 55 KBq / Kg. In embodiments, the total daily dose is about 60 KBq / Kg. In embodiments, the total daily dose is about 65 KBq / Kg. In embodiments, the total daily dose is about 70 KBq / Kg. In embodiments, the total daily dose is about 75 KBq / Kg. In embodiments, the total daily dose is about 85 KBq / Kg. In embodiments, the total daily dose is about 90 KBq / Kg.

[0084] In embodiments, the method of the present disclosure includes administering to a patient an initial dose and subsequent doses of an agent containing a targeted component conjugated to a cancer treatment component. In embodiments, the cumulative amount of the agent administered in the initial and subsequent doses may be, for example, in the range of about 70 KBq / Kg to about 140 KBq / Kg, about 80 KBq / Kg to about 130 KBq / Kg, or 90 KBq / Kg to about 130 KBq / Kg, and includes about 70 KBq / Kg, about 80 KBq / Kg, about 90 KBq / Kg, about 95 KBq / Kg, about 100 KBq / Kg, about 105 KBq / Kg, about 110 KBq / Kg, about 115 KBq / Kg, about 120 KBq / Kg, about 125 KBq / Kg, and about 130 KBq / Kg (including all values ​​and partial ranges between these). In the embodiment, the cumulative amount of the agent administered in the initial and subsequent doses is approximately 70 KBq / Kg, approximately 80 KBq / Kg, approximately 90 KBq / Kg, approximately 110 KBq / Kg, approximately 120 KBq / Kg, or approximately 130 KBq / Kg. In the embodiment, the cumulative amount of the agent administered in the initial and subsequent doses is approximately 90 KBq / Kg. In the embodiment, the initial dose of the agent is approximately 45 KBq / Kg, and the subsequent dose of the agent is approximately 45 KBq / Kg. In the embodiment, the cumulative amount of the agent administered in the initial and subsequent doses is approximately 110 KBq / Kg. In the embodiment, the initial dose of the agent is approximately 55 KBq / Kg, and the subsequent dose of the agent is approximately 55 KBq / Kg. In the embodiment, the cumulative amount of the agent administered in the initial and subsequent doses is approximately 120 KBq / Kg. In this embodiment, the initial dose of the agent is approximately 60 KBq / Kg, and the subsequent dose is approximately 60 KBq / Kg. In this embodiment, the cumulative amount of the agent administered in the initial and subsequent doses is approximately 130 KBq / Kg. In this embodiment, the initial dose of the agent is approximately 65 KBq / Kg, and the subsequent dose is approximately 65 KBq / Kg.

[0085] In embodiments, the method of the present disclosure includes administering to a patient an initial dose and at least one subsequent dose of a drug containing a targeted component conjugated to a cancer treatment component. In embodiments, there is one subsequent dose. In embodiments, there are two subsequent doses. In embodiments, there are three subsequent doses. In embodiments, there are four subsequent doses. In this embodiment, the cumulative amount of the agent administered in the initial and subsequent doses may be in the range of, for example, approximately 70 KBq / Kg to approximately 500 KBq / Kg, approximately 80 KBq / Kg to approximately 400 KBq / Kg, or approximately 90 KBq / Kg to approximately 340 KBq / Kg, and approximately 70 KBq / Kg, approximately 80 KBq / Kg, approximately 90 KBq / Kg, approximately 95 KBq / Kg, approximately 100 KBq / Kg, approximately 105 KBq / Kg, approximately 110 KBq / Kg, approximately 115 KBq / Kg, approximately 120 KBq / Kg, approximately 125 KBq / Kg, approximately 130 KBq / Kg, approximately 140 KBq / Kg, approximately 150 KBq / Kg, approximately 160 KBq / Kg, and approximately 170 KBq Includes KBq / Kg, approximately 180KBq / Kg, approximately 190KBq / Kg, approximately 200KBq / Kg, approximately 210KBq / Kg, approximately 220KBq / Kg, approximately 230KBq / Kg, approximately 240KBq / Kg, approximately 250KBq / Kg, approximately 260KBq / Kg, approximately 270KBq / Kg, approximately 280KBq / Kg, approximately 290KBq / Kg, approximately 300KBq / Kg, approximately 310KBq / Kg, approximately 320KBq / Kg, approximately 330KBq / Kg, approximately 340KBq / Kg, approximately 350KBq / Kg, approximately 360KBq / Kg, approximately 370KBq / Kg, approximately 380KBq / Kg, and approximately 390KBq / Kg (including all values ​​and subranges between these).In this embodiment, the cumulative amount of the agent administered in the initial dose and subsequent doses is approximately 70 KBq / Kg, approximately 80 KBq / Kg, 90 KBq / Kg, approximately 110 KBq / Kg, approximately 120 KBq / Kg, approximately 130 KBq / Kg, 140 KBq / Kg, approximately 150 KBq / Kg, 160 KBq / Kg, approximately 170 KBq / Kg, approximately 180 KBq / Kg, approximately 190 KBq / Kg, and approximately 20 The values ​​are 0 KBq / Kg, approximately 210 KBq / Kg, approximately 220 KBq / Kg, 230 KBq / Kg, approximately 240 KBq / Kg, 250 KBq / Kg, approximately 260 KBq / Kg, approximately 270 KBq / Kg, approximately 280 KBq / Kg, 290 KBq / Kg, approximately 300 KBq / Kg, 310 KBq / Kg, approximately 320 KBq / Kg, approximately 330 KBq / Kg, or approximately 340 KBq / Kg. In the embodiment, the cumulative amount of the agent administered in the initial and subsequent doses is approximately 180 KBq / Kg. In the embodiment, the initial dose of the agent is approximately 45 KBq / Kg, and the subsequent dose of the agent is approximately 45 KBq / Kg. In the embodiment, the cumulative amount of the agent administered in the initial and subsequent doses is approximately 220 KBq / Kg. In one embodiment, the initial dose of the agent is approximately 55 KBq / Kg, and the subsequent dose is approximately 55 KBq / Kg. In another embodiment, the cumulative amount of the agent administered in the initial and subsequent doses is approximately 260 KBq / Kg. In yet another embodiment, the initial dose of the agent is approximately 65 KBq / Kg, and the subsequent dose is approximately 60 KBq / Kg. In yet another embodiment, the cumulative amount of the agent administered in the initial and subsequent doses is approximately 130 KBq / Kg. In yet another embodiment, the initial dose of the agent is approximately 65 KBq / Kg, and the subsequent dose is approximately 65 KBq / Kg.

[0086] In embodiments, the method of the present disclosure involves administering to a patient an initial dose of an agent containing a targeted component conjugated to a cancer treatment component, and a series of subsequent doses, such as 2, 3, 4, 5, or 6 cycles. In certain embodiments, the agent is administered in four separate doses, i.e., one dose is administered in four separate cycles. In embodiments, the cumulative amount of the agent administered in four cycles may be, for example, in the range of about 60 KBq / Kg to about 500 KBq / Kg, about 150 KBq / Kg to about 400 KBq / Kg, about 180 KBq / Kg to about 340 KBq / Kg, and about 220 KBq / Kg to about 300 KBq / Kg, as well as any range in between. In certain embodiments, the cumulative amount over four cycles may be approximately 60 KBq / Kg, approximately 70 KBq / Kg, approximately 80 KBq / Kg, 100 KBq / Kg, approximately 150 KBq / Kg, approximately 180 KBq / Kg, approximately 200 KBq / Kg, approximately 220 KBq / Kg, approximately 260 KBq / Kg, approximately 300 KBq / Kg, approximately 340 KBq / Kg, and approximately 400 KBq / Kg (including all values ​​and partial ranges between these).

[0087] In embodiments, the subsequent dose administered in the method provided herein is administered at least about two weeks after the initial dose. In embodiments, the subsequent dose is administered about two weeks after the initial dose. In embodiments, the subsequent dose is administered about 14 to 20 days after the initial dose. In embodiments, the subsequent dose is administered about 14 days after the initial dose. In embodiments, the subsequent dose is administered about three weeks after the initial dose. In embodiments, the subsequent dose is administered about four weeks after the initial dose. In embodiments, the subsequent dose is administered about five weeks after the initial dose. In embodiments, the subsequent dose is administered about six weeks after the initial dose. In embodiments, the subsequent dose is administered about seven weeks after the initial dose. In embodiments, the subsequent dose is administered about eight weeks after the initial dose. In embodiments, the subsequent dose is administered about nine weeks after the initial dose. In embodiments, the subsequent dose is administered about nine weeks after the initial dose.

