Treatment method for prostate cancer using a bispecific antibody that binds to STEAP1XCD3.

Abstract

This disclosure provides a method for treating patients with prostate cancer with an anti-STEAP1 antigen-binding protein such as zalritamig, either as monotherapy or in combination with another therapeutic agent.

Description

TECHNICAL FIELD

[0001] The present invention relates to the field of oncology. In particular, the present invention relates to the treatment of prostate cancer with STEAP1 T cell engager (TCE) molecules, either as monotherapy or in combination with another pharmaceutical agent.

[0002] Incorporation by Reference The present application incorporates by reference International Publication No. WO 2020 / 010079, filed on July 2, 2019; and International Publication No. WO 2019 / 157340, filed on February 8, 2019, and both of these international patent publications are hereby expressly incorporated by reference in their entireties, particularly with respect to the drawings, legends, and claims contained therein.

[0003] The present application contains a sequence listing in computer readable form (file name: 10649-WO01-SEC_Sequence_Listing.xml; size: 30,872 bytes; date of creation: July 25, 2024) as a separate document of the present disclosure, which is incorporated by reference in its entirety. BACKGROUND ART

[0004] Prostate cancer is cited as the most frequently diagnosed non-skin cancer, and is one of the leading causes of cancer death among men in the United States (U.S.). In the U.S., 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) were projected in 2023 (Siegel et al., Cancer statistics, 2023. CA Cancer J Clin. 2023;73(1):17-48).

[0005] Survival rates vary among men with prostate cancer, but are strongly correlated with the stage and location of the disease (i.e., whether it is localized or metastatic). In the United States, the five-year survival rate for men with localized prostate cancer is nearly 100%, while for men with metastatic disease, the five-year survival rate drops to as low as 31% (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 and 33,600 deaths from prostate cancer in 2016. From 2000 to 2016, the incidence of prostate cancer was on an upward trend. The average annual rate of change was 7.1% (Zheng et al., Cancer Med., 11:2117-2124, 2022).

[0006] Treatment for patients diagnosed with metastatic prostate cancer includes continuous and intermittent androgen deprivation therapy (ADT). Docetaxel and novel hormone therapies (NHTs) such as abiraterone, enzalutamide, apalutamide, and darolutamide are approved for treatment. 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., Cancer Treat Rev. 2017;57:16-27).

[0007] Since 2010, five novel therapeutic agents have been approved for metastatic castration-resistant prostate cancer (mCRPC) based on survival benefit: cabazitaxel (Jevtana®), ciproisel-T (Provenge®), abiraterone (Zytiga®), enzalutamide (Xtandi®), and radium-223 (Xofigo®). However, the optimal order or combination of available treatments for mCRPC remains largely unknown. The Food and Drug Administration (FDA) has also recently approved the following therapies for certain mCRPC patient groups identified by specific biomarkers: the poly-ADP-ribose polymerase (PARP) inhibitors olaparib (Lynparza®) and lucaparib (Rubraca®); the programmed cell death protein 1 (PD-1) inhibitor pembrolizumab (Keytruda®); and the radioligand therapy lutetium Lu177 bipivotide tetraxetan (PLUVICTO®) that targets prostate-specific membrane antigens. These therapies are indicated for limited or pre-selected patient groups; therefore, there is still a need in late-line mCRPC settings that remains unaddressed.

[0008] Prostate 6-transmembrane epithelial antigen 1 (STEAP1) is a surface antigen containing three short extracellular loop regions that is overexpressed in prostate cancer (Hubert et al., Proc Natl Acad Sci USA. 1999;96(25):14523-8) and Ewing's sarcoma (Grunewald et al., Mol Cancer Res. 2012 Jan;10(1):52-65), and its expression level correlates with the stage of prostate cancer (Gomes et al., Urol Oncol. 2014 Jan;32(1):53.e23-9). Zarritamig (also known as "AMG 509") is a novel XmAb® 2+1 bispecific antibody designed to direct T effector cells (via CD3 binding) to prostate cancer cells expressing STEAP1. In nonclinical studies, zarritamig demonstrated potent cytotoxicity in prostate cancer cell lines and tumor regression in a preclinical xenograft model (Nolan-Stevaux et al., Cancer Discov. 14(1):90-103, 2024). Nonclinical evidence supports initiating clinical trials of zarritamig in mCRPC patients. [Prior art documents] [Non-patent literature]

[0009] [Non-Patent Document 1] Siegel et al.,Cancer statistics,2023.CA Cancer J Clin.2023;73(1):17-48 [Non-Patent Document 2] Cancer.Net, 2020 [Non-Patent Document 3] EU Science Hub, 2018 [Non-Patent Document 4] Zheng et al.,Cancer Med.,11:2117-2124,2022 [Non-Patent Document 5] Galletti et al.,Cancer Treat Rev.2017;57:16-27 [Non-Patent Document 6] Hubert et al.,Proc Natl Acad Sci USA.1999;96(25):14523-8 [Non-Patent Document 7] Grunewald et al.,Mol Cancer Res.2012 Jan;10(1):52-65 [Non-Patent Document 8] Gomes et al.,Urol Oncol.2014 Jan;32(1):53.e23-9 [Non-Patent Document 9] Nolan-Stevaux et al.,Cancer Discov.14(1):90-103,2024 [Overview of the project] [Means for solving the problem]

[0010] The present invention provides a method for treating a patient with prostate cancer, comprising administering to the patient a pharmaceutical composition containing an anti-STEAP1 antigen-binding protein in a dose of about 0.1 mg to about 2.0 mg.

[0011] The present invention also provides the use of an anti-STEAP1 antigen-binding protein for the preparation of a therapeutic drug for prostate cancer, wherein the drug is formulated to be administered in doses of approximately 0.1 mg to approximately 2.0 mg.

[0012] The present invention also provides the use of an anti-STEAP1 antigen-binding protein in the manufacture of a therapeutic drug for prostate cancer, wherein the drug is formulated to be administered in a dose of approximately 0.1 mg to approximately 2.0 mg.

[0013] The present invention also provides an anti-STEAP1 antigen-binding protein for the treatment of prostate cancer, which is formulated so that the drug is administered in doses of approximately 0.001 mg to approximately 2.0 mg.

