Combination therapy for treating prostate cancer

Abstract

This disclosure provides a method for treating patients with prostate cancer using an anti-STEAP1 antigen-binding protein such as zalritamig in combination with lutetium Lu177 bipivotide tetraxetan.

Description

[Technical Field]

[0001] This invention relates to the field of oncology. In particular, it relates to the treatment of prostate cancer, either as monotherapy or in combination with other pharmaceutical agents, using the STEAP1 T-cell engager (TCE) molecule.

[0002] Description of electronically submitted text files This application includes a sequence listing submitted electronically in XML format, which is incorporated herein by reference in its entirety. A computer-readable copy of the sequence listing, 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 frequently diagnosed non-skin cancers in the United States and is a leading cause of cancer death in men. In the United States, 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 for 2023 (Siegel et al., Cancer statistics, 2023. CA Cancer J Clin. 2023;73(1):17-48).

[0004] Survival rates vary among men with prostate cancer, but are strongly associated with the stage and location of the disease (i.e., local vs. metastatic). In the United States, the 5-year survival rate for men with localized prostate cancer is nearly 100%, but for men with metastatic disease, the 5-year survival rate drops to a low 31% (Cancer.Net, 2020). In 2015, there were an estimated 365,000 new cases of prostate cancer and an estimated 77,000 deaths from prostate cancer in the European Union (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. Between 2000 and 2016, the incidence of prostate cancer was on an increasing trend. The average annual percentage change was 7.1% (Zheng et al, 2022).

[0005] Treatment for patients diagnosed with metastatic prostate cancer has included continuous and intermittent androgen deprivation therapy (ADT). Docetaxel, as well as novel hormonal therapies (NHT) such as abiraterone, enzalutamide, apalutamide, and darolutamide, are approved therapies. Metastatic prostate cancer often develops resistance to ADT (also known as "castration resistance") due to increased intratumoral steroid production, altered steroid transporter expression, increased androgen receptor expression (e.g., androgen receptor amplification), and other mechanisms (Galletti et al, 2017).

[0006] Since 2010, five novel therapies for metastatic castration-resistant prostate cancer (mCRPC)—cabazitaxel (Jevtana®), ciplucel-T (Provenge®), abiraterone (Zytiga®), enzalutamide (Xtandi®), and radium-223 (Xofigo®)—have been approved based on their survival benefit. However, the optimal order or combination of available therapies for mCRPC remains largely unknown. The U.S. Food and Drug Administration (FDA) has also recently approved the following therapies for subgroups of patients with mCRPC defined by specific biomarkers: the poly-ADP-ribose polymerase (PARP) inhibitors olaparib (Lynparza®) and lucaparib (Rubraca®); the programmed cell death protein 1 (PD-1) inhibitor pembrolizumab (Keytruda®); and the radioligand therapy targeting prostate-specific membrane antigens lutetium Lu177 bipivotide tetraxetan (PLUVICTO®). These therapies are indicated for limited or pre-selected patient subgroups; therefore, unmet needs remain in the retrospective mCRPC situation.

[0007] Six-transmembrane prostatic epithelial antigen 1 (STEAP1) is a surface antigen containing three short extracellular loop regions that is overexpressed in prostate cancer (Hubert et al, 1999) and Ewing's sarcoma (Grunewald et al, 2012), and its expression correlates with the stage of prostate cancer (Gomes et al, 2014). Zarritamig (also known as "AMG 509") 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, zarritamig demonstrated potent cytotoxicity in prostate cancer cell lines and tumor regression in preclinical xenograft models (Nolan-Stevaux et al 2024, Cancer Discov. 2024 Jan 12;14(1):90-103). Nonclinical evidence supported advancing zalritamig to 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 kD, containing an intracellular segment (amino acids 1-18), a transmembrane domain (amino acids 19-43), and a broad 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 of the human body, such as the kidneys, proximal small intestine, and salivary glands. Unlike prostate-specific antigen (PSA) expression, which is downregulated after androgen ablation, 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 diseases. PLUVICTO® (lutetium Lu177 bipivotide tetraxetan) is an approved therapy for mCRPC patients who have previously received androgen receptor (AR) pathway inhibitors (ARPIs) and taxane-based chemotherapy. It targets PSMA-expressing cells using lutetium-177 (177Lu), a beta-particle-emitting radioligand. This treatment provides a benefit of extending overall survival by 4 months to a median of 15.3 months, and therefore there is considerable room for further improvement. PLUVICTO® is currently being explored in patients who have not previously been exposed to chemotherapy. [Overview of the project] [Means for solving the problem]

[0009] The present invention provides a method for treating a patient with prostate cancer, comprising administering to the patient a pharmaceutical composition containing an anti-STEAP1 antigen-binding protein in 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 use in the treatment of prostate cancer, which is formulated for administration in doses of about 0.1 mg to about 2.0 mg.

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

[0012] The present disclosure also provides use of an anti-STEAP1 antigen binding protein in the manufacture of a medicament for treating prostate cancer, wherein the medicament 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 Lu 177 vipivotide tetraxetan. In one embodiment, the anti-STEAP1 antigen binding protein is zrultamig.

[0013] The present disclosure also provides an anti-STEAP1 antigen binding protein for use in 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 Lu 177 vipivotide tetraxetan. In one embodiment, the anti-STEAP1 antigen binding protein is zrultamig.

[0014] The present disclosure also provides use of an 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 is administered in combination with a dose of lutetium Lu 177 vipivotide tetraxetan. In one embodiment, the anti-STEAP1 antigen binding protein is zrultamig.

[0015] The present disclosure also provides an anti-STEAP1 antigen binding protein for use in 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 is administered in combination with a dose of lutetium Lu 177 vipivotide tetraxetan. In one embodiment, the anti-STEAP1 antigen binding protein is zrultamig.

[0016] This disclosure provides a method for administering an anti-STEAP1 antigen-binding protein according to the method of this disclosure. This disclosure also provides an anti-STEAP1 antigen-binding protein for use in the treatment of prostate cancer, which is formulated for administration according to the method of this disclosure. In one embodiment, the dose of the anti-STEAP antigen-binding protein is about 0.1 mg to about 1.5 mg. In one embodiment, the dose of the anti-STEAP antigen-binding protein is about 0.3 mg to about 1.3 mg. In one embodiment, the dose of the anti-STEAP antigen-binding protein is about 0.5 mg to about 1 mg. In one embodiment, the dose of the 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 approximately 0.1 mg, approximately 0.2 mg, approximately 0.3 mg, approximately 0.4 mg, approximately 0.5 mg, approximately 0.6 mg, approximately 0.7 mg, approximately 0.75 mg, approximately 0.8 mg, approximately 0.9 mg, approximately 1.0 mg, approximately 1.1 mg, approximately 1.2 mg, approximately 1.3 mg, approximately 1.4 mg, approximately 1.5 mg, approximately 1.6 mg, or approximately 1.7 mg. In one embodiment, the dose of anti-STEAP antigen-binding protein is approximately 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 anti-STEAP antigen-binding protein is approximately 0.1 mg. In one embodiment, the dose of anti-STEAP antigen-binding protein is approximately 0.3 mg. In one embodiment, the dose of anti-STEAP antigen-binding protein is approximately 0.75 mg. In one embodiment, the dose of anti-STEAP antigen-binding protein is approximately 1 mg. In one embodiment, the dose of anti-STEAP antigen-binding protein is approximately 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 anti-STEAP antigen-binding protein is administered once a week. In one embodiment, the anti-STEAP antigen-binding protein is administered once every two weeks. In one embodiment, the anti-STEAP antigen-binding protein is administered once every three weeks. In one embodiment, the anti-STEAP antigen-binding protein is administered once every four weeks. In one embodiment, the anti-STEAP antigen-binding protein is administered intravenously. In one embodiment, the anti-STEAP antigen-binding protein is administered once a week, starting from cycle 1. In one embodiment, the anti-STEAP antigen-binding protein is administered once a week, starting from cycle 2. In one embodiment, the anti-STEAP antigen-binding protein is administered once every two weeks, starting from cycle 2. In one embodiment, the anti-STEAP antigen-binding protein is administered once every three weeks, starting from cycle 2. In one embodiment, the anti-STEAP antigen-binding protein is administered once every four weeks, starting from cycle 2. In one embodiment, the dose of anti-STEAP antigen-binding protein is administered once a week in the first cycle, and then once every two weeks starting from day 1 of cycle 2. In another embodiment, the dose of anti-STEAP antigen-binding protein is administered once a week in the first cycle, and then once every two weeks once the target dose of anti-STEAP antigen-binding protein is achieved. In yet another embodiment, the dose of anti-STEAP antigen-binding protein is administered once a week in the first cycle, and then once every three weeks once the target dose of anti-STEAP antigen-binding protein is achieved. In yet another embodiment, the dose of anti-STEAP antigen-binding protein is administered once a week in the first cycle, and then once every four weeks once the target dose of anti-STEAP antigen-binding protein is achieved. In some embodiments, cycle 2 is repeated 11 times after the completion of cycle 1 (e.g., over a total treatment period of about 12 months). In some embodiments, cycle 2 is repeated 5 times after the completion of cycle 1 (e.g., over a total treatment period of about 6 months). In one embodiment, the anti-STEAP1 antigen-binding protein is zalritamig.

[0017] The present invention is a method for treating a patient having prostate cancer, comprising administering to the patient a pharmaceutical composition containing an anti-STEAP1 antigen-binding protein, and comprising formula 1: [ka] The present invention provides a method comprising administering a dose of the compound to a patient, wherein the compound is complexed with a metal selected from the group consisting of 90Y, 177Lu, 64Cu, 153Gd, 155Gd, 157Gd, 213Bi, 68Ga, and 225Ac.

[0018] This disclosure provides an anti-STEAP1 antigen-binding protein for use in the treatment of prostate cancer, formulated for administration in doses of about 0.1 mg to about 2.0 mg, and administered 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 an anti-STEAP1 antigen-binding protein in the manufacture of a pharmacopoeia for the treatment of prostate cancer, wherein the pharmacopoeia is formulated for administration in doses of about 0.1 mg to about 2.0 mg, and administered 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 use in the treatment of prostate cancer, administered in doses of approximately 0.1 mg to approximately 2.0 mg, and administered 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 an anti-STEAP1 antigen-binding protein in the manufacture of a pharmacopoeia for the treatment of prostate cancer, wherein the pharmacopoeia is administered in doses of approximately 0.1 mg to approximately 2.0 mg, and administered 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 anti-STEAP antigen-binding protein is approximately 0.1 mg to approximately 1.5 mg. In one embodiment, the dose of anti-STEAP antigen-binding protein is approximately 0.3 mg to approximately 1.3 mg. In one embodiment, the dose of anti-STEAP antigen-binding protein is approximately 0.5 mg to approximately 1 mg. In one embodiment, the dose of anti-STEAP antigen-binding protein is approximately 0.75 mg to approximately 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 lutetium Lu 177 vipivotide tetraxetan is 7.4 GBq.

[0019] The present invention provides a method of 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 the following formula:

Chemical Formula

Chemical Formula

[0020] In one embodiment, the compound complexed with the metal is lutetium Lu177 bipivotide tetraxetan. In one embodiment, the dose of lutetium Lu177 bipivotide tetraxetan is about 2 GBq to about 13 GBq. In one embodiment, the dose of lutetium Lu177 bipivotide tetraxetan is about 5.9 GBq. In one embodiment, the dose of lutetium Lu177 bipivotide tetraxetan is about 7.4 GBq. In one embodiment, the dose of lutetium Lu177 bipivotide tetraxetan is 5.9 GBq. In one embodiment, the dose of lutetium Lu177 bipivotide tetraxetan is 7.4 GBq. In one embodiment, the dose of lutetium Lu177 bipivotide tetraxetan is about 7.4 GBq. In one embodiment, the dose of lutetium Lu177 bipivotide tetraxetan is administered once every six weeks. In one embodiment, the dose of lutetium Lu177 bipivotide tetraxetan is 7.4 GBq, administered once every six weeks, up to a maximum of six doses. In one embodiment, the dose of anti-STEAP antigen-binding protein is approximately 0.1 mg to approximately 1.5 mg. In one embodiment, the dose of anti-STEAP antigen-binding protein is approximately 0.3 mg to approximately 1.3 mg. In one embodiment, the dose of anti-STEAP antigen-binding protein is approximately 0.5 mg to approximately 1 mg. In one embodiment, the dose of anti-STEAP antigen-binding protein is approximately 0.75 mg to approximately 1 mg. In one embodiment, the dose of anti-STEAP antigen-binding protein is approximately 0.1 mg, approximately 0.2 mg, approximately 0.3 mg, approximately 0.4 mg, approximately 0.5 mg, approximately 0.6 mg, approximately 0.7 mg, approximately 0.75 mg, approximately 0.8 mg, approximately 0.9 mg, approximately 1.0 mg, approximately 1.1 mg, approximately 1.2 mg, approximately 1.3 mg, approximately 1.4 mg, approximately 1.5 mg, approximately 1.6 mg, or approximately 1.7 mg. In one embodiment, the dose of anti-STEAP antigen-binding protein is approximately 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 Lu177 bipivotide tetraxetan is 7.4 GBq.

