COMBINATION THERAPY FOR THE TREATMENT OF PROSTATE CANCER

Abstract

The present disclosure provides treatment methods for prostate cancer patients using an antigen-binding anti-STEAP1 protein, such as xaluritamig, in combination with lutetium-Lu-177-vipivotidetetraxetane.

Description

AREA OF INVENTION

[0001] The present invention relates to the field of oncology. In particular, the invention relates to the treatment of prostate cancer with a STEAP1 T-cell engager (TCE) molecule, either as monotherapy or in combination with other pharmaceuticals. DESCRIPTION OF THE ELECTRONICALLY SUBMITTED TEXT FILE

[0002] The present application contains a sequence log, which was submitted electronically in XML format and is hereby incorporated in its entirety by reference. The machine-readable copy of the sequence log, created on July 25, 2024, is named 10655-WO01-SEC_Sequence Listing.xml and is 30,888 bytes in size. BACKGROUND OF THE INVENTION

[0003] Prostate cancer is one of the most frequently diagnosed non-cutaneous cancers and a leading cause of cancer death in men in the United States (US). In the US, an estimated 288,300 new cases of prostate cancer (29% of all new cancer cases in men) and 34,700 prostate cancer-related deaths (11% of cancer deaths in men) are expected in 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 related to the stage and location of the disease (i.e., localized vs. metastatic). While the 5-year survival rate for men with localized prostate cancer in the US is nearly 100%, it drops to 31% for men with metastatic disease (Cancer.Net, 2020). In 2015, there were an estimated 365,000 new cases and 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, there was an increasing trend in the incidence of prostate cancer, with an average annual percentage change of 7.1% (Zheng et al., 2022).

[0005] Treatment for patients with metastatic prostate cancer includes continuous and intermittent androgen deprivation therapy (ADT). Docetaxel and the novel hormone therapies (NHTs) 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 new therapeutics for metastatic castration-resistant prostate cancer (mCRPC) have been approved due to their survival benefit: Cabazitaxel (Jevtana) ® ), Sipuleucel-T (Provenge ® ), Abiraterone (Zytiga ® ), Enzalutamide (Xtandi ® ) and Radium-223 (Xofigo) ®Nevertheless, the optimal sequence or combination of available therapies for mCRPC remains largely unknown. The FDA (Food and Drug Administration) recently approved the following therapies for specific biomarker-defined subgroups of patients with mCRPC: poly-ADP-ribose polymerase (PARP) inhibitors, olaparib (Lynparza). ® ), Rucaparib (Rubraca ® ), the PD-1 (programmed cell death protein 1) inhibitor, pembrolizumab (Keytruda ® ) and a radioligand therapy targeting prostate-specific membrane antigens, lutetium-Lu-177-vipivotide tetraxetane (PLUVICTO®). These therapies are intended for the treatment of limited or pre-selected subgroups of patients, thus an unmet need remains in the advanced mCRPC setting.

[0007] STEAP1 (six-transmembrane epithelial antigen of the prostate 1), a surface antigen containing three short extracellular loop regions, is overexpressed in prostate cancer (Hubert et al., 1999) and Ewing sarcoma (Grunewald et al., 2012), and its expression is related to the stage of prostate cancer (Gomes et al., 2014). Xaluritamig (also known as "AMG 509") is a novel bispecific XmAb® 2+1 antibody designed to direct effector T cells (via CD3 binding) to STEAP1-expressing prostate cancer cells. In non-clinical studies, xaluritamig demonstrated potent cytotoxicity in prostate cancer cell lines and tumor regression in a preclinical xenograft model (Nolan-Stevaux et al 2024, Cancer Discov. 2024 Jan 12;14(1):90-103). These non-clinical findings supported the advancement of xaluritamig to clinical testing in patients with mCRPC.

[0008] Prostate-specific membrane antigen (PSMA) is a cell surface membrane-bound type II glycoprotein with a molecular weight of ~110 kDa, which contains an intracellular segment (amino acids 1-18), a transmembrane domain (amino acids 19-43), and a large extracellular domain (amino acids 44-750). PSMA is highly expressed in most prostate cancer cells and is overexpressed in malignant prostate tissues compared to other organs in the human body, such as the kidneys, proximal small intestine, and salivary glands. In contrast to prostate-specific antigen (PSA), which is downregulated after androgen ablation, PSMA expression is significantly increased in both primary and metastatic tumor samples (Kawakami et al., Wright et al.). PSMA is also highly expressed in secondary prostate tumors and occult metastatic disease. PLUVICTO® (Lutetium-Lu-177-vipivotidetetraxetane) is an approved therapy for patients with mCRPC who have previously received an androgen receptor (AR) pathway inhibitor (ARPI) and taxane-based chemotherapy.It targets PSMA-expressing cells with lutetium-177 (177Lu), a beta-emitting radioligand. This treatment results in a 4-month overall survival benefit compared to a median of 15.3 months, thus offering considerable potential for further improvement. PLUVICTO® is now being investigated in patients who have not received prior chemotherapy. BRIEF DESCRIPTION OF THE INVENTION

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

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

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

[0012] The present disclosure also provides the use of an antigen-binding anti-STEAP1 protein in the manufacture of a medicament for the treatment of prostate cancer, wherein the medicament is formulated for administration at a dose of approximately 0.1 mg to approximately 2.0 mg and is administered in combination with a dose of lutetium-Lu-177-vipivotide tetraxetane. In one embodiment, the antigen-binding anti-STEAP1 protein is xaluritamig.

[0013] The present disclosure also provides an antigen-binding anti-STEAP1 protein for use in the treatment of prostate cancer, wherein the antigen-binding anti-STEAP1 protein is formulated for administration in a dose of approximately 0.1 mg to approximately 2.0 mg and is administered in combination with a dose of lutetium-Lu-177-vipivotide tetraxetane. In one embodiment, the antigen-binding anti-STEAP1 protein is xaluritamig.

[0014] The present disclosure also provides the use of an antigen-binding anti-STEAP1 protein in the manufacture of a medicament for the treatment of prostate cancer, wherein the medicament is administered at a dose of approximately 0.1 mg to approximately 2.0 mg and in combination with a dose of lutetium-Lu-177-vipivotide tetraxetane. In one embodiment, the antigen-binding anti-STEAP1 protein is xaluritamig.

[0015] The present disclosure also provides an antigen-binding anti-STEAP1 protein for use in the treatment of prostate cancer, wherein the antigen-binding anti-STEAP1 protein is administered in a dose of approximately 0.1 mg to approximately 2.0 mg and in combination with a dose of lutetium-Lu-177-vipivotide tetraxetane. In one embodiment, the antigen-binding anti-STEAP1 protein is xaluritamig.

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

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

[0018] wherein the compound is complexed with a metal selected from the group consisting of 90Y, 177Lu, 64Cu, 153Gd, 155Gd, 157Gd, 213Bi, 68Ga and 225Ac.

[0019] The present disclosure provides an antigen-binding anti-STEAP1 protein for use in the treatment of prostate cancer, wherein the antigen-binding anti-STEAP1 protein is formulated for administration in a dose of about 0.1 mg to about 2.0 mg and is 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.The present disclosure also provides the use of an antigen-binding anti-STEAP1 protein in the manufacture of a drug for the treatment of prostate cancer, wherein the drug is formulated for administration in a dose of about 0.1 mg to about 2.0 mg and is 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.The present disclosure provides an antigen-binding anti-STEAP1 protein for use in the treatment of prostate cancer, wherein the antigen-binding anti-STEAP1 protein is administered in a dose of about 0.1 mg to about 2.0 mg and in combination with a dose of a compound of formula 1, wherein the compound is complexed with a metal selected from the group consisting of 90Y, 177Lu, 64Cu, 153Gd, 155Gd, 157Gd, 213Bi, 68Ga, and 225Ac. The present disclosure also provides the use of an antigen-binding anti-STEAP1 protein in the manufacture of a drug for the treatment of prostate cancer, wherein the drug is administered in a dose of about 0.1 mg to about 2.0 mg and in combination with a dose of a compound of formula 1, wherein the compound is complexed with a metal selected from the group consisting of 90Y, 177Lu, 64Cu, 153Gd, 155Gd, 157Gd, 213Bi, 68Ga, and 225Ac.In one embodiment, the dose of the antigen-binding anti-STEAP protein is approximately 0.1 mg to approximately 1.5 mg. In another embodiment, the dose of the antigen-binding anti-STEAP protein is approximately 0.3 mg to approximately 1.3 mg. In another embodiment, the dose of the antigen-binding anti-STEAP protein is approximately 0.5 mg to approximately 1 mg. In yet another embodiment, the dose of the antigen-binding anti-STEAP protein is approximately 0.75 mg to approximately 1 mg. In one embodiment, the dose of the antigen-binding anti-STEAP 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 the antigen-binding anti-STEAP 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 tetraxetane is 7.4 GBq.

[0020] The present invention provides a method for treating a patient with prostate cancer, wherein the method comprises administering a pharmaceutical composition to the patient comprising an antigen-binding anti-STEAP1 protein, and the method further comprises administering a dose of a compound: or of a salt thereof to the patient, where R' represents a chelating agent of the following formula: and 90 Y, 177 Lu, 64 Cu, 153 Gd, 155 Gd, 157 Gd, 213 Bi, 68 Ga or 225Ac is complexed with the chelating agent. In one embodiment, 177 Lu complexed with the chelating agent.

[0021] In one embodiment, the compound complexed with a metal is lutetium-Lu-177-vipivotide tetraxetane. In one embodiment, the dose of lutetium-Lu-177-vipivotide tetraxetane is approximately 2 GBq to approximately 13 GBq. In one embodiment, the dose of lutetium-Lu-177-vipivotide tetraxetane is approximately 5.9 GBq. In one embodiment, the dose of lutetium-Lu-177-vipivotide tetraxetane is approximately 7.4 GBq. In one embodiment, the dose of lutetium-Lu-177-vipivotide tetraxetane is 5.9 GBq. In one embodiment, the dose of lutetium-Lu-177-vipivotide tetraxetane is 7.4 GBq. In one embodiment, the dose of lutetium-Lu-177-vipivotide tetraxetane is approximately 7.4 GBq. In one embodiment, the dose of lutetium-Lu-177-vicivotide tetraxetan is administered once every six weeks. In one embodiment, the dose of lutetium-Lu-177-vicivotide tetraxetan is 7.4 GBq and is administered once every six weeks for up to six doses.In one embodiment, the dose of the antigen-binding anti-STEAP protein is approximately 0.1 mg to approximately 1.5 mg. In another embodiment, the dose of the antigen-binding anti-STEAP protein is approximately 0.3 mg to approximately 1.3 mg. In another embodiment, the dose of the antigen-binding anti-STEAP protein is approximately 0.5 mg to approximately 1 mg. In yet another embodiment, the dose of the antigen-binding anti-STEAP protein is approximately 0.75 mg to approximately 1 mg. In one embodiment, the dose of the antigen-binding anti-STEAP 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 the antigen-binding anti-STEAP 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-vicivotide tetraxetane is 7.4 GBq.

[0022] The present invention provides a method for treating a patient with prostate cancer, wherein the method comprises administering a pharmaceutical composition comprising formula 1: complex with 177Lu and a pharmaceutical formulation in a dose of 0.1–2.0 mg xaluritamig to the patient. In one embodiment, the dose of xaluritamig is 1.5 mg. In one embodiment, the dose of lutetium-Lu-177-vipivotide tetraxetane is 5.9 GBq. In one embodiment, the dose of lutetium-Lu-177-vipivotide tetraxetane is 7.4 GBq. In one embodiment, the dose of lutetium-Lu-177-vipivotide tetraxetane is approximately 7.4 GBq and the dose of xaluritamig is approximately 0.75 mg. In one embodiment, the dose of lutetium-Lu-177-vipivotide tetraxetane is approximately 7.4 GBq and the dose of xaluritamig is approximately 1 mg. In one embodiment, the dose of lutetium-Lu-177-vipivotide tetraxetane is approximately 7.4 GBq and the dose of xaluritamig is approximately 1.5 mg. In another embodiment, the dose of lutetium-Lu-177-vipivotide tetraxetane is 7.4 GBq and the dose of xaluritamig is 0.75 mg.In one embodiment, the dose of lutetium-Lu-177-vipivotide tetraxetane is 7.4 GBq and the dose of xaluritamig is 1 mg. In another embodiment, the dose of lutetium-Lu-177-vipivotide tetraxetane is 7.4 GBq and the dose of xaluritamig is 1.5 mg.

[0023] The present invention provides a method for treating a patient with prostate cancer, wherein the method comprises administering a pharmaceutical composition comprising lutetium-Lu-177-vipivotide tetraxetane and a pharmaceutical formulation containing a dose of 0.1-2.0 mg xaluritamig to the patient. In one embodiment, the dose of xaluritamig is 1.5 mg. In one embodiment, the dose of lutetium-Lu-177-vipivotide tetraxetane is 5.9 GBq. In one embodiment, the dose of lutetium-Lu-177-vipivotide tetraxetane is 7.4 GBq. In one embodiment, the dose of lutetium-Lu-177-vipivotide tetraxetane is approximately 7.4 GBq and the dose of xaluritamig is approximately 0.75 mg. In one embodiment, the dose of lutetium-Lu-177-vipivotide tetraxetane is approximately 7.4 GBq and the dose of xaluritamig is approximately 1 mg. In another embodiment, the dose of lutetium-Lu-177-vipivotide tetraxetane is approximately 7.4 GBq and the dose of xaluritamig is approximately 1.5 mg.In one embodiment, the dose of lutetium-Lu-177-vipivotide tetraxetane is 7.4 GBq and the dose of xaluritamig is 0.75 mg. In another embodiment, the dose of lutetium-Lu-177-vipivotide tetraxetane is 7.4 GBq and the dose of xaluritamig is 1 mg. In yet another embodiment, the dose of lutetium-Lu-177-vipivotide tetraxetane is 7.4 GBq and the dose of xaluritamig is 1.5 mg.

[0024] The present invention provides the use of an antigen-binding anti-STEAP1 protein for the manufacture of a medicament for the treatment of prostate cancer, wherein the medicament is formulated for administration in a dose of about 0.1 mg to about 2.0 mg and the patient is also given a dose of a compound of formula 1 complexed with a metal from the group consisting of 90 Y, 177 Lu, 64 Cu, 153 Gd, 155 Gd, 157 Gd, 68 Ga, 213 Bi and 225Ac is selected. The present invention provides the use of an antigen-binding anti-STEAP1 protein in the manufacture of a medicament for the treatment of prostate cancer, wherein the medicament is formulated for administration in a dose of about 0.1 mg to about 2.0 mg and the patient is also given a dose of a compound of formula 1 complexed with a metal from the group consisting of 90 Y, 177 Lu, 64 Cu, 153 Gd, 155 Gd, 157 Gd, 68 Ga, 213 Bi and 225The present invention provides an antigen-binding anti-STEAP1 protein for use in the treatment of prostate cancer, wherein the antigen-binding anti-STEAP1 protein is formulated for administration in a dose of about 0.1 mg to about 2.0 mg and is 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 the use of an antigen-binding anti-STEAP1 protein in the manufacture of a medicament for the treatment of prostate cancer, wherein the medicament is administered in a dose of about 0.1 mg to about 2.0 mg and is 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 antigen-binding anti-STEAP1 protein for use in the treatment of prostate cancer, wherein the antigen-binding anti-STEAP1 protein is administered in a dose of about 0.1 mg to about 2.0 mg and 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. In one embodiment, the antigen-binding anti-STEAP1 protein is xaluritamig.