[0014] The anti-STEAP1 antigen-binding protein may be administered to the subject in doses ranging from approximately 0.001 mg to approximately 1.5 mg. In one embodiment, the dose is 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 one embodiment, the dose is approximately 0.3 mg. In one embodiment, the dose is approximately 0.75 mg. In one embodiment, the dose is approximately 1 mg. In one embodiment, the dose is approximately 1.5 mg. In one embodiment, the dose is 0.1 mg. In one embodiment, the dose is 0.3 mg. In one embodiment, the dose is 0.75 mg. In another embodiment, the dose is 1 mg. In another embodiment, the dose is 1.5 mg. In another embodiment, the dose is administered once a week. In another embodiment, the dose is administered once every two weeks. In another embodiment, the dose is administered once every three weeks. In another embodiment, the dose is administered once every four weeks. In another embodiment, the dose is administered intravenously. In another embodiment, the dose is administered once a week, starting from cycle 1. In another embodiment, the dose is administered once a week, starting from cycle 2. In another embodiment, the dose is administered once every two weeks, starting from cycle 2. In another embodiment, the dose is administered once every three weeks, starting from cycle 2. In another embodiment, the dose is administered once every four weeks, starting from cycle 2. In another embodiment, the dose is administered once a week for the first cycle, and then once every two weeks, starting from day 1 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 is reached. In another embodiment, the dose is administered once a week for the first cycle, and then once every three weeks once the target dose is 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 is reached. In some embodiments, cycle 2 is repeated 11 times after the completion of cycle 1 (e.g., over a total treatment period of about 12 months). In some embodiments, cycle 2 is repeated 5 times after the completion of cycle 1 (e.g., over a total treatment period of about 6 months).

[0015] The present invention also provides a method for treating a patient having prostate cancer, the method comprising administering to the patient a pharmaceutical composition containing an anti-STEAP1 antigen-binding protein in a dose of about 0.1 mg to about 2.0 mg, and further comprising administering to the patient a certain dose of abiraterone. The present invention provides the use of an anti-STEAP1 antigen-binding protein for the preparation of a pharmaceutical drug for the treatment of prostate cancer, the pharmaceutical drug being formulated to be administered in a dose of about 0.001 mg to about 2.0 mg (e.g., about 0.1 mg to about 2.0 mg), and this use further comprises administering to the patient a certain dose of abiraterone. In one embodiment, the dose of abiraterone is about 500 mg to about 750 mg. In one embodiment, the dose of abiraterone is about 750 mg to about 1000 mg. In one embodiment, the dose of abiraterone is about 1000 mg. In one embodiment, the dose of abiraterone is 1000 mg. In one embodiment, the dose of abiraterone is administered orally. Optionally, abiraterone is administered once daily. In one embodiment, the patient is further administered prednisone (or prednisolone). In various embodiments, the patient is administered 4 mg of prednisone twice daily. In various embodiments, the patient is administered 5 mg of prednisone twice daily. In one embodiment, the patient is further administered 10 mg of prednisolone once daily. In one embodiment, the patient is administered 1000 mg of abiraterone orally once daily, and prednisone at a dose of 5 mg twice daily or 10 mg once daily. In various embodiments, the patient is administered 500 mg of abiraterone orally once daily, and prednisone at a dose of 4 mg twice daily. In one embodiment, the dose of anti-STEAP1 antigen-binding protein is approximately 0.1 mg to approximately 2.0 mg. In one embodiment, the dose of anti-STEAP1 antigen-binding protein is approximately 0.1 mg to approximately 1.5 mg. In another embodiment, the dose of anti-STEAP1 antigen-binding protein is approximately 0.75 mg. In yet another embodiment, the dose of anti-STEAP1 antigen-binding protein is approximately 1 mg. In yet another embodiment, the dose of anti-STEAP1 antigen-binding protein is 1.5 mg.In one embodiment, the anti-STEAP1 antigen-binding protein is administered once a week. In another embodiment, the anti-STEAP1 antigen-binding protein is administered once every two weeks. In one embodiment, the patient is administered a certain dose of anti-STEAP1 antigen-binding protein and a certain dose of abiraterone on the same day. In another embodiment, the patient is administered a certain dose of anti-STEAP1 antigen-binding protein and a certain dose of abiraterone on day 1 of cycle 1. In one embodiment, the prostate cancer is metastatic castration-resistant prostate cancer (mCRPC) with no prior chemotherapy history.

[0016] The present invention also provides a method for treating a patient having prostate cancer, the method comprising administering to the patient a pharmaceutical composition containing an anti-STEAP1 antigen-binding protein in a dose of about 0.1 mg to about 2.0 mg, and further comprising administering to the patient enzalutamide. The present invention provides the use of an anti-STEAP1 antigen-binding protein for the preparation of a pharmaceutical drug for the treatment of prostate cancer, the pharmaceutical drug being formulated to be administered in a dose of about 0.001 mg to about 2.0 mg (e.g., about 0.1 mg to about 2.0 mg), and this use further comprises administering to the patient a certain dose of enzalutamide. In one embodiment, the dose of enzalutamide is about 120 mg to about 160 mg. In one embodiment, the dose of enzalutamide is about 160 mg. In one embodiment, the dose of enzalutamide is 160 mg. In one embodiment, the dose of enzalutamide is administered orally. In one embodiment, the dose of anti-STEAP1 antigen-binding protein is about 0.01 mg to about 2.0 mg. In one embodiment, the dose of anti-STEAP1 antigen-binding protein is approximately 0.1 mg to approximately 1.5 mg. In another embodiment, the dose of anti-STEAP1 antigen-binding protein is approximately 0.75 mg. In yet another embodiment, the dose of anti-STEAP1 antigen-binding protein is approximately 1 mg. In yet another embodiment, the dose of anti-STEAP1 antigen-binding protein is 1.5 mg. In yet another embodiment, the patient is first administered anti-STEAP1 antigen-binding protein until the target dose is reached, followed by a dose of enzalutamide. In yet another embodiment, the patient is first administered anti-STEAP1 antigen-binding protein until the target dose is reached, followed by a dose of enzalutamide on the same day that a dose of anti-STEAP1 antigen-binding protein is administered on day 1 of cycle 1. In yet another embodiment, the prostate cancer is metastatic castration-resistant prostate cancer (mCRPC) with no prior chemotherapy history.

