Combination therapy for treating prostate cancer

Abstract

The present disclosure provides methods of treating a patient with prostate cancer with an anti-STEAP1 antigen binding protein, such as salluritamine, in combination with lutetium Lu 177 vopeptide tetraracetam.

Description

Technical Field

[0001] This invention relates to the field of oncology. In particular, this invention relates to the treatment of prostate cancer using the STEAP1 T-cell conjugate (TCE) molecule as a monotherapy or in combination with another agent. Instructions for electronically submitted text files

[0002] This application contains a sequence list that has been electronically submitted in XML format, and the entire sequence list is hereby incorporated by reference. A computer-readable copy of the sequence list created on July 25, 2024, is named 10655-WO01-SEC_Sequence Listing.xml and has a size of 30,888 bytes. Background Technology

[0003] Prostate cancer is one of the most commonly diagnosed non-skin cancers and is a leading cause of cancer death in men in the United States (US). An estimated 288,300 new cases of prostate cancer (29% of all new cancer cases in men) and 34,700 prostate cancer-related deaths (11% of all cancer deaths in men) are projected in the United States in 2023 (Siegel et al., Cancerstatistics, 2023. CA Cancer J Clin. 2023;73(1):17-48).

[0004] Survival rates for men with prostate cancer vary, but are closely related to disease stage and location (i.e., local versus metastatic). While the 5-year survival rate for men with locally developed prostate cancer in the United States is close to 100%, the 5-year survival rate for men with metastatic disease drops to 31% (Cancer.Net, 2020). In 2015, the European Union estimated 365,000 new cases and 77,000 deaths from prostate cancer (accounting for 10% of all cancer deaths) (EU Science Hub, 2018). In China, there were an estimated 78,300 new cases of prostate cancer and 33,600 deaths in 2016. The incidence of prostate cancer showed an upward trend between 2000 and 2016, with an average annual percentage change of 7.1% (Zheng et al., 2022).

[0005] Treatment for patients diagnosed with metastatic prostate cancer includes continuous and intermittent androgen deprivation therapy (ADT). Docetaxel and novel hormone therapies (NHTs), abiraterone, enzalutamide, apalutamide, and darolutamide are approved treatments. Metastatic prostate cancer often develops resistance to ADT (also known as “castration resistance”) due to increased intratumoral steroid production, altered expression of steroid transporters, increased androgen receptor expression (e.g., androgen receptor amplification), and other mechanisms (Galletti et al., 2017).

[0006] Since 2010, based on survival benefits, five new therapeutic agents have been approved for metastatic castration-resistant prostate cancer (mCRPC): cabazitaxel (Jevtana) ® ), Provenge (sipuleucel-T) ® Abiraterone (Zytiga) ® Enzalutamide (Xtandi) ® ) and radium-223 (Xofigo) ® However, the optimal order or combination of available therapies for mCRPC is largely unknown. The U.S. Food and Drug Administration (FDA) has also recently approved the following therapies for specific biomarker-defined subgroups of mCRPC patients: poly-ADP-ribose polymerase (PARP) inhibitors, olaparib (Lynparza®) and rucaparib (Rubraca®). ® ); Programmed cell death protein 1 (PD-1) inhibitor, pembrolizumab (Keytruda) ® ); and a radioligand therapy targeting prostate-specific membrane antigens, lutetium Lu 177 vipivotide tetraxetan (PLUVICTO®). These therapies are available for limited or pre-selected patient subgroups; therefore, unmet needs remain in the late-stage mCRPC setting.

[0007] Six-transmembrane epithelial antigen 1 (STEAP1) of the prostate is a surface antigen containing three short extracellular loop regions that is overexpressed in prostate cancer (Hubert et al., 1999) and Ewing sarcoma (Grunewald et al., 2012), and its expression is associated with prostate cancer disease stages (Gomes et al., 2014). Xaluritamig (also known as “AMG509”) is a novel XmAb® 2+1 bispecific antibody designed to direct T effector cells (via CD3 binding) to prostate cancer cells expressing STEAP1. In nonclinical studies, xaluritamig has demonstrated potent cytotoxicity in prostate cancer cell lines and tumor regression in preclinical xenograft models (Nolan-Stevaux et al., 2024, Cancer Discov. [Cancer Discovery] Jan 12, 2024; 14(1): 90-103). Nonclinical evidence supports the progress of xaluritamig in clinical trials in patients with mCRPC.

[0008] Prostate-specific membrane antigen (PSMA) is a type II cell surface membrane-bound glycoprotein with a molecular weight of approximately 110 kDa, comprising an intracellular segment (amino acids 1-18), a transmembrane domain (amino acids 19-43), and an extensive extracellular domain (amino acids 44-750). PSMA is highly expressed in most prostate cancer cells and is overexpressed in malignant prostate tissue compared to other organs in the body, such as the kidneys, proximal small intestine, and salivary glands. Unlike the downregulation of PSA expression following androgen blockade, PSMA expression is significantly increased in both primary and metastatic tumor specimens (Kawakami et al., Wright et al.). PSMA is also highly expressed in secondary prostate cancer and occult metastatic disease. PLUVICTO® (lutetium 177 vepleptide tetracetan) is an approved therapy for patients with mCRPC who have previously received androgen receptor (AR) pathway inhibitors (ARPIs) and taxane-based chemotherapy. It targets PSMA-expressing cells with lutetium-177 (177Lu), a radioligand that emits beta particles. This treatment resulted in an overall survival benefit of 4 months, with a median of 15.3 months, indicating ample room for further improvement. PLUVICTO® is currently being explored in patients who have not been exposed to prior chemotherapy. Summary of the Invention

[0009] The present invention provides a method for treating a patient with prostate cancer, comprising administering to the patient a pharmaceutical composition comprising anti-STEAP1 antigen-binding protein at a dose of about 0.1 mg to about 2.0 mg.

[0010] The present invention also provides an anti-STEAP1 antigen-binding protein for the treatment of prostate cancer, wherein the anti-STEAP1 antigen-binding protein is formulated for administration at a dose of about 0.1 mg to about 2.0 mg.

[0011] The present invention also provides the use of anti-STEAP1 antigen-binding protein in the preparation of a medicament for the treatment of prostate cancer, wherein the medicament is formulated for administration at a dose of about 0.1 mg to about 2.0 mg.

[0012] This disclosure also provides the use of the anti-STEAP1 antigen-binding protein in the manufacture of a medicament for the treatment of prostate cancer, wherein the medicament is formulated for administration at a dose of about 0.1 mg to about 2.0 mg and in combination with a dose of lutetium-177 vepletide tetracetan. In one embodiment, the anti-STEAP1 antigen-binding protein is salinomycin.

[0013] This disclosure also provides an anti-STEAP1 antigen-binding protein for the treatment of prostate cancer, wherein the anti-STEAP1 antigen-binding protein is formulated for administration at a dose of about 0.1 mg to about 2.0 mg, and is administered in combination with a dose of lutetium-177 vepletide tetracetan. In one embodiment, the anti-STEAP1 antigen-binding protein is salinomycin.

[0014] This disclosure also provides the use of the anti-STEAP1 antigen-binding protein in the manufacture of a medicament for the treatment of prostate cancer, wherein the medicament is administered at a dose of about 0.1 mg to about 2.0 mg and in combination with a dose of lutetium 177 vepletide tetracetan. In one embodiment, the anti-STEAP1 antigen-binding protein is salinomycin.

[0015] This disclosure also provides an anti-STEAP1 antigen-binding protein for the treatment of prostate cancer, wherein the anti-STEAP1 antigen-binding protein is administered at a dose of about 0.1 mg to about 2.0 mg and in combination with a dose of lutetium-177 vepletide tetracetan. In one embodiment, the anti-STEAP1 antigen-binding protein is salinomycin.

[0016] This disclosure provides a method in which an anti-STEAP1 antigen-binding protein is administered according to the method of this disclosure. This disclosure also provides an anti-STEAP1 antigen-binding protein for the treatment of prostate cancer, wherein the anti-STEAP1 antigen-binding protein is formulated for administration according to the method of this disclosure. In one embodiment, the dose of the anti-STEAP antigen-binding protein is from about 0.1 mg to about 1.5 mg. In one embodiment, the dose of the anti-STEAP antigen-binding protein is from about 0.3 mg to about 1.3 mg. In one embodiment, the dose of the anti-STEAP antigen-binding protein is from about 0.5 mg to about 1 mg. In one embodiment, the dose of the anti-STEAP antigen-binding protein is from about 0.75 mg to about 1 mg. In one embodiment, the dose of the anti-STEAP antigen-binding protein is about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.75 mg, about 0.8 mg, about 0.9 mg, about 1.0 mg, about 1.1 mg, about 1.2 mg, about 1.3 mg, about 1.4 mg, about 1.5 mg, about 1.6 mg, or about 1.7 mg. In one embodiment, the dose of the anti-STEAP antigen-binding protein is 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.75 mg, 0.8 mg, 0.9 mg, 1.0 mg, 1.1 mg, 1.2 mg, 1.3 mg, 1.4 mg, 1.5 mg, 1.6 mg, or 1.7 mg. In one embodiment, the dose of the anti-STEAP antigen-binding protein is about 0.1 mg. In one embodiment, the dose of anti-STEAP antigen-binding protein is about 0.3 mg. In one embodiment, the dose of anti-STEAP antigen-binding protein is about 0.75 mg. In one embodiment, the dose of anti-STEAP antigen-binding protein is about 1 mg. In one embodiment, the dose of anti-STEAP antigen-binding protein is about 1.5 mg. In one embodiment, the dose of anti-STEAP antigen-binding protein is 0.1 mg. In one embodiment, the dose of anti-STEAP antigen-binding protein is 0.3 mg. In one embodiment, the dose of anti-STEAP antigen-binding protein is 0.75 mg. In one embodiment, the dose of anti-STEAP antigen-binding protein is 1 mg. In one embodiment, the dose of anti-STEAP antigen-binding protein is 1.5 mg. In one embodiment, the dose of anti-STEAP antigen-binding protein is administered once a week. In one embodiment, the dose of anti-STEAP antigen-binding protein is administered once every two weeks. In one embodiment, the dose of anti-STEAP antigen-binding protein is administered once every three weeks.In one embodiment, the dose of anti-STEAP antigen-binding protein is administered once every four weeks. In one embodiment, the dose of anti-STEAP antigen-binding protein is administered intravenously. In one embodiment, the dose of anti-STEAP antigen-binding protein is administered once weekly starting from the first cycle. In one embodiment, the dose of anti-STEAP antigen-binding protein is administered once weekly starting from the second cycle. In one embodiment, the dose of anti-STEAP antigen-binding protein is administered once every two weeks starting from the second cycle. In one embodiment, the dose of anti-STEAP antigen-binding protein is administered once every three weeks starting from the second cycle. In one embodiment, the dose of anti-STEAP antigen-binding protein is administered once every four weeks starting from the second cycle. In one embodiment, the dose of anti-STEAP antigen-binding protein is administered once weekly in the first cycle, and then once every two weeks starting from the first day of the second cycle. In one embodiment, the dose of anti-STEAP antigen-binding protein is administered once weekly in the first cycle, and then once every two weeks once the target dose of anti-STEAP antigen-binding protein is reached. In one embodiment, the dose of anti-STEAP antigen-binding protein is administered once weekly in the first cycle, and then once every three weeks once the target dose of anti-STEAP antigen-binding protein is reached. In one embodiment, the dose of anti-STEAP antigen-binding protein is administered weekly during the first cycle, and then every four weeks once the target dose of anti-STEAP antigen-binding protein is reached. In some embodiments, the second cycle is repeated 11 times after the first cycle is completed (e.g., a total treatment period of approximately 12 months). In some embodiments, the second cycle is repeated 5 times after the first cycle is completed (e.g., a total treatment period of approximately 6 months). In one embodiment, the anti-STEAP1 antigen-binding protein is salinomycin.

[0017] The present invention provides a method for treating a patient with prostate cancer, comprising administering to the patient a pharmaceutical composition comprising an anti-STEAP1 antigen-binding protein, and further comprising administering to the patient a dose of a compound of formula 1:

[0018]

[0019] The compound forms a metal complex with metals selected from the group consisting of 90Y, 177Lu, 64Cu, 153Gd, 155Gd, 157Gd, 213Bi, 68Ga and 225Ac.

[0020] This disclosure provides an anti-STEAP1 antigen-binding protein for the treatment of prostate cancer, wherein the anti-STEAP1 antigen-binding protein is formulated for administration at a dose of about 0.1 mg to about 2.0 mg and in combination with a dose of a compound of formula 1, wherein the compound is complexed with a metal selected from the group consisting of 90Y, 177Lu, 64Cu, 153Gd, 155Gd, 157Gd, 213Bi, 68Ga, and 225Ac. This disclosure also provides the use of the anti-STEAP1 antigen-binding protein in the manufacture of a medicament for the treatment of prostate cancer, wherein the medicament is formulated for administration at a dose of about 0.1 mg to about 2.0 mg and in combination with a dose of a compound of formula 1, wherein the compound is complexed with a metal selected from the group consisting of 90Y, 177Lu, 64Cu, 153Gd, 155Gd, 157Gd, 213Bi, 68Ga, and 225Ac. This disclosure provides an anti-STEAP1 antigen-binding protein for treating prostate cancer, wherein the anti-STEAP1 antigen-binding protein is administered at a dose of about 0.1 mg to about 2.0 mg and in combination with a dose of a compound of formula 1, wherein the compound is complexed with a metal selected from the group consisting of 90Y, 177Lu, 64Cu, 153Gd, 155Gd, 157Gd, 213Bi, 68Ga, and 225Ac. This disclosure also provides the use of the anti-STEAP1 antigen-binding protein in the manufacture of a medicament for treating prostate cancer, wherein the medicament is administered at a dose of about 0.1 mg to about 2.0 mg and in combination with a dose of a compound of formula 1, wherein the compound is complexed with a metal selected from the group consisting of 90Y, 177Lu, 64Cu, 153Gd, 155Gd, 157Gd, 213Bi, 68Ga, and 225Ac. In one embodiment, the dose of the anti-STEAP1 antigen-binding protein is about 0.1 mg to about 1.5 mg. In one embodiment, the dose of anti-STEAP antigen-binding protein is about 0.3 mg to about 1.3 mg. In one embodiment, the dose of anti-STEAP antigen-binding protein is about 0.5 mg to about 1 mg. In one embodiment, the dose of anti-STEAP antigen-binding protein is about 0.75 mg to about 1 mg. In one embodiment, the dose of anti-STEAP antigen-binding protein is about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.75 mg, about 0.8 mg, about 0.9 mg, about 1.0 mg, about 1.1 mg, about 1.2 mg, about 1.3 mg, about 1.4 mg, about 1.5 mg, about 1.6 mg, or about 1.7 mg.In one embodiment, the dose of anti-STEAP antigen-binding protein is 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.75 mg, 0.8 mg, 0.9 mg, 1.0 mg, 1.1 mg, 1.2 mg, 1.3 mg, 1.4 mg, 1.5 mg, 1.6 mg, or 1.7 mg. In one embodiment, the dose of lutetium 177 veprotide tetracetan is 7.4 GBq.

[0021] The present invention provides a method for treating a patient with prostate cancer, comprising administering to the patient a pharmaceutical composition comprising an anti-STEAP1 antigen-binding protein, and further comprising administering to the patient a dose of the following compound:

[0022]

[0023] Or its salt, wherein R' is a chelating agent having the following formula:

[0024]

[0025] and 90 Y、 177 Lu、 64 Cu、 153 Gd, 155 Gd, 157 Gd, 213 Bi、 68 Ga or 225 Ac complexes with the chelating agent. In one embodiment, 177 Lu forms a complex with the chelating agent.