[0088] If multiple doses or cycles are included, additional cycles will be delivered at approximately 1-week, 2-week, 3-week, 4-week, 5-week, 6-week, 7-week, 8-week, 9-week, 10-week, 11-week, or 12-week intervals.

[0089] In some embodiments, the agent containing a targeted component conjugated to the cancer therapeutic component administered by the method provided herein may be administered as a single dose in a 6-week cycle (q6w). In some embodiments, the agent containing a targeted component conjugated to the cancer therapeutic component administered by the method provided herein may be administered as a single dose in an 8-week cycle. In other embodiments, there may be one, two, three, four, five, or six cycles.

[0090] In some embodiments, after initiating treatment with the medication and medication schedule described herein, subjects exhibit a bPFS of at least 50 days, at least 100 days, at least 150 days, at least 200 days, at least 250 days, at least 300 days, or at least 1 year. In other embodiments, after initiating treatment, subjects exhibit a bPFS range of about 50 to 500 days, about 100 to about 400 days, or about 200 to about 300 days.

[0091] In one embodiment, an agent comprising a targeted component conjugated to a cancer treatment component administered in the method provided herein can be delivered, for example, as a single bolus injection or as a single dose such as an oral tablet or pill, or over time such as a continuous infusion over time or a divided bolus dose over time. In one embodiment, the agent can be administered repeatedly, if necessary, for example, until the patient's disease stabilizes or regresses, or until the patient's disease worsens or unacceptable toxicity occurs. Stability or absence of disease is determined by methods known in the art, such as evaluation of the patient's symptoms, physical examination, visualization of the tumor imaged using X-ray, CAT, PET, bone scan, or MRI scan and other generally accepted assessment methods. In one embodiment, the agent can be administered repeatedly, if necessary, for example, until the patient experiences progression of PSA, for example, an increase of at least about 25% above pre-treatment levels or the lowest PSA level.

[0092] In some embodiments, the dose-limiting toxicity (DLT) is as follows: a. Any occurrence of Grade 4 neutropenia or febrile neutropenia b. Grade 4 thrombocytopenia, or Grade 3 thrombocytopenia associated with massive bleeding. c. at least 225 Any non-hematological toxicity of grade >2 that is considered potentially associated with Ac-huJ591 is referred to as a dose-limiting toxicity.

[0093] In some embodiments, the maximum tolerated dose (MTD) is the dose level at which only one out of six subjects experiences a DLT during the DLT evaluation period.

[0094] In one embodiment, the patient is treated in a manner provided herein for at least about 8 weeks, at least about 10 weeks, at least about 12 weeks, at least about 14 weeks, at least about 16 weeks, at least about 18 weeks, at least about 20 weeks, at least about 22 weeks, at least about 24 weeks, or at least about 26 weeks.

[0095] In certain embodiments, an agent comprising a targeted component conjugated to a cancer treatment component is administered to the patient in cycles (e.g., a single dose followed by a rest period of up to 6 weeks (e.g., about 2 weeks, 3 weeks, 4 weeks, 5 weeks, or 6 weeks)) in a manner that may be provided herein. Cycling therapy involves administering the active agent for a set period, followed by a rest period, and repeating this sequence of administrations. In embodiments, cycling therapy can reduce the development of resistance to one or more therapies, avoid or reduce one side effect of a therapy, and / or improve the effectiveness of the treatment.

[0096] In embodiments, the methods provided herein include administering an agent containing a targeted component conjugated to a cancer treatment component in 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, or more than 40 cycles. In embodiments, the agent is administered in at least 1 cycle. In embodiments, the agent is administered in up to 4 cycles. In embodiments, the agent is administered in at least 1 cycle. In embodiments, the agent is administered in up to 1 to 4 cycles. In embodiments, the median number of cycles administered to a patient group is about 1. In one embodiment, the median number of cycles administered to a patient group is about 2. In one embodiment, the median number of cycles administered to a patient group is about 3. In one embodiment, the median number of cycles administered to the patient group is approximately 4.

[0097] In certain embodiments, a treatment cycle comprises multiple doses of a drug containing a targeted component conjugated to a cancer treatment component, administered to a patient in need over one or more days (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or more than 14 days), optionally followed by a treatment rest (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, or more than 28 days).

[0098] When carrying out the methods of this disclosure, the administration step is performed to treat cancer in a subject. In one embodiment, a subject having cancer is selected before the administration step. Such administration can be performed systemically, directly or locally, to the tumor site. Suitable systemic administration methods include, but are not limited to, oral, local, transdermal, parenteral, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, or intranasal infusion, intracavitary or intravesical infusion, intraocular, intra-arterial, intrafocal, or topical application to the mucous membrane. Suitable local administration methods include, but are not limited to, catheterization, implantation, direct injection, skin / transdermal application, or portal vein administration to the relevant tissue, or any other local administration technique, method, or procedure generally known in the art. The methods affecting the delivery of the agent vary depending on the type of therapeutic agent and the disease being treated.

[0099] In some embodiments, after treatment, the patient experiences a reduction in the number of circulating tumor cells (CTCs) compared to, for example, baseline before treatment. In embodiments, the patient experiences a reduction in the number of CTCs of at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 55%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or more, compared to baseline before treatment. In embodiments, the patient experiences a reduction in the number of CTCs of at least about 50% compared to baseline before treatment.

[0100] In embodiments, after treatment by the method disclosed herein, the patient has a CTC number of less than about 5, less than about 4, less than about 3, less than about 2, or less than 1.

[0101] In embodiments, after treatment by the method disclosed herein, the patient has an undetectable CTC count. In embodiments, the CTC count is assessed using a CTC assay system. CTC counts by the CellSearch platform have been demonstrated to be prognostic in men with advanced PCa prior to systemic therapy, with a “conversion” from an unfavorable count (>5 CTC / 7.5 mL) associated with a similar median to those who started with a favorable count (<5 CTC / 7.5 mL), leading to FDA approval of this particular trial (de Bono et al. 2008). The combination of CellSearch CTC enumeration and serum LDH has been demonstrated to have prognostic value, meeting the Prentice criterion for survival surrogacy in men with mCRPC previously treated with docetaxel in an abiraterone / prednisone treatment setting (Scher et al. 2015). Recently, five combined Phase III trials have demonstrated that a shift from unfavorable to favorable CTC counts, and from detectable to undetectable CTC counts, is associated with survival (Heller et al. 2018). Blood for CTC enumeration in Blood for CellSearch is collected pre-treatment and at 3 months.

[0102] In embodiments, after treatment by the method disclosed herein, the patient has normal LDL levels.

[0103] In embodiments, after treatment by the method disclosed herein, the patient experiences a decrease in PSA compared to a baseline before treatment. In embodiments, after treatment, the patient experiences a decrease in PSA of at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 55%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or more, compared to a baseline before treatment. In embodiments, after the treatment, the patient experiences a decrease in PSA of at least about 30% compared to a baseline before treatment. In embodiments, after the treatment, the patient experiences a decrease in PSA of at least about 50% compared to a baseline before treatment. In embodiments, the PSA response is determined by comparing the PSA level after therapy with the baseline pre-treatment PSA.

[0104] In embodiments, after treatment with the method disclosed herein, the patient experiences a complete response, a partial response, or stable disease. In embodiments, the patient's response is calculated using the guidelines for evaluating the efficacy of treatment for solid tumors, including the PCWG3 modification (RECIST version 1.1). In embodiments, after treatment with the method disclosed herein, the patient experiences a reduction of 30% or more in the sum of the longest one-dimensional diameters of all measurable lesions. In embodiments, after treatment with the method disclosed herein, the patient experiences complete disappearance of all lesions measurable and evaluable by physical examination or imaging. In embodiments, after treatment with the method disclosed herein, the patient shows no signs of progressive disease for at least one month.

[0105] In embodiments, after treatment by the method disclosed herein, all lesions measurable and evaluable by physical examination or imaging examination completely disappear in the patient, PSA normalizes, and no new lesions appear for, for example, about one month or more.