[0017] The present invention also provides a method for treating a patient having prostate cancer, the method comprising administering to the patient a pharmaceutical composition containing an anti-STEAP1 antigen-binding protein in a dose of about 0.1 mg to about 2.0 mg, and further comprising administering darolutamide to the patient. The present invention provides the use of an anti-STEAP1 antigen-binding protein for the preparation of a pharmaceutical for the treatment of prostate cancer, the pharmaceutical being formulated to be administered in a dose of about 0.001 mg to about 2.0 mg (e.g., about 0.1 mg to about 2.0 mg), and this use further comprises administering to the patient a certain dose of darolutamide. In one embodiment, the dose of darolutamide is about 450 mg to about 600 mg. In one embodiment, the dose of darolutamide is about 600 mg. In one embodiment, the dose of darolutamide is 600 mg. In one embodiment, the dose of darolutamide is administered orally. In one embodiment, the dose of darolutamide is administered orally twice daily. In one embodiment, the dose of darolutamide is administered orally in the form of two 300 mg tablets twice daily. In one embodiment, the dose of anti-STEAP1 antigen-binding protein is approximately 0.01 mg to approximately 2.0 mg. In one embodiment, the dose of anti-STEAP1 antigen-binding protein is approximately 1.5 mg. In one embodiment, the dose of anti-STEAP1 antigen-binding protein is 1.5 mg.

[0018] The present invention also provides a method for treating a patient having prostate cancer, the method comprising administering to the patient a pharmaceutical composition containing an anti-STEAP1 antigen-binding protein in a dose of about 0.1 mg to about 2.0 mg, and further comprising administering apalutamide to the patient. The present invention provides the use of an anti-STEAP1 antigen-binding protein for the preparation of a pharmaceutical for the treatment of prostate cancer, the pharmaceutical being formulated to be administered in a dose of about 0.001 mg to about 2.0 mg (e.g., about 0.1 mg to about 2.0 mg), and this use further comprises administering to the patient a certain dose of apalutamide. 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 in the form of four 60 mg tablets. In one embodiment, the dose of anti-STEAP1 antigen-binding protein is approximately 0.01 mg to approximately 2.0 mg. In one embodiment, the dose of anti-STEAP1 antigen-binding protein is approximately 1.5 mg. In one embodiment, the dose of anti-STEAP1 antigen-binding protein is 1.5 mg.

[0019] In one embodiment, the anti-STEAP1 antigen-binding protein is administered via a step-up dosing regimen. In one embodiment, the anti-STEAP1 antigen-binding protein is administered in two steps. In one embodiment, the anti-STEAP1 antigen-binding protein is administered in three steps. In one embodiment, the anti-STEAP1 antigen-binding protein is administered at a dose ranging from 0.1 mg to 0.2 mg on day 1 or day 2, a dose ranging from 0.2 mg to 0.4 mg on day 7, 8, or 9, a dose ranging from 0.8 mg to 1.2 mg on day 14, 15, or 16, and a dose ranging from 1.3 mg to 1.5 mg on day 21, 22, or 23. In one embodiment, the anti-STEAP1 antigen-binding protein is administered at about 0.1 mg on day 1, about 0.3 mg on day 8, about 0.75 mg on day 15, and about 0.75 mg on day 22. In one embodiment, the anti-STEAP1 antigen-binding protein is administered at about 0.1 mg on day 1, about 0.3 mg on day 8, about 1.0 mg on day 15, and about 1.5 mg on day 22. In one embodiment, the anti-STEAP1 antigen-binding protein is administered at 0.1 mg on day 1, 0.3 mg on day 8, 0.75 mg on day 15, and 0.75 mg on day 22. In one embodiment, the anti-STEAP1 antigen-binding protein is administered at 0.1 mg on day 1, 0.3 mg on day 8, 1.0 mg on day 15, and 1.5 mg on day 22. In one embodiment, the anti-STEAP1 antigen-binding protein is administered at 0.1 mg on day 1, 0.3 mg on day 8, 0.75 mg on day 15, and 0.75 mg on day 22. In one embodiment, the method further comprises administering the anti-STEAP1 antigen-binding protein to the patient once every one week, once every two weeks, once every three weeks, or once every four weeks after administration of the step-up dosing regimen. In one embodiment, the anti-STEAP1 antigen-binding protein is administered at 1.5 mg once every two weeks after the step-up dosing regimen. In one embodiment, the anti-STEAP1 antigen-binding protein is administered at 1.5 mg once every three weeks after the step-up dosing regimen. In one embodiment, the anti-STEAP1 antigen-binding protein is administered at 1.5 mg once every four weeks after the step-up dosing regimen.

[0020] In one embodiment, a dose of the anti-STEAP1 antigen-binding protein is administered once per week for the first cycle, and then once every three weeks after the target dose is reached. In one embodiment, a dose of the anti-STEAP1 antigen-binding protein is administered once per week for the first cycle, and then once every four weeks after the target dose is reached.

[0021] In one embodiment, the anti-STEAP1 antigen-binding protein is administered in two cycles. In one embodiment, Cycle 1 comprises administering the anti-STEAP1 antigen-binding protein at a dose ranging from about 0.1 mg to about 0.3 mg on Day 1 or Day 2, at a dose ranging from about 0.2 mg to about 0.4 mg on Day 7, 8, or 9, at a dose ranging from about 0.8 mg to about 1.2 mg on Day 14, 15, or 16, and at a dose ranging from about 1.3 mg to about 1.6 mg on Day 21, 22, or 23. In one embodiment, Cycle 2 following Cycle 1 comprises administering 1.5 mg of the anti-STEAP1 antigen-binding protein once every two weeks for five months after completion of Cycle 1. Each cycle is optionally 28 days.

[0022] In one embodiment, Cycle 1 comprises administering the anti-STEAP1 antigen-binding protein at about 0.1 mg on Day 1, about 0.3 mg on Day 8, about 1.0 mg on Day 15, and about 1.5 mg on Day 22. In one embodiment, Cycle 2 following Cycle 1 comprises administering about 1.5 mg of the anti-STEAP1 antigen-binding protein once every two weeks for five months after completion of Cycle 1. Each cycle is optionally 28 days.

[0023] In one embodiment, Cycle 1 comprises administering the anti-STEAP1 antigen-binding protein at about 0.1 mg on Day 1, about 0.3 mg on Day 8, about 1.0 mg on Day 15, and about 1.5 mg on Day 22. In one embodiment, Cycle 2 comprises administering about 1.5 mg of the anti-STEAP1 antigen-binding protein once every four weeks for eleven months after completion of Cycle 1. Each cycle is optionally 28 days.

[0024] In one embodiment, Cycle 1 comprises administering anti-STEAP1 antigen-binding protein at doses of 0.1 mg on day 1, 0.3 mg on day 8, 1.0 mg on day 15, and 1.5 mg on day 22. In another embodiment, Cycle 2 following Cycle 1 comprises administering anti-STEAP1 antigen-binding protein at a dose of 1.5 mg every two weeks for five months after the completion of Cycle 1. Each cycle is optionally 28 days long.