[0026] In one embodiment, the metal-complexed compound is lutetium Lu 177 veproptide tetracetan. In one embodiment, the dose of lutetium Lu 177 veproptide tetracetan is about 2 GBq to about 13 GBq. In one embodiment, the dose of lutetium Lu 177 veproptide tetracetan is about 5.9 GBq. In one embodiment, the dose of lutetium Lu 177 veproptide tetracetan is about 7.4 GBq. In one embodiment, the dose of lutetium Lu 177 veproptide tetracetan is 5.9 GBq. In one embodiment, the dose of lutetium Lu 177 veproptide tetracetan is 7.4 GBq. In one embodiment, the dose of lutetium Lu 177 veproptide tetracetan is about 7.4 GBq. In one embodiment, the dose of lutetium Lu 177 veproptide tetracetan is administered once every six weeks. In one embodiment, the dose of lutetium Lu 177 veproptide tetracetan is 7.4 GBq, administered once every six weeks for up to six doses. In one embodiment, the dose of anti-STEAP antigen-binding protein is about 0.1 mg to about 1.5 mg. In one embodiment, the dose of anti-STEAP antigen-binding protein is about 0.3 mg to about 1.3 mg. In one embodiment, the dose of anti-STEAP antigen-binding protein is about 0.5 mg to about 1 mg. In one embodiment, the dose of anti-STEAP antigen-binding protein is about 0.75 mg to about 1 mg. In one embodiment, the dose of anti-STEAP antigen-binding protein is about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.75 mg, about 0.8 mg, about 0.9 mg, about 1.0 mg, about 1.1 mg, about 1.2 mg, about 1.3 mg, about 1.4 mg, about 1.5 mg, about 1.6 mg, or about 1.7 mg. In one embodiment, the dose of anti-STEAP antigen-binding protein is 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.75 mg, 0.8 mg, 0.9 mg, 1.0 mg, 1.1 mg, 1.2 mg, 1.3 mg, 1.4 mg, 1.5 mg, 1.6 mg, or 1.7 mg. In one embodiment, the dose of lutetium 177 veprotide tetracetan is 7.4 GBq.

[0027] This invention provides a method for treating a patient with prostate cancer, comprising administering to the patient a pharmaceutical composition comprising Formula 1:

[0028]

[0029] This compound and 177The formulation comprises lutetium 177 (L-177) veplate tetracetan and a dosage of 0.1-2.0 mg of salidomide. In one embodiment, the dosage of salidomide is 1.5 mg. In one embodiment, the dosage of lutetium 177 veplate tetracetan is 5.9 GBq. In one embodiment, the dosage of lutetium 177 veplate tetracetan is 7.4 GBq. In one embodiment, the dosage of lutetium 177 veplate tetracetan is about 7.4 GBq, and the dosage of salidomide is about 0.75 mg. In one embodiment, the dosage of lutetium 177 veplate tetracetan is about 7.4 GBq, and the dosage of salidomide is about 1 mg. In one embodiment, the dosage of lutetium 177 veplate tetracetan is about 7.4 GBq, and the dosage of salidomide is about 1.5 mg. In one embodiment, the dose of lutetium Lu 177 veplate tetracetan is 7.4 GBq, and the dose of salinomycin is 0.75 mg. In one embodiment, the dose of lutetium Lu 177 veplate tetracetan is 7.4 GBq, and the dose of salinomycin is 1 mg. In one embodiment, the dose of lutetium Lu 177 veplate tetracetan is 7.4 GBq, and the dose of salinomycin is 1.5 mg.

[0030] This invention provides a method for treating a patient with prostate cancer, the method comprising administering to the patient a pharmaceutical composition comprising lutetium-177 veplate tetracetamol and a pharmaceutical formulation comprising salinomycin at a dose of 0.1-2.0 mg. In one embodiment, the dose of salinomycin is 1.5 mg. In one embodiment, the dose of lutetium-177 veplate tetracetamol is 5.9 GBq. In one embodiment, the dose of lutetium-177 veplate tetracetamol is 7.4 GBq. In one embodiment, the dose of lutetium-177 veplate tetracetamol is about 7.4 GBq, and the dose of salinomycin is about 0.75 mg. In one embodiment, the dose of lutetium-177 veplate tetracetamol is about 7.4 GBq, and the dose of salinomycin is about 1 mg. In one embodiment, the dose of lutetium-177 veplate tetracetamol is about 7.4 GBq, and the dose of salinomycin is about 1.5 mg. In one embodiment, the dose of lutetium Lu 177 veplate tetracetan is 7.4 GBq, and the dose of salinomycin is 0.75 mg. In one embodiment, the dose of lutetium Lu 177 veplate tetracetan is 7.4 GBq, and the dose of salinomycin is 1 mg. In one embodiment, the dose of lutetium Lu 177 veplate tetracetan is 7.4 GBq, and the dose of salinomycin is 1.5 mg.

[0031] This invention provides the use of anti-STEAP1 antigen-binding protein in the preparation of a medicament for the treatment of prostate cancer, the medicament being formulated for administration at a dose of about 0.1 mg to about 2.0 mg, and also administering to the patient a dose of a drug selected from... 90 Y、 177 Lu、 64 Cu、 153 Gd, 155 Gd, 157 Gd, 68 Ga、 213 Bihe 225 The present invention provides the use of an anti-STEAP1 antigen-binding protein in the manufacture of a medicament for treating prostate cancer, the medicament being formulated for administration at a dose of about 0.1 mg to about 2.0 mg, and also administering to a patient a dose of a compound of formula 1 that is metal-complexed with a group selected from 90Y, 177Lu, 64Cu, 153Gd, 155Gd, 157Gd, 68Ga, 213Bi, and 225Ac. The present invention provides an anti-STEAP1 antigen-binding protein for treating prostate cancer, the anti-STEAP1 antigen-binding protein being formulated for administration at a dose of about 0.1 mg to about 2.0 mg, and administered in combination with a dose of a compound of formula 1 that is metal-complexed with a group selected from 90Y, 177Lu, 64Cu, 153Gd, 155Gd, 157Gd, 68Ga, 213Bi, and 225Ac. This invention provides the use of an anti-STEAP1 antigen-binding protein in the manufacture of a medicament for treating prostate cancer, administered at a dose of about 0.1 mg to about 2.0 mg, and in combination with a dose of a compound of formula 1 that is metal-complexed with a metal selected from the group consisting of 90Y, 177Lu, 64Cu, 153Gd, 155Gd, 157Gd, 68Ga, 213Bi, and 225Ac. In one embodiment, the anti-STEAP1 antigen-binding protein is salinomycin.

[0032] In one embodiment, the metal-complexed compound is lutetium Lu 177 vepreptide tetracetan. In one embodiment, the dose of lutetium Lu 177 vepreptide tetracetan is about 2 GBq to about 13 GBq. In one embodiment, the dose of lutetium Lu 177 vepreptide tetracetan is about 5.9 GBq. In one embodiment, the dose of lutetium Lu 177 vepreptide tetracetan is about 7.4 GBq. In one embodiment, the dose of lutetium Lu 177 vepreptide tetracetan is 5.9 GBq. In one embodiment, the dose of lutetium Lu 177 vepreptide tetracetan is 7.4 GBq. In one embodiment, the dose of lutetium Lu 177 vepreptide tetracetan is 7.4 GBq. In one embodiment, the dose of lutetium Lu 177 vepreptide tetracetan is administered once every six weeks. In one embodiment, the dose of lutetium Lu 177 vepreptide tetracetan is 7.4 GBq, administered once every six weeks for up to six doses. In one embodiment, after administering lutetium-177 vepletide tetracetan to the patient, anti-STEAP1 antigen-binding protein is administered to the patient. In one embodiment, the dose of anti-STEAP1 antigen-binding protein is from about 0.01 mg to about 2.0 mg. In one embodiment, the dose of anti-STEAP1 antigen-binding protein is from about 0.1 mg to about 1.5 mg. In one embodiment, the dose of anti-STEAP1 antigen-binding protein is 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.75 mg, 0.8 mg, 0.9 mg, 1.0 mg, 1.1 mg, 1.2 mg, 1.3 mg, 1.4 mg, 1.5 mg, 1.6 mg, 1.7 mg, 1.8 mg, 1.9 mg, or 2.0 mg. In one embodiment, the dose of anti-STEAP1 antigen-binding protein is about 0.1 mg. In one embodiment, the dose of anti-STEAP1 antigen-binding protein is about 0.3 mg. In one embodiment, the dose of anti-STEAP1 antigen-binding protein is about 0.75 mg. In one embodiment, the dose of anti-STEAP1 antigen-binding protein is about 1 mg. In one embodiment, the dose of anti-STEAP1 antigen-binding protein is about 1.5 mg. In one embodiment, the dose of anti-STEAP1 antigen-binding protein is 0.1 mg. In one embodiment, the dose of anti-STEAP1 antigen-binding protein is 0.3 mg. In one embodiment, the dose of anti-STEAP1 antigen-binding protein is 0.75 mg. In one embodiment, the dose of anti-STEAP1 antigen-binding protein is 1 mg. In one embodiment, the dose of anti-STEAP1 antigen-binding protein is 1.5 mg. In one embodiment, the dose of anti-STEAP1 antigen-binding protein is administered once a week.In one embodiment, the dose of anti-STEAP1 antigen-binding protein is administered every two weeks. In one embodiment, the dose of anti-STEAP1 antigen-binding protein is administered every three weeks. In one embodiment, the dose of anti-STEAP1 antigen-binding protein is administered every four weeks. In one embodiment, the dose of anti-STEAP1 antigen-binding protein is administered intravenously. In one embodiment, the dose of anti-STEAP1 antigen-binding protein is administered weekly starting from the second cycle. In one embodiment, the dose of anti-STEAP1 antigen-binding protein is administered every two weeks starting from the second cycle. In one embodiment, the dose of anti-STEAP1 antigen-binding protein is administered every three weeks starting from the second cycle. In one embodiment, the dose of anti-STEAP1 antigen-binding protein is administered every four weeks starting from the second cycle. In one embodiment, the dose of lutetium Lu 177 vitrapeptide tetracetan is 7.4 GBq, and the dose of anti-STEAP1 antigen-binding protein is 0.75 mg. In one embodiment, the dose of lutetium Lu 177 vitrapeptide tetracetan is 7.4 GBq, and the dose of anti-STEAP1 antigen-binding protein is 1 mg. In one embodiment, the dose of lutetium Lu 177 veprotide tetracetan is 7.4 GBq, and the dose of anti-STEAP1 antigen-binding protein is 1.5 mg. In one embodiment, the anti-STEAP1 antigen-binding protein is salinomycin.

[0033] This invention provides a method for treating a patient with prostate cancer, wherein the method includes first administering to the patient a pharmaceutical composition comprising an anti-STEAP1 antigen-binding protein until a target dose of the anti-STEAP1 antigen-binding protein is reached, followed by administering to the patient lutetium-177 vepletide tetracetan. In one embodiment, this invention provides a method for treating a patient with prostate cancer, wherein the method includes first administering to the patient a pharmaceutical composition comprising an anti-STEAP1 antigen-binding protein until a target dose of the anti-STEAP1 antigen-binding protein is reached, followed by administering to the patient lutetium-177 vepletide tetracetan in combination with the anti-STEAP1 antigen-binding protein. In one embodiment, the target dose of the anti-STEAP1 antigen-binding protein is 0.75 mg. In one embodiment, the target dose of the anti-STEAP1 antigen-binding protein is 1 mg. In one embodiment, the target dose of the anti-STEAP1 antigen-binding protein is 1.5 mg. In one embodiment, the dose of lutetium-177 vepletide tetracetan is 7.4 GBq. In one embodiment, the anti-STEAP1 antigen-binding protein is salinomycin.

[0034] The present invention also provides a method for treating a patient with prostate cancer, the method comprising administering to the patient a pharmaceutical composition of the present invention comprising a dose of anti-STEAP1 antigen-binding protein and a dose of lutetium-177 veplate tetracetan, the method comprising at least one cycle, wherein in one cycle, the anti-STEAP1 antigen-binding protein is administered on days on which lutetium-177 veplate tetracetan is not administered. In one embodiment, the anti-STEAP1 antigen-binding protein is administered every 7 days during a cycle of lutetium-177 veplate tetracetan administration. In one embodiment, the anti-STEAP1 antigen-binding protein is administered every 7 days during a cycle of lutetium-177 veplate tetracetan administration. In one embodiment, the anti-STEAP1 antigen-binding protein is administered every 14 days during a cycle of lutetium-177 veplate tetracetan administration. In one embodiment, the anti-STEAP1 antigen-binding protein is administered on days 7, 21, and 35 after administration of one dose of lutetium-177 veplate tetracetan in one cycle. In one embodiment, in one cycle, anti-STEAP1 antigen-binding protein is administered on days 2, 16, and 30 after administration of one dose of lutetium Lu 177 vepreptide tetracetan. The present invention provides the use of anti-STEAP1 antigen-binding protein in the preparation of a medicament for treating prostate cancer, said use comprising administering to a patient a dose of a pharmaceutical composition comprising anti-STEAP1 antigen-binding protein and a dose of lutetium Lu 177 vepreptide tetracetan, said use comprising at least one cycle, wherein in one cycle, anti-STEAP1 antigen-binding protein is administered every 14 days during the administration cycle of lutetium Lu 177 vepreptide tetracetan. This invention provides the use of an anti-STEAP1 antigen-binding protein in the manufacture of a medicament for treating prostate cancer, the use comprising administering to a patient a dose of a pharmaceutical composition comprising the anti-STEAP1 antigen-binding protein of the present invention and a dose of lutetium-177 veplate tetracetan, the use comprising at least one cycle, wherein in one cycle, during a cycle of lutetium-177 veplate tetracetan administration, the anti-STEAP1 antigen-binding protein is administered once every 14 days. This invention provides an anti-STEAP1 antigen-binding protein for treating prostate cancer, the use comprising administering to a patient a dose of a pharmaceutical composition comprising the anti-STEAP1 antigen-binding protein of the present invention and a dose of lutetium-177 veplate tetracetan, the use comprising at least one cycle, wherein in one cycle, during a cycle of lutetium-177 veplate tetracetan administration, the anti-STEAP1 antigen-binding protein is administered once every 14 days. In one embodiment, anti-STEAP1 antigen-binding protein is administered on days 7, 21, and 35 after administration of a dose of lutetium-177 vepteptide tetracetan in one cycle.In one embodiment, anti-STEAP1 antigen-binding protein is administered on days 2, 16, and 30 after one dose of lutetium-177 vepreptide tetracetan within a single cycle. In one embodiment, the method comprises one cycle, two cycles, three cycles, four cycles, five cycles, or six cycles. In one embodiment, lutetium-177 vepreptide tetracetan is administered intravenously. In one embodiment, the administration cycle of lutetium-177 vepreptide tetracetan is 6 weeks. In one embodiment, anti-STEAP1 antigen-binding protein is administered via a stepwise approach before reaching the target dose. In one embodiment, anti-STEAP1 antigen-binding protein is administered at the target dose after administration of lutetium-177 vepreptide tetracetan to the patient. In one embodiment, the dose of lutetium-177 vepreptide tetracetan is 7.4 GBq, and the dose of anti-STEAP1 antigen-binding protein is 0.75 mg. In one embodiment, the dose of lutetium Lu 177 vepletide tetracetan is 7.4 GBq, and the dose of anti-STEAP1 antigen-binding protein is 1 mg. In another embodiment, the dose of lutetium Lu 177 vepletide tetracetan is 7.4 GBq, and the dose of anti-STEAP1 antigen-binding protein is 1.5 mg. In yet another embodiment, the anti-STEAP1 antigen-binding protein is salinomycin.