[0106] In some embodiments, the treated subject has a biochemical progression-free survival (bPFS). Biochemical (PSA) progression is defined as an increase of ≥25% above the lowest PSA level (the lowest PSA value reached; this may be the baseline value if PSA does not decrease at all with treatment). PSA may also be considered to have progressed if it increases by at least 2 ng / mL above the lowest level. Confirmation requires two consecutive increases in PSA at least two weeks apart. bPFS is the interval between the initiation of protocol treatment (C1D1) until biological progression or death, whichever comes first, and censoring at the last PSA measurement for subjects who are alive and have not progressed at data cut, or for subjects who initiated new advanced cancer therapy before biological progression.

[0107] In some embodiments, after initiating treatment, subjects exhibit a bPFS of at least 50 days, at least 100 days, at least 150 days, at least 200 days, at least 250 days, at least 300 days, or at least 1 year. In other embodiments, after initiating treatment, subjects exhibit a bPFS range of approximately 50 to 500 days, approximately 100 to approximately 400 days, or approximately 200 to approximately 300 days.

[0108] In some embodiments, the main criteria for being treated by the cancer therapies disclosed herein include:

[0109] Targeting adult males ≥18 years of age who meet the following criteria: a. Adenocarcinoma of prostate origin confirmed histologically or cytologically. b. Confirmed progressive mCRPC based on PCWG3 criteria, including at least one of the following criteria. i.PSA progress ii. Objective imaging progression in soft tissue iii. New bone lesions c.0-2 Eastern Cooperative Oncology Group (ECOG) Performance Status d. The patient has serum testosterone levels less than 50 ng / dL. If the patient has not undergone orchiectomy, primary androgen deprivation with luteinizing hormone-releasing hormone (LHRH) / gonadotropin-releasing hormone (GnRH) analogs (agonists / antagonists) must be continued. e. In any of the following conditions, you have previously been treated for at least one of the following: i. Androgen receptor signaling inhibitors (ARSIs) (e.g., enzalutamide) ii. Cytochrome P450 17-alpha-hydroxylase / 17,20-lyase (CYP17) inhibitors (such as abiraterone acetate) f. The patient has previously received taxane chemotherapy (for any medical condition) and has been deemed unsuitable for taxane chemotherapy by their physician, or has refused taxane chemotherapy.

[0110] Individuals who refuse chemotherapy are informed that toxicity from 225Ac-huJ591 may impair their ability to receive future chemotherapy.

[0111] The organs and bone marrow must have normal function, as defined below. a. Absolute neutrophil count > 2,000 cells / mm³ 3 b. Hemoglobin ≥ 9 g / dL c. Platelet count>150×103 / uL d. Serum creatinine <1.5 × upper limit of normal (ULN), or creatinine clearance ≥ 60 mL / min / 1.73m2 calculated by Cockcroft-Gault. e. Serum total bilirubin < 1.5 × ULN (except in cases of Gilbert's syndrome where direct bilirubin levels must be normal) f. In the absence of liver metastasis, serum aspartate aminotransphenase (AST) and alanine aminotransphenase (ALT) <3 × ULN; in the case of liver metastasis, <5 × ULN (in both situations, bilirubin must meet the registration criteria). g. Having the ability to understand and willing to sign a written informed consent document. h. In a divided dose regimen 177 For subjects enrolled in the Lu-PSMA post-cohort: 177 Lu-PSMA-617 or 177 Patients must be receiving either Lu-PSMA-I&T.

[0112] In some embodiments, the exclusion criteria for treatment by the cancer therapies disclosed herein include the following: a. Current enrollment in an investigational device implantation or oncological investigational drug or device trial ≤4 weeks from treatment visit 1 (C1D1). b. Use of the investigational drug ≤4 weeks or <5 half-lives from C1D1, or current enrollment in an oncological investigational drug or device trial. c. Prior systemic beta-emitting bone-accumulating radioisotopes (e.g., samarium-153, strontium-89) d.177 For subjects enrolled in the post-PSMA-RL cohort: Prior 223Ra. e. Untreated hydronephrosis f. Known active brain metastases or leptomeningeal disease g. History of deep vein thrombosis and / or pulmonary embolism within one month of C1D1 h. Other serious medical conditions affecting the heart, respiratory system, central nervous system (CNS), kidneys, liver, or blood system that could prevent the completion of this study or interfere with determining the causal relationship of any adverse effects experienced in this study. i. Radiation therapy for the treatment of PC with ≤4 weeks of C1D1 Chemotherapy for PC treatment of patients with ≤4 weeks of C1D1 k. Patients receiving a stable dose of bisphosphonate or denosumab, initiated at least four weeks prior to the start of treatment, may continue this medication. However, the subjects were not permitted to initiate bisphosphonate / denosumab therapy during the study's DLT evaluation period. l. Having a partner who may become pregnant and who is unwilling to use any method of contraception deemed acceptable by the principal investigator and the chair of the clinical trial during the trial and for one month after the last dose of the study drug. m. Other currently progressing malignancies other than non-melanoma skin cancer. A patient is considered to have no “currently progressing” malignancies if they have completed any necessary treatments and their attending physician determines that their risk of recurrence is less than 30%. n. Known history of known myelodysplastic syndrome o. Bone scan with fused lesions and lack of urinary tracer, consistent with the "superscan" determined by the principal investigator. [Examples]

[0113] The following embodiments are intended to illustrate, but not to limit, the implementation of the embodiments of the present disclosure.

[0114] Example 1: PSMA-targeted alpha-emitter in a man with metastatic castration-resistant prostate cancer (mCRPC) 225 Dose escalation study of Ac-huJ591 Having progressive mCRPC after at least one potent androgen receptor signaling inhibitor (ARSI) and chemotherapy (or incompatibility / rejection), and prior to therapy (Ra-223 and PSMA-617-Lu 177 Eligible men were those with no limit on the number of times (permitted), an ECOG PS of 0-2, and adequate organ function. Baseline 68 Ga-PSMA11 PET was performed but not used for eligibility. Initially, until transition to a 3+3 cohort at dose level 5 (predicted to have moderate toxicity based on dosimetry), 225 A single infusion of Ac-huJ591 (13.3 KBq / Kg, planned to be increased up to a maximum of 93.3 KBq / Kg) treated one subject in a cohort. Dose-limiting toxicity (DLT) was defined as causal grade (Gr) 4 heme toxicity or Gr3 / 4 non-heme toxicity. Imaging, genomics, patient-reported outcomes (PROs), and immunological correlations were incorporated into the study design.

[0115]

Table 1

[0116] 225 Ac-huJ591 225 The Ac nitrate residue, 37 MBq (1.0 mCi), is a radiochemical grade preparation supplied in a 2 mL glass vial. 225 Ac chloride is reacted with DOTA-huJ591 (3.0 mg) aseptically removed from the packaged pharmaceutical raw material, and the DOTA chelating agent is in tetramethylammonium acetate buffer (TMAA) 225 By enabling Ac to chelate, 225Ac-DOTA-huJ591 mAb injection solution is manufactured. Following the reaction, 225 Ac-DOTA-huJ591 is reacted with an excess of the chelating agent DTPA to remove free or loosely bound 225 Ac. Next, using sterile saline containing 2% human serum albumin as the eluent, Ac-DOTA-huJ591 is separated from 225 Ac-DOTA-huJ591 by gel filtration (Biogel P-6 column, Biorad, CA). Next, the eluate fraction (4 - 8 mL) containing 225Ac-DOTA-huJ59 is sterilized into the final formulation vial by membrane filtration. The QC sample is removed for quality control. The ratio of the 225Ac-DOTA-huJ591 injection solution is estimated based on the measurements of the dose calibrator of the total 225Ac radioactivity (50 - 300 μCi) and the total DOTA-huJ591 (3 mg) precursor used. The expected SA is 16.6 - 100 μCi / mg. 225 Ac-DTPA.

[0117] Results Thirty-two patients with progressive prostate cancer were intravenously treated with a single dose of 225 Ac-huJ591 at seven dose levels. PSMA image preselection was not used, and the patients were, for example, androgen receptor signaling inhibitors (ARSIs), chemotherapy, Ra-223, and PSMA-617-Lu 177They were intensively pre-treated with pre-therapy such as the following. 78% (25 / 32) of the patients had received at least two ARSIs prior to treatment, 63% (20 / 32) had previously received chemotherapy, and 46.9% (15 / 32) had previously received PSMA-617-Lu 177 I had been treated there before.