[0025] In one embodiment, Cycle 1 comprises administering anti-STEAP1 antigen-binding protein at doses of 0.1 mg on day 1, 0.3 mg on day 8, 1.0 mg on day 15, and 1.5 mg on day 22. In another embodiment, Cycle 2 comprises administering anti-STEAP1 antigen-binding protein at a dose of 1.5 mg every four weeks for 11 months after the completion of Cycle 1. Each cycle is optionally 28 days long.

[0026] The disclosure further provides a method for treating a patient having prostate cancer, comprising administering to the patient a pharmaceutical composition comprising zalritamig over at least two 28-day cycles, wherein (i) Cycle 1 comprises administering approximately 0.1 mg to approximately 0.3 mg of zalritamig on day 1 or 2, approximately 0.2 mg to approximately 0.4 mg of zalritamig on day 7, 8 or 9, approximately 0.8 mg to approximately 1.2 mg of zalritamig on day 14, 15 or 16, and approximately 1.3 mg to approximately 1.6 mg of zalritamig on day 21, 22 or 23, followed by one or more additional cycles (Cycle 2) comprising administering 1.5 mg of zalritamig once every two weeks.

[0027] In one embodiment, the anti-STEAP1 antigen-binding protein is the XmAb®2+1 molecule. As used herein, the "XmAb®2+1" molecule (used synonymously with "multi-strand T cell engager molecule" or "central scFv" molecule) comprises two Fab domains and one scFv domain, each Fab domain binding to a target (e.g., STEAP1) and the scFv domain binding to another target (e.g., CD3).

[0028] In one embodiment, the anti-STEAP1 antigen-binding protein comprises two Fab-binding domains, each of which binds to STEAP1.

[0029] In one embodiment, the anti-STEAP1 antigen-binding protein comprises two Fab-binding domains, each Fab-binding domain binding to STEAP1, and each Fab-binding domain comprises a variable heavy chain domain, a variable light chain domain, a CH1 domain, and a constant light chain domain, the variable heavy chain domain comprising HCDR1 containing SEQ ID NO: 9, HCDR2 containing SEQ ID NO: 10, and HCDR3 containing SEQ ID NO: 11; the variable light chain domain comprising LCDR1 containing SEQ ID NO: 12, LCDR2 containing SEQ ID NO: 13, and LCDR3 containing SEQ ID NO: 14.

[0030] In one embodiment, the anti-STEAP1 antigen-binding protein includes an scFv-binding domain, and the scFv-binding domain binds to CD3.

[0031] In one embodiment, the anti-STEAP1 antigen-binding protein comprises an scFv-binding domain, the scFv-binding domain is bound to CD3, and this scFv variable heavy chain domain comprises HCDR1 containing SEQ ID NO: 1, HCDR2 containing SEQ ID NO: 2, and HCDR3 containing SEQ ID NO: 3; an scFv linker; and an scFv variable light chain domain, where the scFv variable light chain domain comprises LCDR1 containing SEQ ID NO: 4, LCDR2 containing SEQ ID NO: 5, and LCDR3 containing SEQ ID NO: 6. In one embodiment, each Fab variable heavy chain domain comprises an amino acid sequence at least 90% identical to SEQ ID NO: 15; each Fab variable light chain domain comprises an amino acid sequence at least 90% identical to SEQ ID NO: 16; the scFv variable heavy chain domain comprises an amino acid sequence at least 90% identical to SEQ ID NO: 7; and the scFv variable light chain domain comprises an amino acid sequence at least 90% identical to SEQ ID NO: 8. In one embodiment, each Fab variable heavy chain domain includes SEQ ID NO: 15 or 20; each Fab variable light chain domain includes SEQ ID NO: 16; the scFv variable heavy chain domain includes SEQ ID NO: 7; and the scFv variable light chain domain includes SEQ ID NO: 8. In one embodiment, the scFv binding domain that binds to CD3 includes an scFv linker. In one embodiment, each Fab variable heavy chain domain includes SEQ ID NO: 15. In one embodiment, each Fab variable heavy chain domain includes SEQ ID NO: 20.

[0032] In one embodiment, the anti-STEAP1 antigen-binding protein comprises a first Fc domain and a second Fc domain. In one embodiment, the first Fc domain comprises amino acid substitutions E233P, L235V, G236A, S267K, R292C, N297G, V302C, E357Q, and S364K; the second Fc domain comprises amino acid substitutions N208D, E233P, L235V, G236A, S267K, R292C, Q295E, N297G, V302C, L368D, K370S, N384D, Q418E, and N421D (EU numbering). In one embodiment, the first and second Fc domains each contain a deletion at position 234.

[0033] In one embodiment, the anti-STEAP1 antigen-binding protein comprises an HC (heavy chain) containing SEQ ID NO: 17, an HC with an inserted CD3 scFv containing SEQ ID NO: 19, and two light chains, each containing SEQ ID NO: 18. In another embodiment, the anti-STEAP1 antigen-binding protein comprises an HC containing SEQ ID NO: 23, an HC with an inserted CD3 scFv containing SEQ ID NO: 26, and two light chains, each containing SEQ ID NO: 18. In another embodiment, the anti-STEAP1 antigen-binding protein is an XmAb® 2+1 molecule.

[0034] In one embodiment, the anti-STEAP1 antigen-binding protein is zalritamig.

[0035] In one embodiment, the patient has metastatic castration-resistant prostate cancer. In one embodiment, the patient has never received chemotherapy before. In one embodiment, the patient has previously been treated for prostate cancer and has recurrent prostate cancer. In one embodiment, the patient has previously received chemotherapy before. [Brief explanation of the drawing]

[0036] [Figure 1] A schematic diagram of the XmAb(registered trademark) 2+1 molecule shows two Fabs that bind to STEAP1 and scFv that binds to CD3. [Figure 2] Best percentage change in tumor target lesion size. The dashed line indicates a 30% reduction from baseline in tumor SLD. [Figure 3] Best percentage change in PSA from baseline. Asterisks indicate confirmed PSA response, and dashed lines indicate PSA reductions of 50 and 90. [Figure 4]Exemplary patient demonstrating response based on PSA and radiographic findings: CT scan and time-series PSA curves of a 65-year-old patient with severely treated stage IV prostate adenocarcinoma. The patient was enrolled in cohort 12 (target dose of zalritamig at 1.5 mg in 3 stages). At screening, CT scans showed three target lesions (two in the liver and one in a lymph node) and multiple non-target lesions in the liver and two lymph nodes. The patient achieved a 99% reduction in PSA from baseline on day 1 of cycle 1 and achieved a partial response (PR) after 2 cycles (37.3% reduction in target lesions), which was confirmed at 16 weeks and maintained at 24 weeks. AEs occurred during the first treatment cycle, including recurrent CRS, tinea-grade (both grade 1), rash, and worsening back pain (both grade 2). During further treatment cycles, rash (grade 1), myalgia, and hyperkalemia (both grade 2) were reported. The patient is continuing treatment at the time of this application. [Figure 5] The percentage change in PSA levels obtained from patients listed in Figure 4. [Modes for carrying out the invention]

[0037] Zarritamig is an XmAb® 2+1 T-cell engager (TCE) molecule designed to direct T-effector cells toward STEAP1-expressing cells. To evaluate the safety, tolerability, pharmacokinetics (PK), and antitumor activity of zarritamig, either intravenously or subcutaneously, as monotherapy or in combination with other therapies, we designed a first-in-human study of zarritamig in patients with metastatic castration-resistant prostate cancer (mCRPC).