[0035] The present invention also provides a method for treating a patient with prostate cancer, wherein the method comprises administering to the patient a dose of a pharmaceutical composition comprising an anti-STEAP1 antigen-binding protein in a dose of about 0.1 mg to about 2.0 mg, and further comprises administering to the patient a dose of abiraterone. The present invention provides the use of the anti-STEAP1 antigen-binding protein in the preparation of a medicament for treating prostate cancer, wherein the medicament is formulated for administration in a dose of about 0.1 mg to about 2.0 mg, and the use further comprises administering to the patient a dose of abiraterone. In one embodiment, the dose of abiraterone is about 750 mg to about 1000 mg. In one embodiment, the dose of abiraterone is about 1000 mg. In one embodiment, the dose of abiraterone is 1000 mg. In one embodiment, the dose of abiraterone is administered orally. Optionally, abiraterone is administered once daily. In one embodiment, prednisone (or prednisolone) is further administered to the patient. In one embodiment, 5 mg of prednisone is further administered to the patient twice daily. In one embodiment, 10 mg of prednisone is further administered to the patient once daily. In one embodiment, YONSA® is administered orally to the patient at a dose of 500 mg once daily, in combination with 4 mg of methylprednisolone twice daily. In one embodiment, the dose of anti-STEAP1 antigen-binding protein is from about 0.1 mg to about 2.0 mg. In one embodiment, the dose of anti-STEAP1 antigen-binding protein is from about 0.1 mg to about 1.5 mg. In one embodiment, the dose of anti-STEAP1 antigen-binding protein is about 0.75 mg. In one embodiment, the dose of anti-STEAP1 antigen-binding protein is about 1 mg. In one embodiment, the dose of anti-STEAP1 antigen-binding protein is about 1.5 mg. In one embodiment, the dose of anti-STEAP1 antigen-binding protein is 0.75 mg. In one embodiment, the dose of anti-STEAP1 antigen-binding protein is 1 mg. In one embodiment, the dose of anti-STEAP1 antigen-binding protein is 1.5 mg. In one embodiment, the dose of anti-STEAP1 antigen-binding protein is 1.5 mg. In one embodiment, the dose of anti-STEAP1 antigen-binding protein is 1.5 mg. In one embodiment, the dose of anti-STEAP1 antigen-binding protein is administered once weekly. In one embodiment, the dose of anti-STEAP1 antigen-binding protein is administered every two weeks. In one embodiment, a dose of anti-STEAP1 antigen-binding protein and a dose of abiraterone are administered to the patient on the same day. In another embodiment, a dose of anti-STEAP1 antigen-binding protein and a dose of abiraterone are administered to the patient on day 1 of cycle 1. In yet another embodiment, a dose of abiraterone is administered to the patient starting on day 1 of cycle 1.

[0036] The present invention also provides a method for treating a patient with prostate cancer, wherein the method comprises administering to the patient a pharmaceutical composition comprising an anti-STEAP1 antigen-binding protein in a dose of about 0.1 mg to about 2.0 mg, and further comprises administering enzalutamide to the patient. The present invention provides the use of the anti-STEAP1 antigen-binding protein in the preparation of a medicament for treating prostate cancer, wherein the medicament is formulated for administration in a dose of about 0.1 mg to about 2.0 mg, and the use further comprises administering a dose of enzalutamide to the patient. In one embodiment, the dose of enzalutamide is about 120 mg to about 160 mg. In one embodiment, the dose of enzalutamide is about 160 mg. In one embodiment, the dose of enzalutamide is 160 mg. In one embodiment, the dose of enzalutamide is administered orally. In one embodiment, the dose of the anti-STEAP1 antigen-binding protein is about 0.01 mg to about 2.0 mg. In one embodiment, the dose of the anti-STEAP1 antigen-binding protein is about 0.75 mg. In one embodiment, the dose of the anti-STEAP1 antigen-binding protein is about 1 mg. In one embodiment, the dose of anti-STEAP1 antigen-binding protein is approximately 1.5 mg. In another embodiment, the dose of anti-STEAP1 antigen-binding protein is 1.5 mg. In yet another embodiment, a dose of enzalutamide is administered to the patient starting on day 1 of cycle 1.

[0037] The present invention also provides a method for treating a patient with prostate cancer, wherein the method comprises administering to the patient a pharmaceutical composition comprising an anti-STEAP1 antigen-binding protein in a dose of about 0.1 mg to about 2.0 mg, and further comprises administering dalolutamide to the patient. The present invention provides the use of the anti-STEAP1 antigen-binding protein in the preparation of a medicament for treating prostate cancer, wherein the medicament is formulated for administration in a dose of about 0.1 mg to about 2.0 mg, and the use further comprises administering a dose of dalolutamide to the patient. In one embodiment, the dose of dalolutamide is about 450 mg to about 600 mg. In one embodiment, the dose of dalolutamide is about 600 mg. In one embodiment, the dose of dalolutamide is 600 mg. In one embodiment, the dose of dalolutamide is administered orally. In one embodiment, the dose of dalolutamide is administered orally twice daily. In one embodiment, the dose of dalolutamide is administered orally twice daily in the form of two 300 mg tablets. In one embodiment, the dose of the anti-STEAP1 antigen-binding protein is about 0.01 mg to about 2.0 mg. In one embodiment, the dose of anti-STEAP1 antigen-binding protein is about 1.5 mg. In one embodiment, the dose of anti-STEAP1 antigen-binding protein is 0.75 mg. In one embodiment, the dose of anti-STEAP1 antigen-binding protein is 1 mg. In one embodiment, the dose of anti-STEAP1 antigen-binding protein is 1.5 mg.

[0038] The present invention also provides a method for treating a patient with prostate cancer, wherein the method comprises administering to the patient a pharmaceutical composition comprising an anti-STEAP1 antigen-binding protein in a dose of about 0.1 mg to about 2.0 mg, and further comprises administering apalutamide to the patient. The present invention provides the use of the anti-STEAP1 antigen-binding protein in the preparation of a medicament for treating prostate cancer, wherein the medicament is formulated for administration in a dose of about 0.1 mg to about 2.0 mg, and the use further comprises administering a dose of apalutamide to the patient. In one embodiment, the dose of apalutamide is about 180 mg to about 240 mg. In one embodiment, the dose of apalutamide is about 240 mg. In one embodiment, the dose of apalutamide is 240 mg. In one embodiment, the dose of apalutamide is administered orally. In one embodiment, the dose of apalutamide is administered orally once daily. In one embodiment, the dose of apalutamide is administered orally in the form of four 60 mg tablets once daily. In one embodiment, the dose of the anti-STEAP1 antigen-binding protein is about 0.01 mg to about 2.0 mg. In one embodiment, the dose of anti-STEAP1 antigen-binding protein is approximately 1.5 mg.

[0039] In one embodiment, anti-STEAP1 antigen-binding protein is administered via a stepwise dosing method. In one embodiment, anti-STEAP1 antigen-binding protein is administered in two steps. In one embodiment, anti-STEAP1 antigen-binding protein is administered in two or three steps. In one embodiment, anti-STEAP1 antigen-binding protein is administered at 0.1 mg on day 1, 0.3 mg on day 8, 1.0 mg on day 15, and 1.5 mg on day 22. In one embodiment, anti-STEAP1 antigen-binding protein is administered at 0.1 mg on day 1, 0.3 mg on day 8, 0.75 mg on day 15, and 0.75 mg on day 22. In one embodiment, the method further includes administering anti-STEAP1 antigen-binding protein to the patient once weekly, once every two weeks, once every three weeks, or once every four weeks after the stepwise dosing. In one embodiment, anti-STEAP1 antigen-binding protein is administered at 1.5 mg every two weeks after the stepwise dosing. In one embodiment, anti-STEAP1 antigen-binding protein is administered at 1.5 mg every three weeks after the stepwise dosing. In one embodiment, anti-STEAP1 antigen-binding protein is administered at a dose of 1.5 mg every four weeks following a stepwise dosing regimen.

[0040] In one embodiment, the dose of anti-STEAP1 antigen-binding protein is administered weekly during the first cycle, and then every three weeks once the target dose is reached. In another embodiment, the dose of anti-STEAP1 antigen-binding protein is administered weekly during the first cycle, and then every four weeks once the target dose is reached.

[0041] In one embodiment, the anti-STEAP1 antigen-binding protein is administered in two cycles. In one embodiment, the first cycle comprises administering the anti-STEAP1 antigen-binding protein at a dose ranging from about 0.1 mg to about 0.3 mg on day 1 or 2, at a dose ranging from about 0.2 mg to about 0.4 mg on day 7, 8, or 9, at a dose ranging from about 0.8 mg to about 1.2 mg on day 14, 15, or 16, and at a dose ranging from about 1.3 mg to about 1.6 mg on day 21, 22, or 23. In one embodiment, the second cycle following the first cycle comprises administering the anti-STEAP1 antigen-binding protein at a dose of 1.5 mg every two weeks for five months after the completion of the first cycle. Each cycle is optionally 28 days.

[0042] In one embodiment, the first cycle comprises administering anti-STEAP1 antigen-binding protein at 0.1 mg on day 1, 0.3 mg on day 8, 1.0 mg on day 15, and 1.5 mg on day 22. In one embodiment, the second cycle following the first cycle comprises administering anti-STEAP1 antigen-binding protein at 1.5 mg every two weeks for five months after the completion of the first cycle. Each cycle is optionally 28 days.

[0043] In one embodiment, the first cycle includes administration of anti-STEAP1 antigen-binding protein at 0.1 mg on day 1, 0.3 mg on day 8, 1.0 mg on day 15, and 1.5 mg on day 22. In one embodiment, the second cycle includes administration of anti-STEAP1 antigen-binding protein at 1.5 mg every four weeks for 11 months after the completion of the first cycle. Each cycle is optionally 28 days. This disclosure further provides a method of treating a patient with prostate cancer, comprising administering a pharmaceutical composition comprising salitoprine to the patient over at least two 28-day cycles, wherein (i) the first cycle comprises administering about 0.1 mg to about 0.3 mg of salitoprine on day 1 or 2, about 0.2 mg to about 0.4 mg of salitoprine on day 7, 8 or 9, about 0.8 mg to about 1.2 mg of salitoprine on day 14, 15 or 16, and about 1.3 mg to about 1.6 mg of salitoprine on day 21, 22 or 23, followed by one or more additional cycles (cycle 2) comprising administering 1.5 mg of salitoprine every two weeks.

[0044] In one embodiment, the anti-STEAP1 antigen-binding protein is the XmAb 2+1 molecule. As used herein, the “XmAb® 2+1” molecule (which may be used interchangeably with the “multi-chain T-cell conjugate molecule” or the “central scFv” molecule) comprises two Fab domains and one scFv domain, wherein each Fab domain binds to one target (e.g., STEAP1) and the scFv domain binds to another target (e.g., CD3).

[0045] In one embodiment, the anti-STEAP1 antigen-binding protein comprises two Fab-binding domains, each of which binds to STEAP1.

[0046] In one embodiment, the anti-STEAP1 antigen-binding protein comprises two Fab-binding domains, each of which binds to STEAP1, and each Fab-binding domain comprises a variable heavy chain domain, a variable light chain domain, a CH1 domain, and a constant light chain domain. The variable heavy chain domain comprises HCDR1 (SEQ ID NO: 9), HCDR2 (SEQ ID NO: 10), and HCDR3 (SEQ ID NO: 11). The variable light chain domain comprises LCDR1 (SEQ ID NO: 12), LCDR2 (SEQ ID NO: 13), and LCDR3 (SEQ ID NO: 14).

[0047] In one embodiment, the anti-STEAP1 antigen-binding protein includes an scFv-binding domain, wherein the scFv-binding domain binds CD3.

[0048] In one embodiment, the anti-STEAP1 antigen-binding protein comprises an scFv binding domain, wherein the scFv binding domain binds CD3, and the scFv variable heavy chain domain comprises: HCDR1 comprising SEQ ID NO: 1, HCDR2 comprising SEQ ID NO: 2, and HCDR3 comprising SEQ ID NO: 3; an scFv linker; and an scFv variable light chain domain, wherein the scFv variable light chain domain comprises: LCDR1 comprising SEQ ID NO: 4, LCDR2 comprising SEQ ID NO: 5, and LCDR3 comprising SEQ ID NO: 6. In one embodiment, each Fab variable heavy chain domain comprises at least 90%, 95%, or 99% of the same amino acid sequence as SEQ ID NO: 15; each Fab variable light chain domain comprises at least 90%, 95%, or 99% of the same amino acid sequence as SEQ ID NO: 16; and the scFv variable heavy chain domain comprises at least 90%, 95%, or 99% of the same amino acid sequence as SEQ ID NO: 7; and the scFv variable light chain domain comprises at least 90%, 95%, or 99% of the same amino acid sequence as SEQ ID NO: 8. In one embodiment, each Fab variable heavy chain domain comprises SEQ ID NO: 15 or 20; each Fab variable light chain domain comprises SEQ ID NO: 16; the scFv variable heavy chain domain comprises SEQ ID NO: 7; and the scFv variable light chain domain comprises SEQ ID NO: 8. In one embodiment, the CD3-binding scFv binding domain comprises an scFv linker. In one embodiment, each Fab variable heavy chain domain comprises SEQ ID NO: 15. In one embodiment, each Fab variable heavy chain structural domain contains SEQ ID NO: 20.

[0049] In one embodiment, the anti-STEAP1 antigen-binding protein comprises a first Fc domain and a second Fc domain. In one embodiment, the first Fc domain comprises amino acid substitutions for E233P, L235V, G236A, S267K, R292C, N297G, V302C, E357Q, and S364K; and the second Fc domain comprises amino acid substitutions for N208D, E233P, L235V, G236A, S267K, R292C, Q295E, N297G, V302C, L368D, K370S, N384D, Q418E, and N421D (all EU designations). In one embodiment, both the first and second Fc domains contain a deletion at position 234.

[0050] In one embodiment, the anti-STEAP1 antigen-binding protein comprises: an HC comprising SEQ ID NO: 17, an HC comprising an inserted CD3 scFv comprising SEQ ID NO: 19, and two light chains, each light chain comprising SEQ ID NO: 18. In one embodiment, the anti-STEAP1 antigen-binding protein comprises: an HC comprising SEQ ID NO: 23, an HC comprising an inserted CD3 scFv comprising SEQ ID NO: 26, and two light chains, each light chain comprising SEQ ID NO: 18. In one embodiment, the anti-STEAP1 antigen-binding protein is an XmAb 2+1 molecule.

[0051] In one embodiment, the anti-STEAP1 antigen-binding protein is salinomycin. In another embodiment, the anti-STEAP1 antigen-binding protein is salinomycin and comprises: an HC comprising SEQ ID NO: 17, an HC comprising an inserted CD3 scFv comprising SEQ ID NO: 19, and two light chains, each light chain comprising SEQ ID NO: 18.

[0052] In one embodiment, the patient has metastatic castration-resistant prostate cancer. In one embodiment, the patient has not previously received chemotherapy. In one embodiment, the patient has previously received prostate cancer treatment and has recurrent prostate cancer. In one embodiment, the patient has previously received chemotherapy. Attached Figure Description

[0053] Figure 1 A schematic diagram of the XmAb® 2+1 molecule, depicting two Fabs, each binding STEAP1 and an scFv, each binding CD3.

[0054] Figure 2 Optimal percentage change in tumor target lesion size. The dashed line indicates a 30% reduction in tumor SLD compared to baseline.

[0055] Figure 3 The best percentage change in PSA compared to baseline. An asterisk indicates a confirmed PSA responder, and a dashed line indicates a decrease in PSA50 and PSA90.

[0056] Figure 4Example patient demonstrating response by PSA and radiological assessment: A 65-year-old patient with stage IV prostate adenocarcinoma who had undergone extensive pretreatment and presented with CT scans and PSA curves over time. The patient was enrolled in cohort 12 (3 steps of 1.5 mg target dose of salinomycin). During screening, CT scans revealed 3 target lesions (2 in the liver, 1 in a lymph node) and multiple non-target lesions in the liver and 2 lymph nodes. The patient's PSA decreased by 99% from baseline on day 1 of cycle 1 and achieved PR (37.3% reduction in target lesions) after 2 cycles, which was confirmed at week 16 and maintained after week 24. AEs occurred during the first treatment cycle and included recurrent CRS, tinea grade (both grade 1), and worsening of rash and back pain (both grade 2). During further treatment cycles, rash (grade 1), myalgia, and hyperkalemia (both grade 2) were reported. At submission, the patient was still on treatment.

[0057] Figure 5 .taken from Figure 4 The percentage change in PSA in the patients described in the text. Detailed Implementation

[0058] Salullitamine is an XmAb® 2+1 T cell conjugate (TCE) molecule designed to direct T effector cells to kill cells expressing STEAP1. The first human study of salullitamine in patients with metastatic castration-resistant prostate cancer (mCRPC) was designed to evaluate its safety, tolerability, pharmacokinetics (PK), and antitumor activity as a monotherapy or in combination with other therapies administered intravenously or subcutaneously.

[0059] This first-in-human study reports monotherapy in patients with metastatic castration-resistant prostate cancer (mCRPC). Ninety-seven patients received ≥1 dose weekly (QW) or Q2W in the range of 0.001–2.0 mg IV. MTD was identified as 0.1 mg on day 1 (D1), 0.3 mg on day 8, 1.0 mg on day 15, and 1.5 mg IV QW on day 22+. The most common treatment-related adverse events were cytokine release syndrome (CRS; 72%), fatigue (45%), and myalgia (34%). CRS occurred primarily during cycle 1 and improved with pre-operative dosing and stepwise administration. Prostate-specific antigen (PSA) and RECIST (response assessment criteria for solid tumors) responses in the cohort were encouraging (49% PSA50; 24% objective response rate [ORR]), with a higher frequency at the target dose of ≥0.75 mg (59% PSA50; 41% ORR). No grade 4 or 5 CRS events were reported. Overall, all CRS events were resolved with standard management (using acetaminophen, IV infusion, and tocilizumab and / or corticosteroids). Salulidestatin demonstrated encouraging responses (PSA and RECIST) and manageable safety in patients with advanced mCRPC compared to established treatments.