[0021] The present invention relates to a method for treating a patient having prostate cancer, 177 Formula 1, which is complexed with Lu: [ka] The present invention provides a method comprising administering to a patient a pharmaceutical composition containing and a pharmaceutical preparation of zalritamig in a dose of 0.1 to 2.0 mg. In one embodiment, the dose of zalritamig is 1.5 mg. In one embodiment, the dose of lutetium Lu177 bipivotide tetraxetan is 5.9 GBq. In one embodiment, the dose of lutetium Lu177 bipivotide tetraxetan is 7.4 GBq. In one embodiment, the dose of lutetium Lu177 bipivotide tetraxetan is approximately 7.4 GBq, and the dose of zalritamig is approximately 0.75 mg. In one embodiment, the dose of lutetium Lu177 bipivotide tetraxetan is approximately 7.4 GBq, and the dose of zalritamig is approximately 1 mg. In one embodiment, the dose of lutetium Lu177 bipivotide tetraxetan is approximately 7.4 GBq, and the dose of zarritamig is approximately 1.5 mg. In one embodiment, the dose of lutetium Lu177 bipivotide tetraxetan is 7.4 GBq, and the dose of zarritamig is 0.75 mg. In one embodiment, the dose of lutetium Lu177 bipivotide tetraxetan is 7.4 GBq, and the dose of zarritamig is 1 mg. In one embodiment, the dose of lutetium Lu177 bipivotide tetraxetan is 7.4 GBq, and the dose of zarritamig is 1.5 mg.

[0022] The present invention provides a method for treating a patient with prostate cancer, comprising administering to the patient a pharmaceutical composition containing lutetium Lu177 bipivotide tetraxetan and a pharmaceutical formulation of zalritamig in a dose of 0.1 to 2.0 mg. In one embodiment, the dose of zalritamig is 1.5 mg. In one embodiment, the dose of lutetium Lu177 bipivotide tetraxetan is 5.9 GBq. In one embodiment, the dose of lutetium Lu177 bipivotide tetraxetan is 7.4 GBq. In one embodiment, the dose of lutetium Lu177 bipivotide tetraxetan is approximately 7.4 GBq and the dose of zalritamig is approximately 0.75 mg. In one embodiment, the dose of lutetium Lu177 bipivotide tetraxetan is approximately 7.4 GBq and the dose of zalritamig is approximately 1 mg. In one embodiment, the dose of lutetium Lu177 bipivotide tetraxetan is approximately 7.4 GBq, and the dose of zarritamig is approximately 1.5 mg. In one embodiment, the dose of lutetium Lu177 bipivotide tetraxetan is 7.4 GBq, and the dose of zarritamig is 0.75 mg. In one embodiment, the dose of lutetium Lu177 bipivotide tetraxetan is 7.4 GBq, and the dose of zarritamig is 1 mg. In one embodiment, the dose of lutetium Lu177 bipivotide tetraxetan is 7.4 GBq, and the dose of zarritamig is 1.5 mg.

[0023] The present invention relates to the use of an anti-STEAP1 antigen-binding protein for the preparation of a pharmaceutical for the treatment of prostate cancer, wherein the pharmaceutical is formulated for administration in doses of about 0.1 mg to about 2.0 mg, and the patient 90 Y, 177 Lu, 64 Cu, 153 Gd, 155 Gd, 157 Gd, 68 Ga, 213 Bi and 225The present invention provides a use in which a dose of the compound of formula 1, which is complexed with a metal selected from the group consisting of Ac, is also administered. The present invention provides a use in which an anti-STEAP1 antigen-binding protein is used in the manufacture of a pharmacopoeia for the treatment of prostate cancer, wherein the pharmacopoeia is formulated for administration in doses of about 0.1 mg to about 2.0 mg, and the patient is also administered a dose of the compound of formula 1, which is complexed with a metal selected from the group consisting of 90Y, 177Lu, 64Cu, 153Gd, 155Gd, 157Gd, 68Ga, 213Bi, and 225Ac. The present invention provides an anti-STEAP1 antigen-binding protein for use in the treatment of prostate cancer, formulated for administration in doses of about 0.1 mg to about 2.0 mg, and administered in combination with a dose of a compound of formula 1 complexed with a metal selected from the group consisting of 90Y, 177Lu, 64Cu, 153Gd, 155Gd, 157Gd, 68Ga, 213Bi, and 225Ac. The present invention also provides the use of an anti-STEAP1 antigen-binding protein in the manufacture of a pharmacopoeia for the treatment of prostate cancer, wherein the pharmacopoeia is administered in doses of about 0.1 mg to about 2.0 mg, and administered in combination with a dose of a compound of formula 1 complexed with a metal selected from the group consisting of 90Y, 177Lu, 64Cu, 153Gd, 155Gd, 157Gd, 68Ga, 213Bi, and 225Ac. The present invention provides an anti-STEAP1 antigen-binding protein for use in the treatment of prostate cancer, which is administered in doses of about 0.1 mg to about 2.0 mg and in combination with a dose of a compound of formula 1 that is 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 zalritamig.

[0024] In one embodiment, the compound complexed with the metal is lutetium Lu177 bipivotide tetraxetan. In one embodiment, the dose of lutetium Lu177 bipivotide tetraxetan is about 2 GBq to about 13 GBq. In one embodiment, the dose of lutetium Lu177 bipivotide tetraxetan is about 5.9 GBq. In one embodiment, the dose of lutetium Lu177 bipivotide tetraxetan is about 7.4 GBq. In one embodiment, the dose of lutetium Lu177 bipivotide tetraxetan is 5.9 GBq. In one embodiment, the dose of lutetium Lu177 bipivotide tetraxetan is 7.4 GBq. In one embodiment, the dose of lutetium Lu177 bipivotide tetraxetan is 7.4 GBq. In one embodiment, the dose of lutetium Lu177 bipivotide tetraxetan is administered once every six weeks. In one embodiment, the dose of lutetium Lu177 bipivotide tetraxetan is 7.4 GBq, administered once every six weeks, up to a maximum of six doses. In one embodiment, the anti-STEAP1 antigen-binding protein is administered to the patient after the patient has been administered lutetium Lu177 bipivotide tetraxetan. In one embodiment, the dose of the anti-STEAP1 antigen-binding protein is approximately 0.01 mg to approximately 2.0 mg. In one embodiment, the dose of the anti-STEAP1 antigen-binding protein is approximately 0.1 mg to approximately 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, 1.9 mg, or 2.0 mg. In one embodiment, the dose of anti-STEAP1 antigen-binding protein is approximately 0.1 mg. In one embodiment, the dose of anti-STEAP1 antigen-binding protein is approximately 0.3 mg. In one embodiment, the dose of anti-STEAP1 antigen-binding protein is approximately 0.75 mg. In one embodiment, the dose of anti-STEAP1 antigen-binding protein is approximately 1 mg. In one embodiment, the dose of anti-STEAP1 antigen-binding protein is approximately 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 once every two weeks. In one embodiment, the dose of anti-STEAP1 antigen-binding protein is administered once every three weeks. In one embodiment, the dose of anti-STEAP1 antigen-binding protein is administered once 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 once a week, starting from cycle 2. In one embodiment, the dose of anti-STEAP1 antigen-binding protein is administered once every two weeks, starting from cycle 2. In one embodiment, the dose of anti-STEAP1 antigen-binding protein is administered once every three weeks, starting from cycle 2. In one embodiment, the dose of anti-STEAP1 antigen-binding protein is administered once every four weeks, starting from cycle 2. In one embodiment, the dose of lutetium Lu177 bipivotide tetraxetan is 7.4 GBq, and the dose of anti-STEAP1 antigen-binding protein is 0.75 mg. In one embodiment, the dose of lutetium Lu177 bipivotide tetraxetan is 7.4 GBq, and the dose of anti-STEAP1 antigen-binding protein is 1 mg. In one embodiment, the dose of lutetium Lu177 bipivotide tetraxetan 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 zalritamig.

[0025] The present invention provides a method for treating a patient with prostate cancer, comprising first administering a pharmaceutical composition containing an anti-STEAP1 antigen-binding protein to the patient until a target dose of the anti-STEAP1 antigen-binding protein is achieved, followed by administering lutetium Lu 177 vipivotide tetraxetanin to the patient. In one embodiment, the present invention provides a method for treating a patient with prostate cancer, comprising first administering a pharmaceutical composition containing an anti-STEAP1 antigen-binding protein to the patient until a target dose of the anti-STEAP1 antigen-binding protein is achieved, followed by administering lutetium Lu 177 vipivotide tetraxetanin to the patient 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 Lu177 bipivotide tetraxetan is 7.4 GBq. In one embodiment, the anti-STEAP1 antigen-binding protein is zalritamig.

[0026] The present invention also provides a method for treating a patient having prostate cancer, comprising administering to the patient a pharmaceutical composition comprising a dose of the anti-STEAP1 antigen-binding protein of the present invention and a dose of lutetium Lu177 bipivotide tetraxetan, comprising at least one cycle, wherein within one cycle, the anti-STEAP1 antigen-binding protein is administered on days when lutetium Lu177 bipivotide tetraxetan is not administered. In one embodiment, the anti-STEAP1 antigen-binding protein is administered every 7 days during the administration cycle of lutetium Lu177 bipivotide tetraxetan. In one embodiment, the anti-STEAP1 antigen-binding protein is administered every 7 days during the administration cycle of lutetium Lu177 bipivotide tetraxetan. In one embodiment, the anti-STEAP1 antigen-binding protein is administered every 14 days during the administration cycle of lutetium Lu177 bipivotide tetraxetan. In one embodiment, within one cycle, the anti-STEAP1 antigen-binding protein is administered 7, 21, and 35 days after a single dose of lutetium Lu177 bipivotide tetraxetan. In another embodiment, within one cycle, the anti-STEAP1 antigen-binding protein is administered 2, 16, and 30 days after a single dose of lutetium Lu177 bipivotide tetraxetan. The present invention provides a use of an anti-STEAP1 antigen-binding protein for the preparation of a pharmacopoeia for the treatment of prostate cancer, comprising administering to a patient a dose of a pharmaceutical composition containing the anti-STEAP1 antigen-binding protein of the present invention and a dose of lutetium Lu177 bipivotide tetraxetan, comprising at least one cycle, wherein within one cycle, the anti-STEAP1 antigen-binding protein is administered every 14 days during the administration cycle of lutetium Lu177 bipivotide tetraxetan. The present invention provides a use of an anti-STEAP1 antigen-binding protein in the manufacture of a pharmaceutical for the treatment of prostate cancer, 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 Lu177 bipivotide tetraxetan, comprising at least one cycle, wherein within one cycle, the anti-STEAP1 antigen-binding protein is administered every 14 days during the administration cycle of lutetium Lu177 bipivotide tetraxetan.The present invention provides an anti-STEAP1 antigen-binding protein for use in the treatment of prostate cancer, wherein the use comprises 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 Lu177 bipivotide tetraxetan, wherein the use comprises at least one cycle, in which the anti-STEAP1 antigen-binding protein is administered every 14 days during the administration cycle of lutetium Lu177 bipivotide tetraxetan. In one embodiment, in one cycle, the anti-STEAP1 antigen-binding protein is administered 7, 21, and 35 days after the administration of a single dose of lutetium Lu177 bipivotide tetraxetan. In another embodiment, in one cycle, the anti-STEAP1 antigen-binding protein is administered 2, 16, and 30 days after the administration of a single dose of lutetium Lu177 bipivotide tetraxetan. In one embodiment, the method includes 1, 2, 3, 4, 5, or 6 cycles. In one embodiment, lutetium Lu177 bipivotide tetraxetan is administered intravenously. In one embodiment, the administration cycle of lutetium Lu177 bipivotide tetraxetan is 6 weeks. In one embodiment, the anti-STEAP1 antigen-binding protein is administered by stepwise dosing before reaching the target dose. In one embodiment, the anti-STEAP1 antigen-binding protein is administered at a target dose after the patient has been administered lutetium Lu177 bipivotide tetraxetan. In one embodiment, the dose of lutetium Lu177 bipivotide tetraxetan is 7.4 GBq and the dose of anti-STEAP1 antigen-binding protein is 0.75 mg. In one embodiment, the dose of lutetium Lu177 bipivotide tetraxetan is 7.4 GBq and the dose of anti-STEAP1 antigen-binding protein is 1 mg. In one embodiment, the dose of lutetium Lu177 bipivotide tetraxetan 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 zalritamig.