[0025] In one embodiment, the compound complexed with a metal is lutetium-Lu-177-vipivotide tetraxetane. In one embodiment, the dose of lutetium-Lu-177-vipivotide tetraxetane is approximately 2 GBq to approximately 13 GBq. In one embodiment, the dose of lutetium-Lu-177-vipivotide tetraxetane is approximately 5.9 GBq. In one embodiment, the dose of lutetium-Lu-177-vipivotide tetraxetane is approximately 7.4 GBq. In one embodiment, the dose of lutetium-Lu-177-vipivotide tetraxetane is 5.9 GBq. In one embodiment, the dose of lutetium-Lu-177-vipivotide tetraxetane is 7.4 GBq. In one embodiment, the dose of lutetium-Lu-177-vipivotide tetraxetane is 7.4 GBq. In one embodiment, the dose of lutetium-Lu-177-vicivotide tetraxetan is administered once every six weeks. In one embodiment, the dose of lutetium-Lu-177-vicivotide tetraxetan is 7.4 GBq and is administered once every six weeks for up to six doses.In one embodiment, the antigen-binding anti-STEAP1 protein is administered to the patient after administration of a dose of lutetium-Lu-177-vicivotide tetraxetans. In one embodiment, the dose of the antigen-binding anti-STEAP1 protein is approximately 0.01 mg to approximately 2.0 mg. In another embodiment, the dose of the antigen-binding anti-STEAP1 protein is approximately 0.1 mg to approximately 1.5 mg. In one embodiment, the dose of the antigen-binding anti-STEAP1 protein is 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.75 mg, 0.8 mg, 0.9 mg, 1.0 mg, 1.1 mg, 1.2 mg, 1.3 mg, 1.4 mg, 1.5 mg, 1.6 mg, 1.7 mg, 1.8 mg, 1.9 mg, or 2.0 mg. In one embodiment, the dose of the antigen-binding anti-STEAP1 protein is approximately 0.1 mg. In one embodiment, the dose of the antigen-binding anti-STEAP1 protein is approximately 0.3 mg. In one embodiment, the dose of the antigen-binding anti-STEAP1 protein is approximately 0.75 mg.In one embodiment, the dose of the antigen-binding anti-STEAP1 protein is approximately 1 mg. In one embodiment, the dose of the antigen-binding anti-STEAP1 protein is approximately 1.5 mg. In one embodiment, the dose of the antigen-binding anti-STEAP1 protein is 0.1 mg. In one embodiment, the dose of the antigen-binding anti-STEAP1 protein is 0.3 mg. In one embodiment, the dose of the antigen-binding anti-STEAP1 protein is 0.75 mg. In one embodiment, the dose of the antigen-binding anti-STEAP1 protein is 1 mg. In one embodiment, the dose of the antigen-binding anti-STEAP1 protein is 1.5 mg. In one embodiment, the dose of the antigen-binding anti-STEAP1 protein is administered once a week. In one embodiment, the dose of the antigen-binding anti-STEAP1 protein is administered once every two weeks.In one embodiment, the dose of the antigen-binding anti-STEAP1 protein is administered once every three weeks. In one embodiment, the dose of the antigen-binding anti-STEAP1 protein is administered once every four weeks. In one embodiment, the dose of the antigen-binding anti-STEAP1 protein is administered intravenously. In one embodiment, the dose of the antigen-binding anti-STEAP1 protein is administered once a week, starting in cycle two. In one embodiment, the dose of the antigen-binding anti-STEAP1 protein is administered once every two weeks, starting in cycle two. In one embodiment, the dose of the antigen-binding anti-STEAP1 protein is administered once every three weeks, starting in cycle two. In one embodiment, the dose of the antigen-binding anti-STEAP1 protein is administered once every four weeks, starting in cycle two.In one embodiment, the dose of lutetium-Lu-177-vipivotide tetraxetane is 7.4 GBq and the dose of the antigen-binding anti-STEAP1 protein is 0.75 mg. In another embodiment, the dose of lutetium-Lu-177-vipivotide tetraxetane is 7.4 GBq and the dose of the antigen-binding anti-STEAP1 protein is 1 mg. In yet another embodiment, the dose of lutetium-Lu-177-vipivotide tetraxetane is 7.4 GBq and the dose of the antigen-binding anti-STEAP1 protein is 1.5 mg. In one embodiment, the antigen-binding anti-STEAP1 protein is xaluritamig.

[0026] The present invention provides a method for treating a patient with prostate cancer, wherein the method first comprises administering a pharmaceutical composition comprising an antigen-binding anti-STEAP1 protein to the patient until a target dose of the antigen-binding anti-STEAP1 protein is reached, followed by administering Lu-177-vipivotide tetraxetan to the patient. In one embodiment, the present invention provides a method for treating a patient with prostate cancer, wherein the method first comprises administering a pharmaceutical composition comprising an antigen-binding anti-STEAP1 protein to the patient until a target dose of the antigen-binding anti-STEAP1 protein is reached, followed by administering Lu-177-vipivotide tetraxetan in combination with the antigen-binding anti-STEAP1 protein to the patient.In one embodiment, the target dose of the antigen-binding anti-STEAP1 protein is 0.75 mg. In another embodiment, the target dose of the antigen-binding anti-STEAP1 protein is 1 mg. In another embodiment, the target dose of the antigen-binding anti-STEAP1 protein is 1.5 mg. In another embodiment, the dose of lutetium-Lu-177-vicivotide tetraxetane is 7.4 GBq. In another embodiment, the antigen-binding anti-STEAP1 protein is xaluritamig.

[0027] The present invention also provides a method for treating a patient with prostate cancer, wherein the method comprises administering the pharmaceutical composition, which includes a dose of an antigen-binding anti-STEAP1 protein and a dose of lutetium-Lu-177-vipivotide tetraxetan of the present invention, to the patient, wherein the method comprises at least one cycle in which, in one cycle, the antigen-binding anti-STEAP1 protein is administered on days on which lutetium-Lu-177-vipivotide tetraxetan is not administered. In one embodiment, the antigen-binding anti-STEAP1 protein is administered every 7 days during an administration cycle of lutetium-Lu-177-vipivotide tetraxetan.In one embodiment, the antigen-binding anti-STEAP1 protein is administered every 14 days during a lutetium-Lu-177-vipivotide tetraxetan administration cycle. In another embodiment, the antigen-binding anti-STEAP1 protein is administered in a cycle 7 days, 21 days, and 35 days after administration of a dose of lutetium-Lu-177-vipivotide tetraxetan. In a third embodiment, the antigen-binding anti-STEAP1 protein is administered in a cycle 2 days, 16 days, and 30 days after administration of a dose of lutetium-Lu-177-vipivotide tetraxetan.The present invention provides the use of an antigen-binding anti-STEAP1 protein in the manufacture of a medicament for the treatment of prostate cancer, wherein the use comprises administering a dose of the pharmaceutical composition comprising an antigen-binding anti-STEAP1 protein and the dose of lutetium-Lu-177-vipivotide tetraxetan of the present invention to the patient, wherein the use comprises at least one cycle in which, in one cycle, the antigen-binding anti-STEAP1 protein is administered every 14 days during one administration cycle of lutetium-Lu-177-vipivotide tetraxetan.The present invention provides the use of an antigen-binding anti-STEAP1 protein in the manufacture of a medicament for the treatment of prostate cancer, wherein the use comprises administering a dose of the pharmaceutical composition comprising an antigen-binding anti-STEAP1 protein and the dose of lutetium-Lu-177-vipivotide tetraxetan of the present invention to the patient, wherein the use comprises at least one cycle in which, in one cycle, the antigen-binding anti-STEAP1 protein is administered every 14 days during one administration cycle of lutetium-Lu-177-vipivotide tetraxetan.The present invention provides an antigen-binding anti-STEAP1 protein for use in the treatment of prostate cancer, wherein the use comprises administering a dose of the pharmaceutical composition, comprising an antigen-binding anti-STEAP1 protein and a dose of lutetium-Lu-177-vipivotide tetraxetan of the present invention, to the patient, wherein the use comprises at least one cycle in which, in one cycle, the antigen-binding anti-STEAP1 protein is administered every 14 days during a lutetium-Lu-177-vipivotide tetraxetan administration cycle. In one embodiment, the antigen-binding anti-STEAP1 protein is administered 7 days, 21 days, and 35 days after administration of a dose of lutetium-Lu-177-vipivotide tetraxetan. In one embodiment, the antigen-binding anti-STEAP1 protein is administered in a cycle 2 days, 16 days and 30 days after administration of a dose of Lutetium-Lu-177-Vipivotidetetraxetan.In one embodiment, the method comprises one cycle, two cycles, three cycles, four cycles, five cycles, or six cycles. In one embodiment, the lutetium-Lu-177-vipivotide tetraxetan is administered intravenously. In one embodiment, the administration cycle of lutetium-Lu-177-vipivotide tetraxetan is 6 weeks long. In one embodiment, the antigen-binding anti-STEAP1 protein is administered in a stepwise dose before reaching a target dose. In one embodiment, the antigen-binding anti-STEAP1 protein is administered at a target dose after administration of lutetium-Lu-177-vipivotide tetraxetan to the patient. In one embodiment, the dose of lutetium-Lu-177-vipivotide tetraxetan is 7.4 GBq and the dose of the antigen-binding anti-STEAP1 protein is 0.75 mg. In one embodiment, the dose of lutetium-Lu-177-vicivotidetetraxetane is 7.4 GBq and the dose of the antigen-binding anti-STEAP1 protein is 1 mg.In one embodiment, the dose of lutetium-Lu-177-vicivotide tetraxetane is 7.4 GBq and the dose of the antigen-binding anti-STEAP1 protein is 1.5 mg. In one embodiment, the antigen-binding anti-STEAP1 protein is xaluritamig.

[0028] The present invention also provides a method for treating a patient with prostate cancer, wherein the method comprises administering a dose of a pharmaceutical composition to the patient, comprising an antigen-binding anti-STEAP1 protein in a dose of about 0.1 mg to about 2.0 mg, and the method further comprises administering a dose of abiraterone to the patient. The present invention provides the use of an antigen-binding anti-STEAP1 protein in the manufacture of a medicament for treating prostate cancer, wherein the medicament is formulated for administration in a dose of about 0.1 mg to about 2.0 mg, and the use further comprises administering a dose of abiraterone to the patient. 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. Abiraterone is optionally administered once daily. In one embodiment, the patient is also given prednisone (or prednisolone). In one embodiment, the patient is also given 5 mg of prednisone twice daily. In one embodiment, the patient is also given 10 mg of prednisone once daily. In one embodiment, the patient is given YONSA® at a dose of 500 mg orally once daily in combination with 4 mg of methylprednisone twice daily. In one embodiment, the dose of the antigen-binding anti-STEAP1 protein is approximately 0.1 mg to approximately 2.0 mg. In one embodiment, the dose of the antigen-binding anti-STEAP1 protein is approximately 0.1 mg to approximately 1.5 mg. In one embodiment, the dose of the antigen-binding anti-STEAP1 protein is approximately 0.75 mg.In one embodiment, the dose of the antigen-binding anti-STEAP1 protein is approximately 1 mg. In one embodiment, the dose of the antigen-binding anti-STEAP1 protein is approximately 1.5 mg. In one embodiment, the dose of the antigen-binding anti-STEAP1 protein is 0.75 mg. In one embodiment, the dose of the antigen-binding anti-STEAP1 protein is 1 mg. In one embodiment, the dose of the antigen-binding anti-STEAP1 protein is 1.5 mg. In one embodiment, the dose of the antigen-binding anti-STEAP1 protein is 1.5 mg. In one embodiment, the dose of the antigen-binding anti-STEAP1 protein is administered once a week. In one embodiment, the dose of the antigen-binding anti-STEAP1 protein is administered once every two weeks. In one embodiment, the patient receives a dose of the antigen-binding anti-STEAP1 protein and a dose of abiraterone on the same day.In one embodiment, the patient is administered a dose of the antigen-binding anti-STEAP1 protein and a dose of abiraterone in cycle 1 on day 1. In another embodiment, the patient is administered a dose of abiraterone in cycle 1 on day 1.

[0029] The present invention also provides a method for treating a patient with prostate cancer, wherein the method comprises administering a pharmaceutical composition to the patient comprising an antigen-binding anti-STEAP1 protein in a dose of about 0.1 mg to about 2.0 mg, and the method further comprises administering enzalutamide to the patient. The present invention provides the use of an antigen-binding anti-STEAP1 protein in the manufacture of a medicament for treating prostate cancer, wherein the medicament is formulated for administration in a dose of about 0.1 mg to about 2.0 mg, and the use further comprises administering a dose of enzalutamide to the patient. In one embodiment, the dose of enzalutamide is about 120 mg to about 160 mg. In one embodiment, the dose of enzalutamide is about 160 mg. In one embodiment, the dose of enzalutamide is 160 mg.In one embodiment, the dose of enzalutamide is administered orally. In one embodiment, the dose of the antigen-binding anti-STEAP1 protein is approximately 0.01 mg to approximately 2.0 mg. In one embodiment, the dose of the antigen-binding anti-STEAP1 protein is approximately 0.75 mg. In one embodiment, the dose of the antigen-binding anti-STEAP1 protein is approximately 1 mg. In one embodiment, the dose of the antigen-binding anti-STEAP1 protein is approximately 1.5 mg. In one embodiment, the dose of the antigen-binding anti-STEAP1 protein is 1.5 mg. In one embodiment, the patient is given a dose of enzalutamide on day 1 of cycle 1.

[0030] The present invention also provides a method for treating a patient with prostate cancer, wherein the method comprises administering a pharmaceutical composition to the patient comprising an antigen-binding anti-STEAP1 protein in a dose of about 0.1 mg to about 2.0 mg, and the method further comprises administering darolutamide to the patient. The present invention provides the use of an antigen-binding anti-STEAP1 protein in the manufacture of a medicament for treating prostate cancer, wherein the medicament is formulated for administration in a dose of about 0.1 mg to about 2.0 mg, and the use further comprises administering a dose of darolutamide to the patient. 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 the antigen-binding anti-STEAP1 protein is approximately 0.01 mg to approximately 2.0 mg. In one embodiment, the dose of the antigen-binding anti-STEAP1 protein is approximately 1.5 mg. In one embodiment, the dose of the antigen-binding anti-STEAP1 protein is 0.75 mg. In one embodiment, the dose of the antigen-binding anti-STEAP1 protein is 1 mg. In one embodiment, the dose of the antigen-binding anti-STEAP1 protein is 1.5 mg.

[0031] The present invention also provides a method for treating a patient with prostate cancer, wherein the method comprises administering a pharmaceutical composition to the patient comprising an antigen-binding anti-STEAP1 protein in a dose of about 0.1 mg to about 2.0 mg, and the method further comprises administering apalutamide to the patient. The present invention provides the use of an antigen-binding anti-STEAP1 protein in the manufacture of a medicament for treating prostate cancer, wherein the medicament is formulated for administration in a dose of about 0.1 mg to about 2.0 mg, and the use further comprises administering a dose of apalutamide to the patient. In one embodiment, the dose of apalutamide is about 180 mg to about 240 mg. In one embodiment, the dose of apalutamide is about 240 mg. In one embodiment, the dose of apalutamide is 240 mg.In one embodiment, the dose of apalutamide is administered orally. In one embodiment, the dose of apalutamide is administered orally once daily. In one embodiment, the dose of apalutamide is administered orally once daily by four 60-mg tablets. In one embodiment, the dose of the antigen-binding anti-STEAP1 protein is approximately 0.01 mg to approximately 2.0 mg. In one embodiment, the dose of the antigen-binding anti-STEAP1 protein is approximately 1.5 mg. In one embodiment, the dose of the antigen-binding anti-STEAP1 protein is 1.5 mg.

[0032] In one embodiment, the antigen-binding anti-STEAP1 protein is administered by stepwise dosing. In another embodiment, the antigen-binding anti-STEAP1 protein is administered in two steps. In another embodiment, the antigen-binding anti-STEAP1 protein is administered in two or three steps. In one embodiment, the antigen-binding anti-STEAP1 protein is administered in 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 another embodiment, the antigen-binding anti-STEAP1 protein is administered in 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 another embodiment, the method further comprises administering an antigen-binding anti-STEAP1 protein to the patient once a week, once every two weeks, once every three weeks, or once every four weeks after administration of the stepwise dosing regimen.In one embodiment, 1.5 mg of antigen-binding anti-STEAP1 protein is administered once every two weeks following the stepwise dosing regimen. In another embodiment, 1.5 mg of antigen-binding anti-STEAP1 protein is administered once every three weeks following the stepwise dosing regimen. In yet another embodiment, 1.5 mg of antigen-binding anti-STEAP1 protein is administered once every four weeks following the stepwise dosing regimen.

[0033] In one embodiment, a dose of the antigen-binding anti-STEAP1 protein is administered once a week during the first cycle and then once every three weeks once the target dose has been reached. In another embodiment, a dose of the antigen-binding anti-STEAP1 protein is administered once a week during the first cycle and then once every four weeks once the target dose has been reached.