[0060] The preliminary efficacy results observed with salitoprine were numerically superior to those reported for other TCEs in prostate cancer. Efficacy measured by PSA and objective response measured by RECIST were encouraging in this heavily pre-treated mCRPC population, and responses occurred with greater frequency in the higher-dose cohort. A decrease in PSA was observed starting with 0.1 mg salitoprine, with 49% of patients achieving a confirmed PSA50 response and 28% achieving a PSA90 response. At higher doses, RECIST-evaluable responses were achieved in 41% of evaluable patients. This trial has demonstrated that a high proportion of patients can achieve significant clinical responses, which could translate into overall clinical benefit.

[0061] The initial efficacy results observed with salitoprine were numerically superior to those reported for other TCEs in prostate cancer. Efficacy measured by PSA and objective response by RECIST were encouraging in this heavily pre-treated mCRPC population, and responses occurred with greater frequency in the higher-dose cohort. A decrease in PSA was observed starting with 0.1 mg salitoprine, with 49% of patients achieving a confirmed PSA50 response and 28% achieving a PSA90 response. At higher doses, responses were achieved in 41% of RECIST-evaluable patients.

[0062] Targeted immunotherapy using TCEs requires the combination of CD3+ T cells and tumor-associated antigens. Saluridemin exhibits dose-dependent changes in peripheral pharmacodynamic biomarkers of TCE activity, namely T cell marginalization, T cell activation, and cytokine induction. The magnitude of these changes in PD biomarkers is consistent with the observed decrease in PSA.

[0063] The overall incidence of ADA during treatment was 54%, with 8 patients exhibiting transient antibody responses. ADA responses were not dose-dependent and did not lead to adverse events (AEs). In approximately one-quarter of patients, the impact on clinical response was assessed due to the presence of neutralizing and / or pharmacokinetic (PK) ADA. Neutralizing ADA typically began after cycle 3, while responses occurred within the first two cycles; it was not expected to affect the overall response rate.

[0064] This is the first clinical report of a TCE therapy targeting STEAP1 in prostate cancer. This study provides proof of concept for TCE as a potential treatment modality for prostate cancer, supported by a large number of observed radiological and PSA responses. To date, the only STEAP1-targeting agent explored clinically is the STEAP1 antibody-drug conjugate (ADC), which is limited by toxicity due to its monomethylolpropionate E (MMAE) payload (Maecker et al., MAbs. [Monoclonal Antibodies] 2023 Jan-Dec;15(1):2229101). In summary, this study demonstrates the feasibility of targeting STEAP1 with TCE and the potential of salinomycin as a novel treatment paradigm for patients with mCRPC.

[0065] In patients with prostate cancer, the dosing regimen of anti-STEAP1 antigen-binding proteins such as salinomycin may optionally include stepwise administration. To help mitigate cytokine release and ensure safe treatment with an active dose of an anti-STEAP1 antigen-binding protein (e.g., salinomycin), stepwise administration may consist of two or three steps, each a relatively small dose increase. The initial dose and target dose are also within a relatively narrow range, demonstrating efficacy in patients with prostate cancer. The dose of anti-STEAP1 antigen-binding proteins (salinomycin) is also relatively low compared to the doses administered in clinical trials of bispecific T-cell conjugates that bind DLL3 and CD3. Ares et al., J. Clin. Oncol. [Journal of Clinical Oncology] 2023 1 June;41(16):2893-2903 describe a maximal pharmacodynamic response following an initial administration of 1 mg of a stepwise dose of a bispecific T-cell conjugate that binds DLL3 and CD3, followed by an extension dose of 100 mg. See also Aggarwal et al., J. Clin. Onc., vol. 42(16), May 29, 2024, which disclosed talatumab at step-up doses of 1 mg and target doses of 100 mg; and Ahn et al., N Engl J Med, 2023;389:2063-2075, which disclosed talatumab at target doses of 10 mg and 100 mg.

[0066] In prostate cancer, several PSMA-targeting TCEs have entered clinical trials, but limited success has been observed due to minimal efficacy, toxicity, and short duration of response (DOR) (see, for example, Sorrentino et al., Cancers (Basel) 2023; 15; Powers et al., J. Hematol Oncol 2020; 13:144; and Tucker et al., Cancer Med 2019; 8:4644-55). For instance, JNJ-63898081 (a bispecific antibody against PSMA and CD3) resulted in a transient decrease in prostate-specific antigen (PSA), with 2 out of 39 patients (5%) experiencing a confirmed PSA50 response without radiological response in a phase 1 study of mCRPC patients (Lim et al., Clin Genitourin Cancer 2023; 21:366-75). The PSMA-targeting TCEHPN424 study reported a PSA50 response in 3 out of 63 patients (5%), a confirmed solid tumor response assessment criteria (RECIST) response in 1 out of 34 patients, and manageable safety (Bono et al., J. Clin. Onc. [Journal of Clinical Oncology] 2021;39:5013-13). Combination therapy can further improve efficacy by inducing synergistic effects and / or overcoming resistance mechanisms. This disclosure considers the use of salinomycin in combination with standard-of-care hormone and radioligand therapy in patients. In some embodiments, the patients had advanced prostate cancer. In some embodiments, the patients had previously received 0 or 1 novel hormone therapy (NHT).

[0067] The compound of Formula 1 may have one of the following radionuclides that are complexed with the chelating agent: 89 Zr、 44 Sc、 111 In、 90 Y、 66 Ga、 67 Ga、 68 Ga、 177 Lu、 99m Tc, 61 Cu、 62 Cu、 64 Cu、 67 Cu、 149 Tb, 152 Tb, 155 Tb, 161 Tb, 153 Gd, 155 Gd, 157Gd, 213 Bi、 225 Ac、 230 U、 223 Ra、 165 Er or Fe.

[0068] Although NHTs (e.g., abiraterone, enzalutamide, apalutamide, and dalolutamide) and taxanes (e.g., docetaxel and cabazitaxel) are standard care agents for non-metastatic and / or metastatic, castration-resistant prostate cancer, most patients will progress after treatment.

[0069] This disclosure provides a treatment regimen in which an anti-STEAP1 antigen-binding protein (e.g., salimethrin) is administered in combination with one or more other agents according to the method of the invention, the other one or more agents including abiraterone, enzalutamide, cabazitaxel, dalostumamide, apalutamide, lutetium 177 vepeptide tetracetan (PLUVICTO®), PSMA radioligand therapy, PSMA immunotherapy, radium-223, PARP inhibitors, PSMA antibody-drug conjugates, B7H3 antibody-drug conjugates, radiotherapy, and / or standard care therapy for prostate cancer.

[0070] Abiraterone is a cytochrome P450 (CYP)17 inhibitor used in combination with prednisone (or prednisolone in some regions) to treat patients with mCRPC, and in some regions, to treat patients with metastatic or high-risk castration-sensitive prostate cancer (CSPC). Among other mechanisms, disease recurrence after abiraterone may be caused by increased androgen receptor expression (e.g., androgen receptor amplification) (Galletti et al., Cancer Treat Rev. 2017 June;57:16-27).

[0071] Enzalutamide is an androgen receptor inhibitor that acts on different steps in the androgen receptor signaling pathway. Enzalutamide has been shown to competitively inhibit the binding of androgens to androgen receptors; thus inhibiting the nuclear translocation of androgen receptors and their interaction with DNA. Enzalutamide is indicated for the treatment of patients with CRPC and, in some regions, for the treatment of patients with metastatic hormone-sensitive prostate cancer. Among other mechanisms, disease relapse after enzalutamide treatment is partly due to mutations in androgen receptors (like ARV7) and increased androgen receptor expression (e.g., androgen receptor amplification) (Galletti et al., ibid.).

[0072] However, it is also envisioned that salinomycin could be administered in early disease settings without concurrent ADT. Prostate-specific membrane antigen (PSMA) is a type II cell surface membrane-bound glycoprotein with a molecular weight of approximately 110 kD, comprising intracellular segments (amino acids 1-18), transmembrane domains (amino acids 19-43), and extensive extracellular domains (amino acids 44-750). PSMA is highly expressed in most prostate cancer cells and is overexpressed in malignant prostate tissue compared to other organs in the body, such as the kidneys, proximal small intestine, and salivary glands. Unlike the downregulation of prostate-specific antigen (PSA) expression following androgen blockade, PSMA expression is significantly increased in both primary and metastatic tumor specimens (Kawakami et al., Wright et al.). PSMA is also highly expressed in secondary prostate tumors and occult metastatic disease. PLUVICTO® (lutetium 177 vitrapeptide tetracetan; 177 Lu-PSMA-617 is an approved therapy for patients with mCRPC who have previously received androgen receptor (AR) pathway inhibitors (ARPIs) and taxane-based chemotherapy. It targets PSMA-expressing cells with lutetium-177 (177Lu), a radioligand that emits beta particles. This treatment resulted in a 4-month overall survival benefit, with a median of 15.3 months, indicating ample room for further improvement. PLUVICTO® is currently being explored in patients who have not been exposed to prior chemotherapy.

[0073] Anti-STEAP1 antigen-binding protein (or STEAP1 antigen-binding protein) is a molecule that binds to human STEAP1. This molecule can further bind to another target, such as a cell surface antigen, like CD3. Non-limiting examples of such molecules include antibodies (including bispecific antibodies) and fragments thereof, as well as T-cell conjugate molecules, including molecules in the form of XmAb 2+1 and bispecific T-cell conjugate molecules.

[0074] For example, when the anti-STEAP1 antigen-binding protein binds with a dissociation constant (KD) of ≤ 10⁻⁷ M, it binds to its target, as measured by surface plasmon resonance technology (e.g., BIACore, GE Healthcare Uppsala, Sweden) or kinetic exclusion assay (KinExA, Sapidyne, Boise, Idaho).

[0075] Bispecific T-cell conjugate molecules are recombinant protein constructs prepared from two flexible, linked antibody-derived binding domains. The term "bispecific T-cell conjugate molecule" includes the "BiTE® molecule". One binding domain of the bispecific T-cell conjugate is specific to a selected tumor-associated surface antigen on the target cell; the second binding domain is specific to CD3 (a subunit of the T-cell receptor complex on T cells). Through its specific design, the bispecific T-cell conjugate molecule is uniquely suited to transiently bind T cells to target cells while simultaneously and potently activating the inherent cytolytic potential of T cells against target cells (Yang, Fa; Wen, Weihong; Qin, Weijun (2016). "Bispecific Antibodies as a Development Platform for New Concepts and Treatment Strategies". International Journal of Molecular Sciences. 18 (1): 48 (2016)). Bispecific T-cell conjugate molecules are bispecific, meaning they bind to two targets on two different types of cells simultaneously (target antigens on target cells, such as STEAP1, and CD3 on T cells).

[0076] As used in this article, the “XmAb 2+1” molecule (which can be used interchangeably with the “multi-chain T-cell conjugate molecule” or the “central scFv molecule”) contains two Fab domains and one scFv domain, where each Fab domain binds to one target (e.g., STEAP1) and the scFv domain binds to another target (e.g., CD3). The XmAb 2+1 molecule is in the form of... Figure 1As shown. An scFv domain (e.g., CD3-binding) is inserted between the Fc domain and the CHI-Fv region, thereby providing a third antigen-binding domain (e.g., two Fabs, each binding STEAP1, and one scFv binding CD3). The anti-CD3 scFv is "inserted" into the HC, meaning the scFv is linked via a linker in the HC. In this embodiment, a polypeptide comprises a first heavy chain containing a first variable heavy chain domain, a CH1 domain (and optionally a linker / hinge), and an Fc domain, wherein the scFv comprises an scFv variable light chain domain, an scFv linker, and an scFv variable heavy chain domain. Using optional domain connectors (VH1-CH1-[optional domain connector]-VH2-scFv connector-VL2-[optional domain connector including hinge]-CH2-CH3, or for the opposite orientation of scFv, VH1-CH1-[optional domain connector]-VL2-scFv connector-VH2-[optional domain connector including hinge]-CH2-CH3), scFv is covalently attached between the C-terminus of the CH1 domain of the heavy chain constant domain and the N-terminus of the first Fc domain. In some embodiments, the first polypeptide is VH1-CH1-domain connector-VH2-scFv connector-VL2-domain connector-CH2-CH3. Other polypeptides are standard Fabs (i.e., VH1-CH1-domain connector (e.g., hinge)-CH2-CH3). This embodiment further utilizes two light chains, each comprising a variable light chain domain and a constant light chain domain, which bind to the heavy chain to form two identical Fabs binding to the target. In certain embodiments, the STEAP1 Fab CD3 scFv central scFv molecule (or the STEAP1 Fab CD3 scFv XmAb 2+1 molecule) comprises two Fab domains each binding to the STEAP1 Fab and one scFv binding to the CD3 scFv. In some specific embodiments, the central-scFv or XmAb 2+1 molecule is salinomycin.

[0077] An example of an anti-STEAP1 antigen-binding protein is salitoprine. Further description of salitoprine can be found in PCT Publication No. WO 2020 / 010079, the entire contents of which are incorporated herein by reference. The sequence of salitoprine is provided in Table 4. Salitoprine comprises: an HC containing SEQ ID NO: 17, an HC containing an inserted CD3 scFv of SEQ ID NO: 19, and two light chains, each containing SEQ ID NO: 18. In an exemplary aspect, the molecule of the present invention comprises a sequence containing a C-terminal lysine, as shown in SEQ ID NO: 17 or 19. In a preferred aspect, the antigen-binding protein comprises one or two HCs without a C-terminal lysine, as shown in SEQ ID NO: 22 and 25. Furthermore, the N-terminal glutamine and / or N-terminal glutamate of the HC or HCVR can be converted to pyroglutamic acid, as shown in SEQ ID NO: 20, 21, 23, and 24. Furthermore, the N-terminal glutamine and / or N-terminal glutamate of HC can be converted to pyroglutamate, and the sequence may lack a C-terminal lysine, as shown in SEQ ID NO: 23 and 26. All forms of the antigen-binding protein of the present invention are envisioned.

[0078] The first and second Fc domains each refer to half of the Fc (fragmentally crystallizable) region. The Fc region contains two CH2 domains and two CH3 domains. Therefore, the first and second Fc domains each contain a CH2 domain and a CH3 domain.

[0079] Anti-STEAP1 antigen-binding protein is typically administered to patients as a pharmaceutical composition, which may include pharmaceutically acceptable carriers, excipients, or diluents. "Pharmaceutically acceptable" means a molecule, compound, or composition that is non-toxic to human recipients at the doses and concentrations used and / or does not cause allergic reactions or adverse reactions when administered to humans. In some embodiments, the pharmaceutical composition may contain formulation substances to adjust, maintain, or retain, for example, the composition's pH, permeability, viscosity, clarity, color, isotonicity, odor, sterility, stability, dissolution or release rate, absorption, or permeation. In such embodiments, suitable formulation materials include, but are not limited to, amino acids (e.g., glycine, glutamine, asparagine, arginine, or lysine); antimicrobial agents; antioxidants (e.g., ascorbic acid, sodium sulfite, or sodium bisulfite); buffers (e.g., borates, bicarbonates, Tris-HCl, citrates, phosphates, or other organic acids); leavening agents (e.g., mannitol or glycine); chelating agents (e.g., ethylenediaminetetraacetic acid (EDTA)); complexing agents (e.g., caffeine, polyvinylpyrrolidone, β-cyclodextrin, or hydroxypropyl-β-cyclodextrin); fillers; monosaccharides; disaccharides; and other carbohydrates (e.g., glucose, mannose, or dextrin); proteins (e.g., serum albumin, gelatin, or immunoglobulins); colorants, flavorings, and diluents; emulsifiers; hydrophilic polymers (e.g., polyvinylpyrrolidone); low molecular weight peptides; and other formulation materials. Salt counterions (e.g., sodium); preservatives (e.g., benzalkonium chloride, benzoic acid, salicylic acid, thimerosal, phenethyl alcohol, methylparaben, propylparaben, chlorhexidine, sorbic acid, or hydrogen peroxide); solvents (e.g., glycerol, propylene glycol, or polyethylene glycol); sugar alcohols (e.g., mannitol or sorbitol); suspending agents; surfactants or wetting agents (e.g., pluronic, PEG, sorbitol esters, polysorbates (e.g., polysorbate 20, polysorbate 80), triton, tromethamine, lecithin, cholesterol, tyloxapal); stability enhancers (e.g., sucrose or sorbitol); tension enhancers (e.g., alkali metal halides, preferably sodium chloride or potassium chloride, mannitol or sorbitol); delivery media; diluents; excipients and / or pharmaceutical adjuvants. Methods and suitable materials for formulating molecules for therapeutic purposes are known in the pharmaceutical field and described, for example, in REMINGTON'S PHARMACEUTICAL SCIENCES, 18th edition (edited by AR Genrmo), 1990, Mack Publishing Company. In some embodiments, the selection of carriers and excipients used for incorporation into the pharmaceutical composition affects the physical state, stability, in vivo release rate, and in vivo clearance rate of the anti-STEAP1 antigen-binding protein.