[0118] Of the 28 patients who were treated and had PSMA PET, all had at least one tumor, PSMA SUVmax > liver SUVmean, and 21 of the 28 (75%) had the most echogenic lesion > 5x liver. Nine patients (28.1%) showed elevated PSA as the best response, while PSA decreased in the remaining patients, including 15 patients (46.9%) whose PSA decrease was consistently > 50% during follow-up.

[0119] A confirmed ≥50% PSA (PSA50) response was observed in 11 out of 32 patients (34.4%). Of the 11 patients with measurable disease at baseline and optional follow-up imaging results, 2 (18.2%) showed a partial response, 7 (63.6%) had stable disease, and 2 (18.2%) experienced disease progression. In patients with pre / post-treatment paired counts, circulating tumor cell (CTC) response was defined in the protocol as a decrease from ≥5 CTCs (per 7.5 mL of blood) to ≤4 CTCs, or remaining at ≤4 CTCs at 12 weeks, and occurred in 13 out of 22 patients (59.1%). Of the 16 patients initially with detectable CTCs, 12 (75%) saw a decrease in CTC count, and 6 (37.5%) became undetectable. Of the 13 patients with unfavorable baseline counts, 5 (41.7%) improved to favorable. Of the six individuals whose CTC count could not be detected initially, five remained undetectable, while one (16.7%) showed an increase.

[0120] The median progression-free survival was 5.6 months (95% CI 3.7–7.9), and the median overall survival was 10.7 months (95% CI 6.5–17.2). In multivariate analysis, only the CALGB prognosis group was associated with survival (HR 0.68, p=0.07).

[0121] 225Ac-huJ591 also demonstrated good durability. Only one patient experienced DLT during dose escalation (dose level 6, 80 KBq / Kg, grade 4 anemia and thrombocytopenia), and no patients experienced DLT at the 7th dose level (0 / ​​6). Since only one patient experienced DLT, the maximum tolerated dose was not achieved. Most of the high-grade adverse events were hematological. In addition to DLT, three patients had grade 3 anemia, two had grade 3 thrombocytopenia, two had grade 4 thrombocytopenia, two had grade 3 neutropenia, and one had grade 4 neutropenia. All were transient. Non-hematological AEs were generally grade 1 or 2, and grade 3 AEs did not occur in multiple patients. Higher administered radioactivity was associated with higher-grade hematological AEs.

[0122] Example 2: Phase I / II Trial in Patients with Metastatic Castration-Resistant Prostate Cancer (mCRPC) 225 Ac-huJ591 This trial is a 225 Phase I / II parallel dose escalation trial of the divided (D1, D15) single-cycle and multiple-dose (q6w) regimens of Ac-huJ591 in patients with mCRPC.

[0123] Divided dose regimen This trial uses two different regimens for men with progressive mCRPC with and without prior 177 Lu PSMA radioligand ( 177 Lu-PSMA-RL) treatment as a Phase I dose escalation trial with Ac-huJ591. The dose-split regimen is a single cycle of the study drug administered at D1 and D15. The frequent-dose regimen is a single dose of Ac-huJ591 per cycle, and each cycle is administered 4 times every 6 weeks. After determination of the RP2D, each cohort will transition to Phase II. 225 225

[0124] ​​This study will enroll up to 130 patients receiving treatment. Eligible patients are adult males >18 years of age with confirmed progressive metastatic CRPC. Approximately 6 to 130 eligible / evaluable patients will be enrolled in a 3+3 study design, including up to 5 dose-escalation cohorts for each regimen (every 2 weeks and every 6 weeks). 177 Lu-PSMA-RL(PSMA 617-Lu 177 For untreated patients (or PSMA I&T-Lu+, etc.), Phase I will enroll up to 30 patients in a regimen every two weeks, up to 18 patients in a regimen every six weeks, and an additional 24-27 PSMA+ patients in Phase II (up to 30 in each phase, including the Phase I cohort). 177 Lu-PSMA-RL(PSMA 617-Lu 177 Or PSMA I&T-Lu 177 For patients who have received treatment such as (etc.), up to 18 patients will be enrolled in Phase I, an additional 16-19 patients will be enrolled in Phase II (up to 22 patients including Phase I), and additional subjects with low PSMA may be enrolled (an additional 10%).

[0125] The Phase I dose-limiting toxicity evaluation stage is 8 weeks for divided-dose regimens, and for frequent-dose regimens, 225 Up to 9 weeks after the second dose of Ac-huJ591 (26 weeks is expected in the treatment portion of the study for those receiving 4 cycles). Following treatment, a short follow-up period is planned until imaging progression is expected to occur, which will last for 6 months.

[0126] 225Ac-huJ591 is administered as a single divided cycle D1 and D15 in a divided-dose regimen, and as a single dose per cycle repeated every 6 weeks in a multiple-dose regimen. 68Ga-PSMA-HBED-CC consists of gallium-68, a PET-emitting radionuclide, linked to PSMA-HBED-CC (also known as PSMA-11), a small molecule that targets PSMA. 68Ga-PSMA-HBED-CC is administered intravenously before PET / CT at screening and two follow-up imaging sessions. Instead of 68Ga-PSMA-HBED-CC, patients may be administered 18F-DCFPyL, which consists of fluorine-18, a PET-emitting radionuclide, linked to the PSMA-targeting small molecule DCFPyL.

[0127] The primary objective of Phase I is to determine dose-limiting toxicity (DLT) and recommended Phase II dose (RP2D). DLT was defined as within 8 weeks from the first dose. Neutropenia (grade 4 or febrile neutropenia), thrombocytopenia (TCP) (grade 4 or grade 3 with clinically significant bleeding), at least 225 Any Grade >2 non-hematological toxicity considered potentially related to Ac-huJ591, or any toxicity causing interference with or delaying the second dose by >2 weeks. Secondary objectives include efficacy metrics (e.g., PSA reduction, radioactive RR, biochemical / radioactive PFS, OS, CTC) and safety (CTCAE v5).

[0128] Study design (divided dose) 225 Ac-huJ591) this is, 225 Ac-huJ591 is an open-label, multicenter, phase I / II dose-escalation trial designed to determine the cumulative MTD in a dose-split regimen given in a single cycle of two doses on D1 and D15. It involves two patient groups, namely, a prior... 177 Patients without Lu-PSMA-RL exposure (Table 2), and previously 177 Lu-PSMA-RL(PSMA 617-Lu 177 Or PSMA I&T-Lu 177Patients treated with (etc.) (Table 3) will be evaluated using a dose-splitting regimen. The dose level planned at our institute for both groups is 45 KBq / Kg per dose, and the dose escalation plan is shown in Tables 2 and 3 below. If dose level 1 is deemed unacceptable (two or more DLTs in the six subjects), the low-dose level group will be enrolled.

[0129] [Table 2]

[0130] Prior 177 Results for subjects without Lu-PSMA-RL: Twenty-four patients were enrolled in Phase I. Median age 73.5 (57-91), PSA 25.78 (3.39-2133.41), 53% (n=13) >1 prior ARSI, 58% (n=14) taxane chemotherapy, and 8% (n=2) anti-PSMA therapy. CALGB prognosis group: 4 (16%) good, 8 (33%) intermediate, 12 (50%) poor.

[0131] Two subjects withdrew before the second dose (due to comorbidity). The most common low-grade non-hematological adverse events were fatigue (95%), psoriasis (69%), and nausea (57%). Of the 21 patients whose PSA changes were evaluable, 18 (86%) experienced a decrease in PSA, and 14 (67%) experienced a 50% decrease. CTC samples were taken from 13 / 21 patients at baseline and at 12 weeks. At baseline, 5 patients were unfavorable (≧5 / 7.5mL), 10 / 13 (77%) remained favorable or changed from unfavorable to favorable, 6 / 12 (50%) experienced a 50% decrease in CTC count, and 5 / 13 (38%) changed from undetectable to undetectable.