[0034] In one embodiment, the antigen-binding anti-STEAP1 protein is administered in two cycles. In one embodiment, cycle one comprises administering the antigen-binding anti-STEAP1 protein on day 1 or day 2 at a dose in the range of approximately 0.1 mg to approximately 0.3 mg, on day 7, 8, or 9 at a dose in the range of approximately 0.2 mg to approximately 0.4 mg, on day 14, 15, or 16 at a dose in the range of approximately 0.8 mg to approximately 1.2 mg, and on day 21, 22, or 23 at a dose in the range of approximately 1.3 mg to approximately 1.6 mg. In one embodiment, cycle two, which follows cycle 1, comprises administering 1.5 mg of antigen-binding anti-STEAP1 protein once every two weeks for five months after completion of cycle one. Each cycle is optionally 28 days long.

[0035] In one embodiment, cycle one comprises administering the antigen-binding anti-STEAP1 protein in 0.1 mg doses on day 1, 0.3 mg on day 8, 1.0 mg on day 15, and 1.5 mg on day 22. In another embodiment, cycle two, which follows cycle one, comprises administering 1.5 mg of antigen-binding anti-STEAP1 protein once every two weeks for five months after completion of cycle one. Each cycle may optionally be 28 days long.

[0036] In one embodiment, cycle one comprises administering the antigen-binding anti-STEAP1 protein in 0.1 mg doses on day 1, 0.3 mg doses on day 8, 1.0 mg doses on day 15, and 1.5 mg doses on day 22. In another embodiment, cycle two comprises administering 1.5 mg of antigen-binding anti-STEAP1 protein once every four weeks for 11 months after completion of cycle one. Each cycle may optionally be 28 days long.The disclosure further provides a method for treating a patient with prostate cancer, comprising administering a pharmaceutical composition comprising xaluritamig to the patient over the course of at least two 28-day cycles, wherein (i) Cycle 1 comprises administering approximately 0.1 mg to approximately 0.3 mg of xaluritamig on day 1 or day 2, administering approximately 0.2 mg to approximately 0.4 mg of xaluritamig on day 7, 8 or 9, administering approximately 0.8 mg to approximately 1.2 mg of xaluritamig on day 14, 15 or 16 and administering approximately 1.3 mg to approximately 1.6 mg of xaluritamig on day 21, 22 or 23, followed by one or more additional cycles (Cycle 2) comprising administering 1.5 mg of xaluritamig once every two weeks.

[0037] In one embodiment, the antigen-binding anti-STEAP1 protein is an XmAb 2+1 molecule. As used here, an “XmAb® 2+1” molecule (used synonymously with a “multichain T-cell engager molecule” or “central scFv” molecule) contains two Fab domains and one scFv domain, with each Fab domain binding one target (e.g., STEAP1) and the scFv domain binding another target (e.g., CD3).

[0038] In one embodiment, the antigen-binding anti-STEAP1 protein comprises two Fab-binding domains, each of which binds STEAP1.

[0039] In one embodiment, the antigen-binding anti-STEAP1 protein comprises two Fab-binding domains, wherein the Fab-binding domains each bind STEAP1 and the Fab-binding domains each comprise a variable heavy chain domain, a variable light chain domain, a CH1 domain and a constant light chain domain, and wherein the variable heavy chain domain comprises HCDR1, which includes SEQ ID NO: 9, HCDR2, which includes SEQ ID NO: 10, and HCDR3, which includes SEQ ID NO: 11, and the variable light chain domain comprises LCDR1, which includes SEQ ID NO: 12, LCDR2, which includes SEQ ID NO: 13, and LCDR3, which includes SEQ ID NO: 14.

[0040] In one embodiment, the antigen-binding anti-STEAP1 protein comprises an scFv-binding domain, wherein the scFv-binding domain binds CD3.

[0041] In one embodiment, the antigen-binding anti-STEAP1 protein comprises an scFv-binding domain, wherein the scFv-binding domain binds CD3 and wherein the scFv-binding domain comprises a variable scFv heavy chain domain comprising HCDR1, SEQ ID NO: 1, HCDR2, SEQ ID NO: 2, and HCDR3, SEQ ID NO: 3, an scFv linker, and a variable scFv light chain domain, wherein the variable scFv light chain domain comprises LCDR1, SEQ ID NO: 4, LCDR2, SEQ ID NO: 5, and LCDR3, SEQ ID NO: 6.In one embodiment, the variable Fab heavy chain domains each comprise an amino acid sequence that is at least 90%, 95% or 99% identical to SEQ ID NO: 15, the variable Fab light chain domains each comprise an amino acid sequence that is at least 90%, 95% or 99% identical to SEQ ID NO: 16, and the variable scFv heavy chain domain comprises an amino acid sequence that is at least 90%, 95% or 99% identical to SEQ ID NO: 7, and the variable scFv light chain domain comprises an amino acid sequence that is at least 90%, 95% or 99% identical to SEQ ID NO: 8. In one embodiment, the variable Fab heavy chain domains each comprise SEQ ID NO: 15 or 20, the variable Fab light chain domains each comprise SEQ ID NO: 16, the variable scFv heavy chain domain comprises SEQ ID NO: 7 and the variable scFv light chain domain comprises SEQ ID NO: 8. In one embodiment, the scFv binding domain that binds CD3 comprises an scFv linker.In one embodiment, the variable Fab heavy chain domains each comprise SEQ ID NO: 15. In one embodiment, the variable Fab heavy chain domains each comprise SEQ ID NO: 20.

[0042] In one embodiment, the antigen-binding anti-STEAP1 protein comprises a first Fc domain and a second Fc domain. In one embodiment, the first Fc domain comprises the amino acid substitutions E233P, L235V, G236A, S267K, R292C, N297G, V302C, E357Q, and S364K, and the second Fc domain comprises the amino acid substitutions N208D, E233P, L235V, G236A, S267K, R292C, Q295E, N297G, V302C, L368D, K370S, N384D, Q418E, and N421D (all according to EU numbering). In one embodiment, both the first Fc domain and the second Fc domain each comprise a deletion at position 234.

[0043] In one embodiment, the antigen-binding anti-STEAP1 protein comprises a hydrochloride (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 antigen-binding anti-STEAP1 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 one embodiment, the antigen-binding anti-STEAP1 protein is an XmAb-2+1 molecule.

[0044] In one embodiment, the antigen-binding anti-STEAP1 protein is xaluritamig. In one embodiment, the antigen-binding anti-STEAP1 protein is xaluritamig and comprises a hydrochloride (HC) comprising SEQ ID NO: 17, an HC with an inserted CD3 scFv comprising SEQ ID NO: 19, and two light chains, each comprising SEQ ID NO: 18.

[0045] In one embodiment, the patient has metastatic castration-resistant prostate cancer. In another embodiment, the patient has not previously received chemotherapy. In yet another embodiment, the patient has previously undergone treatment for prostate cancer and suffers from recurrent prostate cancer. In yet another embodiment, the patient has previously received chemotherapy. BRIEF DESCRIPTION OF THE DRAWINGS Fig.1. Schematic of an XmAb® 2+1 molecule showing two Fabs, each binding STEAP1, and one scFv, binding CD3. Fig. 2. Largest percentage change in the size of the target tumor lesions. The dashed line indicates a 30% reduction in tumor SLD from baseline. Fig. 3. Largest percentage change in PSA from baseline. The asterisk indicates a confirmed PSA response, and dashed lines indicate decreases in PSA50 and PSA90. Fig.4. Example patient whose response is demonstrated by PSA and radiographic assessments: CT scan and time-dependent PSA curve of a heavily pretreated 65-year-old patient with stage IV prostate adenocarcinoma. The patient was enrolled in cohort 12 (3-step target dose of 1.5 mg xaluritamig). CT scans showed 3 target lesions (2 liver, 1 lymph node) and several non-target lesions in the liver and 2 in lymph nodes during screening. The patient achieved a 99% PSA reduction from baseline on day 1 of cycle 1 and primary response (PR) (37.3% reduction in target lesions) after 2 cycles, which was confirmed at week 16 and maintained after 24 weeks. Adverse events occurred during the first treatment cycle and included recurrent chronic rheumatic fever (CRS), tinea (both grade 1), rash, and worsening back pain (both grade 2). During subsequent treatment cycles, skin rash (grade 1), muscle pain and hyperkalemia (both grade 2) were observed.The patient is still receiving treatment at the time of this recording. Fig. 5. Percentage change in PSA derived from the in Fig. The sample was taken from 4 patients described. DETAILED DESCRIPTION

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

[0047] This first-in-human study reports on monotherapy for patients with metastatic castration-resistant prostate cancer (mCRPC). Ninety-seven patients received ≥ 1 dose in the range of 0.001–2.0 mg IV weekly (QW) or Q2W. The MTD was identified as Day 1 (D1) 0.1 mg, Day 8 0.3 mg, Day 15 1.0 mg, and Day 22+ 1.5 mg IV QW. The most common treatment-related adverse events were cytokine release syndrome (CRS; 72%), fatigue (45%), and muscle pain (34%). CRS occurred primarily during Cycle 1 and improved with prior medication and stepwise dosing. The response by prostate-specific antigen (PSA) and RECIST (Response Evaluation Criteria in Solid Tumors) was encouraging (49% PSA50, 24% objective response rate [ORR]), more frequent at target doses of ≥ 0.75 mg (59% PSA50; 41% ORR). There were no grade 4 or 5 CRS events.Overall, all CRS events were resolved with standard management using acetaminophen, IV fluids, and tocilizumab and / or corticosteroids. Xaluritamig demonstrated encouraging response rates (PSA and RECIST) compared to established treatments and acceptable safety in patients with advanced mCRPC.

[0048] The preliminary efficacy results observed with xaluritamig are numerically greater than those reported for other TCEs in prostate cancer. Both PSA-measured efficacy and RECIST-measured response were encouraging in this heavily pretreated mCRPC population, with responses being more frequent in the higher-dose cohorts. PSA reductions were observed starting with 0.1 mg xaluritamig, with 49% of patients achieving a confirmed PSA50 response and 28% achieving a confirmed PSA90 response. At higher doses, a response was achieved in 41% of RECIST-evaluable patients. This study demonstrated that a high proportion of patients were able to achieve a significant clinical response, which translates into overall clinical benefit.

[0049] The preliminary efficacy results observed with xaluritamig are numerically greater than those reported for other TCEs in prostate cancer. Both PSA-measured efficacy and RECIST-measured response were encouraging in this heavily pretreated mCRPC population, with responses occurring more frequently in the higher-dose cohorts. PSA reductions were observed starting with 0.1 mg xaluritamig, with 49% of patients achieving a confirmed PSA50 response and 28% achieving a confirmed PSA90 response. At higher doses, a response was achieved in 41% of RECIST-evaluable patients.

[0050] Targeted immunotherapy with TCEs requires binding to both CD3+ T cells and a tumor-associated antigen. Xaluritamig showed dose-dependent changes in peripheral pharmacodynamic biomarkers of TCE activity, namely T-cell margination, T-cell activation, and cytokine induction. The extent of the PD biomarker changes is consistent with the observed PSA decreases.

[0051] The overall treatment-related incidence of ADA was 54%, with 8 patients exhibiting a transient antibody response. The ADA response was not dose-dependent and did not lead to adverse events (AEs). Since approximately one-quarter of patients developed neutralizing and / or PK-affecting ADAs, it is crucial to assess the impact on clinical response. Because the onset of neutralizing ADAs occurs on average after cycle 3, unlike the response, which occurs in the first two cycles, no impact on the overall response rate is expected.

[0052] This is the first clinical report of a TCE therapy targeting STEAP1 in prostate cancer. This study provides proof-of-concept for TCEs as a potential therapeutic modality in prostate cancer, supported by the substantial magnitude of radiographic and PSA response observed. The only STEAP1-targeting agent explored clinically to date was a STEAP1 antibody-drug conjugate (ADC), which was limited by toxicities due to the monomethyl auristatin E (MMAE) cargo (Maecker et al., MAbs. 2023 Jan-Dec;15(1):2229101). Overall, the current study demonstrates the feasibility of targeting STEAP1 with TCEs and the potential of xaluritamig as a novel treatment paradigm for patients with mCRPC.

[0053] A dosing regimen for an antigen-binding anti-STEAP1 protein, such as xaluritamig, in prostate cancer patients may include stepwise dosing. To reduce cytokine release and ensure treatment with the active dose of an antigen-binding anti-STEAP1 protein (e.g., xaluritamig), the stepwise dosing may involve two or three steps, with each step representing a relatively small dose increase. The priming dose and target dose are also within a relatively narrow range of each other, while demonstrating efficacy in prostate cancer patients. The doses of the antigen-binding anti-STEAP1 protein (xaluritamig) are also relatively small compared to doses administered in a clinical trial for a bispecific T-cell engager that binds both DLL3 and CD3. Ares et al., J. Clin. Oncol.The article published in 2023 Jun 1;41(16):2893-2903 describes that pharmacodynamic responses were strongest after the initial administration of the 1-mg step dose of a bispecific T-cell engager binding both DLL3 and CD3, and that the expansion dose was 100 mg. See also Aggarwal et al., J. Clin. Onc. Vol. 42(16) May 29, 2024, which discloses a 1-mg step dose and a 100-mg target dose of tarlatamab, and Ahn et al., N Engl J Med 2023;389:2063-2075, which discloses a 10-mg target dose and a 100-mg target dose of tarlatamab.

[0054] In prostate cancer, some PSMA-targeted TCEs have entered clinical practice, but have shown only limited success due to minimal efficacy, toxicity and short duration of response (DOS) (see e.g. 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 PSMA and CD3 antibody, led to transient decreases in prostate-specific antigen (PSA), with 2 of 39 (5%) patients experiencing a confirmed PSA50 response and no radiographic response in a phase 1 trial of patients with mCRPC (Lim et al., Clin Genitourin Cancer 2023;21:366-75). The PSMA-targeting TCE HPN424 reported that 3 of 63 (5%) patients experienced a PSA50 response and 1 of 34 (3%) experienced a confirmed RECIST (Response Evaluation Criteria in Solid Tumors) response with acceptable safety (Bono et al., J. Clin. Onc. 2021;39:5013-13).Combination therapy can further enhance efficacy by inducing synergistic effects and / or overcoming resistance mechanisms. The disclosure also provides for the use of xaluritamig in combination with standard-of-care hormone and radioligand therapies in patients. In some embodiments, the patient has advanced prostate cancer. In some embodiments, the patient has previously received treatment with either one or two new hormone therapies (NHT).

[0055] A compound of formula 1 may contain one of the following radionuclides complexed to a chelating agent: 89 Zr, 44 Sc, 111 In, 90 Y, 66 Ga, 67 Ga, 68 Ga, 177 Lu, 99m Tc, 61 Cu, 62 Cu, 64 Cu, 67 Cu, 149 Tb, 152 Tb, 155 Tb, 161 Tb, 153 Gd, 155 Gd, 157 Gd,213 Bi, 225 Ac, 230 U, 223 Ra, 165 He or Fe.

[0056] While NHTs (e.g., abiraterone, enzalutamide, apalutamide, and darolutamide) and taxanes (e.g., docetaxel and cabazitaxel) are standard treatment options for non-metastatic and / or metastatic castration-resistant prostate cancer, disease progression still occurs in a large proportion of patients during therapy.

[0057] The disclosure provides a therapeutic scheme wherein an antigen-binding anti-STEAP1 protein, such as xaluritamig, is administered according to a method of the present invention in combination with another agent or agents, including abiraterone, enzalutamide, cabazitaxel, darolutamide, apalutamide, lutetium-Lu-177-vipivotide tetraxetane (PLUVICTO®), PSMA radioligand therapies, PSMA immunotherapies, radium-223, PARP inhibitors, PSMA antibody-drug conjugates, B7H3 antibody-drug conjugates, radiotherapy and / or standard-of-care therapies for prostate cancer.

[0058] Abiraterone is a cytochrome P450 (CYP) 17 inhibitor indicated in combination with prednisone (or in some regions prednisolone) for the treatment of patients with mCRPC and, in some regions, with metastatic or high-risk castration-sensitive prostate cancer (CSPC). Disease recurrence after abiraterone may be caused by increased androgen receptor expression (e.g., androgen receptor amplification) among other mechanisms (Galletti et al, Cancer Treat Rev. June 2017;57:16-27).