[0038] This first-in-human study reports on monotherapy in patients with metastatic castration-resistant prostate cancer (mCRPC). Ninety-seven patients received one or more doses ranging from 0.001 to 2.0 mg IV weekly (QW) or Q2W. The most common doses (MTDs) were identified as 0.1 mg on day 1 (D1), 0.3 mg on D8, 1.0 mg on D15, and 1.5 mg IV QW on D22+. The most common treatment-related adverse events were cytokine release syndrome (CRS; 72%), fatigue (45%), and myalgia (34%). CRS primarily occurred during cycle 1 and was improved by premedication and a stepwise dosing regimen. Promising responses to prostate-specific antigen (PSA) and RECIST were observed across the entire cohort (49% PSA 50%; 24% objective response rate [ORR]), with a higher frequency at target doses of 0.75 mg or higher (59% PSA 50%; 41% ORR). No grade 4 or 5 CRS events were reported. Overall, all CRS events were resolved with standard management using acetaminophen, intravenous tocilizumab, and / or corticosteroids. Zarritamig demonstrated promising responses (PSA and RECIST) and manageable safety compared to established treatments in late-line mCRPC patients.

[0039] The preliminary efficacy results observed with zalritamig are higher than those reported for other TCEs in prostate cancer. Efficacy, measured by both PSA and objective response criteria (RECIST), is promising in this severely treated mCRPC population, with higher response rates observed in higher-dose cohorts. Starting with 0.1 mg zalritamig, a decrease in PSA was observed, with 49% of patients achieving a confirmed PSA 50 response and 28% achieving a PSA 90 response. At higher doses, RECIST evaluable responses were achieved in 41% of patients. This trial demonstrates that a high proportion of patients can achieve a significant clinical response, which can lead to overall clinical benefit.

[0040] This is the first clinical report of STEAP1-targeted TCE therapy in prostate cancer. This study provides proof of concept for TCE as a promising therapeutic modality for prostate cancer, supported by numerous observed radiographic and PSA responses. To date, the only STEAP1-targeted drug explored clinically has been the STEAP1 antibody-drug conjugate (ADC), which has been limited by toxicity due to the monomethyl auristatin E (MMAE) payload (Maecker et al., MAbs. 2023 Jan-Dec;15(1):2229101). In summary, this study demonstrates the feasibility of targeting STEAP1 with TCE and the potential of zalritamig as a novel therapeutic paradigm for mCRPC patients.

[0041] Targeted immunotherapy with TCEs requires binding to both CD3+ T cells and tumor-associated antigens. Zarritamig demonstrated dose-dependent changes in peripheral pharmacodynamic biomarkers of TCE activity, namely T cell marginal trend, T cell activation, and cytokine induction. The magnitude of the changes in PD biomarkers was consistent with the observed decrease in PSA.

[0042] The overall incidence of ADA in the study treatment was 54%, with 8 patients exhibiting a transient antibody response. The ADA response was not dose-dependent and did not cause adverse events (AEs). Given that approximately one-quarter of patients developed ADA affecting neutralizing ADA and / or PK, it is essential to evaluate the impact on clinical response. Neutralizing ADA occurred on average after cycle 3, while responses occurred within the first two cycles; therefore, no impact on the overall response rate is expected.

[0043] In prostate cancer patients, regimens for anti-STEAP1 antigen-binding proteins such as zalritamig may optionally include a stepwise dosing regimen. To help reduce cytokine release and safely achieve treatment with an active dose of anti-STEAP1 antigen-binding protein (e.g., zalritamig), the stepwise dosing regimen may include two or three stages, with relatively small dose increases at each stage. The priming dose (initial dose) and target dose are also within a relatively narrow range from each other, while demonstrating efficacy in prostate cancer patients. The dose of anti-STEAP1 antigen-binding protein (zalritamig) is also relatively low compared to the doses administered in clinical trials for bispecific T-cell engagers that bind to both DLL3 and CD3. Ares et al., J.Clin.Oncol. 2023 Jun 1;41(16):2893-2903, reported that the greatest pharmacodynamic response was observed after initial administration of a 1 mg step dose in a bispecific T cell engager that binds to both DLL3 and CD3, and that the expansion dose was 100 mg (Aggarwal et al., J.Clin.Oncol., 42, Abstract 5012, 2024).

[0044] In prostate cancer, several PSMA-targeted therapeutic agents (TCEs) have entered clinical practice, but have shown limited success due to minimal efficacy, toxicity, and short duration of response (DOR) (see, for example, Sorrentino et al., Cancers (Basel) 2023;15; Powers et al., J. Hematol Oncol 2020;13:144; and Tucker et al., Cancer Med 2019;8:4644-55). For example, JNJ-63898081, a PSMA and CD3 bispecific antibody, led to a transient decrease in prostate-specific antigen (PSA) in mCRPC patients in a phase 1 study, with a confirmed PSA 50 response in 2 out of 39 patients (5%), and no radiographic response (Lim et al., Clin Genitourin Cancer 2023;21:366-75). In a study targeting PSMA with TCE HPN424, a PSA50 response was observed in 3 out of 63 patients (5%), and a confirmed response according to the Response Evaluation Criteria in Solid Tumors (RECIST) was observed in 1 out of 34 patients (3%), with safety being manageable (Bono et al., J.Clin.Onc.2021;39:5013-13).

[0045] This disclosure provides a method for administering an anti-STEAP1 antigen-binding protein by the method of this disclosure. This disclosure also provides an anti-STEAP1 antigen-binding protein for use in the treatment of prostate cancer, wherein the anti-STEAP1 antigen-binding protein is formulated for administration by the method of this disclosure. In one embodiment, the anti-STEAP1 antigen-binding protein is zalritamig.