[0080] Anti-STEAP1 antigen-binding protein, such as salimethrin, can be formulated as pre-lyophilized preparations, such as pre-lyophilized preparations of 0.3 mg / mL to 2.5 mg / mL salimethrin (e.g., 1 mg / mL) with 10 mM glutamate, 9% (w / v) sucrose, 0.01% (w / v) polysorbate 80, pH 4.20 (i.e., salimethrin is present in a lyophilized preparation containing 0.3 mg / mL to 2.5 mg / mL salimethrin (e.g., 1 mg / mL), 10 mM glutamate, 9% (w / v) sucrose, 0.01% (w / v) polysorbate 80, pH 4.20). Preparations of anti-STEAP1 antigen-binding protein are also disclosed in PCT Publication No. WO2019 / 157340, the entire contents of which are incorporated herein by reference.

[0081] It should be understood that when this article refers to administering a certain dose of anti-STEAP1 antigen-binding protein to a patient, the anti-STEAP1 antigen-binding protein is present in the pharmaceutical composition.

[0082] This study proposes administering lutetium-177 vepletide tetracetan to prostate cancer patients for two to six cycles, followed by administration of anti-STEAP1 antigen-binding protein. The anti-STEAP1 antigen-binding protein can be administered in stepwise doses as described herein until the target dose is reached.

[0083] This document envisions administering anti-STEAP1 antigen-binding protein and lutetium glutamate (L-177) tetracetamol in the same cycle but on different dates. In some embodiments, anti-STEAP1 antigen-binding protein and L-177 tetracetamol will be administered according to Example 2. In some embodiments, L-177 tetracetamol will be administered, and after at least 7 days, anti-STEAP1 antigen-binding protein will be administered in stepwise doses until the target dose of anti-STEAP1 antigen-binding protein is reached. After the target dose of anti-STEAP1 antigen-binding protein is reached, anti-STEAP1 antigen-binding protein will be administered at the target dose.

[0084] This paper proposes administering anti-STEAP1 antigen-binding protein as described herein in a stepwise dose manner, followed by administering anti-STEAP1 antigen-binding protein at the target dose for up to five cycles, and then administering lutetium-177 veprotide tetracetan for up to six cycles.

[0085] The present invention also includes a kit for treating prostate cancer in patients of need. In one embodiment, the kit comprises a pharmaceutical composition against the STEAP1 antigen-binding protein and packaging material providing instructions for use of the pharmaceutical composition. The pharmaceutical composition of the kit may be in a container (such as a vial or syringe). The pharmaceutical composition may be provided as a solution, suspension, gel, emulsion, solid, crystal, or as a dehydrated or lyophilized powder. In embodiments where the pharmaceutical composition is provided as a powder, the kit may also include a diluent (e.g., water, saline, or phosphate-buffered saline) necessary for reconstituted the pharmaceutical composition, and instructions for preparing the composition for administration.

[0086] In some embodiments, the present invention also provides a kit comprising a pharmaceutical composition and instructions for using the pharmaceutical composition to deliver a therapeutically effective dose, for example, by intravenous infusion for treating prostate cancer in patients of need. In embodiments where these pharmaceutical compositions are provided in lyophilized or dry powder form, the kit may include a diluent and instructions for reconstituted the pharmaceutical composition prior to administration.

[0087] Anti-STEAP1 antigen-binding protein can be administered via a “stepwise” approach, which refers to increasing the dose administered to the patient before reaching the target dose level (see also, for example, Ball et al., MAbs. [Monoclonal Antibodies] Jan-Dec 2023;15(1):2181016). Stepwise administration can include one, two, three, four, or five steps (i.e., administering multiple doses, increasing the amount of therapeutic agent administered). Each “step” is an increase in the dose administered to the patient from the previous dose administered. Stepwise administration can include two or three steps. Stepwise administration can include two steps to reach, for example, a target dose of 0.75 mg. Stepwise administration may include three steps to reach, for example, a target dose of 1.5 mg. Stepwise administration can be implemented to reduce the incidence of cytokine release syndrome. For example, stepwise administration may begin with an initial dose on day 1 of cycle 1 and increase by one step on day 8, then continue to reach the target dose. At the end of the stepwise dosing regimen, the target dose can be administered (e.g., once weekly, once every two weeks, once every three weeks, or once every four weeks). The target dose can be administered at any interval over the desired time period (e.g., four weeks, five months, or eleven months) to provide an overall treatment period of, for example, two months, six months, or twelve months.

[0088] Anti-STEAP1 antigen-binding protein (e.g., salinomycin) can be administered first via a stepwise approach to reach the target dose of anti-STEAP1 antigen-binding protein (salinomycin). After reaching the target dose of salinomycin, the patient can be treated with another therapeutic agent (e.g., a combination partner), although this disclosure also considers administering the other therapeutic agent before reaching the target dose (e.g., administration during C1 D1). This other therapeutic agent can be administered together with salinomycin in a cycle.

[0089] A “cycle” refers to a repetitive treatment pattern and can be defined by anti-STEAP1 antigen-binding protein (e.g., salimethrin) or a combination of both. Cycles also provide a basis for patient follow-up. Cycles may persist even with continuous dosing. Depending on the treatment, cycles can include different numbers of days. A cycle refers to a period of time during which the required actions can be repeated. This is the standard way to define the duration of treatment by defined times of treatment administration. For example, an anti-STEAP1 antigen-binding protein (salimethrin) cycle could be every 28 days. A PLUVICTO® cycle could be 42 days (administered every six weeks).

[0090] When more than one therapeutic agent (such as anti-STEAP1 antigen-binding protein and lutetium-177 vepletide tetracetan) is administered to a patient during their treatment process, these therapeutic agents are referred to as being administered in combination. When administered in combination, the therapeutic agents may be administered on the same day, or they may be administered several days, weeks, or months apart. Exemplary dosing regimens are described in this article and in examples.

[0091] In several respects, this disclosure provides a method in which an anti-STEAP1 antigen-binding protein (e.g., salidomide) is administered to a patient in need during a treatment process comprising two or more cycles, each cycle optionally comprising 28 days. Cycle 1 comprises a three-step dosing regimen in which the patient receives 0.1 mg of salidomide on day 1 (C1 D1), 0.3 mg of salidomide on day 8 (C1 D8), 1 mg of salidomide on day 15 (C1 D15), and 1.5 mg of salidomide on day 22 (C1 D22). In this case, 1.5 mg of salidomide is the “target dose.” Following Cycle 1, one or more further treatment cycles (i.e., Cycle 2, Cycle 3, etc.) are administered for a desired duration. In each respect, cycle 2 and thereafter (i.e., each cycle after cycle 1) comprises administering 1.5 mg salitopamine every two weeks; for example, administering 1.5 mg salitopamine on C2 D1 and 1.5 mg salitopamine on C2 D15. Alternatively, cycle 2 may comprise administering salitopamine every three weeks (e.g., 1.5 mg salitopamine on Q3W) or every four weeks (e.g., 1.5 mg salitopamine on Q4W). Cycle 2 may be repeated once or multiple times. For example, cycle 2 may be repeated five times to provide treatment for the patient over six months. Alternatively, cycle 2 may be repeated 11 times to provide treatment for the patient over 12 months. In each respect, the patient administers 1000 mg abiraterone orally once daily, and prednisone at a dose of 5 mg twice daily or at a dose of 10 mg once daily. In each respect, the patient administers 160 mg enzalutamide orally once daily.

[0092] This disclosure provides a method in which an anti-STEAP1 antigen-binding protein, such as salinomycin, is administered according to the method of this disclosure. This disclosure also provides an anti-STEAP1 antigen-binding protein, such as salinomycin, for the treatment of prostate cancer, wherein the anti-STEAP1 antigen-binding protein is formulated for administration according to the method of this disclosure. In one embodiment, the dose of the anti-STEAP1 antigen-binding protein is about 0.001 mg to about 2 mg, about 0.1 mg to about 1.5 mg, about 0.1 mg to about 2 mg, or about 0.1 mg to about 1.5 mg. In one embodiment, the dose is 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.75 mg, 0.8 mg, 0.9 mg, 1.0 mg, 1.1 mg, 1.2 mg, 1.3 mg, 1.4 mg, 1.5 mg, 1.6 mg, or 1.7 mg. In one embodiment, the dose is about 0.1 mg. In one embodiment, the dose is about 0.3 mg. In one embodiment, the dose is about 0.75 mg. In one embodiment, the dose is about 1 mg. In one embodiment, the dose is about 1.5 mg. In one embodiment, the dose is 0.1 mg. In one embodiment, the dose is 0.3 mg. In one embodiment, the dose is 0.75 mg. In one embodiment, the dose is 1 mg. In one embodiment, the dose is 1.5 mg. In one embodiment, the dose is administered once weekly. In one embodiment, the dose is administered once every two weeks. In one embodiment, the dose is administered once every three weeks. In one embodiment, the dose is administered once every four weeks. In one embodiment, the dose is administered intravenously. In one embodiment, the dose is administered once weekly starting from cycle 1. In one embodiment, the dose is administered once weekly starting from cycle 2. In one embodiment, the dose is administered once every two weeks starting from cycle 2. In one embodiment, the dose is administered once every three weeks starting from cycle 2. In one embodiment, the dose is administered once every four weeks starting from cycle 2. In one embodiment, the dose is administered once weekly in cycle 1, and then once every two weeks starting from day 1 of cycle 2. In one embodiment, the dose is administered once weekly in cycle 1, and then once every two weeks once the target dose is reached. In one embodiment, the dose is administered once weekly in cycle 1, and then once every three weeks once the target dose is reached. In one embodiment, the dose is administered weekly during the first cycle, and then every four weeks once the target dose is reached.

[0093] The phrase “a dose” refers to a dose of a molecule (drug) that may be administered to a patient simultaneously (on the same day) with another different molecule or sequentially (e.g., at least one dose of a molecule administered to a patient is temporally separate from at least one dose of another molecule administered to the patient). This text also envisions that a dose of a molecule may be followed by at least one additional dose of the same molecule, and then at least one dose of a different molecule.

[0094] Generally, intravenous (IV) medications can be administered together on the same day. Oral medications and IV medications can also be administered on the same day. For example, salidomide and abiraterone can be administered together on the same day. Medications can also be administered on separate days. For example, salidomide and PLUVICTO® can be administered on separate days.

[0095] As used interchangeably herein, “treatment and / or treating and / or treating” is intended to refer to all processes in which there may be a slowing, interruption, prevention, control, cessation, or reversal of the progression of the disorder described herein, but does not necessarily mean the complete elimination of all disorder symptoms. Treatment includes the administration of anti-STEAP1 antigen-binding protein to treat a human disease or condition, such as prostate cancer, that would benefit from the activity of anti-STEAP1 antigen-binding protein, and includes: (a) inhibiting further development of the disease; and / or (b) alleviating the disease, i.e., resulting in the remission of the disease or disorder or reduction of its symptoms or complications.

[0096] The size of a patient's prostate (and / or metastatic lesions) can be determined using methods known in the art. These methods include computed tomography (CT), MRI, and / or bone scans. PSA can be determined using blood tests known in the art.

[0097] This disclosure contemplates a method of the present invention to reduce the size of a patient's prostate tumor. In one embodiment, the tumor is reduced by 10%. In one embodiment, the tumor is reduced by 20%. In one embodiment, the tumor is reduced by 30%. In one embodiment, the tumor is reduced by 40%. In one embodiment, the tumor is reduced by 50%. In one embodiment, the tumor is reduced by 60%. In one embodiment, the tumor is reduced by 70%. In one embodiment, the tumor is reduced by 80%. In one embodiment, the tumor is reduced by 90%. In one embodiment, the tumor is no longer present.

[0098] This disclosure contemplates a method of the present invention to reduce a patient's PSA. This disclosure also contemplates a method of the present invention to slow or stop the spread of cancer cells to one or more other sites on a patient's body.

[0099] This disclosure contemplates the use of the present invention to reduce the size of a patient's prostate tumor. In one embodiment, the tumor is reduced by 10%. In one embodiment, the tumor is reduced by 20%. In one embodiment, the tumor is reduced by 30%. In one embodiment, the tumor is reduced by 40%. In one embodiment, the tumor is reduced by 50%. In one embodiment, the tumor is reduced by 60%. In one embodiment, the tumor is reduced by 70%. In one embodiment, the tumor is reduced by 80%. In one embodiment, the tumor is reduced by 90%. In one embodiment, the tumor is no longer present.

[0100] This disclosure contemplates the use of the invention for reducing PSA in patients. This disclosure also contemplates a method of the invention to slow or stop the spread of cancer cells to one or more other sites in a patient's body.

[0101] This disclosure contemplates the manufacture of a medicament of the present invention for reducing the size of a patient's prostate tumor. In one embodiment, the tumor is reduced by 10%. In one embodiment, the tumor is reduced by 20%. In one embodiment, the tumor is reduced by 30%. In one embodiment, the tumor is reduced by 40%. In one embodiment, the tumor is reduced by 50%. In one embodiment, the tumor is reduced by 60%. In one embodiment, the tumor is reduced by 70%. In one embodiment, the tumor is reduced by 80%. In one embodiment, the tumor is reduced by 90%. In one embodiment, the tumor is no longer present.

[0102] This disclosure contemplates the manufacture of a medicament of the present invention for lowering a patient's PSA level. This disclosure also contemplates a method of the present invention to slow or stop the spread of cancer cells to one or more other sites in a patient's body.

[0103] The term "about" refers to a value that is within 10% above or below the reference value, and includes the reference value.

[0104] This invention considers stepwise administration of anti-STEAP1 antigen-binding protein to reduce cytokine release syndrome (CRS) that may be induced by T-cell conjugate therapy (compared to non-stepwise administration of anti-STEAP1 antigen-binding protein). CRS can occur with the activation of bystander immune and non-immune cells and may lead to complications. According to Lee et al., ASTCT Consensus Grading for Cytokine Release Syndrome and NeurologicToxicity Associated with Immune Effector Cells. Biol Blood Marrow Transplant. 2019;25(4):625 638, CRS can be graded. Example

[0105] Example 1: Phase 1 Clinical Trial Design

[0106] This study (NCT04221542) was designed to evaluate the safety, tolerability, pharmacokinetics (PK), and antitumor activity of salinomycin as monotherapy or in combination with other drugs in patients with mCRPC (pt), and to determine the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D). Parts 1 through 3 will evaluate monotherapy with different dosing regimens and target doses, as well as SC administration. Part 4 will evaluate combinations with established standard of care mCRPC medications. In 4A and 4B, salinomycin plus abiraterone acetate (4A) or salinomycin plus enzalutamide (4B) will be used in patients previously treated with 0, 1, or 2 NHTs and up to 1 taxane (HSPC). Part 5 will be a dose extension in an outpatient setting based on the efficacy and toxicities of the dose exploration in Part 1. The primary endpoints include dose-limiting toxicities, treatment-associated and treatment-related adverse events, and changes in clinical and laboratory parameters. Key secondary endpoints include pharmacokinetic (PK), objective response according to RECIST 1.1, prostate-specific antigen (PSA) response, radiographic progression-free survival (PFS) according to PCWG3, and overall survival. Key inclusion criteria are men with pathologically confirmed mCRPC, evidence of disease progression, and an ECOG performance status of 0 or 1. Key exclusion criteria are small cell or neuroendocrine prostate cancer, untreated CNS metastases or leptomeningeal disease, and prior or current autoimmune disease or any disease requiring chronic immunosuppressive therapy. In Part 1, dose escalation will be guided by a Bayesian logistic regression model. In Parts 2 and 4, AMG 509 dosing will be based on data from the single-therapy portion, and dose exploration will be guided by an mTPI-2 design. Study sites are located in North America, Australia, Asia, and Europe.