[0132] Regarding tolerability and toxicity, no DLTs were observed in Cohort 1 (n=3). No DLTs were observed in Cohort 2 (n=6). In Cohort 2.5, eight patients were enrolled in the intermediate-dose cohort (2.5) and there was one DLT (Gr 4 TCP). In Cohort 3, 2 out of 6 subjects experienced DLTs (Gr 3 weakness, and in the second proportion, Gr 2 TCP with a delay of >2 weeks). Therefore, at a total dose of 120 KBg / kg, the dose-high density was observed. 225 Ac-huJ591 was delivered in a single split cycle with acceptable toxicity, and preliminary efficacy evidence was obtained at all dose levels through changes in PSA and CTC.

[0133] [Table 3]

[0134] After meeting the patient inclusion and exclusion criteria, and having provided informed consent and signed the HIPAA form, subjects will undergo screening. As part of the screening, subjects will be screened. 18 F-DCFPyL / 68 Undergo a Ga-PSMA-HBED-CC PET / CT or PET / MR scan.

[0135] Study design (frequent doses) 225 Ac-huJ591) This is delivered in up to four cycles, which take place at 6-week intervals. 225 This is an open-label, multicenter, phase I / II dose-escalation study designed to determine the cumulative maximum tolerated dose (MTD) of Ac-huJ591. The initial dose level per cycle was 65 KBq / Kg, and the dose-escalation plan is shown in Table 4 below.

[0136] [Table 4]

[0137] After meeting the patient inclusion and exclusion criteria, and having provided informed consent and signed the HIPAA form, subjects will undergo screening. As part of the screening, subjects will be screened. 18 F-DCFPyL / 68 Undergo a Ga-PSMA-HBED-CC PET / CT or PET / MR scan.

[0138] Example 3: 225 Phase I / II trial of Ac-huJ591 - Prostate-specific membrane antigen (PSMA) targeted lutetium-177 radioligand ( 177 Divided doses of Lu-PSMA-RL in patients with and without prior treatment with metastatic castration-resistant prostate cancer (mCRPC), and 225 Patients treated with frequent doses of Ac-huJ591 This exam is conducted in advance. 177 Lu-PSMA-RL(PSMA617-Lu 177 Or PSMA I&T-Lu 177 Evaluate two different regimens in patients with and without treatment-assisted renal cell tumor (mCRPC), etc. 225 This is an ongoing dose escalation study using Ac-huJ591. The divided dose regimen is administered on day 1 (D) of cycle (C)1 and on C1D15. 225 This is a single cycle of Ac-huJ591. The frequent-dose regimen is per cycle 225 Ac-huJ591 is administered as a single dose, with each cycle administered every 6 weeks (Q6W) for a maximum of 4 cycles. Five dose escalation levels were planned for each regimen. The objective of the Phase 1 portion of this study was to determine the divided dose. 225 Ac-huJ591 and frequent doses 225 The objective is to determine the cumulative maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) for Ac-huJ591.

[0139] Diagnostic and primary trial patient eligibility criteria: Targeting adult males ≥18 years of age who meet the following criteria: a. Adenocarcinoma of prostate origin confirmed histologically or cytologically. b. Confirmed progressive mCRPC based on PCWG3 criteria, including at least one of the following criteria. i.PSA progress ii. Objective imaging progression in soft tissue iii. New bone lesions c.0-2 Eastern Cooperative Oncology Group (ECOG) Performance Status d. The patient has serum testosterone levels less than 50 ng / dL. If the patient has not undergone orchiectomy, primary androgen deprivation with luteinizing hormone-releasing hormone (LHRH) / gonadotropin-releasing hormone (GnRH) analogs (agonists / antagonists) must be continued. e. In any of the following conditions, you have previously been treated for at least one of the following: i. Androgen receptor signaling inhibitors (ARSIs) (e.g., enzalutamide) ii. Cytochrome P450 17-alpha-hydroxylase / 17,20-lyase (CYP17) inhibitors (such as abiraterone acetate) f. The patient has previously received taxane chemotherapy (for any medical condition) and has been deemed unsuitable for taxane chemotherapy by their physician, or has refused taxane chemotherapy.

[0140] Individuals who refuse chemotherapy are informed that toxicity from 225Ac-huJ591 may impair their ability to receive future chemotherapy.

[0141] The organs and bone marrow must have normal function, as defined below. a. Absolute neutrophil count > 2,000 cells / mm³ 3 b. Hemoglobin ≥ 9 g / dL c. Platelet count>150×103 / uL d. Serum creatinine <1.5 × upper limit of normal (ULN), or creatinine clearance ≥ 60 mL / min / 1.73m2 calculated by Cockcroft-Gault. e. Serum total bilirubin < 1.5 × ULN (except in cases of Gilbert's syndrome where direct bilirubin levels must be normal) f. In the absence of liver metastasis, serum aspartate aminotransphenase (AST) and alanine aminotransphenase (ALT) <3 × ULN; in the case of liver metastasis, <5 × ULN (in both situations, bilirubin must meet the registration criteria). g. Having the ability to understand and willing to sign a written informed consent document. h. In a divided dose regimen 177 For subjects enrolled in the Lu-PSMA-RL post-cohort: 177 Lu-PSMA-617 or 177 Patients must be receiving either Lu-PSMA-I&T.

[0142] Exclusion criteria: a. Current enrollment in an investigational device implantation or oncological investigational drug or device trial ≤4 weeks from treatment visit 1 (C1D1). b. Use of the investigational drug ≤4 weeks or <5 half-lives from C1D1, or current enrollment in an oncological investigational drug or device trial. c. Prior systemic beta-emitting bone-accumulating radioisotopes (e.g., samarium-153, strontium-89) d.177 For subjects enrolled in the post-Lu-PSMA-RL cohort: Prior 223Ra e. Untreated hydronephrosis f. Known active brain metastases or leptomeningeal disease g. History of deep vein thrombosis and / or pulmonary embolism within one month of C1D1 h. Other serious medical conditions affecting the heart, respiratory system, central nervous system (CNS), kidneys, liver, or blood system that could prevent the completion of this study or interfere with determining the causal relationship of any adverse effects experienced in this study. i. Radiation therapy for the treatment of PC with ≤4 weeks of C1D1 Chemotherapy for PC treatment of patients with ≤4 weeks of C1D1 k. Patients receiving a stable dose of bisphosphonate or denosumab, initiated at least four weeks prior to the start of treatment, may continue this medication. However, the subjects were not permitted to initiate bisphosphonate / denosumab therapy during the study's DLT evaluation period. l. Having a partner who may become pregnant and who is unwilling to use any method of contraception deemed acceptable by the principal investigator and the chair of the clinical trial during the trial and for one month after the last dose of the study drug. m. Other currently progressing malignancies other than non-melanoma skin cancer. A patient is considered to have no “currently progressing” malignancies if they have completed any necessary treatments and their attending physician determines that their risk of recurrence is less than 30%. n. Known history of known myelodysplastic syndrome o. Bone scan with fused lesions and lack of urinary tracer, consistent with the "superscan" determined by the principal investigator.

[0143] test This study utilized a modified 3+3 dose escalation study design, with the planned initial and subsequent dose escalation levels described in Tables 5, 6, and 7. All adverse events (AEs) were evaluated using NCI CTCAE version 5.0.

[0144] [Table 5]

[0145] [Table 6]

[0146] [Table 7]

[0147] In the case of divided-dose regimens, the DLT evaluation period begins with treatment at C1D1 and continues for 8 weeks.

[0148] For frequent-dose regimens, the DLT evaluation period begins with treatment C1D1 (cycle 1, day 1) and continues until treatment C3D1 (cycle 3, day 1). For subjects not receiving C3 therapy, the DLT evaluation period is 6 weeks after C2.

[0149] According to the definition of DLT, in individuals who do not have DLT after 6 weeks but are not eligible for C3 treatment due to the possibility of associated adverse events, an additional 3-week DLT evaluation period is observed (9 weeks after C2). All subjects in divided-dose and frequent-dose regimens were followed up for radiographic progression (up to 6 months).

[0150] The dose-limiting time (DLT) for the dose-escalation cohort is defined as follows: a. Any occurrence of Grade 4 neutropenia or febrile neutropenia b. Grade 4 thrombocytopenia, or Grade 3 thrombocytopenia associated with massive bleeding. c. at least 225 Any non-hematological toxicity of grade >2 that is considered potentially associated with Ac-huJ591 is referred to as a dose-limiting toxicity.