[0027] The present invention also provides a method for treating a patient having prostate cancer, comprising administering to the patient a dose of a pharmaceutical composition containing an anti-STEAP1 antigen-binding protein in a dose of about 0.1 mg to about 2.0 mg, and further comprising administering to the patient a dose of abiraterone. The present invention provides a use of an anti-STEAP1 antigen-binding protein for the preparation of a pharmacopoeia for the treatment of prostate cancer, wherein the pharmacopoeia is formulated for administration in a dose of about 0.1 mg to about 2.0 mg, and this 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, the patient is further administered prednisone (or prednisolone). In one embodiment, the patient is further administered 5 mg of prednisone twice daily. In one embodiment, the patient is further administered 10 mg of prednisone once daily. In one embodiment, the patient is once daily administered 500 mg of orally administered YONSA® in combination with 4 mg of methylprednisone twice daily. In one embodiment, the dose of anti-STEAP1 antigen-binding protein is approximately 0.1 mg to approximately 2.0 mg. In one embodiment, the dose of anti-STEAP1 antigen-binding protein is approximately 0.1 mg to approximately 1.5 mg. In one embodiment, the dose of anti-STEAP1 antigen-binding protein is approximately 0.75 mg. In one embodiment, the dose of anti-STEAP1 antigen-binding protein is approximately 1 mg. In one embodiment, the dose of anti-STEAP1 antigen-binding protein is approximately 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 administered once a week.In one embodiment, the anti-STEAP1 antigen-binding protein is administered once every two weeks. In one embodiment, the patient receives the anti-STEAP1 antigen-binding protein and the abiraterone on the same day. In one embodiment, the patient receives the anti-STEAP1 antigen-binding protein and the abiraterone on day 1 of cycle 1. In one embodiment, the patient begins receiving the abiraterone on day 1 of cycle 1.

[0028] The present invention also provides a method for treating a patient having prostate cancer, comprising administering to the patient a pharmaceutical composition containing an anti-STEAP1 antigen-binding protein in a dose of about 0.1 mg to about 2.0 mg, and further comprising administering to the patient enzalutamide. The present invention provides a use of an anti-STEAP1 antigen-binding protein for the preparation of a pharmaceutical for the treatment of prostate cancer, wherein the pharmaceutical is formulated for administration in a dose of about 0.1 mg to about 2.0 mg, and this 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 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 0.75 mg. In one embodiment, the dose of anti-STEAP1 antigen-binding protein is approximately 1 mg. In another embodiment, the dose of anti-STEAP1 antigen-binding protein is approximately 1.5 mg. In yet another embodiment, the dose of anti-STEAP1 antigen-binding protein is 1.5 mg. In one embodiment, the patient is administered enzalutamide starting on day 1 of cycle 1.

[0029] The present invention also provides a method for treating a patient having prostate cancer, comprising administering to the patient a pharmaceutical composition containing an anti-STEAP1 antigen-binding protein in a dose of about 0.1 mg to about 2.0 mg, and further comprising administering to the patient darolutamide. The present invention provides a use of an anti-STEAP1 antigen-binding protein for the preparation of a pharmaceutical for the treatment of prostate cancer, wherein the pharmaceutical is formulated for administration in a dose of about 0.1 mg to about 2.0 mg, and this use further comprises administering to the patient a dose of darolutamide. In one embodiment, the dose of darolutamide is about 450 mg to about 600 mg. In one embodiment, the dose of darolutamide is about 600 mg. In one embodiment, the dose of darolutamide is 600 mg. In one embodiment, the dose of darolutamide is administered orally. In one embodiment, the dose of darolutamide is administered orally twice daily. In one embodiment, the dose of darolutamide is administered orally twice daily by two 300 mg tablets. In one embodiment, the dose of anti-STEAP1 antigen-binding protein is approximately 0.01 mg to approximately 2.0 mg. In one embodiment, the dose of anti-STEAP1 antigen-binding protein is approximately 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.

[0030] The present invention also provides a method for treating a patient having prostate cancer, comprising administering to the patient a pharmaceutical composition containing an anti-STEAP1 antigen-binding protein in a dose of about 0.1 mg to about 2.0 mg, and further comprising administering apalutamide to the patient. The present invention provides a use of an anti-STEAP1 antigen-binding protein for the preparation of a pharmaceutical for the treatment of prostate cancer, wherein the pharmaceutical is formulated for administration in a dose of about 0.1 mg to about 2.0 mg, and this 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 once daily by four 60 mg tablets. In one embodiment, the dose of anti-STEAP1 antigen-binding protein is approximately 0.01 mg to approximately 2.0 mg. In one embodiment, the dose of anti-STEAP1 antigen-binding protein is approximately 1.5 mg. In one embodiment, the dose of anti-STEAP1 antigen-binding protein is 1.5 mg.

[0031] In one embodiment, the anti-STEAP1 antigen-binding protein is administered by stepwise dosing. In one embodiment, the anti-STEAP1 antigen-binding protein is administered in two steps. In one embodiment, the anti-STEAP1 antigen-binding protein is administered in two or three steps. In one embodiment, the anti-STEAP1 antigen-binding protein is administered at a 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. In one embodiment, the anti-STEAP1 antigen-binding protein is administered at a dose 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. In one embodiment, the method further comprises administering the anti-STEAP1 antigen-binding protein to the patient once a week, once every two weeks, once every three weeks, or once every four weeks after the stepwise dosing. In one embodiment, the anti-STEAP1 antigen-binding protein is administered at a dose of 1.5 mg once every two weeks after the stepwise dosing. In one embodiment, the anti-STEAP1 antigen-binding protein is administered at a dose of 1.5 mg once every 3 weeks after a stepwise dose. In another embodiment, the anti-STEAP1 antigen-binding protein is administered at a dose of 1.5 mg once every 4 weeks after a stepwise dose.

[0032] In one embodiment, the dose of anti-STEAP1 antigen-binding protein is administered once a week during the first cycle, and then once every three weeks once the target dose is achieved. In another embodiment, the dose of anti-STEAP1 antigen-binding protein is administered once a week during the first cycle, and then once every four weeks once the target dose is achieved.

[0033] In one embodiment, the anti-STEAP1 antigen-binding protein is administered in two cycles. In one embodiment, cycle 1 includes administering the anti-STEAP1 antigen-binding protein in doses ranging from approximately 0.1 mg to approximately 0.3 mg on day 1 or 2, in doses ranging from approximately 0.2 mg to approximately 0.4 mg on day 7, 8 or 9, in doses ranging from approximately 0.8 mg to approximately 1.2 mg on day 14, 15 or 16, and in doses ranging from approximately 1.3 mg to approximately 1.6 mg on day 21, 22 or 23. In one embodiment, cycle 2 following cycle 1 includes administering the anti-STEAP1 antigen-binding protein at a dose of 1.5 mg once every two weeks for five months after the completion of cycle 1. Each cycle is optionally 28 days long.

[0034] In one embodiment, Cycle 1 comprises administering anti-STEAP1 antigen-binding protein at doses 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. In one embodiment, Cycle 2 following Cycle 1 comprises administering anti-STEAP1 antigen-binding protein at a dose of 1.5 mg once every two weeks for five months after the completion of Cycle 1. Each cycle is optionally 28 days long.

[0035] In one embodiment, Cycle 1 comprises administering anti-STEAP1 antigen-binding protein at doses 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. In one embodiment, Cycle 2 comprises administering anti-STEAP1 antigen-binding protein at a dose of 1.5 mg once every four weeks for 11 months following the completion of Cycle 1. Each cycle is optionally 28 days long. The present disclosure provides a method for treating a patient having prostate cancer, comprising administering to the patient a pharmaceutical composition comprising zalritamig over at least two 28-day cycles, (i) cycle 1 comprising administering approximately 0.1 mg to approximately 0.3 mg of zalritamig on day 1 or 2, approximately 0.2 mg to approximately 0.4 mg of zalritamig on day 7, day 8 or 9, approximately 0.8 mg to approximately 1.2 mg of zalritamig on day 14, day 15 or 16, and approximately 1.3 mg to approximately 1.6 mg of zalritamig on day 21, day 22 or 23, and further provides a method comprising one or more additional cycles (cycle 2) comprising administering 1.5 mg of zalritamig once every two weeks.

[0036] In one embodiment, the anti-STEAP1 antigen-binding protein is the XmAb 2+1 molecule. As used herein, the "XmAb® 2+1" molecule (used synonymously with "multi-chain T cell engager molecule" or "central-scFv" molecule) contains two Fab domains and one scFv domain, each Fab domain binding to a target (e.g., STEAP1) and the scFv domain binding to another target (e.g., CD3).

[0037] In one embodiment, the anti-STEAP1 antigen-binding protein comprises two Fab-binding domains, each of which binds to STEAP1.

[0038] In one embodiment, the anti-STEAP1 antigen-binding protein comprises two Fab-binding domains, each Fab-binding domain binding 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, wherein the variable heavy chain domain comprises HCDR1 containing SEQ ID NO: 9, HCDR2 containing SEQ ID NO: 10, and HCDR3 containing SEQ ID NO: 11; and the variable light chain domain comprises LCDR1 containing SEQ ID NO: 12, LCDR2 containing SEQ ID NO: 13, and LCDR3 containing SEQ ID NO: 14.

[0039] In one embodiment, the anti-STEAP1 antigen-binding protein includes an scFv-binding domain, and the scFv-binding domain binds to CD3.

[0040] In one embodiment, the anti-STEAP1 antigen-binding protein includes an scFv-binding domain, the scFv-binding domain is bound to CD3, and the scFv variable heavy chain domain includes HCDR1 containing SEQ ID NO: 1, HCDR2 containing SEQ ID NO: 2, and HCDR3 containing SEQ ID NO: 3; an scFv linker; and an scFv variable light chain domain; and the scFv variable light chain domain includes LCDR1 containing SEQ ID NO: 4, LCDR2 containing SEQ ID NO: 5, and LCDR3 containing SEQ ID NO: 6. In one embodiment, each Fab variable heavy chain domain contains an amino acid sequence that is at least 90%, 95%, or 99% identical to SEQ ID NO: 15; each Fab variable light chain domain contains an amino acid sequence that is at least 90%, 95%, or 99% identical to SEQ ID NO: 16; and the scFv variable heavy chain domain contains an amino acid sequence that is at least 90%, 95%, or 99% identical to SEQ ID NO: 7; and the scFv variable light chain domain contains an amino acid sequence that is at least 90%, 95%, or 99% identical to SEQ ID NO: 8. In one embodiment, each Fab variable heavy chain domain includes SEQ ID NO: 15 or 20; each Fab variable light chain domain includes SEQ ID NO: 16; the scFv variable heavy chain domain includes SEQ ID NO: 7; and the scFv variable light chain domain includes SEQ ID NO: 8. In one embodiment, the scFv binding domain that binds to CD3 includes an scFv linker. In one embodiment, each Fab variable heavy chain domain includes SEQ ID NO: 15. In one embodiment, each Fab variable heavy chain domain includes SEQ ID NO: 20.

[0041] 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 E233P, L235V, G236A, S267K, R292C, N297G, V302C, E357Q and S364K; and the second Fc domain comprises amino acid substitutions N208D, E233P, L235V, G236A, S267K, R292C, Q295E, N297G, V302C, L368D, K370S, N384D, Q418E and N421D (all EU numbered). In one embodiment, the first Fc domain and the second Fc domain each contain a deletion at position 234.

[0042] In one embodiment, the anti-STEAP1 antigen-binding protein comprises an HC containing SEQ ID NO: 17, an HC with an inserted CD3 scFv containing SEQ ID NO: 19, and two light chains each containing SEQ ID NO: 18. In another embodiment, the anti-STEAP1 antigen-binding protein comprises an HC containing SEQ ID NO: 23, an HC with an inserted CD3 scFv containing SEQ ID NO: 26, and two light chains each containing SEQ ID NO: 18. In yet another embodiment, the anti-STEAP1 antigen-binding protein is an XmAb 2+1 molecule.

[0043] In one embodiment, the anti-STEAP1 antigen-binding protein is zalritamig. In one embodiment, the anti-STEAP1 antigen-binding protein is zalritamig and comprises an HC containing SEQ ID NO: 17, an HC with an inserted CD3 scFv containing SEQ ID NO: 19, and two light chains each containing SEQ ID NO: 18.