[0059] Enzalutamide is an androgen receptor inhibitor that affects various steps in the androgen receptor signaling pathway. It has been shown to competitively inhibit androgen binding to androgen receptors, thereby inhibiting the translocation of androgen receptors into the nucleus and their interaction with DNA. Enzalutamide is indicated for the treatment of patients with castration-resistant prostate cancer (CRPC) and, in some regions, metastatic hormone-sensitive prostate cancer. Disease relapse after enzalutamide treatment occurs partly due to androgen receptor mutations (such as AR V7) and increased androgen receptor expression (e.g., androgen receptor amplification), among other mechanisms (Galletti et al., supra).

[0060] However, it is also intended that Xaluritamig can be administered in earlier stages of the disease without concomitant ADT. Prostate-specific membrane antigen (PSMA) is a cell surface membrane-bound type II glycoprotein with a molecular weight of approximately 110 kDa, comprising an intracellular segment (amino acids 1-18), a transmembrane domain (amino acids 19-43), and a large extracellular domain (amino acids 44-750). PSMA is highly expressed in most prostate cancer cells and is overexpressed in malignant prostate tissues compared to other organs in the human body, such as the kidneys, proximal small intestine, and salivary glands. In contrast to prostate-specific antigen (PSA), which is downregulated after androgen ablation, PSMA expression is significantly increased in both primary and metastatic tumor samples (Kawakami et al., Wright et al.).PSMA is also highly expressed in secondary prostate tumors and occult metastatic diseases. PLUVICTO® (Lutetium-Lu-177-vipivotide tetraxetane; . 177 Lu-PSMA-617 is an approved therapy for patients with mCRPC who have previously received an androgen receptor (AR) pathway inhibitor (ARPI) and taxane-based chemotherapy. It targets PSMA-expressing cells with lutetium-177 (177Lu), a beta-emitting radioligand. This treatment results in a 4-month overall survival benefit compared to a median of 15.3 months, thus offering considerable potential for further improvement. PLUVICTO® is now being investigated in patients who have not received prior chemotherapy.

[0061] An antigen-binding anti-STEAP1 protein (or an antigen-binding STEAP1 protein) is a molecule that binds human STEAP1. Such molecules may also bind to another target, such as a cell surface antigen, like CD3. Non-restrictive examples of formats of such molecules include antibodies (including bispecific antibodies) and fragments thereof, and T-cell engager molecules, including XmAb 2+1 format molecules and bispecific T-cell engager molecules.

[0062] An antigen-binding anti-STEAP1 protein binds to its targets, for example, when it binds with a dissociation constant (KD) ≤ 10-7 M, as measured by a surface plasma resonance technique (e.g., BIACore, GE-Healthcare Uppsala, Sweden) or a kinetic exclusion assay (KinExA, Sapidyne, Boise, Idaho).

[0063] Bispecific T-cell engager molecules are recombinant protein constructs built from two flexibly linked antibody-derived binding domains. A bispecific T-cell engager molecule comprises a BiTE® molecule. One binding domain of a bispecific T-cell engager is specific for a selected tumor-associated surface antigen on target cells; the second binding domain is specific for CD3, a subunit of the T-cell receptor complex on T cells. Due to their unique design, bispecific T-cell engager molecules are uniquely suited to temporarily link T cells to target cells while simultaneously and potently activating the inherent cytolytic potential of T cells against target cells (Yang, Fa; Wen, Weihong; Qin, Weijun (2016). “Bispecific Antibodies as a Development Platform for New Concepts and Treatment Strategies”. International Journal of Molecular Sciences. 18 (1): 48 (2016)).A bispecific T-cell engager molecule is bispecific, meaning that it binds to two targets on two different cell types simultaneously (target antigen such as STEAP1 on a target cell and CD3 on a T cell).

[0064] As used here, an “XmAb 2+1” molecule (used synonymously with a “multichain T-cell engager molecule” or “central scFv” molecule) contains two Fab domains and one scFv domain, with each Fab domain binding one target (e.g., STEAP1) and the scFv domain binding another target (e.g., CD3). A format of an XmAb 2+1 molecule is shown in Fig.Figure 1 shows that the scFv domain (which binds, for example, CD3) is inserted between an Fc domain and a CH1-Fv region, thus providing a third antigen-binding domain (e.g., two Fabs, each binding STEAP1, and one scFv, which binds CD3). The anti-CD3 scFv is "inserted" into the heavy chain (HC), meaning that the scFv is linked to the HC by a linker. In this embodiment, a polypeptide comprises a first heavy chain, which includes a first variable heavy chain domain, a CH1 domain (and optionally a linker / hinge), and an Fc domain, with an scFv comprising a variable scFv light chain domain, an scFv linker, and a variable scFv heavy chain domain.The scFv is covalently linked between the C-terminus of the CH1 domain of the constant heavy chain domain and the N-terminus of a first Fc domain using optional domain linkers (VH1-CH1-[optional domain linker]-VH2-scFv-linker-VL2-[hinge-containing optional domain linker]-CH2-CH3 or the reverse orientation for the scFv, VH1-CH1-[optional domain linker]-VL2-scFv-linker-VH2-[hinge-containing optional domain linker]-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., a VH1-CH1 domain linker (e.g., Hinge)-CH2-CH3). This embodiment further utilizes two light chains, each comprising a variable light chain domain and a constant light chain domain, which align with the heavy chains to form two identical Fabs that bind to a target.In particular embodiments, a STEAP1 Fab CD3 scFv central-scFv molecule (or a STEAP1 Fab CD3 scFv XmAb 2+1 molecule) comprises two Fab domains, each binding STEAP1, and an scFv that binds CD3. In some particular embodiments, the central-scFv or XmAb 2+1 molecule is xaluritamig.

[0065] Xaluritamig is an example of an antigen-binding anti-STEAP1 protein. A further description of xaluritamig can be found in PCT publication no. WO 2020 / 010079, which is incorporated here in full by reference. Xaluritamig sequences are provided in Table 4. Xaluritamig comprises a hydrochloride (HC) containing SEQ ID NO: 17, an HC with inserted CD3, a scFv containing SEQ ID NO: 19, and two light chains, each containing SEQ ID NO: 18. In exemplary aspects, a molecule of the present invention comprises a sequence including a C-terminal lysine, as in SEQ ID NO: 17 or 19. In preferred aspects, the antigen-binding protein comprises one or both HCs without the C-terminal lysine, as in SEQ ID NO: 22 and 25. Additionally, the N-terminal HC or HCVR glutamine and / or the N-terminal glutamic acid can be converted to pyroglutamic acid, as in SEQ ID NOs: 20, 21, 23 and 24.Additionally, the N-terminal HC-glutamine and / or the N-terminal glutamic acid can be converted to pyroglutamic acid, and the sequence may lack a C-terminal lysine, as in SEQ ID NOs: 23 and 26. All forms are provided for the antigen-binding proteins of the present invention.

[0066] A first Fc domain and a second Fc domain each refer to one half of an Fc (fragment crystallizable) region. An Fc region comprises two CH2 domains and two CH3 domains. Thus, a first Fc domain and a second Fc domain each comprise one CH2 domain and one CH3 domain.

[0067] The antigen-binding anti-STEAP1 protein is generally administered to the patient in a pharmaceutical composition that may contain pharmaceutically safe carriers, excipients, or diluents. "Pharmaceutically safe" refers to molecules, compounds, and compositions that are non-toxic to human recipients at the dosages and concentrations used and / or do not cause allergic or adverse reactions when administered to humans. In certain embodiments, the pharmaceutical composition may contain formulation materials for modifying, maintaining, or preserving, for example, pH, osmolarity, viscosity, clarity, color, isotonicity, odor, sterility, stability, dissolution rate, or release rate.Adsorption or penetration of the composition is included. In such embodiments, suitable formulation materials include, among others, amino acids (such as glycine, glutamine, asparagine, arginine, or lysine), antimicrobial agents, antioxidants (such as ascorbic acid, sodium sulfite, or sodium hydrogen sulfite), buffers (such as borate, bicarbonate, tris-HCl, citrates, phosphates, or other organic acids), extenders (such as mannitol or glycine), chelating agents (such as ethylenediaminetetraacetic acid (EDTA)), complexing agents (such as caffeine, polyvinylpyrrolidone, beta-cyclodextrin, or hydroxypropyl beta-cyclodextrin), fillers, monosaccharides, disaccharides, and other carbohydrates (such as glucose, mannose, or dextrins), proteins (such as serum albumin, gelatin, or immunoglobulins), coloring, flavoring, and diluent agents, emulsifiers, and hydrophilic polymers (such as... Polyvinylpyrrolidone), low molecular weight polypeptides,Salt-forming counterions (such as sodium), preservatives (such as bezalkonium chloride, benzoic acid, salicylic acid, thimerosal, phenethyl alcohol, methylparaben, propylparaben, chlorhexidine, sorbic acid or hydrogen peroxide), solvents (such as glycerin, propylene glycol or polyethylene glycol), sugar alcohols (such as mannitol or sorbitol), suspending agents, surfactants or wetting agents (such as pluronics, PEG, sorbitan esters, polysorbates, such as polysorbate 20, polysorbate 80, Triton, tromethamine, lecithin, cholesterol, tyloxapal), stability enhancers (such as sucrose or sorbitol), tonicity enhancers (such as alkali metal halides, preferably sodium or potassium chloride, mannitol or sorbitol), delivery vehicles, diluents,Excipients and / or pharmaceutical excipients. Methods for formulating molecules for therapeutic use and suitable materials for formulating molecules for therapeutic use are known in the pharmaceutical prior art and are described, for example, in REMINGTON'S PHARMACEUTICAL SCIENCES, 18th Edition, (AR Genrmo, ed.), 1990, Mack Publishing Company. In some embodiments, the selection of carriers and excipients for incorporation into the pharmaceutical compositions influences the physical state, stability, rate of in vivo release, and rate of in vivo clearance of the antigen-binding anti-STEAP1 protein.

[0068] An antigen-binding anti-STEAP1 protein, such as xaluritamig, can be formulated as a pre-lyophilized formulation, such as a pre-lyophilized formulation of 0.3 mg / ml to 2.5 mg / ml xaluritamig (e.g., 1 mg / ml) containing 10 mM glutamic acid, 9 (w / v)% sucrose, 0.01 (w / v)% polysorbate 80, pH 4.20 (i.e., xaluritamig is in a formulation comprising 0.3 mg / ml to 2.5 mg / ml xaluritamig (e.g., 1 mg / ml), 10 mM glutamic acid, 9 (w / v)% sucrose, 0.01 (w / v)% polysorbate 80, pH 4.20, and lyophilized). Formulations for an antigen-binding anti-STEAP1 protein are disclosed in PCT publication no. WO 2019 / 157340, which is incorporated herein in full by reference.

[0069] It should be understood that the antigen-binding anti-STEAP1 protein is contained in a pharmaceutical composition when reference is made here to the administration of a dose of an antigen-binding anti-STEAP1 protein to a patient.

[0070] The proposed treatment involves administering lutetium-Lu-177-vipivotide tetraxetan to the prostate cancer patient for two to six cycles, followed by administration of an antigen-binding anti-STEAP1 protein. The antigen-binding anti-STEAP1 protein can be administered in stepwise doses, as described here, before reaching the target dose.

[0071] It is proposed here that the antigen-binding anti-STEAP1 protein and lutetium-Lu-177-vipivotide tetraxetan are administered in the same cycle, but on different days. In some embodiments, the antigen-binding anti-STEAP1 protein and lutetium-Lu-177-vipivotide tetraxetan are administered according to Example 2. In some embodiments, lutetium-Lu-177-vipivotide tetraxetan is administered, and at least 7 days later, the antigen-binding anti-STEAP1 protein is administered in stepwise doses until a target dose of the antigen-binding anti-STEAP1 protein is reached. After reaching the target dose of the antigen-binding anti-STEAP1 protein, the antigen-binding anti-STEAP1 protein is administered at the target dose.

[0072] The plan is to administer the antigen-binding anti-STEAP1 protein in stepwise doses as described here, followed by administration of the antigen-binding anti-STEAP1 protein for up to five additional cycles at the target dose, followed by administration of lutetium-Lu-177-vipivotide tetraxetane for up to six additional cycles.

[0073] The present invention also includes kits for treating prostate cancer in a patient for whom such treatment is needed. In one embodiment, the kit comprises a pharmaceutical composition of an antigen-binding anti-STEAP1 protein and packaging material that provides instructions for the use of 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 as a dehydrated or lyophilized powder. In embodiments in which the pharmaceutical composition is provided as a powder, the kit may also include a diluent (e.g., a solvent).The package shall include water, saline solution or phosphate buffer saline solution), which are necessary to reconstitute the pharmaceutical composition, as well as instructions for preparing the composition for administration.

[0074] In some embodiments, the present invention also provides kits comprising a pharmaceutical composition and instructions for using the pharmaceutical composition to administer a therapeutically effective amount, for example by IV injection, to treat prostate cancer in a patient where such treatment is required. In embodiments in which the pharmaceutical composition is provided in the form of a lyophilized or dry powder, the kit may include a diluent and instructions for reconstituted the pharmaceutical composition prior to administration.

[0075] An antigen-binding anti-STEAP1 protein can be administered via "stepped dosing," which refers to increasing the dose given to a patient before reaching the target dose level (see also, e.g., Ball et al., MAbs 2023 Jan-Dec;15(1):2181016). Stepped dosing can involve one, two, three, four, or five steps (i.e., administering multiple doses, increasing the amount of therapeutic agent given). Each "step" is an increase in the dose given to the patient compared to the last dose given. Stepped dosing can involve two or three steps. Stepped dosing can involve two steps to reach a target dose of, for example, 0.75 mg. Stepped dosing can involve three steps to reach a target dose of, for example, 1.5 mg. Stepped dosing can be used to reduce the incidence of cytokine release syndrome.For example, step-up dosing could begin with a priming dose on day 1 of cycle 1, escalate on day 8 (step 1), and then continue at the target dose. Once step-up is complete, the target dose (e.g., once a week, once every two weeks, once every three weeks, or once every four weeks) can be administered. The target dose can be given at any interval over a desired period (e.g., four weeks, five months, or eleven months), providing a total treatment duration of, for example, two months, six months, or twelve months.

[0076] The antigen-binding anti-STEAP1 protein (e.g., xaluritamig) can first be administered in a stepwise dose to reach the target dose of xaluritamig. After reaching the target dose of xaluritamig, a patient can be treated with another therapeutic agent (e.g., a combination partner), although the disclosure also provides for the administration of another therapeutic agent prior to reaching the target dose (e.g., administration of C1 D1). Such another therapeutic agent can be administered in a cycle with xaluritamig.

[0077] A "cycle" refers to the repeated treatment pattern and can be defined by antigen-binding anti-STEAP1 protein (e.g., xaluritamig) or a combination partner. A cycle can also provide the basis for patient follow-up care. A cycle may still be in place even if a drug is administered continuously. A cycle can encompass a varying number of days depending on the treatment. A cycle refers to a period during which the procedures to be performed can be repeated. It is standard practice to define the treatment duration with specific times for treatment administration. For example, the antigen-binding anti-STEAP1 protein (xaluritamig) cycle may be 28 days long. The PLUVICTO® cycle may be 42 days long (administered every six weeks).

[0078] When more than one therapeutic agent (e.g., antigen-binding anti-STEAP1 protein and lutetium-Lu-177-vipivotide tetraxetan) is administered to a patient during the course of treatment, the therapeutic agents are said to be administered in combination. When administered in combination, they may be given on the same day or separated by days, weeks, or months. Exemplary dosing regimens are described here and in the examples.

[0079] The disclosure provides, in some aspects, a procedure whereby the antigen-binding anti-STEAP1 protein (e.g., xaluritamig) is administered to a patient requiring it over a course of treatment comprising two or more cycles, each cycle optionally lasting 28 days. Cycle 1 comprises a three-step dosing schedule, with the patient receiving a dose of 0.1 mg xaluritamig on day 1 (C1 D1), 0.3 mg xaluritamig on day 8 (C1 D8), 1 mg xaluritamig on day 15 (C1 D15), and 1.5 mg xaluritamig on day 22 (C1 D22). In this scenario, 1.5 mg xaluritamig is the "target dose." Following Cycle 1, one or more additional treatment cycles are administered over a desired period (i.e., Cycle 2, Cycle 3, etc.). In several aspects, Cycle 2 and beyond (i.e.Each cycle following Cycle 1) involves administering 1.5 mg of xaluritamig once every two weeks; for example, 1.5 mg of xaluritamig is administered to C2 D1 and 1.5 mg of xaluritamig is administered to C2 D15. Alternatively, Cycle 2 may involve administering xaluritamig once every three weeks (e.g., 1.5 mg of xaluritamig administered every 3 weeks) or administering xaluritamig once every four weeks (e.g., 1.5 mg of xaluritamig administered every 4 weeks). Cycle 2 may be repeated once or multiple times. For example, Cycle 2 may be repeated five times, providing treatment to the patient for a period of six months. Alternatively, Cycle 2 may be repeated 11 times, providing treatment to the patient for a period of 12 months. In several aspects, the patient is given 1000 mg of abiraterone orally once daily and prednisone at a dose of 5 mg twice daily or 10 mg once daily.In several aspects, the patient is given 160 mg of enzalutamide orally once daily.