[0046] This disclosure also provides an anti-STEAP1 antigen-binding protein for use in the treatment of prostate cancer, wherein the anti-STEAP1 antigen-binding protein is formulated to be administered in doses of approximately 0.1 mg to approximately 2.0 mg. In one embodiment, the anti-STEAP1 antigen-binding protein is zalritamig.

[0047] This disclosure also provides an anti-STEAP1 antigen-binding protein for use in the treatment of prostate cancer, where the anti-STEAP1 antigen-binding protein is administered in doses of approximately 0.1 mg to approximately 2.0 mg. In one embodiment, the anti-STEAP1 antigen-binding protein is zalritamig.

[0048] This disclosure also provides the use of anti-STEAP1 antigen-binding protein in the manufacture of a therapeutic drug for prostate cancer, wherein the drug is formulated to be administered in doses ranging from approximately 0.1 mg to approximately 2.0 mg. The doses of anti-STEAP1 antigen-binding protein are 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 some embodiments, the doses are 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 some embodiments, the dose is approximately 0.1 mg. In some embodiments, the dose is approximately 0.3 mg. In some embodiments, the dose is approximately 0.75 mg. In one embodiment, the dose is approximately 1 mg. In one embodiment, the dose is approximately 1.5 mg. In one embodiment, the dose is 0.1 mg. In one embodiment, the dose is 0.3 mg. In one embodiment, the dose is 0.75 mg. In one embodiment, the dose is 1 mg. In one embodiment, the dose is 1.5 mg. In one embodiment, the dose is administered once a week. In one embodiment, the dose is administered once every two weeks. In one embodiment, the dose is administered once every three weeks. In one embodiment, the dose is administered once every four weeks. In one embodiment, the dose is administered intravenously. In one embodiment, the dose is administered once a week, starting from cycle 1. In one embodiment, the dose is administered once a week, starting from cycle 2. In one embodiment, the dose is administered once every two weeks, starting from cycle 2. In one embodiment, the dose is administered once every three weeks, starting from cycle 2. In one embodiment, the dose is administered once every four weeks, starting from cycle 2. In another embodiment, the dose is administered once a week for the first cycle, and then once every two weeks, starting from day 1 of cycle 2.In one embodiment, the dose is administered once a week for the first cycle, then once every two weeks once the target dose is reached, and then once every four weeks once the target dose is reached. In one embodiment, the anti-STEAP1 antigen-binding protein is zalritamig.

[0049] In one embodiment, the dose is administered once a week for the first cycle, and then once every four weeks once the target dose is reached. In some embodiments, cycle 2 is repeated 11 times after cycle 1 is completed (e.g., over a total treatment period of about 12 months). In some embodiments, cycle 2 is repeated 5 times after cycle 1 is completed (e.g., over a total treatment period of about 6 months).

[0050] Combination therapy can further improve efficacy by inducing synergistic effects and / or overcoming resistance mechanisms. This disclosure envisions the use of zalritamig in combination with standard hormonal therapy and radioligand therapy in patients. In some embodiments, the patient has advanced prostate cancer. In some embodiments, the patient has received prior treatment with zero or one novel hormonal therapy (NHT).

[0051] NHTs (e.g., abiraterone, enzalutamide, apalutamide, and darolutamide) and taxanes (e.g., docetaxel and cabazitaxel) are standard treatments for non-metastatic and / or metastatic, castration-resistant prostate cancer, although the vast majority of patients will experience disease progression during treatment.

[0052] This disclosure provides therapeutic regimens in which an anti-STEAP1 antigen-binding protein, such as zalritamig, is administered by the method of the present invention in combination with one or more other agents, including abiraterone, enzalutamide, cabazitaxel, darolutamide, apalutamide, PSMA radioligand therapy, PSMA immunotherapy, radium-223, PARP inhibitors, PSMA antibody-drug conjugates, B7H3 antibody-drug conjugates, radiotherapy, and / or standard treatments for prostate cancer.

[0053] Abiraterone is a cytochrome P450 (CYP) 17 inhibitor indicated in combination with prednisone (or prednisolone in some regions) for the treatment of patients with mCRPC, and in some regions, metastatic or high-risk castration-sensitive prostate cancer (CSPC). Disease relapse after abiraterone may be caused by increased androgen receptor expression (e.g., androgen receptor amplification), among other mechanisms (Galletti et al, Cancer Treat Rev. 2017 Jun;57:16-27).

[0054] Enzalutamide is an androgen receptor inhibitor that acts on different stages of the androgen receptor signaling pathway. Enzalutamide has been shown to competitively inhibit androgen binding to the androgen receptor; consequently, it inhibits the nuclear translocation of the androgen receptor and its interaction with DNA. Enzalutamide is indicated for the treatment of CRPC, and in some regions, for patients with metastatic hormone-sensitive prostate cancer. Disease relapse after enzalutamide is partly due to mutations in the androgen receptor (such as AR V7) and increased androgen receptor expression (e.g., androgen receptor amplification), among other mechanisms (Galletti et al., op. cit.).

[0055] However, in the initial disease setting, it is also conceivable that zalritamig may be administered without concomitant use of ADT. Anti-STEAP1 antigen-binding proteins (or STEAP1 antigen-binding proteins) are molecules that bind to human STEAP1. Such molecules may further bind to other targets, such as cell surface antigens like CD3. Non-limiting examples of the format of such molecules include antibodies (including bispecific antibodies) and their fragments, as well as T cell engager molecules, including XmAb® 2+1 format molecules and bispecific T cell engager molecules.

[0056] An example of an anti-STEAP1 antigen-binding protein is zarritamig, also known as AMG 509. Further information on zarritamig can be found in International Publication No. 2020 / 010079. The zarritamig sequence is provided in Table 4.

[0057] The anti-STEAP1 antigen-binding protein has a dissociation constant (KD) of 10 for one or more of its targets, as measured by, for example, surface plasma resonance techniques (e.g., BIACore, GE-Healthcare Uppsala, Sweden) or binding equilibrium exclusion assays (KinExA, Sapidyne, Boise, Idaho). -7 When they join at M or less, they join together.

[0058] Bispecific T cell engager molecules are recombinant protein constructs made up of two mobile, linked antibody-derived binding domains. "Bispecific T cell engager molecules" include "BiTE® molecules." One binding domain of a bispecific T cell engager is specific to a tumor-associated surface antigen of choice on target cells; the second binding domain is specific to 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 transiently binding T cells to target cells while simultaneously potently activating the intrinsic cytolytic ability of T cells against target cells (Yang, Fa; Wen, Weihong; Qin, Weijun (2016). “Bispecific Antibodies as a Development Platform for New Concepts and Treatment Strategies”. International Journal of Molecular Sciences. 18(1):48(2016)). Bispecific T cell engager molecules are bispecific, meaning they simultaneously bind to two targets on two different types of cells (target antigens such as STEAP1 on target cells and CD3 on T cells).