[0107] This is an open-label, escalation, multiple-dose, phase 1, multi-cohort study evaluating salururitamine in patients with mCRPC. The study will include up to 441 patients. The study comprised the following parts: Part 1: Salurate tamine monotherapy administered via IV infusion to patients previously treated with NHT and 1 to 2 taxanes; Part 2: Salurate tamine monotherapy administered via SC injection to patients previously treated with NHT and 1 to 2 taxanes (Part 2 completed); Part 3: Salurate tamine monotherapy administered via IV infusion to patients who had not previously used or had used 1 NHT (possibly for hormone-sensitive prostate cancer [HSPC]) and had not previously used taxanes; Part 4: Salurate tamine administered via IV in combination with abiraterone acetate (Part 4A) or enzalutamide (Part 4B) to patients previously treated with 0-2 NHTs (for hormone-sensitive or castration-resistant diseases) in Parts 4A and 4B, and to patients previously without or with 1 taxane for hormone-sensitive diseases in Parts 4A and 4B. In Part 4A, salurulitamine is administered intravenously starting on day 1 of cycle 1, and abiraterone is administered according to the abiraterone label. In Part 4B, salurulitamine is administered intravenously, and enzalutamide is administered according to the enzalutamide label one week after the target dose of salurulitamine is reached (or, based on an alternative based on emerging safety data). Part 5: Salurulitamine monotherapy is administered via intravenous infusion in an outpatient setting to patients previously treated with 1-2 NHTs and 1-2 taxanes.

[0108] In Parts 1, 3, 4, and 5, salinomycin will be administered weekly (QW) or Q2W as a short-term IV infusion (approximately 60 minutes) based on emerging data and DLRT recommendations, with Q3W or Q4W schedules potentially being explored. The dosing regimens and schedules in Parts 3 and 4 will be adjusted based on emerging data and DLRT recommendations to follow the regimens and schedules explored in Part 1. The dosing regimen and schedule for Part 5 will be selected based on emerging data and DLRT recommendations. This may include stepwise dosing. In Part 2, salinomycin will be administered via deep subcutaneous injection QW or Q2W. Salullitam IV monotherapy dose escalation will occur concurrently with combination and SC dose escalation, and more than one dosing regimen may be evaluated in parallel. The dose in Part 3 will be the MTD or RP2D determined in the dose exploration or expansion in Part 1. In all parts, patients will require ADT while being treated with AMG 509.

[0109] Part 1, the dose exploration phase, will enroll up to 100 mCRPC patients. The dose exploration will be conducted in two phases: a single-patient cohort, followed by a multi-patient cohort (2 to 4 patients per cohort). Planned dose levels are QW IV administration of 0.001, 0.003, 0.01, 0.03, 0.1, 0.3, 1, 1.5, and 2 mg. A 2-week (Q2W) schedule can be introduced earlier, and DLRT can recommend exploring a 3-week (Q3W) or 4-week (Q4W) schedule starting from cycle 2.

[0110] Table 1. Salrutitam dosage and dosing regimen in Part 1.

[0111]

[0112] The dose escalation / decrease decisions in Part 1 will be guided by a dose-toxicity BLRM model. The MTD of BLRM is the dose level that predicts the highest probability of DLT incidence within the target range of 20% to 33% under overdose control conditions. To control the risk of overdose, the MTD must be less than 40% of the predicted overdose probability (DLT incidence > 33%).

[0113] The MTDs in Parts 2 and 4 are the dose levels that predict the highest probability of DLT incidence within the target range of 30% to 40%.

[0114] The primary endpoints included dose-limiting toxicity, adverse events occurring during treatment, treatment-related adverse events, and changes in vital signs, ECG, and clinical laboratory tests.

[0115] Secondary endpoints included: pharmacokinetic parameters, including but not limited to maximum serum concentration (Cmax), time to maximum concentration (Tmax), minimum serum concentration (Cmin), area under the concentration-time curve (AUC) within the dosing interval, cumulative effect after multiple doses, and half-life (t1 / 2) (if feasible); objective response (OR) according to RECIST 1.1 criteria for evaluation of response in solid tumors; prostate-specific antigen (PSA) response (30%, 50%, 70%, and 90%); PSA50 response at 12 weeks; duration of response (DOR) according to RECIST 1.1; PSA DOR based on PSA50; time to progression (radiological and PSA); progression-free survival (PFS) (radiological and PSA); and 6-month radiological PFS. 1, 2, and 3-year overall survival (OS); circulating tumor cell (CTC) response (CTC0) and CTC transformation rate; other PCWG3 recommended endpoints (time to symptomatic skeletal events, alkaline phosphatase [total, bone], lactate dehydrogenase [LDH], hemoglobin, neutrophil-to-lymphocyte ratio, urinary N-terminal peptide).

[0116] Once the mean time to drug delivery (MTD) is determined, enrollment will begin in the dose expansion phase to confirm safety and tolerability by evaluating three selected dosing regimens, and to further assess drug-induced disease (PD) and antitumor activity to select the most appropriate dose and schedule. These dosing regimens will be administered in parallel during the expansion phase and will include different dose levels and / or schedules, as shown in Table 2.

[0117] Table 2. Dosing schedule for salidomide during the extended phase of clinical trials.

[0118]

[0119] Patients will be randomly assigned to different expansion cohorts in a 1:1:1 ratio. Each expansion cohort is expected to include up to 50 patients (pts).

[0120] As of March 23, 2023, 97 patients had received ≥ 1 dose of salinomycin at 15 dose levels / timetables (DL) (28 patients [28.3%] for ≥ 6 months); 25 patients were still receiving treatment. The median (range) age was 67 (40–86) years; 67 patients (69.1%) had received > 3 prior lines of therapy. Treatment-interventional adverse events (TEAEs) were reported in 100% of patients (≥ Grade 3, 74.2%). The most common AE was cytokine release syndrome (CRS; 72.2%), predominantly Grade 1 / 2 (cycle 1), with one Grade 3 event (no Grade 4 / 5 CRS). In the 2 mg TD cohort, 3 / 6 patients with evaluable DLT experienced DLT, with 1.5 mg defined as MTD. Treatment-related TEAEs leading to discontinuation occurred in 17.5% of patients. Overall, 89 patients were evaluable for PSA; 66 patients were evaluable for RECIST. Forty-two patients (47.2%) experienced a PSA50 response (≥ 50% decrease in PSA); 24 patients (27.0%) experienced a PSA90 response. PSA responses were more frequent at higher doses (0.75 mg–2 mg) than at lower doses (0.001–0.3 mg): ≥ 90% (34.8% vs. 18.6%) patients and ≥ 50% (54.3% vs. 39.5%) patients. RECIST responses included 15 (22.7%) confirmed PRs and 30 (45.5%) confirmed SDs. At higher doses, 14 patients (38.9%) achieved confirmed PRs and 12 (33.3%) achieved confirmed SDs. Preliminary pharmacokinetic analysis showed that exposure increased proportionally to dose, ranging from 0.003 mg to 1.5 mg, with a mean terminal half-life of approximately 3–4 days.

[0121] Patients were initially enrolled in cohorts 1–6, receiving fixed (non-stepwise) weekly (QW) intravenous (IV) doses of 0.001 (n = 2), 0.003 (n = 4), 0.01 (n = 4), 0.03 (n = 4), 0.1 (n = 10), and 0.3 (n = 6) mg. In cohort 6, at 0.3 mg, two out of six patients experienced grade 3 CRS / encephalopathy and back pain, a dose level determined to be intolerable and exceeding the maximum tolerated dose (MTD) on day 1 of cycle 1. After adjusting preoperative medication, the 0.3 mg starting dose (cohort 8) remained intolerable, and the MTD for the first dose (initial dose) was confirmed to be 0.1 mg.

[0122] Start with a stepwise dosing regimen of 0.1 mg on day 1, and use one step (increase on day 8), two steps (increase on days 8 and 15), or three steps (increase on days 8, 15, and 22) to reach the target dose on day 8, day 15, or day 22.

[0123] In cohorts 7a and 10, a step-up dosing regimen of 0.1 to 0.3 mg or 0.1 to 1.0 mg was employed. The 0.1 to 0.3 mg regimen (cohort 7a) was well-tolerated, but the larger step-up dosing of 0.1 to 1.0 mg (cohort 10) was not well-tolerated because three of the four patients experienced DLT, including grade 3 atrial fibrillation / QT interval prolongation, grade 3 fasciitis / pharyngitis, and grade 3 arthralgia (one patient each). Based on the findings of the one-step dosing regimen, cohorts 7b, 7c, and 9 evaluated two-step dosing regimens with an initial dose of 0.1 mg, a dose of 0.3 mg on day 8, and a dose of 0.75 or 1.0 mg on day 15; all of these were determined to be well-tolerated.

[0124] Based on the findings of the two-step dosing regimen, cohorts 11, 12, and 13 evaluated three-step dosing regimens with an initial dose of 0.1 mg, a day 8 dose of 0.3 mg, a day 15 dose of 0.75 or 1.0 mg, and a day 22 dose of 1.5 or 2 mg. The target day 22 dose of 1.5 mg was found to be tolerable in cohorts 11 (day 15 dose of 0.75 mg) and 12 (day 15 dose of 1.0 mg). The highest day 22 dose of 2.0 mg was tested in cohort 13, but was deemed intolerable due to DLT occurring in 3 of the 4 evaluable patients (grade 3 myalgia [n = 2]; grade 3 back pain and arthralgia [n = 1]).

[0125] In summary, the maximum tolerated initial dose for the complete prevention regimen was 0.1 mg, and three stepwise dosing regimens, including 0.3 mg on day 8, 1.0 mg on day 15, and 1.5 mg IV QW on day 22, were identified as the MTD.

[0126] Salluritamine is well-tolerated for low-grade CRS (primarily in cycle 1) and has shown encouraging preliminary clinical efficacy in patients with mCRPC who have undergone extensive pretreatment.

[0127] Preliminary efficacy, as measured by PSA and RECIST, was encouraging in a large pre-treated mCRPC cohort, and responses occurred with greater frequency in the higher-dose cohort. Consistent with PD markers of T-cell activity, a decrease in PSA was observed starting from 0.1 mg salinomycin, with a large number of patients achieving confirmed PSA50 and PSA90 responses. At higher doses, these translated into ORs, with RECIST-assessable responses observed in 50% of patients.

[0128] The maximum tolerated dose was determined to be 1.5 mg, administered once weekly via a three-step schedule (0.1 mg on day 1 of cycle 1, 0.3 mg on day 8 of cycle 1, 1 mg on day 15 of cycle 1, and 1.5 mg on day 22 of cycle 1). In dose expansion, a second dosing schedule of 0.75 mg once weekly via a two-step schedule (0.1 mg on day 1 of cycle 1, 0.3 mg on day 8 of cycle 1, and 0.75 mg on day 15 of cycle 1) will be explored. A 1.5 mg dose every two weeks (Q2W) will also be explored. In this schedule, the three-step schedule will be used. Starting from cycle 2, the target dose of 1.5 mg will be administered every Q2W.

[0129] During the study, preliminary signs of clinical efficacy based on PSA reduction were observed at target dose levels of 0.1 mg or higher for salinomycin, with one OR observed in the cohort using a target dose of 0.3 mg. A higher incidence of OR was observed in the high-dose cohort (QW administration, target dose above 0.3 mg, considered safe and tolerable). Of the 67 patients with RECIST-evaluable disease, 16 (24%) achieved a confirmed partial response (PR); 32 (48%) had stable disease (SD); 13 (19%) had progressive disease (PD); and 6 (9%) had no evaluable disease. Figure 2(Table 3). RECIST OR was greater at higher doses, with 10 patients (50%) achieving confirmed PR. Response was typically achieved within the first two cycles of treatment, and the duration of response in the higher-dose cohort remains immature. Preliminary clinical benefits were observed in patients with varying disease burdens during the study, according to RECIST version 1.1, including reduced bone lesions and imaging responses.

[0130] Table 3. Summary of efficacy data in patients receiving salbutamol.

[0131]

[0132] PSA response is defined as a decrease of ≥ 50% and ≥ 90% compared to baseline PSA.

[0133] The PSA response evaluable analysis set was defined as all included patients who received ≥ 1 dose of salinomycin, had a measurable (i.e. > 0) baseline PSA, and had the opportunity to be followed up for ≥ 8 weeks from day 1. If the data cutoff was ≥ 8 weeks after day 1, patients who stopped disease assessment 8 weeks prior were included in this analysis set.

[0134] The RECIST version 1.1 remission evaluable analysis set was defined as enrolled patients with baseline measurable disease who had the opportunity to be followed up for ≥ 8 weeks from the first dose of salinomycin.

[0135] ‡ The best overall response that could not be evaluated included 5 patients who did not undergo post-baseline scans.

[0136] CR, complete response; PD, disease progression; PR, partial response; PSA, prostate-specific antigen; QW, weekly; RECIST, criteria for evaluating response in solid tumors; SD, stable disease.

[0137] In the PSA-evaluable analysis set (N = 87), 43 patients (49%) reported a confirmed PSA50 response, and 24 patients (28%) reported a confirmed PSA90 response. Figure 3In the low-dose (n = 43 evaluable patients) and high-dose (n = 44) cohorts, confirmed PSA50 responses were reported in 17 (40%) and 26 (59%) patients, respectively, while confirmed PSA90 responses occurred in 8 (19%) and 16 (36%) patients, respectively. One patient was a 65-year-old male with a preliminary diagnosis of stage IV prostate adenocarcinoma (Gleason score 9). The subject was receiving androgen deprivation therapy and had previously received treatment with bicalutamide, abiraterone, docetaxel, cabazitaxel, and carboplatin. After receiving IV salinomycin at a target dose of 1.5 mg in three steps, the subject demonstrated a confirmed PSA50 response, with a maximum 99% decrease in PSA from baseline on day 1 of cycle 7. CT scans showed three target lesions and multiple non-target lesions during screening. According to RECIST 1.1 criteria, imaging after two treatment cycles showed lesion shrinkage consistent with partial response (PR) (target lesion reduction of 37.3%), which was confirmed at 16 weeks and maintained at 24 weeks. Figure 4 and Figure 5 During the first treatment cycle, adverse events (AEs) were ≤ Grade 2 and included recurrent CRS, rash, worsening back pain, and tinea pedis. During subsequent treatment cycles, AEs of ≤ Grade 2 were reported, including rash, myalgia, and hyperkalemia.

[0138] Preliminary PK results showed that exposure increased proportionally with dose at the explored dose levels, with a mean terminal half-life of approximately 3–4 days. Based on preclinical studies, the lower and upper black horizontal dashed lines represent the 90% effective concentration (EC90) (74 ng / mL) in the in vitro mediated cell killing assay and the half-maximal inhibitory concentration (IC50) (259 ng / mL) in the xenograft PK / PD model, respectively. Starting from cohort 5 (0.1 mg QW), the observed pre-dose (C-valence) concentrations were close to the predicted minimum effective exposure, suggesting that these doses may lead to clinical remission.

[0139] Following the first infusion of salinomycin, a rapid decline in peripheral T cell counts was observed. Lymphocyte redistribution was accompanied by transient expression of the T cell activation marker CD69. Serum cytokines (including IFN-γ, IL-2, IL-6, and TNF-α) were increased compared to baseline after salinomycin infusion. Cytokine concentrations peaked within 6–24 hours and returned to baseline before subsequent infusions. T cell marginalization, T cell activation, and cytokine induction were all dose-dependent, with FDR-corrected p-values ​​reaching significance at multiple time points post-infusion.

[0140] The overall incidence of ADA during treatment was 49 (54%) out of 90 evaluable patients, with 8 of these patients experiencing transient antibody remission. The median time to ADA binding was day 1 of cycle 2. The impact of ADA in ADA-positive patients on drug activity, exposure, and association with safety events was assessed. Observed ADA was not associated with adverse events. A subset of ADA-positive patients were identified as having effects on neutralization and / or exposure.