[0080] The disclosure provides a method in which an antigen-binding anti-STEAP1 protein, such as xaluritamig, is administered according to a method of the present disclosure. The present disclosure also provides an antigen-binding anti-STEAP1 protein, such as xaluritamig, for use in the treatment of prostate cancer, wherein the antigen-binding anti-STEAP1 protein is formulated for administration according to a method of the present disclosure. In one embodiment, the dose of the antigen-binding anti-STEAP1 protein is approximately 0.001 mg to approximately 2 mg, approximately 0.1 mg to approximately 1.5 mg, approximately 0.1 mg to approximately 2 mg, or approximately 0.1 mg to approximately 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 approximately 0.1 mg. In another 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, beginning in cycle 1. In one embodiment, the dose is administered once a week, beginning in cycle 2.In one embodiment, the dose is administered once every two weeks, beginning in cycle 2. In one embodiment, the dose is administered once every three weeks, beginning in cycle 2. In one embodiment, the dose is administered once every four weeks, beginning in cycle 2. In one embodiment, the dose is administered once a week for the first cycle and then once every two weeks, beginning on day one of cycle 2. In one embodiment, the dose is administered once a week for the first cycle and then once every two weeks once the target dose has been reached. In one embodiment, the dose is administered once a week for the first cycle and then once every three weeks once the target dose has been reached. In one embodiment, the dose is administered once a week for the first cycle and then once every four weeks once the target dose has been reached.

[0081] The term "with one dose" refers to a dose of a molecule (drug) that can be administered to a patient at the same time (on the same day) as another different molecule, or administered after another different molecule (e.g., at least one dose of one molecule administered to a patient is separated in time from at least one dose of another molecule administered to a patient). It also implies that at least one additional dose of the same molecule can follow a dose of one molecule, and at least one dose of another molecule can follow that.

[0082] 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, xaluritamig and abiraterone can be administered together on the same day. Medications can also be administered on separate days. For example, xaluritamig and PLUVICTO® can be administered on separate days.

[0083] As used synonymously herein, “treatment” and / or “treat” and / or “manage” shall refer to all procedures that slow, interrupt, halt, control, suspend, or reverse the progression of the conditions described herein, although this does not necessarily imply the complete elimination of all symptoms. Treatment includes the administration of an antigen-binding anti-STEAP1 protein to treat a disease or disorder, such as prostate cancer, in a person in whom antigen-binding anti-STEAP1 protein activity would be beneficial, and includes: (a) inhibiting the further progression of the disease and / or (b) alleviating the disease, i.e., causing regression of the disease or disorder or reducing its symptoms or complications.

[0084] The size of a patient's prostate (and / or metastatic lesions) can be determined using established techniques. These techniques include computed tomography (CT), magnetic resonance imaging (MRI), and / or bone scans. PSA levels can be determined using an established blood test.

[0085] The present disclosure provides a method of the present invention for reducing the size of the 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] The present disclosure provides a method of the present invention for reducing the PSA level of the patient. The present disclosure provides a method of the present invention that is used to slow down or stop the spread of cancer cells to another part or parts of the patient's body.

[0087] The present disclosure provides for the use of the present invention in reducing the size of the 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] The present disclosure provides for the use of the present invention in reducing the patient's PSA level. The present disclosure provides for a method of the present invention that is used in slowing down or halting the spread of cancer cells to another part or parts of the patient's body.

[0089] The present disclosure provides for the manufacture of a medicament of the present invention for reducing the size of the 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.

[0090] The present disclosure provides for the manufacture of a medicament of the present invention for reducing the PSA level of the patient. The present disclosure provides for a method of the present invention that is used to slow down or stop the spread of cancer cells to another part or parts of the patient's body.

[0091] The term "approximately" refers to values ​​that are 10% below or above the value in question and includes the value in question.

[0092] The present invention provides for the stepwise dosing of an antigen-binding anti-STEAP1 protein to reduce cytokine release syndrome (compared to treatment with an antigen-binding anti-STEAP1 protein without stepwise dosing), which can be caused by T-cell engager therapy. Cytokine release syndrome can occur with activation of bystander immune and non-immune cells and may lead to comorbidities. CRS can be classified 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. EXAMPLE EXAMPLE 1: DESIGN OF THE CLINICAL PHASE 1 STUDY

[0093] This study (NCT04221542) was designed to evaluate the safety, tolerability, pharmacokinetics (PK), and antitumor activity of xaluritamig as monotherapy or in combination in patients (pts) with mCRPC and to determine the maximum tolerated dose (MTD) or the recommended Phase 2 dose (RP2D). Parts 1 to 3 will evaluate monotherapy with different dosing schedules and target doses and subcutaneous administration. Part 4 will evaluate combinations with established, standard-of-care mCRPC drugs: xaluritamig plus abiraterone acetate (4A) or xaluritamig plus enzalutamide (4B) in patients previously treated with 0, 1, or 2 non-steroidal anti-inflammatory drugs (NSAIDs) and up to 1 taxane (HSPC) in 4A and 4B. Part 5 is an outpatient dose expansion based on the efficacy and toxicity results from Part 1 of the dose-finding study.Primary endpoints include dose-limiting toxicities, treatment-related and treatment-induced adverse events, and changes in clinical and laboratory parameters. Key secondary endpoints include prostate cancer (PC), objective response according to RECIST 1.1, prostate-specific antigen (PSA) response, radiographic progression-free survival (PCWG3), and overall survival. Key inclusion criteria include men with pathologically confirmed metastatic castration-resistant prostate cancer (mCRPC), evidence of progressive disease, and an ECOG performance status of 0 or 1. Key exclusion criteria include small cell or neuroendocrine prostate cancer, untreated central nervous system (CNS) metastases or leptomeningeal disease, and a history of or current autoimmune disease or disease requiring chronic immunosuppressive therapy. In Part 1, dose escalation is driven by a Bayesian logistic regression model.In parts 2 and 4, doses of AMG 509 are based on data from the monotherapy parts, and dose research is conducted using an mTPI-2 design. Research sites are located in North America, Australia, Asia, and Europe.

[0094] This is an open-label, multi-dose, multi-cohort Phase 1 trial evaluating xaluritamig in patients with mCRPC. Up to 441 patients will be enrolled in the study.The study comprises the following parts: Part 1: Xaluritamig monotherapy is administered by IV infusion to patients previously treated with NHT and 1 to 2 prior taxanes; Part 2: Xaluritamig monotherapy is administered by SC injection to patients previously treated with NHT and 1 to 2 prior taxanes (Part 2 is complete); Part 3: Xaluritamig monotherapy is administered to patients previously treated with no or 1 NHT (which may be given in hormone-sensitive prostate cancer [HSPC]) and no prior taxanes; Part 4: Xaluritamig is administered by IV infusion in combination with abiraterone acetate (Part 4A) or enzalutamide (Part 4B) to patients previously treated with 0-2 NHT (for hormone-sensitive or castration-resistant disease) in Parts 4A and 4B and no or 1 prior taxane for hormone-sensitive disease in Parts 4A and 4B.In Part 4A, xaluritamig is administered IV, and abiraterone is administered according to the abiraterone label, starting on day 1 of cycle 1. In Part 4B, xaluritamig is administered IV, and enzalutamide is administered according to the enzalutamide label, starting one week after the target dose of xaluritamig has been reached (or alternative plans based on emerging safety data). Part 5: Xaluritamig monotherapy is administered on an outpatient basis by IV infusion to patients previously treated with 1-2 NHTs and 1-2 prior taxanes.

[0095] In Parts 1, 3, 4, and 5, xaluritamig will be administered weekly (QW) or every 2 weeks (Q2W) as a short-term IV infusion (approximately 60 minutes), with the possibility of exploring Q3W or Q4W schedules based on emerging data and DLRT recommendations. Part 3 and Part 4 dosing regimens and schedules will be adjusted based on emerging data and DLRT recommendations to follow the regimen and schedule explored in Part 1. The Part 5 dosing regimen and schedule will be selected based on emerging data and DLRT recommendations. This may include stepwise dosing. In Part 2, xaluritamig will be administered as a deep subcutaneous injection, either QW or Q2W. IV xaluritamig monotherapy dose escalation will occur alongside combination and subcutaneous dose escalation, and more than one dosing regimen may be evaluated concurrently. The dose in Part 3 is the MTD or RP2D determined in the dose finding or expansion in Part 1.In all parts, patients must undergo ADT while being treated with AMG 509.

[0096] The dose-finding phase of Part 1 enrolls 100 patients with mCRPC. Dose finding proceeds in two phases: single-patient cohort(s) followed by multi-patient cohort(s) (2 to 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 two weeks (Q2W). Every-two-week (Q2W) schedules may be introduced earlier, and DLRT may recommend that every-three-week (Q3W) or every-four-week (Q4W) schedules be explored from Cycle 2 onward. Table 1. Xaluritamig doses and dosing regimens in Part 1. cohort N Step dosage target dose frequency 1 2 No 0.001 mg QW 2 4 No 0.003 mg QW 3 4 No 0.01 mg QW 4 4 No 0.03 mg QW 5 10 No 0.1 mg QW 6 6 No 0.3 mg QW 7a 15 Level 1 0.3 mg QW 7b 12 Stage 2 1 mg QW 7c 7 Stage 2 1 mg Q2W 8 5 Level 1 1 mg QW 9 5 Stage 2 0.75 mg QW 10 5 Level 1 1 mg QW 11 6 Stage 3 1.5 mg QW 12 6 Stage 3 1.5 mg QW 13 7 Stage 3 2 mg QW

[0097] Dose escalation / de-escalation decisions in Part 1 are guided by the BLRM dose-toxicity model. The MTD in the BLRM is the dose level for which the highest probability of a DLT rate within the target interval of 20% to 33% was predicted. To limit the risk of overdose, the MTD must have a predicted probability of overdose of less than 40% (DLT rate > 33%).

[0098] The MTD for parts 2 and 4 is the dose level for which the highest probability of a DLT rate within the target interval of 30% to 40% was predicted.

[0099] Primary endpoints include dose-limiting toxicities, treatment-related adverse events, treatment-related adverse events, and changes in vital signs, ECG, and clinical laboratory tests.

[0100] Secondary endpoints include: PK parameters, including but not limited to maximum serum concentration (Cmax), time to maximum concentration (Tmax), minimum serum concentration (Cmin), area under the concentration-time curve (AUC) over the dosing interval, accumulation after multiple doses and, if feasible, half-life (t1 / 2), objective response (OR) according to RECIST 1.1 (Response Evaluation Criteria in Solid Tumors), prostate-specific antigen (PSA) response (30%, 50%, 70% and 90%), PSA50 response at week 12, and duration of response (DOR) according to RECIST 1.1, PSA-DOR based on PSA50, time to progression (radiographic and PSA), progression-free survival (PFS) (radiographic and PSA), radiographic 6-month PFS1, 2- and 3-year overall survival (OS = overall survival), response (CTC0) and CTC conversion rate of circulating tumor cells (CTCs), other PCWG3-recommended endpoints (time to symptomatic skeletal events, alkaline phosphatase [total, bone], lactate dehydrogenase [LDH], hemoglobin, neutrophil-to-lymphocyte ratio, urine N-telopeptide).

[0101] Once the MTD has been identified, enrollment begins in the dose expansion phase to confirm safety and tolerability by evaluating three selected dosing regimens and to further assess PD and antitumor activity, thus selecting the most appropriate dose and plan. These dosing regimens are tracked in parallel during the expansion and include different dose levels and / or schedules, as shown in Table 2. Table 2. Clinical trial expansion phase Xaluritamig dosing schedules cohort Xaluritamig 1.5 mg QW (3 step: C1D1 0.1 mg, C1D8 0.3 mg, C1D15 1 mg C1D22 1.5 mg) Xaluritamig 0.75 mg QW (2 step: C1D1 0.1 mg, C1D8 0.3 mg, C1D15 0.75 mg) Xaluritamig 1.5 mg Q2W (3 step: C1D1 0.1 mg, C1D8 0.3 mg, C1D15 1 mg, C1D22 1.5 mg)

[0102] Patients will be randomized 1:1:1 into different expansion cohorts. Up to 50 patients (pts) are expected to be enrolled in each expansion cohort.

[0103] As of March 23, 2023, 97 patients had received ≥ 1 dose of xaluritamig across 15 dose levels / plans (DLs) (28 [28.3%] patients for ≥ 6 months); 25 patients continued treatment. The median age (range) was 67 (40–86) years; 67 patients (69.1%) had received > 3 prior lines of therapy. Treatment-emergent adverse events (TEAEs) were recorded in 100% of patients (grade ≥ 3, 74.2%). The most common AE was cytokine release syndrome (CRS; 72.2%), primarily grade 1 / 2 (cycle 1), with one grade 3 event (no grade 4 / 5 CRS). In the 2-mg TD cohort, 3 / 6 evaluable DLT patients received DLTs, with the MTD defined as 1.5 mg. Treatment-related TEAEs leading to discontinuation occurred in 17.5% of patients. Overall, 89 patients were PSA-evaluable, and 66 patients were RECIST-evaluable. A PSA50 response (≥ 50%; PSA decrease) occurred in 42 patients (47.2%); a PSA90 response in 24 patients (27.0%).PSA responses were more frequent with larger DLs (0.75 mg, 2 mg) than with smaller DLs (0.001–0.3 mg). ≥ 90% (34.8% vs. 18.6%) pts, ≥ 50% (54.3% vs. 39.5%) pts. RECIST responses included 15 (22.7%) confirmed PR and 30 (45.5%) SD. With larger DLs, 14 pts (38.9%) PR and 12 (33.3%) SD were confirmed. Preliminary PK showed a dose-proportional increase in exposure in the range of 0.003 mg to 1.5 mg with a mean terminal half-life of approximately 3–4 days.

[0104] Patients were initially enrolled on a fixed (non-step) dose administered intravenously (IV) weekly (QW) in cohorts 1–6 as 0.001 mg (n=2), 0.003 mg (n=4), 0.01 mg (n=4), 0.03 mg (n=4), 0.1 mg (n=10), and 0.3 mg (n=6). At the 0.3 mg dose in cohort 6, 2 of 6 patients experienced grade 3 dose-limiting toxicities (DLTs) of chronic spinal cord syndrome (CRS) / encephalopathy and back pain, and the dose level was deemed intolerable, exceeding the maximum tolerated dose (MTD) for cycle 1 day 1. Following adjustments to premedication, the 0.3 mg starting dose (cohort 8) was still deemed intolerable, and the MTD for the initial (priming) dose was confirmed to be 0.1 mg.

[0105] Stepwise dosing began with 0.1 mg on day 1 and comprised either 1 step (increase on day 8), 2 steps (increases on days 8 and 15), or 3 steps (increases on days 8, 15, and 22) to reach a target dose on days 8, 15, or 22, respectively.

[0106] In cohorts 7a and 10, the single-step dosing regimen was 0.1 to 0.3 mg or 0.1 to 1.0 mg. The 0.1 to 0.3 mg regimen (cohort 7a) was tolerated, but the larger step dose of 0.1 to 1.0 mg (cohort 10) was poorly tolerated because three of the four patients experienced DLT consisting of grade 3 atrial fibrillation / QT prolongation, grade 3 fasciitis / pharyngitis, and grade 3 arthralgia (one patient each). Based on the single-step dosing findings, cohorts 7b, 7c, and 9 were evaluated on two-step dosing regimens with a priming dose of 0.1 mg, a day-8 dose of 0.3 mg, and a day-15 dose of either 0.75 or 1.0 mg; all were rated as tolerated.