[0059] As used herein, the "XmAb® 2+1" molecule (used synonymously with "multi-strand T cell engager molecule" or "central scFv" molecule) comprises two Fab domains and one scFv domain, each Fab domain binding to a target (e.g., STEAP1) and the scFv domain binding to another target (e.g., CD3). The XmAb® 2+1 molecular format is shown in Figure 1. The scFv domain (e.g., this binds to CD3) is inserted between the Fc domain and the CHl-Fv region, thereby providing a third antigen-binding domain (e.g., two Fabs, each binding to STEAP1, and one scFv, each binding to CD3). The anti-CD3 scFv is "inserted" into the HC, meaning that the scFv is linked to the HC by a linker. In this embodiment, one polypeptide comprises a first heavy chain including a first variable heavy chain domain, a CH1 domain (and an optional linker / hinge), and an Fc domain, and scFv comprises an scFv variable light chain domain, an scFv linker, and an scFv variable heavy chain domain. scFv is covalently attached between the C-end of the CH1 domain of the heavy chain steady domain and the N-end of the first Fc domain using an optional domain linker (VH1-CH1-[optional domain linker]-VH2-scFv linker-VL2-[optional domain linker including hinge]-CH2-CH3, or in the reverse direction for scFv, VH1-CH1-[optional domain linker]-VL2-scFv linker-VH2-[optional domain linker including hinge]-CH2-CH3). In some embodiments, the first polypeptide is VH1-CH1-domain linker-VH2-scFv linker-VL2-domain linker-CH2-CH3. The other polypeptide is a standard Fab (i.e., VH1-CH1-domain linker (e.g., hinge)-CH2-CH3). This embodiment further utilizes two light chains, each containing a variable light chain domain and a constant light chain domain, which associate with a heavy chain to form two identical Fabs that bind to a target.In detailed embodiments, the STEAP1 Fab CD3 scFv central-scFv molecule (or STEAP1 Fab CD3 scFv XmAb® 2+1 molecule) comprises two Fab domains, each bound to STEAP1 Fab, and an scFv that binds to CD3 scFv. In some detailed embodiments, the central-scFv or XmAb® 2+1 molecule is zalritamig.

[0060] In various embodiments of this disclosure, the anti-STEAP1 antigen-binding protein comprises two Fab-binding domains, each Fab-binding domain binding to STEAP1, and each Fab-binding domain comprises a variable heavy chain domain, a variable light chain domain, a CH1 domain, and a constant light chain domain, wherein the variable heavy chain domain comprises HCDR1 containing SEQ ID NO: 9, HCDR2 containing SEQ ID NO: 10, and HCDR3 containing SEQ ID NO: 11; the variable light chain domain comprises LCDR1 containing SEQ ID NO: 12, LCDR2 containing SEQ ID NO: 13, and LCDR3 containing SEQ ID NO: 14. The anti-STEAP1 antigen-binding protein further comprises a CD3-binding scFv-binding domain comprising an scFv variable heavy chain domain comprising HCDR1 containing SEQ ID NO: 1, HCDR2 containing SEQ ID NO: 2, and HCDR3 containing SEQ ID NO: 3; an scFv linker; and an scFv-binding domain comprising an scFv variable light chain domain comprising LCDR1 containing SEQ ID NO: 4, LCDR2 containing SEQ ID NO: 5, and LCDR3 containing SEQ ID NO: 6. In various embodiments, each Fab variable heavy chain domain contains an amino acid sequence at least 90% identical to SEQ ID NO: 15 or 20; each Fab variable light chain domain contains an amino acid sequence at least 90% identical to SEQ ID NO: 16; the scFv variable heavy chain domain contains an amino acid sequence at least 90% identical to SEQ ID NO: 7; and the scFv variable light chain domain contains an amino acid sequence at least 90% identical to SEQ ID NO: 8. For example, each Fab variable heavy chain domain may contain SEQ ID NO: 15 or 20; each Fab variable light chain domain may contain SEQ ID NO: 16; the scFv variable heavy chain domain may contain SEQ ID NO: 7; and the scFv variable light chain domain may contain SEQ ID NO: 8. The anti-STEAP1 antigen-binding protein may further comprise a first Fc domain and a second Fc domain. In various embodiments, the anti-STEAP1 antigen-binding protein comprises a heavy chain (HCP containing SEQ ID NO: 17 or 23, an HC with inserted CD3 scFv containing SEQ ID NO: 19 or 26, and two light chains (LCs), each containing SEQ ID NO: 18.

[0061] For all positions considered in this disclosure with respect to antibodies and other antigen-binding proteins, unless otherwise noted, amino acid position numbering follows the EU index. The EU index or EU numbering scheme as found in Kabat refers to the EU antibody numbering (Edelman et al., 1969, Proc Natl Acad Sci USA 63:78-85, incorporated herein by reference in whole).

[0062] An example of an anti-STEAP1 antigen-binding protein is zarritamig. The zarritamig sequence is provided in Table 4. Zarritamig comprises an HC containing SEQ ID NO: 17, an HC with an inserted CD3 scFv containing SEQ ID NO: 19, and two light chains, each containing SEQ ID NO: 18. In exemplary embodiments, the molecule of the present invention comprises a sequence containing C-terminal lysine, as shown in SEQ ID NO: 17 or 19. In alternative embodiments, the antigen-binding protein comprises one or both HCs without C-terminal lysine, as shown in SEQ ID NOs: 22 and 25. In addition, the N-terminal glutamine and / or N-terminal glutamate of the HC or HCVR may be converted to pyroglutamate, as shown in SEQ ID NOs: 20, 21, 23, and 24. In addition, the N-terminal glutamine and / or N-terminal glutamate of the HC may be converted to pyroglutamate, as shown in SEQ ID NOs: 23 and 26, and the sequence may lack C-terminal lysine. All forms of the antigen-binding protein of the present invention are envisioned.

[0063] The first Fc domain and the second Fc domain each refer to one half of the Fc (fragment crystallizable) region. The Fc region contains two CH2 domains and two CH3 domains. Therefore, the first Fc domain and the second Fc domain each contain a CH2 domain and a CH3 domain.