[0141] Safety analysis in this study primarily included clinically manageable Grade 1 and 2 adverse events (AEs), and no Grade 5 events related to salinomycin were identified. 19% of patients discontinued treatment due to transarterial adverse events (TRAEs), partly due to limitations on the duration of dosing interruptions.

[0142] The most common TRAE was low-grade CRS, primarily occurring in cycle 1. CRS was expected in this study due to the biological mechanisms of salinomycin and clinical experience with other TCEs (11). Three cases (3%) of grade 3 CRS were reported, one of which regressed to grade 1 after the data cutoff date. Grade 3 events (cohorts 6 and 7a) occurred before the second dose of dexamethasone and before post-dose IV hydration in subsequent cohorts. Almost all CRS events presented with fever, with or without hypotension, tachycardia, and rarely hypoxia. No grade 4 or 5 CRS events were observed. Overall, all CRS events were resolved with standard management (using acetaminophen, IV infusion, and tocilizumab and / or corticosteroids).

[0143] A favorable and predictable dose-exposure relationship was observed following administration of salinomycin. The preliminary terminal half-life was approximately 3–4 days, supporting the QW dosing schedule. PK indicated, based on preclinical studies, trough concentration levels at the lowest effective exposure in patients receiving a target dose of 0.75 mg or higher. This allows for further analysis to evaluate clinical outcomes in both low-dose (< 0.75 mg) and high-dose (≥ 0.75 mg) cohorts.

[0144] Additional analyses were performed on mCRPC patients in the dose extension phase, who were randomly assigned 1:1:1 to receive IV salinomycin at a target dose of 0.75 mg QW, 1.5 mg QW, or 1.5 mg Q2W using a 2-step or 3-step dosing regimen in cycle 1. Results are presented in the table below.

[0145]

[0146] While both doses were effective, in this randomized dose expansion / optimization study of heavily pretreated mCRPC patients, a target dose of 1.5 mg improved the efficacy of salinomycin compared to 0.75 mg, with manageable side effects. The higher target dose of 1.5 mg showed a trend toward superior efficacy and similar safety profiles compared to 0.75 mg.

[0147] PSA50 0.75 mg: 36%, 1.5 mg: 53%-60%

[0148] PSA90 0.75 mg: 21%, 1.5 mg: 30%-34%

[0149] ORR 0.75 mg: 15%, 1.5 mg: 19%-29%

[0150] In most patients, grade 3 adverse events were transient, manageable, reversible, and allowed for continued treatment. Discontinuation due to musculoskeletal inflammatory events or cytokine release syndrome (CRS) was rare, with most grade 3 CRS events occurring in cycle 1 (no grade 4 / 5 CRS). The Q2W dosing schedule showed an improved adverse event profile, with a lower overall incidence of treatment-related musculoskeletal inflammatory events (69% vs. 74% and 86% in the QW dosing schedule) and a reduced number of higher-grade events (grade 2 / 3: 22% / 33% vs. 31% / 37% and 34% / 43%).

[0151] Example 2: Clinical trial design of the combination of AMG 509 and lutetium 177 vitrapeptide tetracetan

[0152] A phase 1b clinical trial can be conducted to determine the safety and efficacy of the combination of salidomide and PLUVICTO® (lutetium 177 vepteptide tetracetan) in patients with mCRPC.

[0153] The expected dosing regimen is as follows:

[0154] Monotherapy adjustment phase: Incremental dosing of IV salbutamol.

[0155] The duration of a single-drug regimen of salbutamol is 28 days. Treatment will be administered in the following cohorts: Cohort 1 (0.1 mg D1 / 0.3 mg D8 / 0.75 mg D15 / 0.75 mg D22) and Cohort 2 (0.1 mg D1 / 0.3 mg D8 / 1.0 mg D15 / 1.5 mg D22).

[0156] Single-therapy bridging phase: Target dose of IV salbutamol

[0157] After reaching the target dose (e.g., 0.75 mg or 1.5 mg), AMG509 will be administered Q2W until the patient receives PLUVICTO® on day 1 of cycle 1 of the combination phase (“C1D1”). Unless contraindicated, treatment continuation and ordering criteria for PLUVICTO® will be established to ensure continued transition to the combination. During the monotherapy bridging phase, the target dose is administered Q2W until combination phase C1D1 can be administered. This phase will consist of 2 or 3 doses of salinomycin administered Q2W at the target dose (e.g., 0.75 mg or 1.5 mg) randomly assigned to the patient.

[0158] Combination stage: PLUVICTO® and salbutamol combined.

[0159] The combination phase of salbutamol and PLUVICTO® begins on C1D1, with PLUVICTO® administered at the approved dose of 7.4 GBq, followed by C1D8, with AMG509 administered at the target dose, and then on a Q2W schedule at the target dose. During the combination phase, the cycle length is 6 weeks, therefore AMG509 will be administered on days 8, 22, and 36 of each combination cycle. A maximum of 6 cycles of combination therapy are planned.

[0160] Maintenance phase of monotherapy with IV salbutamol

[0161] After the combination phase is completed, the investigator may decide to continue salbutamol at the target dose (e.g., 0.75 mg or 1.5 mg) according to the Q2W schedule.

[0162] The primary endpoint will include dose-limiting toxicities, adverse events occurring during treatment, treatment-related adverse events, and changes in vital signs, electrocardiogram, and clinical laboratory tests. The pharmacokinetic (PK) and preliminary antitumor activity of the salinomycin-PLUVICTO® combination will also be evaluated as secondary endpoints.

[0163] The proposed timeline for target doses of 0.75 mg or 1.5 mg salinomycin, as identified in protocol 20180146, is safe and tolerable and has been selected for further exploration in dose expansion. Recruiting and safety assessments will continue throughout the trial.

[0164] Table 4. Sequences

[0165] .

Claims

1. A method of treating a patient with prostate cancer, comprising administering to the patient a pharmaceutical composition comprising an anti-STEAP1 antigen-binding protein at a dose of about 0.1 mg to about 2.0 mg, and administering to the patient a dose of a compound of formula 1: This compound and selected 90 Y、 177 Lu、 64 Cu、 153 Gd, 155 Gd, 157 Gd, 213 Bihe 225 Metal complexes consisting of groups of Ac.

2. The method of claim 1, wherein the metal-complexed compound is lutetium Lu 177 vepteptide tetracetan.

3. The method of claim 2, wherein the dose of the lutetium Lu 177 veprotide tetracetan is about 2 GBq to about 13 GBq.

4. The method of claim 2 or claim 3, wherein the dose of the lutetium Lu 177 veprotide tetracetan is 5.9 GBq.

5. The method according to any one of claims 2-4, wherein the dose of the lutetium Lu 177 veprotide tetracetan is 7.4 GBq.

6. The method of any one of claims 2-5, wherein the dose of lutetium Lu 177 veprotide tetracetan is administered once every six weeks.

7. The method of any one of claims 2-6, wherein the anti-STEAP1 antigen-binding protein is administered to the patient after administering a dose of lutetium-177 vepteptide tetracetan to the patient.

8. The method of any one of claims 1-7, wherein the method comprises at least one cycle, and in one cycle, the anti-STEAP1 antigen-binding protein is administered every 7 days after administration of a dose of lutetium Lu 177 vepteptide tetracetan.

9. The method of claim 8, wherein the method comprises one cycle, two cycles, three cycles, four cycles, five cycles, or six cycles.

10. The method of any one of claims 2-9, wherein the lutetium Lu 177 veprotide tetracetan is administered intravenously.

11. The method of any one of claims 1-10, wherein the dose of the anti-STEAP1 antigen-binding protein is about 0.1 mg to about 2 mg.

12. The method of any one of claims 1-10, wherein the dose of the anti-STEAP1 antigen-binding protein is about 0.1 mg to about 1.5 mg.

13. The method of any one of claims 1-12, wherein the dose of the anti-STEAP1 antigen-binding protein is about 0.1 mg.

14. The method of any one of claims 1-12, wherein the dose of the anti-STEAP1 antigen-binding protein is about 0.3 mg.

15. The method of any one of claims 1-12, wherein the dose of the anti-STEAP1 antigen-binding protein is about 0.75 mg.

16. The method of any one of claims 1-12, wherein the dose of the anti-STEAP1 antigen-binding protein is about 1 mg.

17. The method of any one of claims 1-12, wherein the dose of the anti-STEAP1 antigen-binding protein is about 1.5 mg.

18. The method of any one of claims 1-12, wherein the dose of the anti-STEAP1 antigen-binding protein is 1.5 mg.

19. The method of any one of claims 1-18, wherein the dose is administered once a week.

20. The method of any one of claims 1-18, wherein the dose is administered once every 2 weeks.

21. The method of any one of claims 1-20, wherein the dose is administered intravenously.

22. The method of any one of claims 1-21, wherein the anti-STEAP1 antigen-binding protein is first administered via a stepwise administration method.

23. The method of claim 22, wherein the anti-STEAP1 antigen-binding protein is administered via a stepwise administration method in two or three steps.

24. The method of claim 23, wherein the anti-STEAP1 antigen-binding protein is administered in a stepwise manner at 0.1 mg on day 1, 0.3 mg on day 8, 1.0 mg on day 15, and 1.5 mg on day 22.

25. The method of claim 23, wherein the anti-STEAP1 antigen-binding protein is administered in a stepwise manner at 0.1 mg on day 1, 0.3 mg on day 8, 0.75 mg on day 15, and 0.75 mg on day 22.

26. The method of any one of claims 31-34, further comprising administering the anti-STEAP1 antigen-binding protein to the patient once weekly, once every two weeks, once every three weeks, or once every four weeks after the stepwise dosing is completed and the target dose of the anti-STEAP1 antigen-binding protein is reached.

27. The method of any one of claims 1-26, wherein the anti-STEAP1 antigen-binding protein comprises two Fab-binding domains, each Fab-binding domain binding STEAP1, and each Fab-binding domain comprises a variable heavy chain domain, a variable light chain domain, a CH1 domain, and a constant light chain domain, and the variable heavy chain domain comprises: HCDR1 comprising SEQ ID NO: 9, HCDR2 comprising SEQ ID NO: 10, and HCDR3 comprising SEQ ID NO: 11; and the variable light chain domain comprises: LCDR1 comprising SEQ ID NO: 12, LCDR2 comprising SEQ ID NO: 13, and LCDR3 comprising SEQ ID NO:

14.

28. The method of any one of claims 1-27, wherein the anti-STEAP1 antigen-binding protein comprises two Fab domains, each binding STEAP1, and one scFv domain, binding CD3.

29. The method of any one of claims 1-28, wherein the anti-STEAP1 antigen-binding protein comprises two Fab-binding domains, and each Fab-binding domain binds STEAP1.

30. The method of any one of claims 1-29, wherein the anti-STEAP1 antigen-binding protein comprises two Fab-binding domains, each Fab-binding domain binding STEAP1, and each Fab-binding domain comprises a variable heavy chain domain, a variable light chain domain, a CH1 domain, and a constant light chain domain, and the variable heavy chain domain comprises: HCDR1 comprising SEQ ID NO: 9, HCDR2 comprising SEQ ID NO: 10, and HCDR3 comprising SEQ ID NO: 11; and the variable light chain domain comprises: LCDR1 comprising SEQ ID NO: 12, LCDR2 comprising SEQ ID NO: 13, and LCDR3 comprising SEQ ID NO:

14.

31. The method of any one of claims 1-30, wherein the anti-STEAP1 antigen-binding protein comprises a CD3-binding scFv-binding domain.

32. The method of any one of claims 1-31, wherein the anti-STEAP1 antigen-binding protein comprises a CD3-binding scFv-binding domain, and the scFv variable heavy chain domain comprises: HCDR1 comprising SEQ ID NO: 1, HCDR2 comprising SEQ ID NO: 2, and HCDR3 comprising SEQ ID NO: 3; an scFv linker; and a scFv variable light chain domain comprising: LCDR1 comprising SEQ ID NO: 4, LCDR2 comprising SEQ ID NO: 5, and LCDR3 comprising SEQ ID NO:

6.

33. The method of any one of claims 1-32, wherein the anti-STEAP1 antigen-binding protein comprises a first Fc domain and a second Fc domain.

34. The method of any one of claims 31-33, wherein each Fab variable heavy chain domain comprises at least 90% of the same amino acid sequence as SEQ ID NO: 15 or 20; each Fab variable light chain domain comprises at least 90% of the same amino acid sequence as SEQ ID NO: 16; and the scFv variable heavy chain domain comprises at least 90% of the same amino acid sequence as SEQ ID NO: 7; and the scFv variable light chain domain comprises at least 90% of the same amino acid sequence as SEQ ID NO:

8.

35. The method of any one of claims 31-34, wherein each Fab variable heavy chain domain comprises SEQ ID NO: 15 or 20; each Fab variable light chain domain comprises SEQ ID NO: 16; the scFv variable heavy chain domain comprises SEQ ID NO: 7; and the scFv variable light chain domain comprises SEQ ID NO:

8.

36. The method of any one of claims 31-35, wherein the scFv bonding structure domain of the CD3 comprises an scFv connector.

37. The method of any one of claims 33-36, wherein the first Fc domain comprises amino acid substitutions of E233P, L235V, G236A, S267K, R292C, N297G, V302C, E357Q, and S364K; and the second Fc domain comprises amino acid substitutions of N208D, E233P, L235V, G236A, S267K, R292C, Q295E, N297G, V302C, L368D, K370S, N384D, Q418E, and N421D.

38. The method of any one of claims 33-37, wherein the first Fc structural domain and the second Fc structural domain each contain a missing value at position 234.

39. The method of any one of claims 1-38, wherein the anti-STEAP1 antigen-binding protein comprises: an HC comprising SEQ ID NO: 17 or 23, an HC comprising an inserted CD3 scFv comprising SEQ ID NO: 19 or 26, and two light chains, each light chain comprising SEQ ID NO:

18.

40. The method of any one of claims 1-39, wherein the anti-STEAP1 antigen-binding protein is salinomycin.

41. The method of any one of claims 1-40, wherein the patient has metastatic castration-resistant prostate cancer.

42. Use of anti-STEAP1 antigen-binding protein in the manufacture of a medicament for the treatment of prostate cancer, wherein the medicament is formulated for administration at a dose of about 0.1 mg to about 2.0 mg, and further comprises administering to the patient a dose of a compound of formula 1: The compound is selected from 90 Y、 177 Lu、 64 Cu、 153 Gd, 155 Gd, 157 Gd, 213 Bihe 225 Metal complexes consisting of groups of Ac.

43. The use as described in claim 42, wherein the metal-complexed compound is lutetium Lu 177 vepteptide tetracetan.

44. The use as described in claim 43, wherein the dose of the lutetium Lu 177 veprotide tetracetan is about 2 GBq to about 13 GBq.

45. The use as described in claim 43 or claim 3, wherein the dose of the lutetium Lu 177 veprotide tetracetan is 5.9 GBq.

46. ​​The use as described in any one of claims 43-45, wherein the dose of the lutetium Lu 177 veprotide tetracetan is 7.4 GBq.

47. The use as described in any one of claims 43-46, wherein the dose of lutetium Lu 177 veprotide tetracetan is administered once every six weeks.

48. The use as described in any one of claims 43-47, wherein the anti-STEAP1 antigen-binding protein is administered to the patient after administration of a dose of lutetium-177 veprotide tetracetan.

49. The use as described in any one of claims 43-48, wherein the use comprises at least one cycle, and in one cycle, the anti-STEAP1 antigen-binding protein is administered every 14 days following administration of a dose of lutetium Lu 177 veproptide tetracetan.

50. The use as described in claim 49, wherein the use includes one cycle, two cycles, three cycles, four cycles, five cycles, or six cycles.

51. The use as described in any one of claims 43-50, wherein the lutetium Lu 177 veprotide tetracetan is administered intravenously.

52. The use as described in any one of claims 42-51, wherein the dose of the anti-STEAP1 antigen-binding protein is about 0.1 mg to about 2 mg.

53. The use as described in any one of claims 42-52, wherein the dose of the anti-STEAP1 antigen-binding protein is about 0.1 mg to about 1.5 mg.

54. The use as described in any one of claims 42-53, wherein the dose of the anti-STEAP1 antigen-binding protein is about 0.1 mg.

55. The use as described in any one of claims 42-53, wherein the dose of the anti-STEAP1 antigen-binding protein is about 0.3 mg.