[0107] Based on the findings of the two-step dosing regimen, cohorts 11, 12, and 13 were evaluated using three-step dosing regimens with a priming dose of 0.1 mg, a day 8 dose of 0.3 mg, a day 15 dose of either 0.75 or 1.0 mg, and a day 22 dose of either 1.5 or 2 mg. Cohorts 11 (day 15 dose of 0.75 mg) and 12 (day 15 dose of 1.0 mg) had target day 22 doses of 1.5 mg, and both were rated as tolerable. In cohort 13, the highest day-22 dose of 2.0 mg was tested, which was considered intolerable due to DLTs in 3 of the 4 evaluable patients (grade 3 muscle pain [n=2], grade 3 back pain and grade 3 arthralgia [n=1]).

[0108] Overall, the maximum tolerated priming dose with the full prophylaxis regimen was 0.1 mg, and a 3-step dosing regimen consisting of 0.3 mg on day 8, 1.0 mg on day 15, and 1.5 mg on day 22+ IV QW was classified as MTD.

[0109] Xaluritamig was tolerated with low-grade CRS (primarily cycle 1) and showed encouraging preliminary clinical efficacy in heavily pretreated patients with mCRPC.

[0110] Preliminary efficacy, as measured by both PSA and RECIST, was encouraging in a heavily pretreated mCRPC population, with responses being more frequent in higher-dose cohorts. Consistent with PD markers of T-cell activity, PSA reductions were observed starting with 0.1 mg xaluritamig, with a significant number of patients achieving confirmed PSA50 and PSA90 responses. At higher doses, these were converted into responses, with response rates observed in 50% of RECIST-evaluable patients.

[0111] A three-step plan was used to determine that the maximum tolerated dose is 1.5 mg (Cycle 1 Day 1 0.1 mg / Cycle 1 Day 8 0.3 mg / Cycle 1 Day 15 1 mg / Cycle 1 Day 22 1.5 mg) administered once weekly. In the dose expansion phase, a second dosing plan using 0.75 mg is being investigated via a two-step plan (Cycle 1 Day 1 0.1 mg / Cycle 1 Day 8 0.3 mg / Cycle 1 Day 15 0.75 mg) administered once weekly. A dosage of 1.5 mg once every two weeks (Q2W) is also being investigated. This plan uses the three-step plan. From Cycle 2 onward, the target dose of 1.5 mg Q2W is administered.

[0112] During the study, initial signs of clinical efficacy based on PSA reductions were observed at all xaluritamig target dose levels of 0.1 mg or higher, with an odds ratio (OR) observed in cohorts receiving a 0.3 mg target dose. Higher OR rates were observed in patients in the high-dose cohorts (QW administration; target doses above 0.3 mg are considered safe and well-tolerated). Among 67 patients with RECIST-evaluable disease, 16 patients (24%) achieved a confirmed partial response (PR), 32 patients (48%) achieved stable disease (SD), and 13 patients (19%) achieved progressive disease (PD). 6 patients (9%) were not evaluable. Fig.2, Table 3). RECIST-OR was stronger at higher doses, with 10 patients (50%) achieving a confirmed PR. Response was usually achieved within the first 2 treatment cycles, and the duration of response in higher-dose cohorts is still immature. During the study, initial clinical benefit, including reduction in bone lesions and imaging response according to RECIST version 1.1, was observed in patients with a diverse spectrum of disease burdens. Table 3. Summary of efficacy data in patients receiving xaluritamig All cohorts Cohorts with low dose Cohorts with high dose PPE-evaluable* , n 87 43 44 PSA response , confirmed* , n (%) PSA50 43 (49) 17 (40 26 (59) PSA90 24 (28) 8 (19) 16 (36) RECIST v1.1 evaluable , n 67 30 37 R ECIST v1.1 address , confirmed , n (%) CR 0 0** 0 PR 16 (24) 1 (3)** 15 (41)** SD 32 (48) 18 (60)** 14 (38)** PD 13 (19) 6 (20)** 7 (19)** Not assessable 6 (9) 5 (17)** 1 (3)** PSA response was defined as a ≥ 50% reduction and a ≥ 90% reduction in baseline PSA.* The PSA response-evaluable analysis set was defined such that all patients who were enrolled and received ≥ 1 dose of xaluritamig had a measurable (i.e., > 0) baseline PSA and it was possible to follow these patients for ≥ 8 weeks starting from day 1. Patients who discontinued disease monitoring before 8 weeks were included in this analysis set if the cutoff date was ≥ 8 weeks after Day 1. The analysis set evaluable for RECIST version 1.1 response included enrolled patients with measurable baseline disease who could be followed for ≥ 8 weeks starting from the first dose of xaluritamig. The best overall response of non-evaluable patients includes 5 patients without post-baseline scans.CR, complete response; PD, progressive disease; PR, partial response; PSA, prostate-specific antigen; QW, weekly; RECIST, solid tumor response assessment criteria; SD, stable disease.

[0113] In the PSA-evaluable analysis set (N=87), confirmed PSA50 response was recorded in 43 patients (49%) and PSA90 response in 24 patients (28%). Fig.3) In the low-dose (n=43 evaluable patients) and high-dose (n=44) cohorts, PSA50 responses were observed in 17 (40%) and 26 (59%) patients, respectively, while PSA90 responses occurred in 8 (19%) and 16 (36%) patients, respectively. One patient was a 65-year-old man with an initial diagnosis of stage IV prostate adenocarcinoma (Gleason score 9). This individual received androgen deprivation therapy prior to treatments including bicalutamide, abiraterone, docetaxel, cabazitaxel, and carboplatin. Following administration of IV xaluritamig at a 3-step target dose of 1.5 mg, the individual showed a confirmed PSA50 response, with the maximum PSA decrease from baseline of 99% occurring on day 1 of cycle 7. CT scans revealed 3 target lesions and several non-target lesions during screening.Images taken after 2 treatment cycles showed shrinkage of lesions, consistent with the PR (37.3% reduction of target lesions) according to RECIST-1.1 criteria, confirmed at week 16 and maintained at week 24 (. Fig. 4 and Fig. 5) Adverse events (AEs) during the first treatment cycle were grade ≤ 2 and included recurrent CRS, rash, worsening back pain, and tinea faciei. During subsequent treatment cycles, grade ≤ 2 AEs included rash, muscle pain, and hyperkalemia.

[0114] Preliminary PK showed a dose-proportional increase in exposure at the investigated dose levels, with a mean terminal half-life of approximately 3–4 days. Based on preclinical studies, the lower and upper black horizontal dashed lines represent the EC90 (90% effective concentration) of the in vitro cell-killing assay (74 ng / ml) and the half-maximal inhibitory concentration (IC50) of the PK / PD xenograph model, respectively (259 ng / ml). Starting with cohort 5 (0.1 mg QW), the observed through-dose concentrations approach the minimum predicted effective exposure, suggesting that these doses may elicit a clinical response.

[0115] Following the first infusion of xaluritamig, a rapid decrease in peripheral T-cell count was observed. Lymphocyte redistribution was accompanied by transient expression of the T-cell activation marker CD69. Measured serum cytokines, including IFNγ, IL-2, IL-6, and TNF-α, increased from baseline after the xaluritamig infusion. Cytokine concentrations peaked within 6–24 hours and returned to baseline before subsequent infusions. T-cell margination, T-cell activation, and cytokine induction were all dose-dependent, with FDR-corrected p-values ​​reaching significance at several time points after the infusion.

[0116] The overall treatment-related incidence of ADA was 49 out of 90 evaluable patients (54%), of whom 8 patients exhibited a transient antibody response. The median onset of ADA binding occurred on day 1 of cycle 2. ADA-binding-positive patients were assessed for ADA influence on drug activity, exposure, and association with safety events. The observed ADAs were not associated with adverse events. A subset of ADA-binding-positive patients were classified as neutralizing and / or exposure-influencing.

[0117] The safety profile in this study consisted mainly of grade 1 and 2 adverse events (AEs) that were clinically manageable, and no grade 5 events related to xaluritamig were observed. Nineteen percent of patients discontinued treatment due to a transient adverse event (TRAE), partly due to restrictions on the duration of dosing interruptions.

[0118] The most common TRAE was low-grade CRS, which occurred primarily in cycle 1. CRS was expected in this study due to the biological mechanism of xaluritamig and clinical experience with other TCEs (11). Three (3%) grade 3 CRS cases were recorded, one of which was later downgraded to grade 1 after the cut-off date. The grade 3 events (cohorts 6 and 7a) occurred before the addition of the second pre-dose of dexamethasone and after the IV hydration dose, which was initiated in later cohorts. Almost all CRS events presented as fever with or without hypotension, tachycardia, and rarely hypoxia. There were no grade 4 or 5 CRS events. Overall, all CRS events were resolved with standard management using acetaminophen, IV fluids, along with tocilizumab and / or corticosteroids.

[0119] A favorable, predictable dose-exposure relationship was observed following xaluritamig administration. The preliminary terminal half-life was ~3–4 days, supporting a quarter-week dosing regimen. PK indicated that patients at the 0.75 mg target dose and above would exhibit a minimum concentration level at minimum effective exposure based on preclinical studies. This enabled further analysis evaluating clinical outcomes in low-dose (< 0.75 mg) and high-dose (≥ 0.75 mg) cohorts.

[0120] Additional analysis was performed in a dose-expansion phase in patients with mCRPC who were randomized 1:1:1 to receive IV xaluritamig at target doses of 0.75 mg QW, 1.5 mg QW, or 1.5 mg Q2W using a 2- or 3-step dosing approach in Cycle 1. Results are provided in the table below. 0.75 mg QW 1.5 mg QW 1.5 mg Q2W Total Dose expansion PSA assessable N = 33 N = 30 N = 32 N = 95 PSA50 response confirmed, n (%) 12 (36,4) 18 (60,0) 17 (53,1) 47 (49,5) PSA90 response confirmed, n (%) 7 (21,2) 9 (30,0) 11 (34,4) 27 (28,4) RECIST-evaluable N = 27 N = 21 N = 21 N = 69 Confirmed complete response, n (%) 0 (0,0) 0 (0,0) 1 (4,8) 1 (1,4) Confirmed partial response, n(%) 4 (14,8 %) 4 (19,0) 5 (23,8) 13 (18,8) Stable disease, n (%) 10 (37,0) 14 (66,7) 10 (47,6) 34 (49,3) Progressive disease, n (%) 12 (44,4) 1 (4,8) 4 (19,0) 17 (24,6) not assessable, n (%) 1 (3,7) 2 (9,5) 1 (4,8) 4 (5,8)

[0121] While both doses were effective, a target dose of 1.5 mg vs. 0.75 mg improved the efficacy of xaluritamig with a tolerable side effect profile in this randomized dose-expansion / optimization study of heavily pretreated patients with mCRPC. A higher target dose of 1.5 mg showed trends toward superior efficacy and similar safety compared to 0.75 mg.

[0122] PSA50 0.75 mg: 36%, 1.5 mg: 53%-60%

[0123] PSA90 0.75 mg: 21%, 1.5 mg: 30%-34%

[0124] ORR 0.75 mg: 15%, 1.5 mg: 19%-29%

[0125] Grade 3 adverse events were mostly transient, manageable, reversible, and allowed most patients to continue treatment. There were few discontinuations due to musculoskeletal inflammatory events or cytokine release syndrome (CRS), with most Grade 3 CRS events occurring in Cycle 1 (no Grade 4 / 5 CRS). A Q2W dosing regimen demonstrated an improved adverse event profile, with a reduced incidence of overall treatment-related musculoskeletal inflammatory events (69% vs. 74% and 86% with QW dosing regimens) and a lower number of high-grade events (Grade 2 / 3: 22% / 33% vs. 31% / 37% and 34% / 43%). EXAMPLE 2: CLINICAL STUDY DESIGN FOR COMBINATION OF AMG 509 AND LUTETIUM-LU-177-VIPIVOTIDE TETRAXETANE

[0126] A Phase 1b clinical trial can be conducted to determine the safety and efficacy of Xaluritamig in combination with PLUVICTO® (Lutetium-Lu-177-Vipivotidetetraxetane) in mCRPC patients.

[0127] The dosage regimen is expected to be as follows: Monotherapy start-up phase: Stepwise dosing of IV Xaluritamig.

[0128] The cycle duration for xaluritamig monotherapy is 28 days. Treatment is administered in the following cohorts: Cohort 1 (0.1 mg D1 / 0.3 mg D8 / 0.75 mg D15 / 0.75 mg D22) and Cohort 2 (0.1 mg D1 / 0.3 mg D8 / 1.0 mg D15 / 1.5 mg D22). Monotherapy bridging phase: Target dose of IV Xaluritamig

[0129] Once the target dose is reached (e.g., 0.75 mg or 1.5 mg), AMG509 is administered every two weeks (Q2W) until the patient receives PLUVICTO® in combination phase cycle 1 on day 1 (“C1D1”). Criteria for treatment continuation and ordering of PLUVICTO® have been established to ensure that the transition to combination therapy is pursued only when not contraindicated. During the monotherapy bridging phase, the target dose is administered every two weeks (Q2W) until the combination phase C1D1 can be administered. This phase will include two or three doses of xaluritamig administered every two weeks (Q2W) at the target dose to which the patient was randomized (e.g., 0.75 mg or 1.5 mg). Combination phase: Combining PLUVICTO® and Xaluritamig

[0130] The combination phase of Xaluritamig with PLUVICTO® begins on day 1, day 1 (D1) with PLUVICTO® administration at the approved dose of 7.4 GBq, followed by AMG509 at the target dose on day 1, day 8 (D1), and then a Q2W schedule at the target dose. During the combination phase, the cycle length will be 6 weeks, with AMG509 administered on days 8, 22, and 36 in each combination cycle. A maximum of 6 cycles of combination therapy are planned. Maintenance phase of monotherapy with IV Xaluritamig

[0131] Following completion of the combination phase, Xaluritamig may be continued at the target dose (e.g. 0.75 mg or 1.5 mg) in a Q2W plan at the investigator's discretion.

[0132] Primary endpoints include dose-limiting toxicities, treatment-related adverse events, and changes in vital signs, electrocardiogram, and clinical laboratory tests. Pharmacokinetics and preliminary antitumor activity of xaluritamig in combination with PLUVICTO® are also being investigated as secondary endpoints.