[0151] Furthermore, in divided-dose regimens, any grade of toxicity caused by the study drug that interferes with D15 therapy for more than two weeks is considered a DLT. In multiple-dose regimens, any grade of toxicity caused by the study drug that interferes with C2 or C3 therapy for more than three weeks is considered a DLT. However, delays in subsequent doses of therapy due to issues such as scheduling or radionuclide availability are not considered DLTs.

[0152] All of the above-mentioned toxicities are determined by the principal investigator, at least 225 If potentially related to Ac-huJ591, all toxicity will be considered DLT. Attribution will be reviewed by the test director, and any questions regarding severity or attribution will be consulted with the medical monitor.

[0153] In some embodiments, the MTD is defined as the dose level at which no more than one out of six subjects experiences a DLT during the DLT evaluation period.

[0154] Treatment duration: The treatment duration for the divided dose regimen was 15 days, with doses administered on C1D1 and C1D15.

[0155] Outcomes and exposure: Subjects with mCPRC are, 177 Four dose levels consisting of subjects before and after Lu-PSMA-RL therapy, and 177 After Lu-PSMA-RL, all 28 subjects were enrolled in a split-dose regimen at one dose level. 225 Twenty-five patients received at least one dose of Ac-huJ591 and completed the study with two complete dose regimens (see Table 8).

[0156] [Table 8]

[0157] This exam begins with a preliminary assessment. 177 Lu-PSMA-RL therapy ( 177 Subjects with and without pre- and post-Lu-PSMA-RL therapy were enrolled in a divided dose regimen at three increasing dose levels (45 KBq / Kg, 55 KBq / Kg, and 65 KBq / Kg). Subsequently, the 65 KBq / Kg level was reduced to 60 KBq / Kg. 177 Four subjects who had previously received Lu-PSMA therapy were enrolled at a dose level of 50 KBq / Kg.

[0158] Treatment duration: The treatment duration for the frequent-dose regimen was up to 24 weeks, with doses administered at Q6W for up to 4 cycles.

[0159] Eighteen subjects with mCPRC were enrolled in a frequent-dose regimen at three dose levels. All 18 enrolled subjects received at least one dose. 225 Seventeen subjects who received Ac-huJ591 received a two-dose regimen. 225Eight subjects who received Ac-huJ591 received three doses. 225 Four subjects received Ac-huJ591 and completed the study with four full dose regimens. See Table 9.

[0160] [Table 9]

[0161] Demographic and baseline characteristics of the divided-dose regimen: The median age at enrollment was 74 years (range 57–91 years), and the median PSA at C1D1 was 30 ng / mL. The majority of subjects were Caucasian and non-Hispanic / Latino. Most subjects had an ECOG PS1 performance status. 75% (21 / 28) of subjects had received prior chemotherapy, and 18% (5 / 28) had prior [unclear text]. 177 They received Lu-PSMA-RL therapy. 11% (3 / 28 people) of the subjects had received radium-223 (Ra-223) prior to the treatment, and 4% (1 / 28 people) had received prior treatment. 177 Lu-PSMA-RL was administered. 46% (13 / 28) of the subjects had received one androgen receptor signaling inhibitor (ARSI) prior to treatment, 43% (12 / 28) had received two ARSIs prior to treatment, and 11% (3 / 28) had received three ARSIs prior to treatment. At baseline, 43% (12 / 28) of the subjects had metastatic disease affecting only bone, 32% (9 / 28) had involvement of both bone and soft tissue, and 14% (4 / 28) had disease affecting only soft tissue. The disease location of three subjects was not reported. The median enumerated number of circulating tumor cells (CTCs) at baseline was 12 cells.

[0162] Demographic and baseline characteristics of the high-dose regimen: The median age at enrollment was 71 years (range 51–95 years), and the median PSA at C1D1 was 122 ng / mL. The majority of subjects were Caucasian and non-Hispanic / Latino. Most subjects had an ECOG PS1 performance status. 89% (16 / 18) of subjects had received prior chemotherapy, and 6% (1 / 18) had received prior treatment. 177 The patients received Lu-PSMA-RL therapy. 39% (7 / 18) of the subjects had received one ARSI prior to treatment, 44% (8 / 18) had received two ARSIs prior to treatment, and 17% (3 / 18) had received three ARSIs prior to treatment. 89% (16 / 18) of the subjects had bone and soft tissue involvement, and 11% (2 / 18) had soft tissue-only disease. The median enumerated number of circulating tumor cells (CTCs) at baseline was 12 cells.

[0163] Safety results: In a divided dose regimen, 177 No dose-limiting toxicity (DLT) was observed at 45 or 55 KBq / kg dose levels in the Lu-PSMA-RL pre / post cohorts. 177 In the Lu-PSMA pre / post-cohort, two dose-limiting disorders (DLTs) were observed at a dose level of 65 KBq / Kg (grade 2 platelet count depletion leading to a >2-week treatment delay, and grade 4 platelet count depletion). As a result of these DLTs, the dose was reduced to a 60 KBq / Kg level, and another grade 4 platelet count depletion DLT was observed, expanding the dose level to six subjects. To date, 177 In the Lu-PSMA-RL post-cohort, one DLT (depressive thrombocytopenia) of grade 4 was observed at the ongoing dose level of 50 KBq / Kg. 177 For mCRPC with and without Lu-PSMA-RL treatment, the RP2D of the divided dose regimen for patients who have received prior chemotherapy is 120 KBq / kg, consisting of two divided doses of 60 KBq / kg.

[0164] All subjects (28 / 28) included in the divided-dose regimen experienced at least one treatment-induced adverse event (TAEA) and at least one treatment-related adverse event (TRAE). Grade 3 or higher TAEAs were reported in 93% (26 / 28) of subjects in the divided-dose regimen, and 89% (25 / 28) experienced at least one grade 3 or higher TRAE. 18% (5 / 28) of subjects in the divided-dose regimen experienced at least one serious TAEA, one of which was considered drug-related (grade 4 platelet count decrease). No subjects died as a result of TAEA in the divided-dose regimen.

[0165] In the frequent-dose regimen, two dose-limiting trials (DLTs) were observed at a dose level of 65 KBq / Kg (a decrease in grade 3 platelet count and a decrease in grade 1 platelet count, ruling out treatment with C3). As a result of these DLTs, the dose was reduced to a dose level of 55 KBq / Kg, and three more DLTs were observed (a decrease in grade 3 platelet count and two decreases in grade 4 platelet counts). As a result of these DLTs, the subsequent dose was reduced to a dose level of 45 KBq / Kg, and two more DLTs were observed (a decrease in grade 1 platelet count, ruling out treatment with C3, and a decrease in grade 2 platelet count, ruling out treatment with C3).

[0166] All patients (18 / 18) in the frequent-dose regimen experienced at least one TEAE and at least one TRAE. Grade 3 or higher TEAEs were reported in 89% (16 / 18) of patients in the frequent-dose regimen, all of whom experienced at least one grade 3 or higher TRAE. 50% (9 / 18) of patients in the frequent-dose regimen experienced at least one serious TEAE.

[0167] As expected, thrombocytopenia (decreased platelet count), lymphopenia (decreased lymphocyte count), and neutropenia (decreased neutrophil count) were the most common TRAEs, experienced by 89% (25 / 28 patients), 89% (25 / 28 patients), and 68% (19 / 28 patients), respectively, in divided-dose regimens, and by 83% (15 / 18 patients), 83% (15 / 18 patients), and 50% (9 / 18 patients), respectively, in multiple-dose regimens. In multiple-dose regimens, seven TRAEs led to treatment discontinuation in six patients. Specifically, the main adverse events were decreased neutrophil count (1 / 18 of subjects, 6%), anemia (1 / 18 of subjects, 6%), and decreased platelet count (5 / 18 of subjects, 28%). The combination of decreased platelet count and anemia was the cause of treatment discontinuation in one subject (7 TRAEs led to treatment discontinuation in 6 / 18 of subjects, 33%). Increased transaminases, judged to be related to the study drug, were observed in 50% of subjects (14 / 28) with the divided-dose regimen, but all events were grade 1 and did not result in treatment delay or discontinuation. Other grade 3 or higher TRAEs reported in three or more subjects of the divided-dose regimen included, overall, decreased lymphocyte count (23 / 28 subjects, 82%), decreased white blood cell count (8 / 28 subjects, 29%), decreased neutrophil count (6 / 28 subjects, 21%), decreased platelet count (5 / 28 subjects, 18%), and anemia (3 / 28 subjects, 11%).