[0044] In one embodiment, the patient has metastatic castration-resistant prostate cancer. In one embodiment, the patient has never been treated with chemotherapy. In one embodiment, the patient has previously been treated for prostate cancer and has recurrent prostate cancer. In one embodiment, the patient has previously been treated with chemotherapy. [Brief explanation of the drawing]

[0045] [Figure 1] A schematic diagram of the XmAb(registered trademark) 2+1 molecule, showing the two Fabs that bind to STEAP1 and the scFv that binds to CD3. [Figure 2] Best percentage change in tumor target lesion size. The dashed line indicates a 30% reduction in tumor SLD from baseline. [Figure 3] Best percentage change in PSA from baseline. Asterisks indicate confirmed PSA response, and dashed lines indicate PSA reductions of 50 and 90. [Figure 4] Exemplary patient demonstrating response based on PSA and radiological evaluation: Sequential CT scan and PSA curves of a 65-year-old patient with stage IV prostate adenocarcinoma who had received numerous prior treatments. The patient was enrolled in cohort 12 (three-stage 1.5 mg targeted dose of zalritamig). CT scans revealed three target lesions (two in the liver and one in a lymph node) and multiple non-target lesions within the liver, as well as two lymph nodes, during screening. The patient achieved a 99% reduction in PSA from baseline on day 1 of cycle 1 and a partial response (PR) after 2 cycles (37.3% reduction in target lesions), which was confirmed at week 16 and maintained at week 24. AEs occurred during the first cycle of treatment and included recurrent CRS, tinea grade (both grade 1), rash, and worsening back pain (both grade 2). During subsequent treatment cycles, rash (grade 1), myalgia, and hyperkalemia (both grade 2) were reported. The patient is still receiving treatment at the time of this application. [Figure 5] The percentage change in PSA obtained from patients listed in Figure 4. [Modes for carrying out the invention]

[0046] Zarritamig is an XmAb® 2+1 T-cell engager (TCE) molecule designed to guide T effector cells to kill STEAP1-expressing cells. The human first-instance study of zarritamig in patients with metastatic castration-resistant prostate cancer (mCRPC) was designed to evaluate the safety, tolerability, pharmacokinetics (PK), and antitumor activity of zarritamig when administered intravenously or subcutaneously, either as monotherapy or in combination with other therapies.

[0047] This human first-dose study reports on monotherapy in patients with metastatic castration-resistant prostate cancer (mCRPC). Ninety-seven patients received one or more doses ranging from 0.001 to 2.0 mg intravenously once weekly (QW) or Q2W. The most common daily dose (MTD) was identified as 0.1 mg on day 1 (D1), 0.3 mg on D8, 1.0 mg on D15, and 1.5 mg intravenously on D22+ (QW). The most common treatment-related adverse events were cytokine release syndrome (CRS; 72%), fatigue (45%), and myalgia (34%). CRS primarily occurred during cycle 1 and was improved by pre-administration and gradual dosing. Prostate-specific antigen (PSA) responses and RECIST (Reported Criteria for Immunotherapy) responses across the cohort were promising (PSA50 49%; Objective Response Rate [ORR] 24%), and were more frequent at target doses of 0.75 mg or higher (PSA50 59%; ORR 41%). There were no grade 4 or 5 CRS events. Overall, all CRS events resolved with standard management using acetaminophen IV infusion in combination with tocilizumab and / or corticosteroids. Zarritamig demonstrated promising responses (PSA and RECIST) and manageable safety compared to established therapies in retrospective mCRPC patients.

[0048] The preliminary efficacy results observed with zalritamig were numerically higher than those reported for other TCEs in prostate cancer. Efficacy, measured by both objective responses (PSA and RECIST), was promising in this highly pre-treated mCRPC population, and responses occurred more frequently in the higher-dose cohort. PSA reduction began to be observed with 0.1 mg of zalritamig, with 49% of patients achieving a confirmed PSA 50 response and 28% achieving a PSA 90 response. At higher doses, responses were achieved in 41% of RECIST-evaluable patients. This study demonstrated that a high proportion of patients have the potential to achieve a significant clinical response, which can translate into overall clinical benefit.

[0049] The preliminary efficacy results observed with zalritamig are numerically higher than those reported for other TCEs in prostate cancer. Efficacy, measured by both objective responses (PSA and RECIST), is promising in this highly pre-treated mCRPC population, and responses occurred more frequently in higher-dose cohorts. PSA reduction began with 0.1 mg of zalritamig, with 49% of patients achieving a confirmed PSA 50 response and 28% achieving a PSA 90 response. At higher doses, responses were achieved in 41% of RECIST-evaluable patients.

[0050] Targeted immunotherapy using TCEs requires binding to both CD3+ T cells and tumor-associated antigens. Zarritamig demonstrated dose-dependent changes in peripheral pharmacodynamic biomarkers related to TCE activity, namely T cell marginal trend, T cell activation, and cytokine induction. The magnitude of the changes in PD biomarkers was consistent with the observed decrease in PSA.

[0051] The overall incidence of ADA occurring under treatment was 54%, with eight patients showing a transient antibody response. The ADA response was not dose-dependent and did not cause adverse events (AEs). Since approximately one-quarter of patients developed ADA affecting neutralizing ADA and / or PK, it is crucial to evaluate its impact on clinical response. While responses occurred in the first two cycles, neutralizing ADA occurred on average from cycle 3 onwards, so its impact on the overall response rate is not expected.

[0052] This is the first clinical report on STEAP1-targeted TCE therapy in prostate cancer. This trial provides proof of concept for TCE as a potential therapeutic modality for prostate cancer, supported by a significant number of observed radiological and PSA responses. To date, the only STEAP1-targeted agent explored clinically is a STEAP1 antibody-drug conjugate (ADC), limited by toxicity due to the monomethyl auristatin E (MMAE) payload (Maecker et al., MAbs. 2023 Jan-Dec;15(1):2229101). In summary, this trial demonstrates the feasibility of STEAP1 targeting with TCE and the potential of zalritamig as a novel therapeutic paradigm for patients with mCRPC.

[0053] Drug regimens for anti-STEAP1 antigen-binding proteins such as zalritamig in prostate cancer patients may optionally include stepwise dosing. To help reduce cytokine release and to safely achieve treatment with the active dose of anti-STEAP1 antigen-binding protein (e.g., zalritamig), stepwise dosing may consist of two or three stages, each stage involving a relatively small dose increase. The priming dose (initial dose) and target dose have also been shown to be effective in prostate cancer patients, although they are within a relatively narrow range from each other. The dose of anti-STEAP1 antigen-binding protein (zalritamig) is also relatively low compared to the doses administered in clinical trials for bispecific T-cell engagers that bind to both DLL3 and CD3. Ares et al., J.Clin.Oncol. 2023 Jun 1;41(16):2893-2903, describes that the pharmacodynamic response was maximal after the initial dose of a 1 mg step-dose of a bispecific T cell engager that binds to both DLL3 and CD3, with an expanded dose of 100 mg. See also Aggarwal et al., J.Clin.Onc. volume 42(16) May 29, 2024, which discloses the 1 mg step-dose and 100 mg target dose of tarlatamab, and Ahn et al., N Engl J Med 2023;389:2063-2075, which discloses the 10 mg and 100 mg target doses of tarlatamab. In prostate cancer, several TCEs targeting PSMA have progressed to clinical trials, but have shown limited success 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 example, JNJ-63898081, a bispecific antibody against PSMA and CD3, resulted in a transient decrease in prostate-specific antigen (PSA) in patients with mCRPC in a phase 1 trial, with 2 out of 39 patients (5%) experiencing a confirmed PSA 50 response, but no radiological response (Lim et al., Clin Genitourin Cancer 2023;21:366-75). In a study using HPN424, a PSMA-targeted TCE, 3 out of 63 patients (5%) experienced a PSA50 response, and 1 out of 34 patients (3%) experienced a confirmed response according to the Recognition of Clinical Immunology and Stabilization (RECIST) criteria for solid tumors, with manageable safety (Bono et al., J.Clin.Onc.2021;39:5013-13). Combination therapy may further improve efficacy by inducing synergistic effects and / or overcoming resistance mechanisms. This disclosure envisions the use of zalritamig in combination with standard hormonal therapy and radioligand therapy in patients. In some embodiments, the patient has advanced prostate cancer. In some embodiments, the patient has not previously received novel hormonal therapy (NHT) or has received treatment with one novel hormonal therapy (NHT).

[0054] The compound in formula 1 is complexed with the following radionuclides in the chelator: 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, 157 Gd, 213 Bi, 225 Ac, 230 U, 223 Ra, 165 It may contain one of Er or Fe.

[0055] NHTs (e.g., abiraterone, enzalutamide, apalutamide, and darolutamide) and taxanes (e.g., docetaxel and cabazitaxel) are standard treatments for non-metastatic and / or metastatic castration-resistant prostate cancer, but the majority of patients experience disease progression during therapy.

[0056] This disclosure provides a therapeutic regime in which an anti-STEAP1 antigen-binding protein, such as zalritamig, is administered in combination with another agent, including abiraterone, enzalutamide, cabazitaxel, darolutamide, apalutamide, lutetium Lu177 bipivotide tetraxetan (PLUVICTO®), PSMA radioligand therapy, PSMA immunotherapy, radium-223, PARP inhibitors, PSMA antibody-drug conjugates, B7H3 antibody-drug conjugates, radiotherapy, and / or standard treatment for prostate cancer, according to the methods of the present invention.

[0057] Abiraterone is a cytochrome P450 (CYP) 17 inhibitor indicated in combination with prednisone (or prednisolone in some areas) for the treatment of patients with mCRPC and, in some areas, metastatic or high-risk castration-sensitive prostate cancer (CSPC). Disease recurrence after abiraterone may be due to increased androgen receptor expression (e.g., androgen receptor amplification), among other mechanisms (Galletti et al, Cancer Treat Rev. 2017 Jun;57:16-27).

[0058] Enzalutamide is an androgen receptor inhibitor that acts at various stages in the androgen receptor signaling pathway. Enzalutamide has been shown to competitively inhibit androgen binding to androgen receptors, thereby inhibiting nuclear translocation of androgen receptors and their interaction with DNA. Enzalutamide is indicated for the treatment of patients with CRPC and, in some areas, patients with metastatic hormone-sensitive prostate cancer. Disease relapse after enzalutamide is partly attributable to mutations in androgen receptors (such as AR V7) and increased androgen receptor expression (e.g., androgen receptor amplification), among other mechanisms (Galletti et al., cited above).

[0059] However, in earlier stages of the disease, zalritamig may be administered without simultaneous ADT. Prostate-specific membrane antigen (PSMA) is a type II cell surface membrane-bound glycoprotein with a molecular weight of approximately 110 kD, containing an intracellular segment (amino acids 1-18), a transmembrane domain (amino acids 19-43), and a broad 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 of the human body such as the kidneys, proximal small intestine, and salivary glands. Unlike prostate-specific antigen (PSA) expression, which is downregulated after androgen ablation, 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 diseases. PLUVICTO® (Lutetium Lu177 bipivotide tetraxetan) 177Lu-PSMA-617 is an approved therapy for mCRPC patients who have previously received androgen receptor (AR) pathway inhibitors (ARPIs) and taxane-based chemotherapy. It targets PSMA-expressing cells using lutetium-177 (177Lu), a beta-particle-emitting radioligand. This therapy provides a benefit of extending overall survival by 4 months to a median of 15.3 months, and therefore there is considerable room for further improvement. PLUVICTO® is currently being explored for patients who have not been previously exposed to chemotherapy.

[0060] Anti-STEAP1 antigen-binding proteins (or STEAP1 antigen-binding proteins) are molecules that bind to human STEAP1. Such molecules may further bind to other targets, such as cell surface antigens (e.g., CD3). Non-limiting examples of the format of such molecules include antibodies (including bispecific antibodies) and their fragments, as well as T cell engager molecules, including molecules in the XmAb 2+1 format and bispecific T cell engager molecules.

[0061] Anti-STEAP1 antigen-binding proteins bind to their target, for example, when their dissociation constant (KD), measured by surface plasma resonance techniques (e.g., BIACore, GE-Healthcare Uppsala, Sweden) or binding equilibrium exclusion techniques (KinExA, Sapidyne, Boise, Idaho), is ≤10⁻⁷ M.

[0062] Bispecific T cell engager molecules are recombinant protein constructs constructed from two flexibly linked antibody-derived binding domains. "Bispecific T cell engager molecules" include "BiTE® molecules." One binding domain of a bispecific T cell engager is specific to a selected tumor-associated surface antigen on target cells; the second binding domain is specific to CD3, a subunit of the T cell receptor complex on T cells. Their special design makes bispecific T cell engager molecules unparalleled for transiently binding T cells to target cells while simultaneously potently activating the intrinsic cytolytic ability 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 engager molecules are bispecific, meaning they simultaneously bind to two targets on two different types of cells (target antigens such as STEAP1 on target cells and CD3 on T cells).