[0133] The proposed plans with target doses of 0.75 mg or 1.5 mg xaluritamig were found to be safe and well-tolerated in protocol 20180146 and were selected for further investigation in dose expansion. This study features continuous enrollment and ongoing safety assessment. TABLE 4 SEQUENCES SEQ ID NO : Designation sequence 1. XaluritamigCD3 scFvHCDR1 TYAMN 2. XaluritamigCD3 scFvHCDR2 RIRSKYNNYATYYADSVKG 3. XaluritamigCD3 scFvHCDR3 HGNFGDSYVSWFAY 4. XaluritamigCD3 scFvLCDR1 GSSTGAVTTSNYAN 5. XaluritamigCD3 scFvLCDR1 GTNKRAP 6. XaluritamigCD3 scFvLCDR1 ALWYSNHWV 7. XaluritamigCD3 scFvHCVR EVQLVESGGGLVQPGGSLRLSCAASGFTFSTYAMNWVRQAPGKGLEWVGRIRSKYNNYATYYADSVKGRFTISRDDSKNTLYLQMNSLRAEDTAVYYCVRHGNFGDSYVSWFAYWGQGTLVTVSS 8. XaluritamigCD3 scFvLCVR QAVVTQEPSLTVSPGGTVTLTCGSSTGAVTTSNYANWVQQKPGKSPRGLIGGTNKRAPGVPARFSGSLLGGKAALTISGAQPEDEADYYCALWYSNHWVFGGGTKLTVL 9. XaluritamigSTEAP1 FabHCDR1 TYWIE 10. XaluritamigSTEAP1 FabHCDR2 EILPGSGQTDFNEKFQG 11. XaluritamigSTEAP1 FabHCDR3 WGYYGTRGYFNV 12. XaluritamigSTEAP1 FabLCDR1 RASSSVSYMH 13. XaluritamigSTEAP1 FabLCDR2 STSNLAS 14. XaluritamigSTEAP1 FabLCDR3 QQRRSFPYT 15. XaluritamigSTEAP1 FabHCVR QVQLVQSGAEVKKPGASVKVSCKASGYTFSTYWIEWVRQA PGQRLEWMGEILPGSGQTDFNEKFQGRVTFTADTSSDTAYMELSSLRSEDTAVYYCTRWGYYGTRGYFNVWGQGTLVTVSS 16. XaluritamigSTEAP1 FabLCVR EIVLTQSPATLSLSPGERATLSCRASSSVSYMHWFQQKPGQAPRLLIYSTSNLASGIPARFSGSGSGTDYTLTISSLEPEDFAVYYCQQRRSFPYTFGQGTKLEIK 17. XaluritamigSTEAP1 HC QVQLVQSGAEVKKPGASVKVSCKASGYTFSTYWIEWVRQAPGQRLEWMGEILPGSGQTDFNEKFQGRVTFTADTSSDTAYMELSSLRSEDTAVYYCTRWGYYGTRGYFNVWG QGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSDTKVDKKVEPKSCD KTHTCPPCPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVDVKHEDPEVKFNWYVDGVEVHNAKTKPCEEEYGSTYRCVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEK TISKAKGQPREPQVYTLPPSREEMTKNQVSLTCDVSGFYPSDIAVEWESDGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWEQGDVFSCSVMHEALHNHYTQKSLSLSPGK 18. XaluritamigSTEAP1 LC EIVLTQSPATLSLSPGERATLSCRASSSVSYMHWFQQKPGQAPRLLIYSTSNLASGIPARFSGSGSGTDYTLTISSLEPEDFAVYYCQQRRSFPYTFGQGTKLEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 19. XaluritamigHC with added CD3 scFv QVQLVQSGAEVKKPGASVKVSCKASGYTFSTYWIEWVRQAPGQRLEWMGEILPGSGQTDFNEKFQGRVTFTADTSSDTAYMELSSLRSEDTAVYYCTRWGYYGTRGYFNVWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCGGGGSGGGGSEVQLVESGGGLVQPGGSLRLSCAASGFTFSTYAMNWVRQAPGKGLEWVGRIRSKYNNYATYYADSVKGRFTISRDDSKNTLYLQMNSLRAEDTAVYYCVRHGNFGDSYVSWFAYWGQGTLVTVSSGKPGSGKPGSGKPGSGKPGSQAVVTQEPSLTVSPGGTVTLTCGSSTGAVTTSNYANWVQQKPGKSPRGLIGGTNKRAPGVPARFSGSLLGGKAALTISGAQPEDEADYYCALWYSNHWVFGGGTKLTVLGGGGSGGGGSKTHTCPPCPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVDVKHEDPEVKFNWYVDGVEVHNAKTKPCEEQYGSTYRCVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREQMTKNQVKLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 20. XaluritamigSTEAP1 FabHCVR pyro-glu PyrogluVQLVQSGAEVKKPGASVKVSCKASGYTFSTYWIEWVRQAPGQRLEWMGEILPGSGQTDFNEKFQGRVTFTADTSSDTAYMELSSLRSEDTAVYYCTRWGYYGTRGYFNVWGQGTLVTVSS 21. XaluritamigSTEAP1 HCpyro-glu PyrogluVQLVQSGAEVKKPGASVKVSCKASGYTFSTYWIEWVRQAPGQRLEWMGEILPGSGQTDFNEKFQGRVTFTADTSSDTAYMELSSLRSEDTAVYYCTRWGYYGTRGYFNVWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVS WNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSDTKVDKKVEPKSCDKTHTCPPCPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVDVKHEDPEVKFNWYVDGVEVHNAKTKPCEEEYGSTYRCVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCDVSGFYPSDIAVEWESDGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWEQGDVFSCSVMHEALHNHYTQKSLSLSPGK 22. STEAP1 HCkein C-termLysin QVQLVQSGAEVKKPGASVKVSCKASGYTFSTYWIEWVRQAPGQRLEWMGEILPGSGQTDFNEKFQGRVTFTADTSSDTAYMELSSLRSEDTAVYYCTRWGYYGTRGYFNVWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSDTKVDKKVEPKSCDKTHTCPPCPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVDVKHEDPEVKFNWYVDGVEVHNAKTKPCEEEYGSTYRCVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCDVSGFYPSDIAVEWESDGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWEQGDVFSCSVMHEALHNHYTQKSLSLSPG 23. STEAP1 HCpyro-glu undkein C-termLysin PyrogluVQLVQSGAEVKKPGASVKVSCKASGYTFSTYWIEWVRQAPGQRLEWMGEILPGSGQTDFNEKFQGRVTFTADTSSDTAYMELSSLRSEDTAVYYCTRWGYYGTRGY FNVWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSDTKVDKKVEP KSCDKTHTCPPCPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVDVKHEDPEVKFNWYVDGVEVHNAKTKPCEEEYGSTYRCVSVLTVLHQDWLNGKEYKCKVSNKALPAPI EKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCDVSGFYPSDIAVEWESDGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWEQGDVFSCSVMHEALHNHYTQKSLSLSPG 24. XaluritamigHC with inserted CD3 scFv;pyro-glu PyrogluVQLVQSGAEVKKPGASVKVSCKASGYTFSTYWIEWVRQAPGQRLEWMGEILPGSGQTDFNEKFQGRVTFTADTSSDTAYMELSSLRSEDTAVYYCTRWGYYGTRGYFNVWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPA VLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCGGGGSGGGGSEVQLVESGGGLVQPGGSLRLSCAASGFTFSTYAMNWVRQAPGKGLEWVGRIRSKYNNYATYADSVKGRFTISRDDSKNTLYLQMNSLRAEDTAVYCVRHGNFGDSYVSWFAYWGQGTLVTVS SGKPGSGKPGSGKPGSGKPGSQAVVTQEPSLTVSPGGTVTLTCGSSTGAVTTSNYANWVQQKPGKSPRGLIGGTNKRAPGVPARFSGSLLGGKAALTISGAQPEDEADYYCALWYSNHWVFGGGTKLTVLGGGGSGGGGSKTHTCPPCPAPPVAGPSVFLFPKPKDTLMISRTPEVTCVVV DVKHEDPEVKFNWYVDGVEVHNAKTKPCEEQYGSTYRCVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREQMTKNQVKLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLPGK 25. XaluritamigHC miteingefüghtemCD3 scFv; noC-term Lysine QVQLVQSGAEVKKPGASVKVSCKASGYTFSTYWIEWVRQAPGQRLEWMGEILPGSGQTDFNEKFQGRVTFTADTSSDTAYMELSSLRSEDTAVYYCTRWGYYGTRGYFNVWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQS SGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCGGGGSGGGGSEVQLVESGGGLVQPGGSLRLSCAASGFTFSTYAMNWVRQAPGKGLEWVGRIRSKYNNYATYYADSVKGRFTISRDDSKNTLYLQMNSLRAEDTAVYYCVRHGNFGDSYVSWFAYWGQGTLVTVSSGK PGSGKPGSGKPGSGKPGSQAVVTQEPSLTVSPGGTVTLTCGSSTGAVTTSNYANWVQQKPGKSPRGLIGGTNKRAPGVPARFSGSLLGGKAALTISGAQPEDEADYYCALWYSNHWVFGGGTKLTVLGGGGSGGGGSKTHTCPPCPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVD VKHEDPEVKFNWYVDGVEVHNAKTKPCEEQYGSTYRCVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSR EQMTKNQVKLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG 26. XaluritamigHC with incorporated CD3 scFv;pyro-glu and no C-termLysine PyrogluVQLVQSGAEVKKPGASVKVSCKASGYTFSTYWIEWVRQAPGQRLEWMGEILPGSGQTDFNEKFQGRVTFTADSSDTAYMELSSLRSEDTAVYCTRWGYYGTRGYFNVWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPA VLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCGGGGSGGGGSEVQLVESGGGLVQPGGSLRLSCAASGFTFSTYAMNWVRQAPGKGLEWVGRIRSKYNNYATYYADSVKGRFTISRDDSKNTLYLQMNSLRAEDTAVYCVRHGNFGDSYVSWFAYWGQGTLVTVS SGKPGSGKPGSGKPGSGKPGSQAVVTQEPSLTVSPGGTVTLTCGSSTGAVTTSNYANWVQQKPGKSPRGLIGGTNKRAPGVPARFSGSLLGGKAALTISGAQPEDEADYCALWYSNHWVFGGGTKLTVLGGGGSGGGGSKTHTCPPCPAPPVAGPSVFLFPKPKDTLMISRTPEVTCVVV DVKHEDPEVKFNWYVDGVEVHNAKTKPCEQYGSTYRCVSVLTVLHQDWLNGKEYKCCVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREQMTNKNQVKLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG QUOTES INCLUDED IN THE DESCRIPTION

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[0075]

Claims

Method for treating a patient with prostate cancer, comprising administering to the patient a pharmaceutical composition comprising an antigen-binding anti-STEAP1 protein in a dose of approximately 0.1 mg to approximately 2.0 mg and administering to the patient a dose of the compound of formula 1: complexed with a metal belonging to the group consisting of 90 Y, 177 Lu, 64 Cu, 153 Gd, 155 Gd, 157 Gd, 213 Bi and 225 Ac is selected. Method according to claim 1, wherein the compound complexed with a metal is lutetium-Lu-177-vipivotidetetraxetane. The method of claim 2, wherein the dose of lutetium-Lu-177-vicivotidetetraxetane is about 2 GBq to about 13 GBq. Method according to claim 2 or claim 3, wherein the dose of lutetium-Lu-177-vicivotide tetraxetane is about 5.9 GBq. Method according to one of claims 2-4, wherein the dose of lutetium-Lu-177-vicivotidetetraxetane is about 7.4 GBq. Method according to any one of claims 2-5, wherein the dose of lutetium-Lu-177-vicivotidetetraxetane is administered once every six weeks. Method according to any one of claims 2-6, wherein the antigen-binding anti-STEAP1 protein is administered to the patient after administration of a dose of Lutetium-Lu-177-Vipivotidetetraxetan to the patient. Method according to any one of claims 1-7, wherein the method comprises at least one cycle and the antigen-binding anti-STEAP1 protein is administered in a cycle every 7 days following the administration of a dose of lutetium-Lu-177-vicivotide tetraxetane. The method of claim 8, wherein the method comprises one cycle, two cycles, three cycles, four cycles, five cycles or six cycles. Method according to any one of claims 2-9, wherein the dose of lutetium-Lu-177-vicivotidetetraxetane is administered by intravenous administration. Method according to any one of claims 1-10, wherein the dose of the antigen-binding anti-STEAP1 protein is about 0.1 mg to about 2 mg. Method according to any one of claims 1-10, wherein the dose of the antigen-binding anti-STEAP1 protein is about 0.1 mg to about 1.5 mg. Method according to any one of claims 1-12, wherein the dose of the antigen-binding anti-STEAP1 protein is about 0.1 mg. Method according to any one of claims 1-12, wherein the dose of the antigen-binding anti-STEAP1 protein is about 0.3 mg. Method according to any one of claims 1-12, wherein the dose of the antigen-binding anti-STEAP1 protein is about 0.75 mg. Method according to any one of claims 1-12, wherein the dose of the antigen-binding anti-STEAP1 protein is about 1 mg. Method according to any one of claims 1-12, wherein the dose of the antigen-binding anti-STEAP1 protein is about 1.5 mg. Method according to any one of claims 1-12, wherein the dose of the antigen-binding anti-STEAP1 protein is 1.5 mg. Method according to any one of claims 1-18, wherein the dose is administered once per week. Method according to any one of claims 1-18, wherein the dose is administered once every two weeks. Method according to any one of claims 1-20, wherein the dose is administered by intravenous administration. Method according to one of claims 1-21, wherein the antigen-binding anti-STEAP1 protein is first administered by stepwise dosing. Method according to claim 22, wherein the antigen-binding anti-STEAP1 protein is administered by stepwise dosing in two or three steps. Method according to claim 23, wherein the antigen-binding anti-STEAP1 protein is administered by stepwise dosing on day 1 in 0.1 mg, day 8 in 0.3 mg, day 15 in 1.0 mg and day 22 in 1.5 mg. Method according to claim 23, wherein the antigen-binding anti-STEAP1 protein is administered by stepwise dosing on day 1 in 0.1 mg, day 8 in 0.3 mg, day 15 in 0.75 mg and day 22 in 0.75 mg. Method according to one of claims 31-34, further comprising administering the antigen-binding anti-STEAP1 protein according to one of claims 1-10 to the patient once a week, once every two weeks, once every three weeks or once every four weeks after completion of the step dosage and achievement of a target dose of the antigen-binding anti-STEAP1 protein. A method according to any one of claims 1-26, wherein the antigen-binding anti-STEAP1 protein comprises two Fab-binding domains, wherein the Fab-binding domains each bind STEAP1 and the Fab-binding domains each comprise a variable heavy chain domain, a variable light chain domain, a CH1 domain and a constant light chain domain, and wherein the variable heavy chain domain comprises HCDR1, which includes SEQ ID NO: 9, HCDR2, which includes SEQ ID NO: 10, and HCDR3, which includes SEQ ID NO: 11, and the variable light chain domain comprises LCDR1, which includes SEQ ID NO: 12, LCDR2, which includes SEQ ID NO: 13, and LCDR3, which includes SEQ ID NO:

14. Method according to any one of claims 1-27, wherein the antigen-binding anti-STEAP1 protein comprises two Fab domains, each binding STEAP1, and one scFv domain, which binds CD3. Method according to one of claims 1-28, wherein the antigen-binding anti-STEAP1 protein comprises two Fab-binding domains and the Fab-binding domains each bind STEAP1. A method according to any one of claims 1-29, wherein the antigen-binding anti-STEAP1 protein comprises two Fab-binding domains, each Fab-binding domain binding 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, comprising SEQ ID NO: 9, HCDR2, comprising SEQ ID NO: 10, and HCDR3, comprising SEQ ID NO: 11, and the variable light chain domain comprises LCDR1, comprising SEQ ID NO: 12, LCDR2, comprising SEQ ID NO: 13, and LCDR3, comprising SEQ ID NO:

14. Method according to any one of claims 1-30, wherein the antigen-binding anti-STEAP1 protein comprises an scFv-binding domain that binds CD3. A method according to any one of claims 1-31, wherein the antigen-binding anti-STEAP1 protein comprises an scFv-binding domain that binds CD3, and the variable scFv heavy chain domain HCDR1, comprising SEQ ID NO: 1, HCDR2, comprising SEQ ID NO: 2, and HCDR3, comprising SEQ ID NO: 3, an scFv linker, and a variable scFv light chain domain comprising LCDR1, comprising SEQ ID NO: 4, LCDR2, comprising SEQ ID NO: 5, and LCDR3, comprising SEQ ID NO:

6. Method according to any one of claims 1-32, wherein the antigen-binding anti-STEAP1 protein comprises a first Fc domain and a second Fc domain. Method according to one of claims 31-33, wherein the variable Fab heavy chain domains each comprise an amino acid sequence that is at least 90% identical to SEQ ID NO: 15 or 20, the variable Fab light chain domains each comprise an amino acid sequence that is at least 90% identical to SEQ ID NO: 16, and the variable scFv heavy chain domain comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 7, and the variable scFv light chain domain comprises an amino acid sequence that is at least 90% identical to SEQ ID NO:

8. Method according to one of claims 31-34, wherein the variable Fab heavy chain domains each comprise SEQ ID NO: 15 or 20, the variable Fab light chain domains each comprise SEQ ID NO: 16, the variable scFv heavy chain domain comprises SEQ ID NO: 7 and the variable scFv light chain domain comprises SEQ ID NO:

8. Method according to one of claims 31-35, wherein the scFv binding domain that binds CD3 comprises an scFv linker. Method according to one of claims 33-36, 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. Method according to one of claims 33 - 37, wherein the first Fc domain and the second Fc domain each comprise a deletion at position 234. Method according to any one of claims 1-38, wherein the antigen-binding anti-STEAP1 protein comprises an HC comprising SEQ ID NO: 17 or 23, an HC with inserted CD3 scFv comprising SEQ ID NO: 19 or 26, and two light chains, each comprising SEQ ID NO:

18. Method according to any one of claims 1-39, wherein the antigen-binding anti-STEAP1 protein is Xaluritamig. Method according to any one of claims 1-40, wherein the patient has metastatic castration-resistant prostate cancer. Use of an antigen-binding anti-STEAP1 protein in the manufacture of a drug for the treatment of prostate cancer, wherein the drug is formulated for administration in a dose of approximately 0.1 mg to approximately 2.0 mg, and furthermore a dose of the compound of formula 1 is administered to the patient: wherein the compound is complexed with a metal belonging to the group consisting of 90 Y, 177 Lu, 64 Cu, 153 Gd, 155 Gd, 157 Gd, 213 Bi and 225 Ac is selected. Use according to claim 42, wherein the compound complexed with a metal is lutetium-Lu-177-vipivotidetetraxetane. Use according to claim 43, wherein the dose of lutetium-Lu-177-vicivotidetetraxetane is about 2 GBq to about 13 GBq. Use according to claim 43 or claim 3, wherein the dose of lutetium-Lu-177-vicivotidetetraxetane is 5.9 GBq. Use according to any one of claims 43-45, wherein the dose of lutetium-Lu-177-vicivotidetetraxetane is 7.4 GBq. Use according to one of claims 43-46, wherein the dose of Lutetium-Lu-177-Vipivotidetetraxetan is administered once every six weeks. Use according to any one of claims 43-47, wherein the antigen-binding anti-STEAP1 protein is administered to the patient after administration of a dose of Lutetium-Lu-177-Vipivotidetetraxetan to the patient. Use according to any one of claims 43-48, wherein the use comprises at least one cycle and the antigen-binding anti-STEAP1 protein is administered in a cycle every 14 days following the administration of a dose of lutetium-Lu-177-vicivotide tetraxetane. Use according to claim 49, wherein the use comprises one cycle, two cycles, three cycles, four cycles, five cycles or six cycles. Use according to one of claims 43-50, wherein the lutetium-Lu-177-vicivotidetetraxetane is administered by intravenous administration. Use according to one of claims 42-51, wherein the dose of the antigen-binding anti-STEAP1 protein is about 0.1 mg to about 2 mg. Use according to one of claims 42-52, wherein the dose of the antigen-binding anti-STEAP1 protein is about 0.1 mg to about 1.5 mg. Use according to one of claims 42-53, wherein the dose of the antigen-binding anti-STEAP1 protein is about 0.1 mg. Use according to one of claims 42-53, wherein the dose of the antigen-binding anti-STEAP1 protein is about 0.3 mg. Use according to one of claims 42-53, wherein the dose of the antigen-binding anti-STEAP1 protein is about 0.75 mg. Use according to one of claims 42-53, wherein the dose of the antigen-binding anti-STEAP1 protein is about 1 mg. Use according to one of claims 42-53, wherein the dose of the antigen-binding anti-STEAP1 protein is about 1.5 mg. Use according to one of claims 42-53, wherein the dose of the antigen-binding anti-STEAP1 protein is 1.5 mg. Use according to any one of claims 42-59, wherein the dose is administered once per week. Use according to any one of claims 42-59, wherein the dose is administered once every two weeks. Use according to any one of claims 42-61, wherein the dose is administered by intravenous administration. Use according to one of claims 42-62, wherein the antigen-binding anti-STEAP1 protein is first administered by stepwise dosing. Use according to claim 63, wherein the antigen-binding anti-STEAP1 protein is administered by stepwise dosing in two or three steps. Use according to claim 64, wherein the antigen-binding anti-STEAP1 protein is administered by stepwise dosing on day 1 in 0.1 mg, day 8 in 0.3 mg, day 15 in 1.0 mg and day 22 in 1.5 mg. Use according to claim 64, wherein the antigen-binding anti-STEAP1 protein is administered by stepwise dosing on day 1 in 0.1 mg, day 8 in 0.3 mg, day 15 in 0.75 mg and day 22 in 0.75 mg. Use according to any one of claims 42-67, further comprising administering the antigen-binding anti-STEAP1 protein to the patient once a week, once every two weeks, once every three weeks or once every four weeks after completion of the step dosage and achievement of a target dose of the antigen-binding anti-STEAP1 protein. Use according to any one of claims 42-67, wherein the antigen-binding anti-STEAP1 protein comprises two Fab-binding domains, the Fab-binding domains each binding STEAP1 and the Fab-binding domains each 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, comprising SEQ ID NO: 9, HCDR2, comprising SEQ ID NO: 10 and HCDR3, comprising SEQ ID NO: 11, and the variable light chain domain comprises LCDR1, comprising SEQ ID NO: 12, LCDR2, comprising SEQ ID NO: 13 and LCDR3, comprising SEQ ID NO:

14. Use according to any one of claims 42-68, wherein the antigen-binding anti-STEAP1 protein is an XmAb-2+1 molecule. Use according to any one of claims 42-69, wherein the antigen-binding anti-STEAP1 protein comprises two Fab-binding domains and the Fab-binding domains each bind STEAP1. Use according to any one of claims 42-70, wherein the antigen-binding anti-STEAP1 protein comprises two Fab-binding domains, the Fab-binding domains each binding STEAP1 and the Fab-binding domains each 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, comprising SEQ ID NO: 9, HCDR2, comprising SEQ ID NO: 10 and HCDR3, comprising SEQ ID NO: 11, and the variable light chain domain comprises LCDR1, comprising SEQ ID NO: 12, LCDR2, comprising SEQ ID NO: 13 and LCDR3, comprising SEQ ID NO:

14. Use according to any one of claims 42-71, wherein the antigen-binding anti-STEAP1 protein comprises an scFv-binding domain that binds CD3. Use according to claim 72 or 73, wherein the antigen-binding anti-STEAP1 protein comprises an scFv-binding domain that binds CD3, and the variable scFv heavy chain domain HCDR1, comprising SEQ ID NO: 1, HCDR2, comprising SEQ ID NO: 2, and HCDR3, comprising SEQ ID NO: 3, an scFv linker, and a variable scFv light chain domain comprising LCDR1, comprising SEQ ID NO: 4, LCDR2, comprising SEQ ID NO: 5, and LCDR3, comprising SEQ ID NO:

6. Use according to any one of claims 42-73, wherein the antigen-binding anti-STEAP1 protein comprises a first Fc domain and a second Fc domain. Use according to any one of claims 72-74, wherein the variable Fab heavy chain domains each comprise an amino acid sequence that is at least 90% identical to SEQ ID NO: 15 or 20, the variable Fab light chain domains each comprise an amino acid sequence that is at least 90% identical to SEQ ID NO: 16, and the variable scFv heavy chain domain comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 7, and the variable scFv light chain domain comprises an amino acid sequence that is at least 90% identical to SEQ ID NO:

8. Use according to any one of claims 72-75, wherein the variable Fab heavy chain domains each comprise SEQ ID NO: 15 or 20, the variable Fab light chain domains each comprise SEQ ID NO: 16, the variable scFv heavy chain domain comprises SEQ ID NO: 7 and the variable scFv light chain domain comprises SEQ ID NO:

8. Use according to one of claims 72-76, wherein the scFv binding domain that binds CD3 comprises an scFv linker. Use according to any one of claims 74-77, 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. Use according to one of claims 74-78, wherein the first Fc domain and the second Fc domain each comprise a deletion at position 234. Use according to any one of claims 42-79, wherein the antigen-binding anti-STEAP1 protein comprises an HC comprising SEQ ID NO: 17 or 23, an HC with inserted CD3 scFv comprising SEQ ID NO: 19 or 26, and two light chains, each comprising SEQ ID NO:

18. Use according to any one of claims 42-80, wherein the antigen-binding anti-STEAP1 protein is Xaluritamig. Use according to any one of claims 42-81, wherein the patient has metastatic castration-resistant prostate cancer. Antigen-binding anti-STEAP1 protein for use in the treatment of prostate cancer, wherein the antigen-binding protein is formulated for administration in a dose of approximately 0.1 mg to approximately 2.0 mg, and the use further comprises administering a dose of the compound of formula 1 to the patient: wherein the compound is complexed with a metal belonging to the group consisting of 90 Y, 177 Lu, 64 Cu, 153 Gd, 155 Gd, 157 Gd, 213 Bi and 225 Ac is selected. Antigen-binding anti-STEAP1 protein according to claim 83, wherein the compound complexed with a metal is lutetium-Lu-177-vicivotidetetraxetane. Antigen-binding anti-STEAP1 protein according to claim 83, wherein the dose of lutetium-Lu-177-vicivotide tetraxetane is about 2 GBq to about 13 GBq. Antigen-binding anti-STEAP1 protein according to claim 83, wherein the dose of lutetium-Lu-177-vicivotide tetraxetane is about 5.9 GBq. Antigen-binding anti-STEAP1 protein according to one of claims 83-85, wherein the dose of lutetium-Lu-177-vicivotide tetraxetane is about 7.4 GBq. Antigen-binding anti-STEAP1 protein according to one of claims 83-87, wherein the dose of lutetium-Lu-177-vicivotide tetraxetan is administered once every six weeks. Antigen-binding anti-STEAP1 protein according to one of claims 83-87, wherein the antigen-binding anti-STEAP1 protein is administered to the patient after administration of a dose of Lutetium-Lu-177-Vipivotidetetraxetan to the patient. Antigen-binding anti-STEAP1 protein according to one of claims 83-89, wherein the use comprises at least one cycle, wherein the antigen-binding anti-STEAP1 protein is administered in a cycle every 14 days following the administration of a dose of Lutetium-Lu-177-Vipivotidetetraxetane. Antigen-binding anti-STEAP1 protein according to claim 90, wherein the use comprises one cycle, two cycles, three cycles, four cycles, five cycles or six cycles. Antigen-binding anti-STEAP1 protein according to one of claims 83-91, wherein the dose of lutetium-Lu-177-vicivotide tetraxetane is administered by intravenous administration. Antigen-binding anti-STEAP1 protein according to one of claims 83-92, wherein the dose of the antigen-binding anti-STEAP1 protein is about 0.1 mg to about 2 mg. Antigen-binding anti-STEAP1 protein according to one of claims 83-92, wherein the dose of the antigen-binding anti-STEAP1 protein is about 0.1 mg to about 1.5 mg. Antigen-binding anti-STEAP1 protein according to one of claims 83-93, wherein the dose of the antigen-binding anti-STEAP1 protein is about 0.1 mg. Antigen-binding anti-STEAP1 protein according to one of claims 83-93, wherein the dose of the antigen-binding anti-STEAP1 protein is about 0.3 mg. Antigen-binding anti-STEAP1 protein according to one of claims 83-93, wherein the dose of the antigen-binding anti-STEAP1 protein is about 0.75 mg. Antigen-binding anti-STEAP1 protein according to one of claims 83-93, wherein the dose of the antigen-binding anti-STEAP1 protein is about 1 mg. Antigen-binding anti-STEAP1 protein according to one of claims 83-93, wherein the dose of the antigen-binding anti-STEAP1 protein is about 1.5 mg. Antigen-binding anti-STEAP1 protein according to one of claims 83-93, wherein the dose of the antigen-binding anti-STEAP1 protein is 1.5 mg. Antigen-binding anti-STEAP1 protein according to any one of claims 83-100, wherein the dose is administered once per week. Antigen-binding anti-STEAP1 protein according to one of claims 83-100, wherein the dose is administered once every two weeks. Antigen-binding anti-STEAP1 protein according to one of claims 83-102, wherein the dose is administered by intravenous administration. Antigen-binding anti-STEAP1 protein according to one of claims 83-103, wherein the antigen-binding anti-STEAP1 protein is first administered by stepwise dosing. Antigen-binding anti-STEAP1 protein according to one of claims 83-104, wherein the antigen-binding anti-STEAP1 protein is administered by stepwise dosing in two or three steps. Antigen-binding anti-STEAP1 protein according to claim 104 or claim 105, wherein the antigen-binding anti-STEAP1 protein is administered by stepwise dosing on day 1 in 0.1 mg, day 8 in 0.3 mg, day 15 in 1.0 mg and day 22 in 1.5 mg. Antigen-binding anti-STEAP1 protein according to claim 104 or claim 105, wherein the antigen-binding anti-STEAP1 protein is administered by stepwise dosing on day 1 in 0.1 mg, day 8 in 0.3 mg, day 15 in 0.75 mg and day 22 in 0.75 mg. Antigen-binding anti-STEAP1 protein according to one of claims 83-107, further comprising administering the antigen-binding anti-STEAP1 protein to the patient once a week, once every two weeks, once every three weeks or once every four weeks after completion of the step dosage and achievement of a target dose of the antigen-binding anti-STEAP1 protein. Antigen-binding anti-STEAP1 protein according to one of claims 83-107, wherein the antigen-binding anti-STEAP1 protein comprises two Fab-binding domains, the Fab-binding domains each binding STEAP1 and the Fab-binding domains each 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, comprising SEQ ID NO: 9, HCDR2, comprising SEQ ID NO: 10, and HCDR3, comprising SEQ ID NO: 11, and the variable light chain domain comprises LCDR1, comprising SEQ ID NO: 12, LCDR2, comprising SEQ ID NO: 13, and LCDR3, comprising SEQ ID NO:

14. Antigen-binding anti-STEAP1 protein according to one of claims 83-109, wherein the antigen-binding anti-STEAP1 protein is an XmAb-2+1 molecule. Antigen-binding anti-STEAP1 protein according to one of claims 83-110, wherein the antigen-binding anti-STEAP1 protein comprises two Fab-binding domains and the Fab-binding domains each bind STEAP1. Antigen-binding anti-STEAP1 protein according to one of claims 83-111, wherein the antigen-binding anti-STEAP1 protein comprises two Fab-binding domains, the Fab-binding domains each binding STEAP1 and the Fab-binding domains each 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, comprising SEQ ID NO: 9, HCDR2, comprising SEQ ID NO: 10, and HCDR3, comprising SEQ ID NO: 11, and the variable light chain domain comprises LCDR1, comprising SEQ ID NO: 12, LCDR2, comprising SEQ ID NO: 13, and LCDR3, comprising SEQ ID NO:

14. Antigen-binding anti-STEAP1 protein according to one of claims 83-112, wherein the antigen-binding anti-STEAP1 protein comprises an scFv-binding domain, wherein the scFv-binding domain binds CD3. Antigen-binding anti-STEAP1 protein according to one of claims 83-113, wherein the antigen-binding anti-STEAP1 protein comprises an scFv-binding domain that binds CD3, and wherein the variable scFv heavy chain domain HCDR1, comprising SEQ ID NO: 1, HCDR2, comprising SEQ ID NO: 2, and HCDR3, comprising SEQ ID NO: 3, comprises an scFv linker, and a variable scFv light chain domain comprising LCDR1, comprising SEQ ID NO: 4, LCDR2, comprising SEQ ID NO: 5, and LCDR3, comprising SEQ ID NO:

6. Antigen-binding anti-STEAP1 protein according to one of claims 83-114, wherein the antigen-binding anti-STEAP1 protein comprises a first Fc domain and a second Fc domain. Antigen-binding anti-STEAP1 protein according to one of claims 83-115, wherein the variable Fab heavy chain domains each comprise an amino acid sequence that is at least 90% identical to SEQ ID NO: 15 or 20, the variable Fab light chain domains each comprise an amino acid sequence that is at least 90% identical to SEQ ID NO: 16, and the variable scFv heavy chain domain comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 7, and the variable scFv light chain domain comprises an amino acid sequence that is at least 90% identical to SEQ ID NO:

8. Antigen-binding anti-STEAP1 protein according to one of claims 83-115, wherein the variable Fab heavy chain domains each comprise SEQ ID NO: 15 or 20, the variable Fab light chain domains each comprise SEQ ID NO: 16, the variable scFv heavy chain domain comprises SEQ ID NO: 7 and the variable scFv light chain domain comprises SEQ ID NO:

8. Antigen-binding anti-STEAP1 protein according to one of claims 83-117, wherein the scFv-binding domain that binds CD3 comprises an scFv linker. Antigen-binding anti-STEAP1 protein according to one of claims 83-118, 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. Antigen-binding anti-STEAP1 protein according to one of claims 83-119, wherein the first Fc domain and the second Fc domain each comprise a deletion at position 234. Antigen-binding anti-STEAP1 protein according to one of claims 83-120, wherein the antigen-binding anti-STEAP1 protein comprises an HC comprising SEQ ID NO: 17 or 23, an HC with an inserted CD3 scFv comprising SEQ ID NO: 19 or 26, and two light chains, each comprising SEQ ID NO:

18. Antigen-binding anti-STEAP1 protein according to one of claims 83-121, wherein the antigen-binding anti-STEAP1 protein is xaluritamig. Antigen-binding anti-STEAP1 protein according to one of claims 83-122, wherein the patient has metastatic castration-resistant prostate cancer.

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