[0168] The most commonly reported TEAEs across all grades that occurred in >50% of patients with the divided-dose regimen included decreased platelet count, decreased lymphocyte count, decreased neutrophil count, decreased white blood cell count, fatigue, dry mouth, and increased transamylase. No grade 5 TEAEs were observed with the divided-dose regimen.

[0169] In the frequent-dose regimen, other grade 3 or higher TRAEs reported in three or more subjects included, overall, decreased lymphocyte count (15 / 18 subjects, 83%), decreased platelet count (8 / 18 subjects, 44%), decreased white blood cell count (5 / 18 subjects, 28%), and anemia (5 / 18 subjects, 28%).

[0170] The most commonly reported TEAEs across all grades, occurring in >50% of patients with the frequent-dose regimen, included anemia, nausea, decreased appetite, fatigue, decreased platelet count, decreased lymphocyte count, decreased white blood cell count, increased transamylase, and dry mouth. Decreased platelet and neutrophil counts were transient in both regimens, lasting a median of 34 and 22 days, respectively, from the worst grade to resolution in the divided-dose regimen, and a median of 28 and 13 days, respectively, in the frequent-dose regimen. Only one grade 5 TEAE was observed in the frequent-dose regimen (grade 5 pneumonia).

[0171] Results of effectiveness: In the divided-dose regimen, with the exception of three subjects who showed an increase in PSA as the best PSA response (one at the 45 KBq / Kg, 50 KBq / Kg, and 60 KBq / Kg dose levels, respectively; see Figure 1), the majority of subjects (24 / 27, 89%) showed a decrease in PSA levels. PSA decreased by ≥50% in 67% (18 / 27) of the overall subjects, 67% (2 / 3) at the 45 KBq / Kg dose level, 50% (2 / 4) at the 50 KBq / Kg dose level, 57% (4 / 7) at the 55 KBq / Kg dose level, 71% (5 / 7) at the 60 KBq / Kg dose level, and 83% (5 / 6) at the 65 KBq / Kg dose level. Among the 18 subjects on a divided-dose regimen who experienced a PSA decrease of ≥25% and underwent follow-up PSA measurements, the median duration of PSA response was 49 days following the initial ≥25% decrease, with the longest median duration of response at the 65 KBq / Kg dose level (98 days). See Table 10. Subjects not included in the calculation of PSA response duration were excluded either because they did not experience a ≥25% decrease in PSA or because PSA measurements following the initial decrease were unavailable, as noted in the table.

[0172] [Table 10]

[0173] In the frequent-dose regimen, with the exception of five subjects who showed an increase in PSA as the best PSA response, two subjects at the 65 KBq / kg dose level, and three subjects at the 55 KBq / kg dose level, the majority of subjects (13 / 18, 72%) showed a decrease in PSA levels (see Figure 2). PSA decreased by ≥50% in 28% (5 / 18) of the overall subjects, 33% (2 / 6) at the 65 KBq / kg dose level, 17% (1 / 6) at the 55 KBq / kg dose level, and 33% (2 / 6) at the 45 KBq / kg dose level. Among the seven subjects in the frequent-dose regimen who showed a decrease in PSA by ≥25% and underwent follow-up PSA measurements, the median duration of the PSA response was 49 days following the initial ≥25% decrease, with the longest median duration of response at the 55 KBq / kg dose level (77 days). See Table 11.

[0174] [Table 11]

[0175] Table 12 summarizes the bPFS for divided-dose regimens.

[0176] [Table 12]

[0177] Table 13 summarizes the bPFS for frequent-dose regimens.

[0178] [Table 13]

[0179] Patients treated with a divided-dose regimen at a dose level of 65 KBq / kg showed the best response in biochemical progression-free survival (bPFS) (243 days). Except for the 60 KBq / kg dose level, where the median bPFS was 105 days, compared to 112 days at the 45 KBq / kg dose level and 138 days at the 55 KBq / kg dose level, a trend toward a dose-response bPFS was observed as the dose level increased.

[0180] In the frequent-dose regimen, the 45 KBq / kg dose level showed the best improvement in bPFS, with a median bPFS of 198 days, compared to 152 days at 65 KBq / kg and 113 days at 55 KBq / kg.

[0181] conclusion In men with progressive mCRPC who have received intensive prior treatment... 225 This ongoing study evaluating dose escalation in divided-dose and multiple-dose regimens of Ac-huJ591 showed a satisfactory safety profile with the divided-dose regimen. While the safety profile of the multiple-dose regimen remains under evaluation, preliminary results suggest it is less effective and less tolerable than the divided-dose regimen. The majority of subjects experienced a decrease in PSA levels, with 64% of those in the divided-dose regimen and 28% of those in the multiple-dose regimen experiencing a PSA response of ≥50% PSA. There were four DLTs in the divided-dose regimen; no DLTs were observed at the lower dose levels (45 KB / kg and 55 KB / kg), leading to a determination of a cumulative MTD and RP2D of 120 KBq / kg. There were seven DLTs in the multiple-dose regimen, occurring at all dose levels. It is important to note that platelet count decreases, neutrophil count decreases, and dry mouth were transient in both regimens, lasting a median of 34, 22, and 76 days, respectively, from the worst grade to resolution in the divided-dose regimen, and a median of 28, 13, and 7 days, respectively, in the frequent-dose regimen.

[0182] While preferred embodiments have been illustrated and described in detail in this specification, it will be obvious to those skilled in the art that various modifications, additions, and substitutions can be made without departing from the spirit of the invention, and therefore these are considered to be within the scope of the invention as defined in the following claims.

Claims

1. A method of treating cancer in patients who need it, The procedure includes administering to the patient an agent containing a targeted component bound to a cancer treatment component, The targeting component is huJ591, and the cancer treatment component is Ac ２２５ It is a radioactive nuclide, The aforementioned patient had received prior treatment with PSMA radioactive ligand. The aforementioned method.

2. The aforementioned PSMA radioactive ligand is PSMA617-Lu １７７ and / or PSMA I&T-Lu １７７ The method according to claim 1.

3. The method according to claim 1 or 2, wherein the cancer is prostate cancer.

4. The method according to claim 1 or 2, wherein the cancer is a PSMA-expressing cancer.

5. The method according to claim 3, wherein the prostate cancer is metastatic castration-resistant prostate cancer (mCRPC).

6. The method according to claim 3, wherein the prostate cancer is castration-sensitive prostate cancer.

7. The method according to any one of claims 1 to 6, wherein the cancer is a recurrent cancer.

8. The method according to any one of claims 1 to 6, wherein the cancer is an intractable cancer.

9. A method for treating or improving prostate cancer in patients who require it, The procedure includes administering to the patient an agent containing a targeted component bound to a cancer treatment component, The targeting component is huJ591, and the cancer treatment component is Ac ２２５ It is a radioactive nuclide, The aforementioned patient has not undergone or does not require a pre-treatment PSMA PET scan. The aforementioned method.

10. The aforementioned agent is huJ591-DOTA-Ac ２２５ The method according to any one of claims 1 to 9.

11. The method according to any one of claims 1 to 10, wherein the agent is administered to the patient in a dose of approximately 10 KBq / kg to approximately 130 KBq / kg.

12. The method according to claim 11, wherein the agent is administered to the patient in a dose of approximately 13.3 KBq / kg to approximately 93.3 KBq / kg.

13. The method according to claim 12, wherein the agent is administered to the patient in a dose of approximately 40 KBq / kg to approximately 65 KBq / kg.

14. The method according to claim 13, wherein the agent is administered to the patient in doses of approximately 40 KBq / kg, 45 KBq / kg, approximately 55 KBq / kg, approximately 60 KBq / kg, and approximately 65 KBq / kg.

15. The method according to claim 14, wherein the agent is administered to the patient in a dose of approximately 45 KBq / kg.