[0063] As used herein, the “XmAb 2+1” molecule (used synonymously with “multi-chain T cell engager molecule” or “central-scFv” molecule) contains two Fab domains and one scFv domain, where each Fab domain binds to a target (e.g., STEAP1) and the scFv domain binds to another target (e.g., CD3). The XmAb 2+1 molecule format is shown in Figure 1. The scFv domain (e.g., the one that binds to CD3) is inserted between the Fc domain and the CHl-Fv region, thus providing a third antigen-binding domain (e.g., two Fabs that bind to STEAP1 and one scFv that binds to CD3). The anti-CD3 scFv is “inserted” in the HC, meaning that the scFv is linked in the HC by a linker. In this embodiment, one polypeptide comprises a first heavy chain including a first variable heavy chain domain, a CH1 domain (and an optional linker / hinge), and an Fc domain, together with an scFv including an scFv variable light chain domain, an scFv linker, and an scFv variable heavy chain domain. The scFv is covalently linked between the C-terminus of the CH1 domain of the heavy chain constant domain and the N-terminus of the first Fc domain using an optional domain linker (VH1-CH1-[optional domain linker]-VH2-scFv linker-VL2-[optional domain linker including hinge]-CH2-CH3 or in the opposite direction with respect to the scFv, VH1-CH1-[optional domain linker]-VL2-scFv linker-VH2-[optional domain linker including hinge]-CH2-CH3). In some embodiments, the first polypeptide is VH1-CH1-domain linker-VH2-scFv linker-VL2-domain linker-CH2-CH3. The other polypeptide is a standard Fab (i.e., VH1-CH1-domain linker (e.g., hinge)-CH2-CH3). This embodiment further utilizes two light chains, each containing a variable light chain domain and a constant light chain domain, which associate with a heavy chain to form two identical Fabs that bind to the target.In certain embodiments, the STEAP1 Fab CD3 scFv central-scFv molecule (or STEAP1 Fab CD3 scFv XmAb 2+1 molecule) comprises two Fab domains, each bound to STEAP1 Fab, and an scFv that binds to CD3 scFv. In some specific embodiments, the central-scFv molecule or XmAb 2+1 molecule is zalritamig.

[0064] An example of an anti-STEAP1 antigen-binding protein is zarritamig. A further description of zarritamig can be found in International Publication No. 2020 / 010079 (which is incorporated herein by reference in its entirety). The sequence of zarritamig is shown in Table 4. Zarritamig comprises an HC containing SEQ ID NO: 17, an HC with CD3 scFv inserted, containing SEQ ID NO: 19, and two light chains, each containing SEQ ID NO: 18. In exemplary embodiments, the molecule of the present invention comprises a sequence containing C-terminal lysine, as in SEQ ID NO: 17 or 19. In preferred embodiments, this antigen-binding protein comprises one or both HCs that do not contain C-terminal lysine, as in SEQ ID NOs: 22 and 25. In addition, the N-terminal glutamine and / or N-terminal glutamic acid of the HC or HCVR may be converted to pyroglutamic acid, as in SEQ ID NOs: 20, 21, 23 and 24. In addition, the N-terminal glutamine and / or N-terminal glutamic acid of HC may be converted to pyroglutamic acid, and its sequence may lack C-terminal lysine, as in SEQ ID NOs. 23 and 26. All forms of the antigen-binding protein of the present invention are envisioned.

[0065] The first Fc domain and the second Fc domain each refer to half of the Fc (crystallizable fragment) region. The Fc region contains two CH2 domains and two CH3 domains. Therefore, the first Fc domain and the second Fc domain each contain a CH2 domain and a CH3 domain.

[0066] Anti-STEAP1 antigen-binding proteins are generally administered to patients in pharmaceutical compositions that may include pharmaceutically acceptable carriers, excipients, or diluents. "Pharmacologically acceptable" means molecules, compounds, and compositions that are nontoxic to human recipients at the doses and concentrations used and / or do not cause allergic or adverse reactions when administered to humans. In certain embodiments, the pharmaceutical composition may contain, for example, formulation materials to modify, maintain, or preserve the composition's pH, osmotic pressure, viscosity, clarity, color, isotonicity, odor, sterility, stability, dissolution rate or release rate, adsorption, or permeability.In such embodiments, suitable formulation materials include amino acids (e.g., glycine, glutamine, asparagine, arginine, or lysine); antibacterial agents; antioxidants (e.g., ascorbic acid, sodium sulfite, or sodium bisulfite); buffers (e.g., borates, bicarbonates, tris-HCl, citrates, phosphates, or other organic acids); fillers (e.g., mannitol or glycine); chelating agents (e.g., ethylenediaminetetraacetic acid (EDTA)); complexing agents (e.g., caffeine, polyvinylpyrrolidone, beta-cyclodextrin, or hydroxypropyl-beta-cyclodextrin); fillers; monosaccharides; disaccharides; and other carbohydrates (e.g., glucose, mannose, or dextrin); proteins (e.g., serum albumin, gelatin, or immunoglobulin); colorants, flavoring agents, and diluents; emulsifiers; hydrophilic polymers (e.g., polyvinylpyrrolidone); low molecular weight polypeptides; and salt-forming counterions (e.g., na Thorium); preservatives (e.g., benzalkonium chloride, benzoic acid, salicylic acid, thimerosal, phenethyl alcohol, methylparaben, propylparaben, chlorhexidine, sorbic acid, or hydrogen peroxide); solvents (e.g., glycerin, propylene glycol, or polyethylene glycol); sugar alcohols (e.g., mannitol or sorbitol); suspending agents; surfactants or wetting agents (e.g., Pluronic®, PEG, sorbitan esters, polysorbates such as polysorbate 20, polysorbate 80, Triton, tromethamine, lecithin, cholesterol, tyloxapal); stability enhancers (e.g., sucrose or sorbitol); isotonic enhancers (e.g., alkali metal halides, preferably sodium chloride or potassium chloride, mannitol, or sorbitol); delivery vehicles; diluents; excipients and / or pharmaceutical adjuvants. Methods and suitable materials for formulating molecules for therapeutic use are publicly known in the pharmaceutical field, for example, as described in REMINGTON'S PHARMACEUTICAL SCIENCES, 18th Edition, (ARGenrmo, ed.), 1990, Mack Publishing Company.In some embodiments, the selection of carriers and excipients 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.

[0067] Anti-STEAP1 antigen-binding proteins such as zalritamig can be formulated as a pre-lyophilized formulation of 0.3 mg / mL to 2.5 mg / mL zalritamig (e.g., 1 mg / mL) formulated with 10 mM glutamic acid, 9% (w / v) sucrose, and 0.01% (w / v) polysorbate 80 (pH 4.20) (i.e., zalritamig is present in a formulation containing 0.3 mg / mL to 2.5 mg / mL zalritamig (e.g., 1 mg / mL), 10 mM glutamic acid, 9% (w / v) sucrose, and 0.01% (w / v) polysorbate 80 (pH 4.20), which is then lyophilized). Formulations of anti-STEAP1 antigen-binding proteins are also disclosed in International Publication No. 2019 / 157340 (the entirety of which is incorporated herein by reference).

[0068] In this specification, when a dose of anti-STEAP1 antigen-binding protein is referred to as being administered to a patient, it is intended to be understood that the anti-STEAP1 antigen-binding protein is present in the pharmaceutical composition.

[0069] This specification assumes that lutetium Lu177 bipivotide tetraxetan is administered to prostate cancer patients for 2 to 6 cycles, followed by administration of anti-STEAP1 antigen-binding protein. The anti-STEAP1 antigen-binding protein may be administered in stepwise doses as described herein before reaching the target dose.

[0070] In this specification, it is assumed that the anti-STEAP1 antigen-binding protein and lutetium Lu177 bipivotide tetraxetan are administered on different days within the same cycle. In some embodiments, the anti-STEAP1 antigen-binding protein and lutetium Lu177 bipivotide tetraxetan are administered according to Example 2. In some embodiments, lutetium Lu177 bipivotide tetraxetan is administered, and at least 7 days later, the anti-STEAP1 antigen-binding protein is administered in stepwise doses until the target dose of the anti-STEAP1 antigen-binding protein is reached. After the target dose of the anti-STEAP1 antigen-binding protein is reached, the anti-STEAP1 antigen-binding protein is administered at the target dose.

[0071] In this specification, it is assumed that anti-STEAP1 antigen-binding protein is administered in a stepwise dose as described herein, followed by additional administration of anti-STEAP1 antigen-binding protein at a target dose for up to 5 cycles, and then additional administration of lutetium Lu177 bipivotide tetraxetan for up to 6 cycles.

[0072] The present invention also includes a kit for treating prostate cancer in patients requiring treatment for prostate cancer. In one embodiment, the kit includes a pharmaceutical composition of an anti-STEAP1 antigen-binding protein and packaging material providing instructions for using the pharmaceutical composition. The pharmaceutical composition of the kit may be contained in a container such as a vial or syringe. The pharmaceutical composition may be provided as a solution, suspension, gel, emulsion, solid, crystal or dehydrated powder 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 to reconstitute the pharmaceutical composition and instructions for preparing the composition for administration. 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 (e.g., by IV injection) for the purpose of treating prostate cancer in patients requiring treatment for prostate cancer. In embodiments where the pharmaceutical composition is provided in lyophilized or dry powder form, the kit may include a diluent for reconstituting the pharmaceutical composition before administration and instructions.

[0073] Anti-STEAP1 antigen-binding protein may be administered by “gradual dosing,” which refers to increasing the dose administered to the patient before reaching a target dose level (see also, e.g., Ball et al., MAbs. 2023 Jan-Dec;15(1):2181016). Gradual dosing may consist of one, two, three, four, or five stages (i.e., multiple doses in which the amount of therapeutic agent administered increases). Each “stage” is an increase in the dose administered to the patient from the last dose administered to the patient. Gradual dosing may consist of two or three stages. Gradual dosing may consist of two stages to reach a target dose (e.g., 0.75 mg). Gradual dosing may consist of three stages to reach a target dose (e.g., 1.5 mg). Gradual dosing may be performed to reduce the incidence of cytokine release syndrome. For example, a gradual dosing regimen may begin with a priming dose on day 1 of cycle 1, gradually increasing on day 8 (one step), and then continuing with the target dose. At the end of the gradual dosing regimen, the target dose may be administered (e.g., once a week, once every two weeks, once every three weeks, or once every four weeks). The target dose may be administered at any intervals over a desired period (e.g., four weeks, five months, or eleven months), resulting in a total treatment period of, for example, two months, six months, or twelve months.

[0074] The anti-STEAP1 antigen-binding protein (e.g., zalritamig) is initially administered by stepwise dosing until the target dose of the anti-STEAP1 antigen-binding protein (zalritamig) is reached. After reaching the target dose of zalritamig, the patient may be treated with another therapeutic agent (e.g., a combination partner), although this disclosure also intends for the administration of another therapeutic agent before reaching the target dose (e.g., administration in C1-D1). Such another therapeutic agent may be administered in cycles with zalritamig.

[0075] A “cycle” refers to a repeated treatment pattern and may be defined by an anti-STEAP1 antigen-binding protein (e.g., zalritamig) or a combination partner. Cycles can also provide a basis for patient follow-up. Cycles can still exist even when the drug is administered continuously. Cycles may consist of different numbers of days depending on the treatment. A cycle refers to a period during which the necessary actions can be repeated. This is a standard way of defining the treatment duration using prescribed points in time when treatment is administered. For example, a cycle of anti-STEAP1 antigen-binding protein (zalritamig) may be every 28 days. A cycle of PLUVICTO® may be 42 days (administered every 6 weeks).

[0076] When multiple therapeutic agents (e.g., anti-STEAP1 antigen-binding protein and lutetium Lu177 bipivotide tetraxetan) are administered to a patient during the course of treatment, these therapeutic agents are said to be administered concomitantly. When administered concomitantly, the therapeutic agents may be administered on the same day, or they may be administered several days, weeks, or months apart. Exemplary dose regimens are described herein and in the examples.

[0077] This disclosure provides a method for administering an anti-STEAP1 antigen-binding protein (e.g., zalritamig) to a patient requiring its administration over a course of treatment comprising two or more cycles (each cycle optionally consisting of 28 days), in various embodiments. Cycle 1 comprises a three-step dosing schedule, in which the patient is administered doses of 0.1 mg of zalritamig on day 1 (C1 D1), 0.3 mg of zalritamig on day 8 (C1 D8), 1 mg of zalritamig on day 15 (C1 D15), and 1.5 mg of zalritamig on day 22 (C1 D22). In this scenario, 1.5 mg of zalritamig is the “target dose.” Following Cycle 1, one or more additional treatment cycles are performed over a desired period (i.e., Cycle 2, Cycle 3, etc.). In various embodiments, Cycle 2 and subsequent cycles (i.e., each cycle following Cycle 1) include administration of 1.5 mg of zalritamig once every two weeks; for example, 1.5 mg of zalritamig is administered on C2 D1 and 1.5 mg of zalritamig is administered on C2 D15. In alternative embodiments, Cycle 2 may include administration of zalritamig once every three weeks (e.g., 1.5 mg of zalritamig administered Q3W) or once every four weeks (e.g., 1.5 mg of zalritamig administered Q4W). Cycle 2 may be repeated one or more times. For example, Cycle 2 may be repeated five times, thereby providing treatment to the patient over a period of six months. Alternatively, Cycle 2 may be repeated eleven times, thereby providing treatment to the patient over a period of twelve months. In various embodiments, the patient receives 1000 mg of abiraterone orally once daily, and prednisone at a dose of 5 mg twice daily or 10 mg once daily. In various embodiments, the patient receives 160 mg of enzalutamide orally once daily.