56. The use as described in any one of claims 42-53, wherein the dose of the anti-STEAP1 antigen-binding protein is about 0.75 mg.

57. The use as described in any one of claims 42-53, wherein the dose of the anti-STEAP1 antigen-binding protein is about 1 mg.

58. The use as described in any one of claims 42-53, wherein the dose of the anti-STEAP1 antigen-binding protein is about 1.5 mg.

59. The use as described in any one of claims 42-53, wherein the dose of the anti-STEAP1 antigen-binding protein is 1.5 mg.

60. The use as described in any one of claims 42-59, wherein the dose is administered once weekly.

61. The use as described in any one of claims 42-59, wherein the dose is administered once every 2 weeks.

62. The use as described in any one of claims 42-61, wherein the dose is administered intravenously.

63. The use as described in any one of claims 42-62, wherein the anti-STEAP1 antigen-binding protein is first administered via a stepwise administration method.

64. The use as described in claim 63, wherein the anti-STEAP1 antigen-binding protein is administered via a two- or three-step administration method.

65. The use as described in claim 64, wherein the anti-STEAP1 antigen-binding protein is administered via a stepwise dose of 0.1 mg on day 1, 0.3 mg on day 8, 1.0 mg on day 15, and 1.5 mg on day 22.

66. The use as described in claim 64, wherein the anti-STEAP1 antigen-binding protein is administered via a stepwise dosing regimen of 0.1 mg on day 1, 0.3 mg on day 8, 0.75 mg on day 15, and 0.75 mg on day 22.

67. The use as described in any one of claims 42-67, further comprising administering the anti-STEAP1 antigen-binding protein to the patient once weekly, once every two weeks, once every three weeks, or once every four weeks after the completion of the stepwise dosing and the attainment of the target dose of the anti-STEAP1 antigen-binding protein.

68. The use as described in any one of claims 42-67, wherein the anti-STEAP1 antigen-binding protein comprises two Fab-binding domains, each Fab-binding domain binding STEAP1, and each Fab-binding domain comprises a variable heavy chain domain, a variable light chain domain, a CH1 domain, and a constant light chain domain, the variable heavy chain domain comprising: HCDR1 comprising SEQ ID NO: 9, HCDR2 comprising SEQ ID NO: 10, and HCDR3 comprising SEQ ID NO: 11; and the variable light chain domain comprising: LCDR1 comprising SEQ ID NO: 12, LCDR2 comprising SEQ ID NO: 13, and LCDR3 comprising SEQ ID NO:

14.

69. The use as described in any one of claims 42-68, wherein the anti-STEAP1 antigen-binding protein is an XmAb 2+1 molecule.

70. The use as described in any one of claims 42-69, wherein the anti-STEAP1 antigen-binding protein comprises two Fab-binding domains, each of which binds STEAP1.

71. The use according to any one of claims 42-70, wherein the anti-STEAP1 antigen-binding protein comprises two Fab binding domains, each Fab binding domain binding STEAP1, and each Fab binding domain comprises a variable heavy chain domain, a variable light chain domain, a CH1 domain, and a constant light chain domain, the variable heavy chain domain comprising: HCDR1 comprising SEQ ID NO: 9, HCDR2 comprising SEQ ID NO: 10, and HCDR3 comprising SEQ ID NO: 11; and the variable light chain domain comprising: LCDR1 comprising SEQ ID NO: 12, LCDR2 comprising SEQ ID NO: 13, and LCDR3 comprising SEQ ID NO:

14.

72. The use as described in any one of claims 42-71, wherein the anti-STEAP1 antigen-binding protein comprises a CD3-binding scFv-binding domain.

73. The use of any one of claims 72-73, wherein the anti-STEAP1 antigen-binding protein comprises a CD3-binding scFv-binding domain, and the scFv variable heavy chain domain comprises: HCDR1 comprising SEQ ID NO: 1, HCDR2 comprising SEQ ID NO: 2, and HCDR3 comprising SEQ ID NO: 3; an scFv linker; and a scFv variable light chain domain comprising: LCDR1 comprising SEQ ID NO: 4, LCDR2 comprising SEQ ID NO: 5, and LCDR3 comprising SEQ ID NO:

6.

74. The use as described in any one of claims 42-73, wherein the anti-STEAP1 antigen-binding protein comprises a first Fc domain and a second Fc domain.

75. The use according to any one of claims 72-74, wherein each Fab variable heavy chain domain comprises at least 90% of the same amino acid sequence as SEQ ID NO: 15 or 20; each Fab variable light chain domain comprises at least 90% of the same amino acid sequence as SEQ ID NO: 16; and the scFv variable heavy chain domain comprises at least 90% of the same amino acid sequence as SEQ ID NO: 7; and the scFv variable light chain domain comprises at least 90% of the same amino acid sequence as SEQ ID NO:

8.

76. The use as claimed in any one of claims 72-75, wherein each Fab variable heavy chain domain comprises SEQ ID NO: 15 or 20; each Fab variable light chain domain comprises SEQ ID NO: 16; the scFv variable heavy chain domain comprises SEQ ID NO: 7; and the scFv variable light chain domain comprises SEQ ID NO:

8.

77. The use as described in any one of claims 72-76, wherein the scFv bonding structure domain of the CD3 comprises an scFv connector.

78. The use according to any one of claims 74-77, wherein the first Fc domain comprises amino acid substitutions of E233P, L235V, G236A, S267K, R292C, N297G, V302C, E357Q, and S364K; and the second Fc domain comprises amino acid substitutions of N208D, E233P, L235V, G236A, S267K, R292C, Q295E, N297G, V302C, L368D, K370S, N384D, Q418E, and N421D.

79. The use as described in any one of claims 74-78, wherein the first Fc structural domain and the second Fc structural domain each contain a missing value at position 234.

80. The use of any one of claims 42-79, wherein the anti-STEAP1 antigen-binding protein comprises: an HC comprising SEQ ID NO: 17 or 23, an HC comprising an inserted CD3 scFv comprising SEQ ID NO: 19 or 26, and two light chains, each light chain comprising SEQ ID NO:

18.

81. The use as described in any one of claims 42-80, wherein the anti-STEAP1 antigen-binding protein is salinomycin.

82. The use as described in any one of claims 42-81, wherein the patient has metastatic castration-resistant prostate cancer.

83. An anti-STEAP1 antigen-binding protein for use in the treatment of prostate cancer, wherein the antigen-binding protein is formulated for administration at a dose of about 0.1 mg to about 2.0 mg, and the use further comprises administering to the patient a dose of a compound of formula 1: The compound is selected from 90 Y、 177 Lu、 64 Cu、 153 Gd, 155 Gd, 157 Gd, 213 Bihe 225 Metal complexes consisting of groups of Ac.

84. The anti-STEAP1 antigen-binding protein of claim 83, wherein the metal-complexed compound is lutetium Lu177 vepteptide tetracetan.

85. The anti-STEAP1 antigen-binding protein of claim 83, wherein the dose of the lutetium Lu 177 vepletide tetracetan is about 2 GBq to about 13 GBq.

86. The anti-STEAP1 antigen-binding protein of claim 83, wherein the dose of the lutetium Lu 177 vepletide tetracetan is about 5.9 GBq.

87. The anti-STEAP1 antigen-binding protein according to any one of claims 83-85, wherein the dose of the lutetium Lu 177 vepletide tetracetan is about 7.4 GBq.

88. The anti-STEAP1 antigen-binding protein according to any one of claims 83-87, wherein the dose of lutetium Lu 177 vepletide tetracetan is administered once every six weeks.

89. The anti-STEAP1 antigen-binding protein according to any one of claims 83-87, wherein the anti-STEAP1 antigen-binding protein is administered to the patient after administration of a dose of lutetium-177 veptetide tetracetan.

90. The anti-STEAP1 antigen-binding protein according to any one of claims 83-89, wherein the use comprises at least one cycle, wherein in one cycle, the anti-STEAP1 antigen-binding protein is administered every 14 days after administration of a dose of lutetium Lu 177 vepteptide tetracetan.

91. The anti-STEAP1 antigen-binding protein of claim 90, wherein the use comprises one cycle, two cycles, three cycles, four cycles, five cycles, or six cycles.

92. The anti-STEAP1 antigen-binding protein according to any one of claims 83-91, wherein the lutetium Lu 177 vepletide tetracetan is administered intravenously.

93. The anti-STEAP1 antigen-binding protein according to any one of claims 83-92, wherein the dose of the anti-STEAP1 antigen-binding protein is from about 0.1 mg to about 2 mg.

94. The anti-STEAP1 antigen-binding protein according to any one of claims 83-92, wherein the dose of the anti-STEAP1 antigen-binding protein is about 0.1 mg to about 1.5 mg.

95. The anti-STEAP1 antigen-binding protein according to any one of claims 83-93, wherein the dose of the anti-STEAP1 antigen-binding protein is about 0.1 mg.

96. The anti-STEAP1 antigen-binding protein according to any one of claims 83-93, wherein the dose of the anti-STEAP1 antigen-binding protein is about 0.3 mg.

97. The anti-STEAP1 antigen-binding protein according to any one of claims 83-93, wherein the dose of the anti-STEAP1 antigen-binding protein is about 0.75 mg.

98. The anti-STEAP1 antigen-binding protein according to any one of claims 83-93, wherein the dose of the anti-STEAP1 antigen-binding protein is about 1 mg.

99. The anti-STEAP1 antigen-binding protein according to any one of claims 83-93, wherein the dose of the anti-STEAP1 antigen-binding protein is about 1.5 mg.

100. The anti-STEAP1 antigen-binding protein according to any one of claims 83-93, wherein the dose of the anti-STEAP1 antigen-binding protein is 1.5 mg.

101. The anti-STEAP1 antigen-binding protein according to any one of claims 83-100, wherein the dose is administered once weekly.

102. The anti-STEAP1 antigen-binding protein according to any one of claims 83-100, wherein the dose is administered once every 2 weeks.

103. The anti-STEAP1 antigen-binding protein according to any one of claims 83-102, wherein the dose is administered intravenously.

104. The anti-STEAP1 antigen-binding protein according to any one of claims 83-103, wherein the anti-STEAP1 antigen-binding protein is first administered via a stepwise administration method.

105. The anti-STEAP1 antigen-binding protein according to any one of claims 83-104, wherein the anti-STEAP1 antigen-binding protein is administered via a stepwise administration method in two or three steps.

106. The anti-STEAP1 antigen-binding protein of claim 104 or claim 105, wherein the anti-STEAP1 antigen-binding protein is administered via a stepwise dose of 0.1 mg on day 1, 0.3 mg on day 8, 1.0 mg on day 15, and 1.5 mg on day 22.

107. The anti-STEAP1 antigen-binding protein of claim 104 or claim 105, wherein the anti-STEAP1 antigen-binding protein is administered via a stepwise dosing regimen of 0.1 mg on day 1, 0.3 mg on day 8, 0.75 mg on day 15, and 0.75 mg on day 22.

108. The anti-STEAP1 antigen-binding protein according to any one of claims 83-107, further comprising administering the anti-STEAP1 antigen-binding protein to the patient once weekly, once every two weeks, once every three weeks, or once every four weeks after the completion of the stepwise dosing and the attainment of the target dose of the anti-STEAP1 antigen-binding protein.

109. The anti-STEAP1 antigen-binding protein according to any one of claims 83-107, wherein the anti-STEAP1 antigen-binding protein comprises two Fab binding domains, wherein each Fab binding domain binds STEAP1, and wherein each Fab binding domain comprises a variable heavy chain domain, a variable light chain domain, a CH1 domain, and a constant light chain domain, wherein the variable heavy chain domain comprises: HCDR1 comprising SEQ ID NO: 9, HCDR2 comprising SEQ ID NO: 10, and HCDR3 comprising SEQ ID NO: 11; and the variable light chain domain comprises: LCDR1 comprising SEQ ID NO: 12, LCDR2 comprising SEQ ID NO: 13, and LCDR3 comprising SEQ ID NO:

14.

110. The anti-STEAP1 antigen-binding protein according to any one of claims 83-109, wherein the anti-STEAP1 antigen-binding protein is an XmAb 2+1 molecule.

111. The anti-STEAP1 antigen-binding protein according to any one of claims 83-110, wherein the anti-STEAP1 antigen-binding protein comprises two Fab binding domains, wherein each Fab binding domain binds STEAP1.

112. The anti-STEAP1 antigen-binding protein according to any one of claims 83-111, wherein the anti-STEAP1 antigen-binding protein comprises two Fab binding domains, wherein each Fab binding domain binds STEAP1, and wherein each Fab binding domain comprises a variable heavy chain domain, a variable light chain domain, a CH1 domain, and a constant light chain domain, wherein the variable heavy chain domain comprises: HCDR1 comprising SEQ ID NO: 9, HCDR2 comprising SEQ ID NO: 10, and HCDR3 comprising SEQ ID NO: 11; and the variable light chain domain comprises: LCDR1 comprising SEQ ID NO: 12, LCDR2 comprising SEQ ID NO: 13, and LCDR3 comprising SEQ ID NO:

14.

113. The anti-STEAP1 antigen-binding protein according to any one of claims 83-112, wherein the anti-STEAP1 antigen-binding protein comprises an scFv binding domain, wherein the scFv binding domain binds CD3.

114. The anti-STEAP1 antigen-binding protein according to any one of claims 83-113, wherein the anti-STEAP1 antigen-binding protein comprises an scFv binding domain, wherein the scFv binding domain binds CD3, and wherein the scFv variable heavy chain domain comprises: HCDR1 comprising SEQ ID NO: 1, HCDR2 comprising SEQ ID NO: 2, and HCDR3 comprising SEQ ID NO: 3; an scFv linker; and an scFv variable light chain domain, wherein the scFv variable light chain domain comprises: LCDR1 comprising SEQ ID NO: 4, LCDR2 comprising SEQ ID NO: 5, and LCDR3 comprising SEQ ID NO:

6.

115. The anti-STEAP1 antigen-binding protein according to any one of claims 83-114, wherein the anti-STEAP1 antigen-binding protein comprises a first Fc domain and a second Fc domain.

116. The anti-STEAP1 antigen-binding protein according to any one of claims 83-115, wherein each Fab variable heavy chain domain comprises at least 90% of the same amino acid sequence as SEQ ID NO: 15 or 20; each Fab variable light chain domain comprises at least 90% of the same amino acid sequence as SEQ ID NO: 16; and the scFv variable heavy chain domain comprises at least 90% of the same amino acid sequence as SEQ ID NO: 7; and the scFv variable light chain domain comprises at least 90% of the same amino acid sequence as SEQ ID NO:

8.

117. The anti-STEAP1 antigen-binding protein according to any one of claims 83-115, wherein each Fab variable heavy chain domain comprises SEQ ID NO: 15 or 20; each Fab variable light chain domain comprises SEQ ID NO: 16; the scFv variable heavy chain domain comprises SEQ ID NO: 7; and the scFv variable light chain domain comprises SEQ ID NO:

8.

118. The anti-STEAP1 antigen-binding protein according to any one of claims 83-117, wherein the scFv binding domain of the CD3-binding protein comprises an scFv linker.

119. The anti-STEAP1 antigen-binding protein according to any one of claims 83-118, wherein the first Fc domain comprises amino acid substitutions of E233P, L235V, G236A, S267K, R292C, N297G, V302C, E357Q, and S364K; and the second Fc domain comprises amino acid substitutions of N208D, E233P, L235V, G236A, S267K, R292C, Q295E, N297G, V302C, L368D, K370S, N384D, Q418E, and N421D.

120. The anti-STEAP1 antigen-binding protein according to any one of claims 83-119, wherein the first Fc domain and the second Fc domain each contain a deletion at position 234.

121. The anti-STEAP1 antigen-binding protein according to any one of claims 83-120, wherein the anti-STEAP1 antigen-binding protein comprises: an HC comprising SEQ ID NO: 17 or 23, an HC comprising an inserted CD3 scFv comprising SEQ ID NO: 19 or 26, and two light chains, each light chain comprising SEQ ID NO:

18.

122. The anti-STEAP1 antigen-binding protein according to any one of claims 83-121, wherein the anti-STEAP1 antigen-binding protein is salimethrin.

123. The anti-STEAP1 antigen-binding protein according to any one of claims 83-122, wherein the patient has metastatic castration-resistant prostate cancer.

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