16. The method according to claim 14, wherein the agent is administered to the patient in a dose of approximately 55 KBq / kg.

17. The method according to claim 14, wherein the agent is administered to the patient in a dose of approximately 60 KBq / kg.

18. The method according to claim 14, wherein the agent is administered to the patient in a dose of approximately 65 KBq / kg.

19. The method according to any one of claims 1 to 18, comprising administering an initial dose and at least one subsequent dose of the agent to the patient.

20. The method according to claim 19, wherein the cumulative amount of the agent administered in the initial dose and the subsequent one or more doses is about 60 KBq / kg to about 130 KBq / kg or about 60 KBq / kg to about 340 KBq / kg.

21. The method according to claim 19 or 20, wherein the cumulative amount of the agent administered in the initial dose and the subsequent dose is approximately 80 KBq / Kg, approximately 90 KBq / Kg, approximately 90 KBq / Kg, approximately 110 KBq / Kg, approximately 120 KBq / Kg, or approximately 130 KBq / Kg.

22. The method according to any one of claims 19 to 21, wherein the initial dose of the agent is about 45 KBq / Kg, and the subsequent dose of the agent is about 45 KBq / Kg.

23. The method according to any one of claims 19 to 21, wherein the initial dose of the agent is about 55 KBq / Kg, and the subsequent dose of the agent is about 55 KBq / Kg.

24. The method according to any one of claims 19 to 21, wherein the initial dose of the agent is about 60 KBq / Kg, and the subsequent dose of the agent is about 60 KBq / Kg.

25. The method according to any one of claims 19 to 21, wherein the initial dose of the agent is about 65 KBq / Kg, and the subsequent dose of the agent is about 65 KBq / Kg.

26. The method according to any one of claims 19 to 25, wherein the subsequent dose is administered at least about two weeks after the initial dose.

27. The method according to claim 26, wherein the subsequent dose is administered 2 to 3 weeks after the initial dose.

28. The method according to claim 26, wherein the subsequent dose is administered 14 days after the initial dose.

29. The method according to any one of claims 1 to 18, wherein the agent is administered as a single dose repeated in a 6-week cycle (q6w).

30. The method according to claim 29, wherein the agent is administered for at least one cycle.

31. The method according to claim 30, wherein the agent is administered for a maximum of four cycles.

32. The method according to any one of claims 1 to 31, wherein the patient is treated for at least about 8 weeks, at least about 10 weeks, at least about 12 weeks, at least about 14 weeks, at least about 16 weeks, at least about 18 weeks, at least about 20 weeks, at least about 22 weeks, at least about 24 weeks, or at least about 26 weeks.

33. A method of treating cancer in patients who need it, This includes administering an initial dose and subsequent doses of a drug containing a targeted component bound to a cancer treatment component to the patient. The targeting component is huJ591, and the cancer treatment component is ２２５ Ac is a radioactive nuclide, The cumulative amount of the agent administered in the initial dose and the subsequent dose is within the range of approximately 90 KBq / kg to approximately 130 KBq / kg or approximately 90 KBq / kg to approximately 340 KBq / kg. The aforementioned method.

34. The method according to claim 33, wherein the cumulative amount of the agent is about 90 KBq / kg, about 110 KBq / kg, about 120 KBq / kg, or about 130 KBq / kg.

35. The method according to claim 33 or 34, wherein the initial dose of the agent is approximately 45 KBq / Kg, and the subsequent dose of the agent is approximately 45 KBq / Kg.

36. The method according to claim 33 or 34, wherein the initial dose of the agent is approximately 55 KBq / Kg, and the subsequent dose of the agent is approximately 55 KBq / Kg.

37. The method according to claim 33 or 34, wherein the initial dose of the agent is about 60 KBq / Kg, and the subsequent dose of the agent is about 60 KBq / Kg.

38. The method according to claim 33 or 34, wherein the initial dose of the agent is approximately 65 KBq / Kg, and the subsequent dose of the agent is approximately 65 KBq / Kg.

39. The method according to any one of claims 33 to 38, wherein the subsequent dose is administered at least about two weeks after the initial dose.

40. The method according to claim 39, wherein the subsequent dose is administered approximately 14 days after the initial dose.

41. The method according to any one of claims 33 to 40, wherein the cancer is a PSMA-expressing cancer.

42. The method according to any one of claims 33 to 41, wherein the cancer is prostate cancer.

43. The method according to claim 42, wherein the prostate cancer is metastatic castration-resistant prostate cancer (mCRPC).

44. The method according to claim 42, wherein the prostate cancer is castration-sensitive prostate cancer.

45. The method according to any one of claims 1 to 18, comprising administering an initial dose of the agent and three additional cycles to the patient.

46. The method according to claim 45, wherein the cumulative amount of the agent administered over four cycles is approximately 100 KBq / kg to approximately 500 KBq / kg.

47. The method according to claim 45, wherein the cumulative amount of the agent administered over four cycles is approximately 150 KBq / kg to approximately 400 KBq / kg.

48. The method according to claim 45, wherein the cumulative amount of the agent administered over four cycles is approximately 180 KBq / kg to approximately 340 KBq / kg.

49. The method according to any one of claims 45 to 48, wherein the cumulative amount of the administered agent is about 180 KBq / kg, about 220 KBq / kg, about 260 KBq / kg, about 300 KBq / kg, or about 340 KBq / kg.

50. The method according to any one of claims 45 to 49, wherein each dose of the agent per cycle is approximately 30 KBq / kg to approximately 100 KBq / kg.

51. The method according to any one of claims 45 to 49, wherein each dose of the agent per cycle is approximately 40 KBq / kg to approximately 90 KBq / kg.

52. The method according to any one of claims 45 to 49, wherein each dose of the agent per cycle is approximately 45 KBq / kg to approximately 85 KBq / kg.

53. A method of treating cancer in patients who need it, The procedure involves administering to the patient a total of four cycles, consisting of an initial dose and three subsequent doses of a drug containing a targeted component bound to a cancer treatment component. The targeting component is huJ591, and the cancer treatment component is Ac ２２５ The radionuclide is such that the cumulative amount of the administered agent in the cumulative dose is in the range of approximately 100 KBq / kg to approximately 500 KBq / kg. The aforementioned method.

54. The method according to claim 53, wherein the cumulative amount of the agent administered over four cycles is approximately 150 KBq / kg to approximately 400 KBq / kg.

55. The method according to claim 53, wherein the cumulative amount of the agent administered over four cycles is approximately 180 KBq / kg to approximately 340 KBq / kg.

56. The method according to any one of claims 53 to 55, wherein the cumulative amount of the administered agent is about 180 KBq / kg, about 220 KBq / kg, about 260 KBq / kg, about 300 KBq / kg, or about 340 KBq / kg.

57. The method according to any one of claims 53 to 55, wherein each dose of the agent per cycle is approximately 30 KBq / kg to approximately 100 KBq / kg.

58. The method according to any one of claims 53 to 55, wherein each dose of the agent per cycle is approximately 40 KBq / kg to approximately 90 KBq / kg.

59. The method according to any one of claims 53 to 55, wherein each dose of the agent per cycle is approximately 45 KBq / kg to approximately 85 KBq / kg.

60. The method according to any one of claims 45 to 59, wherein each dose is administered at intervals of at least two weeks, three weeks, four weeks, five weeks, approximately six weeks, seven weeks, or eight weeks.

61. The aforementioned agent is huJ591-DOTA-Ac ２２５ The method according to any one of claims 1 to 60.

62. The method according to any one of claims 1 to 61, wherein any non-cumulative dose is the daily dose.

63. The method according to any one of claims 1 to 62, wherein, after the treatment, the patient experiences a decrease in PSA compared to baseline before treatment.

64. The method according to claim 63, wherein, after the treatment, the patient experiences a reduction of at least about 50% in PSA compared to baseline before treatment.

65. The method according to any one of claims 1 to 64, wherein, after the treatment, the patient experiences a decrease in the number of CTCs.

66. The method according to claim 65, wherein, after the treatment, the patient has an undetectable number of CTCs.

67. The method according to any one of claims 1 to 66, wherein the agent is administered intravenously.

68. The method according to any one of claims 1 to 67, wherein the patient is a human.

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