[0078] This disclosure provides a method for administering an anti-STEAP1 antigen-binding protein, such as zalritamig, according to the method of this disclosure. This disclosure also provides an anti-STEAP1 antigen-binding protein, such as zalritamig, for use in the treatment of prostate cancer, which 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 approximately 0.3 mg. In one embodiment, the dose is approximately 0.75 mg. In one embodiment, the dose is approximately 1 mg. In one embodiment, the dose is approximately 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 a week. 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 a week, starting from cycle 1. In one embodiment, the dose is administered once a week, 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 another embodiment, the dose is administered once a week in the first cycle, and then once every two weeks, starting from day 1 of cycle 2. In yet another embodiment, the dose is administered once a week in the first cycle, and then once every two weeks once the target dose is achieved.In one embodiment, the dose is administered once a week in the first cycle, and then once every three weeks once the target dose is achieved. In another embodiment, the dose is administered once a week in the first cycle, and then once every four weeks once the target dose is achieved.

[0079] The phrase "by dose" refers to the doses of molecules (drugs) that may be administered to a patient simultaneously (on the same day) with other different molecules, or the doses of molecules (drugs) that may be administered sequentially (for example, at least one dose of one molecule administered to a patient is time-separated from at least one dose of another molecule administered to the patient). In this specification, it is also intended that a dose of one molecule may be followed by at least one additional dose of the same molecule, and then at least one dose of a different molecule.

[0080] In general, intravenous (IV) medications can be administered together on the same day. Oral and IV medications can also be administered on the same day. For example, zalritamig and abiraterone can be administered together on the same day. Medications can also be administered on separate days. For example, zalritamig and PLUVICTO® can be administered on separate days.

[0081] Where used synonymously herein, “treatment” and / or “treating” and / or “to treat” are intended to mean all processes which may result in slowing, interrupting, inhibiting, controlling, stopping or reversing the progression of the disorders described herein, but not necessarily indicating the complete disappearance of all disorder symptoms. Treatment includes administering anti-STEAP1 antigen-binding protein for the treatment of a disease or condition in a person who would benefit from the activity of the anti-STEAP1 antigen-binding protein, such as prostate cancer, and includes (a) inhibiting further progression of the disease; and / or (b) alleviating the disease, i.e., causing regression of the disease or disorder or relieving its symptoms or complications.

[0082] The size of a patient's prostate (and / or metastatic lesions) can be determined by methods known in the art. Such methods include computed tomography (CT), MRI, and / or bone scans. PSA can be determined by blood tests known in the art.

[0083] This disclosure aims to describe the present invention's method 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.

[0084] This disclosure envisions a method of the present invention for reducing a patient's PSA level. This disclosure envisions a method of the present invention used to delay or stop cancer cells from spreading to other parts of a patient's body.

[0085] This disclosure intends to describe 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.

[0086] This disclosure intends to describe the use of the present invention to reduce a patient's PSA level. This disclosure also intends to describe the method of the present invention used to delay or stop cancer cells from spreading to other parts of a patient's body.

[0087] This disclosure aims to manufacture a pharmaceutical product 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.

[0088] This disclosure envisions the manufacture of the pharmaceutical of the present invention for reducing a patient's PSA. This disclosure envisions the method of the present invention used to delay or stop cancer cells from spreading to another part of a patient's body.

[0089] The term "approximately" refers to a value within 10% above or below the reference value, and includes the reference value itself.

[0090] This invention aims to reduce cytokine release syndrome (CRS) that may result from T-cell engager therapy by administering anti-STEAP1 antigen-binding protein in a graded manner (compared to treatment with anti-STEAP1 antigen-binding protein without graded administration). Cytokine release syndrome can occur due to the activation of bystander immune cells and bystander non-immune cells, potentially leading to comorbidities. CRS can be graded according to Lee et al., ASTCT Consensus Grading for Cytokine Release Syndrome and Neurologic Toxicity Associated with Immune Effector Cells. Biol Blood Marrow Transplant. 2019;25(4):625 638. [Examples]

[0091] Example 1: Design of a Phase 1 Clinical Trial This study (NCT04221542) was designed to evaluate the safety, tolerability, pharmacokinetics (PK), and antitumor activity of zalritamig as monotherapy or in combination with other therapies in patients with mCRPC (pts), and to determine the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D). Parts 1-3 evaluate monotherapy using various dosing schedules and target doses, as well as SC administration. Part 4 evaluates combination therapy with established standard treatments for mCRPC. Parts 4A and 4B evaluate zalritamig plus abiraterone acetate (4A) or zalritamig plus enzalutamide (4B) in patients previously treated with 0, 1, or 2 NHTs and up to 1 taxane (HSPC). Part 5 is dose expansion in an outpatient setting based on efficacy and toxicity from the dose exploration in Part 1. Primary endpoints include dose-limiting toxicity, adverse events and treatment-related adverse events occurring during treatment, and changes in clinical and laboratory parameters. The primary secondary endpoints include PK, objective response according to RECIST 1.1, prostate-specific antigen response, radiological progression-free survival according to PCWG3, and overall survival. The primary inclusion criteria are men with pathologically confirmed mCRPC, evidence of progressive disease, and an ECOG performance status of 0 or 1. The primary exclusion criteria are small cell prostate cancer or neuroendocrine prostate cancer, untreated CNS metastases or leptomeningeal disease, a history of or current autoimmune disease, or any disease requiring long-term immunosuppressive therapy. In Part 1, dose escalation will be guided by a Bayesian logistic regression model. In Parts 2 and 4, the AMG 509 dose will be based on data from the monotherapy part, and dose exploration will be guided by an mTPI-2 design. The clinical trial sites are located in North America, Australia, Asia, and Europe.

[0092] This study is an open-label, escalation-based, multi-dose, phase 1 multi-cohort study evaluating zalritamig in patients with mCRPC. Up to 441 patients will be enrolled in this study. The study will include the following parts: Part 1: Zalritamig monotherapy administered via IV infusion to patients who have previously been treated for NHT and have a history of treatment with 1-2 taxanes; Part 2: Zalritamig monotherapy administered via SC injection to patients who have previously been treated for NHT and have a history of treatment with 1-2 taxanes (Part 2 is complete); Part 3: Zalritamig monotherapy administered via SC injection to patients who have never been treated for NHT or who have previously been treated for one type of NHT (administered for hormone-sensitive prostate cancer [HSPC]). Zalritamig monotherapy administered via IV infusion to patients who may have been treated with taxanes in the past and have not been treated with taxanes in the past; Part 4: In Parts 4A and 4B, zalritamig administered via IV infusion in combination with abiraterone acetate (Part 4A) or enzalutamide (Part 4B) to patients who have been previously treated with 0-2 NHTs (for hormone-sensitive disorders or castration-resistant disorders) and who have not been previously treated with taxanes or have been previously treated with one taxane for hormone-sensitive disorders in the past. In Part 4A, zalritamig is administered IV, and abiraterone is administered starting on day 1 of cycle 1, in accordance with the abiraterone package insert. In Part 4B, zalritamig is administered IV, and enzalutamide is administered starting one week after zalritamig reaches the target dose, in accordance with the enzalutamide package insert (or an alternative schedule based on newly available safety data). Part 5: Zarritamig monotherapy administered via IV infusion in an outpatient setting to patients who have previously been treated with 1-2 types of NHT and have a history of being treated with 1-2 types of taxanes.

[0093] In Parts 1, 3, 4, and 5, zalritamig is administered weekly (QW) or Q2W as a short IV infusion (approximately 60 minutes), but a Q3W or Q4W schedule may be explored based on newly available data and DLRT recommendations. The dosing regimens and schedules in Parts 3 and 4 will be adjusted to follow the regimens and schedules explored in Part 1, based on newly available data and DLRT recommendations. The dosing regimen and schedule in Part 5 will be selected based on newly available data and DLRT recommendations. This may include step-by-step dosing. In Part 2, zalritamig was administered as a deep subcutaneous injection either QW or Q2W. Dose escalation of zalritamig as IV monotherapy will be carried out in parallel with dose escalation of combination and SC, and multiple dose regimens may be evaluated in parallel. The dose in Part 3 is the MTD or RP2D determined in the dose exploration or dose escalation in Part 1. Throughout all parts of the treatment, patients are required to continue ADT during treatment with AMG 509.

[0094] In the Part 1 dose-finding phase, up to 100 patients with mCRPC will be enrolled. Dose-finding will be conducted in two stages: a single-patient cohort followed by a multi-patient cohort (2-4 patients per cohort). Planned dose levels are 0.001, 0.003, 0.01, 0.03, 0.1, 0.3, 1, 1.5, and 2 mg administered IV every quarter week (QW). A 2-week (Q2W) schedule may be introduced earlier, and the DLRT may recommend starting in cycle 2 and exploring 3-week (Q3W) or 4-week (Q4W) schedules thereafter.

[0095] [Table 1]

[0096] The decision to increase or decrease the dose in Part 1 is guided by the BLRM model of dose toxicity. In BLRM, the MTD is the dose level at which the probability of the DLT rate falling within the target interval of 20% to 33% is highest, provided that overdose is controlled. To control the risk of overdose, the MTD must have a predicted probability of overdose (DLT rate greater than 33%) of less than 40%.

[0097] The MTD in Parts 2 and 4 is the dose level at which the DLT rate is most likely to fall within the target interval of 30% to 40%.

[0098] The primary endpoints include dose-limiting toxicity, adverse events occurring during treatment, treatment-related adverse events, and changes in vital signs, ECG, and laboratory tests.

[0099] Secondary endpoints include: PK parameters, including but not limited to peak serum concentration (Cmax), time to peak concentration (Tmax), minimum serum concentration (Cmin), area under the concentration-time curve (AUC) over the dosing interval, accumulation after multiple dosings, and, if possible, half-life (t1 / 2); objective response (OR) according to the criteria for evaluating the effectiveness of treatment for solid tumors (RECIST) 1.1; 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; progression-free survival (radiological and PSA); progression-free survival (PFS) (radiological and PSA); radiological 6-month PFS 1, 2, and 3-year overall survival (OS); circulating tumor cells (CTCs) - response (CTC0) and CTC conversion rate; other endpoints recommended by PCWG3 (time to symptomatic bone-related event, alkaline phosphatase [total, bone type], lactate dehydrogenase [LDH], hemoglobin, neutrophil-to-lymphocyte ratio, urinary N-telopeptide).

[0100] Once the MTD is identified, enrollment in the dose expansion phase will be initiated to confirm safety and tolerability by evaluating the three selected drug regimens, and to further assess PD and antitumor activity to select the most appropriate dose and schedule. These drug regimens will be administered in parallel during the expansion phase and will include different dose levels and / or schedules as shown in Table 2.

[0101] [Table 2]

[0102] Patients will be randomly assigned in a 1:1:1 ratio to different expanded cohorts. Up to 50 patients (pts) are expected to be enrolled in each expanded cohort.

[0103] As of March 23, 2023, 97 patients were receiving at least one dose of zalritamig at 15 dose levels / schedules (DLs) (28 patients [28.3%] had received treatment for more than 6 months); 25 patients were continuing treatment. The median age (range) was 67 (40-86) years; 67 patients (69.1%) had previously received more than three lines of therapy. Treatment-induced adverse events (TEAEs) were reported in 100% of patients (74.2% were grade 3 or higher). The most common AE was cytokine release syndrome (CRS; 72.2%), which was mainly grade 1 / 2 (cycle 1) with one case of grade 3 (no grade 4 / 5 CRS). In the 2 mg TD cohort, 3 out of 6 DLT-evaluable patients experienced DLT, and 1.5 mg was defined as the MTD. Treatment-related TEAEs leading to discontinuation occurred in 17.5% of patients. Overall, 89 patients were PSA evaluable; 66 patients were RECIST evaluable. PSA 50 (a decrease of 50% or more in PSA) responses occurred in 42 patients (47.2%); PSA 90 occurred in 24 patients (27.0%). PSA responses occurred more frequently in patients with higher DL (0.75 mg to 2 mg) than in patients with lower DL (0.001 to 0.3 mg): ≥90% (34.8% vs. 18.6%) and ≥50% (54.3% vs. 39.5%). RECIST responses included 15 confirmed PRs (22.7%) and 30 stable diseases (SD) (45.5%). In patients with higher DL, 14 patients (38.9%) had confirmed PRs and 12 patients (33.3%) had SD. Preliminary pharmacokinetics (PK) showed a dose-proportional increase at exposure levels ranging from 0.003 mg to 1.5 mg, with a mean terminal phase half-life of approximately 3 to 4 days.

[0104] Patients were initially enrolled in cohorts 1-6, receiving fixed (non-graded) dosing at 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 once weekly (QW) intravenously (IV). In cohort 6, at 0.3 mg, two out of six patients experienced grade 3 CRS / encephalopathy and back pain dose-limiting toxicity (DLT), and this dose level was determined to be unacceptable and exceed the maximum tolerated dose (MTD) on day 1 of cycle 1. After adjustment of pre-dosage, the starting dose of 0.3 mg (cohort 8) was still determined to be unacceptable, and the MTD for the initial dose (priming dose) was confirmed to be 0.1 mg.

[0105] The drug was administered in stages, starting with 0.1 mg on day 1, and the target dose was reached by day 8, day 15, or day 22, using one of the following methods: stage 1 (increase on day 8), stage 2 (increase on days 8 and 15), or stage 3 (increase on days 8, 15, and 22).

[0106] In cohorts 7a and 10, the one-step dosing regimen consisted of 0.1 mg to 0.3 mg or 0.1 mg to 1.0 mg. The 0.1 mg to 0.3 mg regimen (cohort 7a) was tolerable, but the larger step-up dose of 0.1 mg to 1.0 mg (cohort 10) was intolerable, as 3 out of 4 patients experienced DLTs consisting of grade 3 atrial fibrillation / QT interval prolongation, grade 3 fasciitis / pharyngitis, and grade 3 arthralgia (1 patient each). Based on the findings of the one-step dosing regimen, two-step dosing regimens with a priming dose of 0.1 mg, a dose of 0.3 mg on day 8, and a dose of 0.75 mg or 1.0 mg on day 15 were evaluated in cohorts 7b, 7c, and 9; all were judged to be tolerable.

[0107] Based on findings from two-stage dosing, cohorts 11, 12, and 13 evaluated a three-stage dosing regimen with a priming dose of 0.1 mg, a dose of 0.3 mg on day 8, either 0.75 mg or 1.0 mg on day 15, and either 1.5 mg or 2 mg on day 22. Cohorts 11 (0.75 mg on day 15) and 12 (1.0 mg on day 15) had a target dose of 1.5 mg on day 22, and both were judged to be tolerable. In cohort 13, the highest dose on day 22, 2.0 mg, was tested, but this was considered tolerable due to DLT in 3 out of 4 evaluable patients (grade 3 myalgia [n=2]; grade 3 back pain and arthralgia [n=1]).

[0108] In summary, the maximum tolerated priming dose with a complete prophylactic regimen was 0.1 mg, and a three-step dosing regimen consisting of 0.3 mg on day 8, 1.0 mg on day 15, and 1.5 mg (IV QW) from day 22 onward was determined to be the MTD.

[0109] Zarritamig is well-tolerated, even with low-grade CRS (primarily cycle 1), and shows promising preliminary clinical efficacy in many previously treated mCRPC patients.

[0110] Preliminary efficacy, measured by both PSA and RECIST, was promising in the many previously treated mCRPC populations, and responses occurred more frequently in higher-dose cohorts. Consistent with PD markers for T cell activity, PSA reduction began to be observed from 0.1 mg zalritamig, with a significant number of patients achieving confirmed PSA 50 and confirmed PSA 90 responses. At higher doses, these were converted in OR, with a response rate of 50% observed in RECIST-evaluable patients.

[0111] The maximum tolerated dose was determined to be 1.5 mg using a three-stage schedule of once-weekly administration (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 / 1.5 mg on day 22 of cycle 1). For dose expansion, a second administration schedule using 0.75 mg with a two-stage schedule of once-weekly administration (0.1 mg on day 1 of cycle 1 / 0.3 mg on day 8 of cycle 1 / 0.75 mg on day 15 of cycle 1) will be explored. Administration of 1.5 mg once every two weeks (Q2W) will also be explored. This schedule will use the three-stage schedule. From cycle 2 onward, the target dose of 1.5 mg will be administered Q2W.

[0112] During this study, early signs of clinical efficacy based on PSA reduction were observed across all target dose levels of zalritamig ≥0.1 mg, with one OR observed in the cohort with a target dose of 0.3 mg. Higher OR rates were observed in patients in the high-dose cohort (QW administration, target doses above 0.3 mg, deemed safe and tolerable). Of the 67 patients with RECIST-evaluable disease, 16 patients (24%) achieved confirmed partial response (PR); 32 patients (48%) were stable disease (SD); 13 patients (19%) had progressive disease (PD); and 6 patients (9%) were unevaluable (Figure 2; Table 3). RECIST-based OR was higher at higher doses, with 10 patients (50%) achieving confirmed PR. Responses were typically achieved within the first two cycles of treatment, and the duration of response in the higher-dose cohort remains immature. During this study, initial clinical benefits, including a reduction in bone lesions and imaging responses in accordance with RECIST version 1.1, were observed across patients with diverse disease burdens.

[0113] [Table 3]

[0114] In the PSA-evaluable analysis population (N=87), confirmed PSA50 responses were reported in 43 patients (49%) and confirmed PSA90 responses were reported in 24 patients (28%) (Figure 3). In the low-dose cohort (evaluable patients n=43) and high-dose cohort (n=44), confirmed PSA50 responses were reported in 17 patients (40%) and 26 patients (59%), respectively, while confirmed PSA90 responses occurred in 8 patients (19%) and 16 patients (36%), respectively. One patient was a 65-year-old male initially diagnosed with stage IV adenocarcinoma of the prostate (Gleason score 9). This subject had been receiving androgen deprivation therapy, and his previous treatments included bicalutamide, abiraterone, docetaxel, cabazitaxel, and carboplatin. Upon receiving IV zalritamig at a three-stage targeted dose of 1.5 mg, this subject demonstrated a confirmed PSA 50 response, with a maximum PSA reduction of 99% from baseline on day 1 of cycle 7. CT scans revealed three target lesions and several non-target lesions during screening. Post-treatment imaging after two cycles showed lesion reduction consistent with a partial response (37.3% reduction of target lesions) according to RECIST 1.1 criteria, confirmed at week 16 and maintained at week 24 (Figures 4 and 5). AEs during the first cycle of treatment were grade 2 or less and included recurrent CRS, rash, exacerbation of back pain, and tinea faculita. During subsequent cycles of treatment, grade 2 or less AEs of rash, myalgia, and hyperkalemia were reported.

[0115] Preliminary PK showed a dose-proportional increase in exposure across the explored dose levels, with a mean terminal phase half-life of approximately 3–4 days. Based on preclinical studies, the black horizontal dashed lines at the bottom and top represent the 90% effective concentration (EC90) (74 ng / mL) in the in vitro mediated cell killing assay and the median inhibitory concentration (IC50) (259 ng / mL) in the xenograph PK / PD model, respectively. From Cohort 5 (0.1 mg QW), the observed pre-dose (Ctrough) concentration approached the predicted minimum effective exposure, suggesting that these doses may lead to clinical response.

[0116] A rapid decrease in peripheral T cell count was observed after the initial infusion of zalritamig. Lymphocyte redistribution was accompanied by transient expression of CD69, a T cell activation marker. Measured serum cytokines, including IFN-gamma, IL-2, IL-6, and TNF-alpha, increased from baseline after zalritamig infusion. Cytokine concentrations peaked within 6–24 hours and returned to baseline before subsequent infusions. T cell periphery, T cell activation, and cytokine induction were all dose-dependent, and FDR-corrected p-values ​​were significant at multiple time points after infusion.

[0117] The overall incidence of ADA occurring under treatment was 49 out of 90 evaluable patients (54%), of which 8 patients had a transient antibody response. The median time to the occurrence of bound ADA was day 1 of cycle 2. The impact of ADA on drug activity, exposure, and safety events was evaluated in patients who were ADA-positive. No adverse events (AEs) were associated with the observed ADA. A subset of patients who were ADA-positive were determined to be neutralizing and / or affecting exposure.

[0118] The safety profile in this study consisted mostly of clinically manageable Grade 1 and 2 adverse events, with no Grade 5 events found to be related to zalritamig. 19% of patients discontinued treatment due to TRAEs, partly due to limitations on the duration of treatment interruption.

[0119] The most frequent TRAE was low-grade CRS, primarily occurring in cycle 1. CRS was anticipated in this study based on the biological mechanism of zalritamig and clinical experience with other TCEs (11). Three cases (3%) of grade 3 CRS were reported, one of which subsequently decreased to grade 1 after the data cutoff. Grade 3 events (cohorts 6 and 7a) occurred before the addition of the second premedication of dexamethasone and before post-medication IV fluid resuscitation initiated in the later cohorts. Almost all CRS events presented as fever, which was accompanied or absent by hypotension, tachycardia, and rarely hypoxia. There were no grade 4 or 5 CRS events. Overall, all CRS events resolved with standard management using acetaminophen and IV fluids in combination with tocilizumab and / or corticosteroids.

[0120] A favorable and predictable dose-exposure relationship was observed after zalritamig administration. The preliminary terminal phase half-life was approximately 3-4 days, which supports the QW dosing schedule. PK suggested that patients receiving 0.75 mg or more of the target dose would have trough concentration levels at the minimum effective exposure based on preclinical studies. This allows for further analysis to evaluate clinical outcomes in the low-dose (<0.75 mg) and high-dose (≧0.75 mg) cohorts.

[0121] An additional analysis was conducted in patients with mCRPC in the dose expansion phase who were randomly assigned in a 1:1:1 ratio to receive IV zalritamig at a target dose of 0.75 mg QW, 1.5 mg QW, or 1.5 mg Q2W using a two-step or three-step dosing approach in Cycle 1. The results are shown in the table below.

[0122] [Table 4]

[0123] While both doses were effective, in this randomized dose-expansion / optimization trial involving many previously treated mCRPC patients, the 1.5 mg target dose improved the efficacy of zalritamig compared to 0.75 mg, with a manageable side effect profile. The higher target dose of 1.5 mg showed a tendency toward better efficacy and similar safety compared to 0.75 mg.

[0124] PSA50 0.75mg:36%, 1.5mg:53%~60%

[0125] PSA90 0.75mg:21%, 1.5mg:30%~34%

[0126] ORR 0.75mg:15%, 1.5mg:19%~29%

[0127] Grade 3 adverse events were mostly transient, manageable, and reversible, and most patients were able to continue treatment. Discontinuation due to musculoskeletal inflammatory events or cytokine release syndrome (CRS) was rare, and most Grade 3 CRS events occurred in Cycle 1 (no Grade 4 / 5 CRS). The Q2W dosing schedule showed an improved adverse event profile, with a reduced overall incidence of treatment-related musculoskeletal inflammatory events (69% compared to 74% and 86% in the QW dosing schedule) and a decrease in the number of high-grade events (Grade 2 / 3 events were 22% / 33% compared to 31% / 37% and 34% / 43% respectively).

[0128] Example 2: Clinical trial design of AMG 509 in combination with lutetium Lu177 bipivotide tetraxetan A Phase 1b clinical trial can be conducted to determine the safety and efficacy of zalritamig in combination with PLUVICTO® (lutetium Lu177 bipivotide tetraxetan) in mCRPC patients.

[0129] The expected medication regimen is as follows: Initiation phase of monotherapy: Gradual dose increase of IV zalritamig. The cycle duration for zalritamig monotherapy is 28 days. Treatment is administered to the following cohorts: Cohort 1 (D1 0.1 mg / D8 0.3 mg / D15 0.75 mg / D22 0.75 mg) and Cohort 2 (D1 0.1 mg / D8 0.3 mg / D15 1.0 mg / D22 1.5 mg).

[0130] Monotherapy bridging phase: Target dose of IV zalritamig 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 therapy phase ("C1D1"). Criteria for continuing treatment and ordering PLUVICTO® will be established to ensure a smooth transition to combination therapy, unless contraindicated. During the monotherapy bridging phase, the target dose will be administered Q2W until the patient is ready to receive C1D1 of the combination therapy phase. This phase will consist of two or three doses of zalritamig administered Q2W at a randomly assigned target dose (e.g., 0.75 mg or 1.5 mg) to the patient.

[0131] Combination therapy period: Combination therapy with PLUVICTO (registered trademark) and zalritamig. The combination therapy period for zalritamig with PLUVICTO® begins with the approved dose of PLUVICTO® (7.4 GBq) on C1D1, followed by the target dose of AMG509 on C1D8, and then the target dose of AMG509 on a Q2W schedule. Since the cycle length is 6 weeks during the combination therapy period, AMG509 is administered on D8, D22, and D36 in all combination cycles. A maximum of 6 cycles of combination therapy are planned.

[0132] Maintenance phase of IV zalritamig monotherapy After the completion of the combination therapy period, zalritamig may be continued at a target dose (e.g., 0.75 mg or 1.5 mg) on ​​a Q2W schedule at the discretion of the principal investigator.

[0133] The primary endpoints include dose-limiting toxicity, adverse events occurring during treatment, treatment-related adverse events, and changes in vital signs, electrocardiogram, and laboratory tests. The pharmacokinetic (PK) and preliminary antitumor activity of zalritamig in combination with PLUVICTO® will also be evaluated as secondary endpoints.

[0134] The proposed schedule, with a target dose of 0.75 mg or 1.5 mg of zalritamig, was found to be safe and tolerable in Protocol 20180146 and was selected for further exploration of dose expansion. This study will undergo ongoing enrollment and ongoing safety evaluation.

[0135] [Table 5]

[0136] [Table 6]

[0137] [Table 7]

[0138] [Table 8]

[0139] [Table 9]

Claims

1. A method for treating a patient with prostate cancer, comprising administering to the patient a pharmaceutical composition containing an anti-STEAP1 antigen-binding protein in a dose of approximately 0.1 mg to approximately 2.0 mg, and ９０ Y, １７７ Lu, ６４ Cd, １５３ Gd, １５５ Gd, １５７ Gd, ２１３ Bi and ２２５ Formula 1, which is complexed with a metal selected from the group consisting of Ac: 【Chemistry 1】 A method comprising administering a dose of the compound to the patient.

2. The method according to claim 1, wherein the compound complexed with the metal is lutetium Lu177 bipivotidetetraxetane.

3. The method according to claim 2, wherein the dose of lutetium Lu177 bipivotide tetraxetan is about 2 GBq to about 13 GBq.

4. The method according to claim 2 or claim 3, wherein the dose of lutetium Lu177 bipivotide tetraxetan is 5.9 GBq.

5. The method according to any one of claims 2 to 4, wherein the dose of lutetium Lu177 bipivotide tetraxetan is 7.4 GBq.

6. The method according to any one of claims 2 to 5, wherein the dose of lutetium Lu177 bipivotide tetraxetan is administered once every six weeks.

7. The method according to any one of claims 2 to 6, wherein the anti-STEAP1 antigen-binding protein is administered to the patient after administering a dose of lutetium Lu177 bipivotide tetraxetan to the patient.

8. The method according to any one of claims 1 to 7, comprising at least one cycle, wherein within one cycle, the anti-STEAP1 antigen-binding protein is administered every seven days after a single dose of lutetium Lu177 bipivotide tetraxetan.

9. The method according to claim 8, comprising one cycle, two cycles, three cycles, four cycles, five cycles, or six cycles.

10. The method according to any one of claims 2 to 9, wherein the lutetium Lu177 bipivotide tetraxetan is administered by intravenous administration.

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

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

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

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

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

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

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

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

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

20. The method according to any one of claims 1 to 18, wherein the aforementioned dose is administered once every two weeks.

21. The method according to any one of claims 1 to 20, wherein the aforementioned dose is administered by intravenous administration.

22. The method according to any one of claims 1 to 21, wherein the anti-STEAP1 antigen-binding protein is first administered by stepwise dosing.

23. The method according to claim 22, wherein the anti-STEAP1 antigen-binding protein is administered by a two- or three-step stepwise drug delivery.

24. The method according to claim 23, wherein the anti-STEAP1 antigen-binding protein is administered by a stepwise dosing regimen 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.

25. The method according to claim 23, wherein the anti-STEAP1 antigen-binding protein is administered by 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.

26. The method according to any one of claims 31 to 34, further comprising administering the anti-STEAP1 antigen-binding protein according to any one of claims 1 to 10 to the patient once a week, once every two weeks, once every three weeks, or once every four weeks, after the stepwise drug administration has been completed and the target dose of the anti-STEAP1 antigen-binding protein has been reached.

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

14.

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

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

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

14.

31. The method according to any one of claims 1 to 30, wherein the anti-STEAP1 antigen-binding protein comprises an scFv-binding domain that binds to CD3.

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

6.

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

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

8.

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

8.

36. The method according to any one of claims 31 to 35, wherein the scFv binding domain that binds to the CD3 includes an scFv linker.

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

38. The method according to any one of claims 33 to 37, wherein the first Fc domain and the second Fc domain each contain a deletion at position 234.

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

18.

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

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

42. The use of an anti-STEAP1 antigen-binding protein in the manufacture of a pharmaceutical product for the treatment of prostate cancer, wherein the pharmaceutical product is formulated for administration in doses of about 0.1 mg to about 2.0 mg, and the formula is Formula 1: 【Chemistry 2】 further comprising administering a dose of the compound to a patient, wherein the compound is ９０ Y, １７７ Lu, ６４ Cu, １５３ Gd, １５５ Gd, １５７ Gd, ２１３ Bi and ２２５ is complexed with a metal selected from the group consisting of Ac, for use.

43. The use according to claim 42, wherein the compound complexed with the metal is lutetium Lu177 bipivotide tetraxetane.

44. The use according to claim 43, wherein the dose of lutetium Lu177 bipivotide tetraxetan is about 2 GBq to about 13 GBq.

45. The use according to claim 43 or claim 3, wherein the dose of lutetium Lu177 bipivotide tetraxetan is 5.9 GBq.

46. The use according to any one of claims 43 to 45, wherein the dose of lutetium Lu177 bipivotide tetraxetan is 7.4 GBq.

47. The use of lutetium Lu177 bipivotide tetraxetan as described in any one of paragraphs 43 to 46, where the dose is administered once every six weeks.

48. The use according to any one of claims 43 to 47, wherein the anti-STEAP1 antigen-binding protein is administered to the patient after administering a dose of lutetium Lu177 bipivotide tetraxetan to the patient.

49. The use according to any one of claims 43 to 48, comprising at least one cycle, during which the anti-STEAP1 antigen-binding protein is administered every 14 days following a single dose of lutetium Lu177 bipivotide tetraxetan.

50. The use according to claim 49, including one cycle, two cycles, three cycles, four cycles, five cycles, or six cycles.

51. The use according to any one of claims 43 to 50, wherein the lutetium Lu177 bipivotide tetraxetan is administered by intravenous administration.

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

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

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

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

56. The use according to any one of claims 42 to 53, wherein the dose of the anti-STEAP1 antigen-binding protein is approximately 0.75 mg.

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

58. The use according to any one of claims 42 to 53, wherein the dose of the anti-STEAP1 antigen-binding protein is approximately 1.5 mg.

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

60. The use according to any one of claims 42 to 59, wherein the aforementioned dose is administered once a week.

61. The use according to any one of claims 42 to 59, wherein the aforementioned dose is administered once every two weeks.

62. The use according to any one of claims 42 to 61, wherein the aforementioned dose is administered by intravenous administration.

63. The use according to any one of claims 42 to 62, wherein the anti-STEAP1 antigen-binding protein is initially administered by stepwise dosing.

64. The use according to claim 63, wherein the anti-STEAP1 antigen-binding protein is administered by a two- or three-step stepwise drug delivery.

65. The use according to claim 64, wherein the anti-STEAP1 antigen-binding protein is administered by a stepwise dosing regimen 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 according to claim 64, wherein the anti-STEAP1 antigen-binding protein is administered by 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 according to any one of claims 42 to 67, further comprising administering the anti-STEAP1 antigen-binding protein to the patient once a week, once every two weeks, once every three weeks, or once every four weeks, after the aforementioned stepwise drug administration has been completed and the target dose of the anti-STEAP1 antigen-binding protein has been reached.

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

14.

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

70. The use according to any one of claims 42 to 69, wherein the anti-STEAP1 antigen-binding protein comprises two Fab-binding domains, each Fab-binding domain binding to STEAP1.

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

14.

72. The use according to any one of claims 42 to 71, wherein the anti-STEAP1 antigen-binding protein comprises an scFv-binding domain that binds to CD3.

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

6.

74. The use according to any one of claims 42 to 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 to 74, wherein each Fab variable heavy chain domain contains an amino acid sequence that is at least 90% identical to SEQ ID NO: 15 or 20; each Fab variable light chain domain contains an amino acid sequence that is at least 90% identical to SEQ ID NO: 16; and the scFv variable heavy chain domain contains an amino acid sequence that is at least 90% identical to SEQ ID NO: 7; and the scFv variable light chain domain contains an amino acid sequence that is at least 90% identical to SEQ ID NO:

8.

76. The use according to any one of claims 72 to 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 according to any one of claims 72 to 76, wherein the scFv binding domain that binds to the CD3 includes an scFv linker.

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

79. The use according to any one of claims 74 to 78, wherein the first Fc domain and the second Fc domain each contain a deletion at position 234.

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

18.

81. The use according to any one of claims 42 to 80, wherein the anti-STEAP1 antigen-binding protein is zalritamig.

82. The use according to any one of claims 42 to 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, formulated for administration in doses of approximately 0.1 mg to approximately 2.0 mg, wherein the use is based on formula 1: 【Transformation 3】 The further comprising administering a dose of the compound to a patient, wherein the compound is ９０ Y, １７７ Lu, ６４ Cd, １５３ Gd, １５５ Gd, １５７ Gd, ２１３ Bi and ２２５ An anti-STEAP1 antigen-binding protein that is complexed with a metal selected from the group consisting of Ac.

84. The anti-STEAP1 antigen-binding protein according to claim 83, wherein the compound complexed with the metal is lutetium Lu177 bipivotide tetraxetan.

85. The anti-STEAP1 antigen-binding protein according to claim 83, wherein the dose of lutetium Lu177 bipivotide tetraxetan is approximately 2 GBq to approximately 13 GBq.

86. The anti-STEAP1 antigen-binding protein according to claim 83, wherein the dose of lutetium Lu177 bipivotide tetraxetan is approximately 5.9 GBq.

87. The anti-STEAP1 antigen-binding protein according to any one of claims 83 to 85, wherein the dose of lutetium Lu177 bipivotide tetraxetan is approximately 7.4 GBq.

88. A dose of lutetium Lu177 bipivotide tetraxetan administered once every six weeks, the anti-STEAP1 antigen-binding protein as described in any one of items 83 to 87.

89. The anti-STEAP1 antigen-binding protein according to any one of claims 83 to 87, which is administered to the patient after administering a dose of lutetium Lu177 bipivotide tetraxetan to the patient.

90. The anti-STEAP1 antigen-binding protein according to any one of claims 83 to 89, wherein the use comprises at least one cycle, during which the anti-STEAP1 antigen-binding protein is administered every 14 days after a single dose of lutetium Lu177 bipivotide tetraxetan.

91. The anti-STEAP1 antigen-binding protein according to 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 to 91, wherein the lutetium Lu177 bipivotide tetraxetan is administered by intravenous administration.

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

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

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

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

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

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

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

104. An anti-STEAP1 antigen-binding protein according to any one of claims 83 to 103, which is initially administered by a stepwise drug regimen.

105. An anti-STEAP1 antigen-binding protein according to any one of claims 83 to 104, administered by a two- or three-stage drug dosing regimen.

106. The anti-STEAP1 antigen-binding protein according to claim 104 or claim 105, which is administered by a stepwise dosing regimen 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 according to claim 104 or claim 105, which is administered by 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 to 107, further comprising administering the anti-STEAP1 antigen-binding protein to the patient once a week, once every two weeks, once every three weeks, or once every four weeks after the aforementioned stepwise drug administration has been completed and the target dose of the anti-STEAP1 antigen-binding protein has been reached.

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

14.

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

111. An anti-STEAP1 antigen-binding protein according to any one of claims 83 to 110, comprising two Fab-binding domains, each of which binds to STEAP1.

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

14.

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

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

6.

115. An anti-STEAP1 antigen-binding protein according to any one of claims 83 to 114, comprising a first Fc domain and a second Fc domain.

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

8.

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

119. The anti-STEAP1 antigen-binding protein according to any one of claims 83 to 118, wherein the first Fc domain comprises amino acid substitutions E233P, L235V, G236A, S267K, R292C, N297G, V302C, E357Q and S364K; and the second Fc domain comprises amino acid substitutions 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 to 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 to 120, comprising an HC containing SEQ ID NO: 17 or 23, an HC with an inserted CD3 scFv containing SEQ ID NO: 19 or 26, and two light chains each containing SEQ ID NO:

18.

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

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

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