[0064] Anti-STEAP1 antigen-binding proteins are generally administered to patients in pharmaceutical compositions that may contain pharmaceutically acceptable carriers, excipients, or diluents. "Pharmacologically acceptable" means molecules, compounds, and compositions that are nontoxic to human subjects at the dosage and concentration used and / or do not cause allergic or adverse reactions upon administration to humans. In certain embodiments, the pharmaceutical composition may contain formulation materials to modify, maintain, or preserve the composition's pH, osmolality, viscosity, clarity, color, isotonicity, odor, sterility, stability, solubility or release rate, adsorption, or permeability.In such embodiments, suitable formulation materials include, but are not limited to, amino acids (such as glycine, glutamine, asparagine, arginine, or lysine); antimicrobial agents; antioxidants (such as ascorbic acid, sodium sulfite, or sodium bisulfite); buffers (such as borates, bicarbonates, tris-HCl, citrates, phosphates, or other organic acids); bulking agents (such as mannitol or glycine); chelating agents (such as ethylenediaminetetraacetic acid (EDTA)); complexing agents (such as caffeine, polyvinylpyrrolidone, β-cyclodextrin, or hydroxypropyl-β-cyclodextrin); fillers; monosaccharides; disaccharides; and other carbohydrates (such as glucose, mannose, or dextrin); proteins (such as serum albumin, gelatin, or immunoglobulin); colorants, flavorings, and diluents; emulsifiers; hydrophilic polymers (such as polyvinylpyrrolidone); low molecular weight polypeptides; and salt formation agents. Counterions (such as sodium); preservatives (such as benzalkonium 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 pluronic acid, PEG, sorbitan esters, polysorbates such as polysorbate 20 and polysorbate 80, triton, tromethamine, lecithin, cholesterol, tyloxapal, etc.); stabilizing agents (such as sucrose or sorbitol); isotonic activators (such as alkali metal halides, preferably sodium or potassium chloride, mannitol, or sorbitol); delivery media; diluents; excipients and / or pharmaceutical adjuvants. Methods for formulating molecules for therapeutic use and suitable materials for this purpose are publicly known in the pharmaceutical technology field, and are described, for example, in REMINGTON'S PHARMACEUTICAL SCIENCES, 18th Edition, (ARGenrmo, ed.), 1990, Mack Publishing Company.In some embodiments, the selection of carriers and excipients incorporated into the pharmaceutical composition affects the physical state, stability, in vivo release rate, and in vivo clearance rate of the anti-STEAP1 antigen-binding protein.

[0065] Anti-STEAP1 antigen-binding proteins, such as zalritamig, may be formulated as pre-lyophilized preparations, such as a pre-lyophilized preparation of 0.3 mg / mL to 2.5 mg / mL zalritamig (e.g., 1 mg / mL) formulated with 10 mM glutamic acid, 9% (w / v) sucrose, 0.01% (w / v) polysorbate 80, pH 4.20 (i.e., zalritamig is present in a preparation containing 0.3 mg / mL to 2.5 mg / mL zalritamig (e.g., 1 mg / mL), 10 mM glutamic acid, 9% (w / v) sucrose, 0.01% (w / v) polysorbate 80, pH 4.20, which is lyophilized). Preparations of anti-STEAP1 antigen-binding proteins are also disclosed in International Publication No. 2019 / 157340 (in whole, incorporated herein by reference).

[0066] The present invention also includes a kit for treating prostate cancer in patients requiring treatment for prostate cancer. In one embodiment, the kit includes a pharmaceutical composition of an anti-STEAP1 antigen-binding protein and packaging material providing instructions for the use of the pharmaceutical composition. The pharmaceutical composition of the kit may be in a container, such as a vial or syringe. The pharmaceutical composition may be provided as a solution, suspension, gel, emulsion, solid, crystal, or as a dehydrated or lyophilized powder. In embodiments in which the pharmaceutical composition is provided as a powder, the kit may also include diluents necessary for reconstituting the pharmaceutical composition (e.g., water, saline, or phosphate-buffered saline) and instructions for preparing the composition for administration.

[0067] In this specification, when it is referred to that a certain dose of anti-STEAP1 antigen-binding protein is administered to a patient, it is intended to be understood that the anti-STEAP1 antigen-binding protein is present in a pharmaceutical composition.

[0068] In some embodiments, the present invention also provides a kit comprising a pharmaceutical composition and instructions for using the pharmaceutical composition to deliver, for example, an effective dose for treating prostate cancer in a patient requiring treatment for prostate cancer, by intravenous injection. In embodiments in which the pharmaceutical composition is provided in lyophilized or dry powder form, the kit may include a diluent and instructions for reconstituting the pharmaceutical composition before administration.

[0069] Anti-STEAP1 antigen-binding protein may be administered by “stepped dosing,” which means increasing the dose administered to the patient until the target dose level is reached (see also, e.g., Ball et al., MAbs. 2023 Jan-Dec;15(1):2181016). Stepped dosing may include one, two, three, four, or five steps (i.e., administration of multiple doses in increasing amounts of the therapeutic agent). Each “step” is an increase in the dose administered to the patient from the previous dose administered to the patient. Stepped dosing may include two or three steps. Stepped dosing may include reaching a target dose of 0.75 mg in two steps. Stepped dosing may include reaching a target dose of 1.5 mg in three steps. Stepped dosing may be implemented to reduce the incidence of cytokine release syndrome. For example, in a step-by-step dosing regimen, treatment may begin with a priming dose on day 1 of cycle 1, gradually increasing on day 8 (one step), and then continuing at the target dose. At the end of the step-by-step dosing regimen, the target dose may be administered (e.g., once a week, once every two weeks, once every three weeks, or once every four weeks). The target dose may be administered at any interval over a desired period (e.g., four weeks, five months, or eleven months) for a total treatment period of, for example, two months, six months, or twelve months.

[0070] The anti-STEAP1 antigen-binding protein (e.g., zalritamig) is initially administered by a stepwise dosing regimen until the target dose of the anti-STEAP1 antigen-binding protein (e.g., zalritamig) is reached. After reaching the target dose of zalritamig, the patient may be treated with another therapeutic agent (i.e., a combination partner), however, this disclosure also intends for the administration of another therapeutic agent before reaching the target dose (e.g., administration at C1D1). Such another therapeutic agent may be administered in conjunction with zalritamig in some cycles.

[0071] A “cycle” refers to a repeated treatment pattern and can be defined by an anti-STEAP1 antigen-binding protein (e.g., zalritamig) or a combination partner. Cycles can also provide a basis for patient follow-up. Cycles can still exist even when drugs are administered continuously. Cycles can include different numbers of days depending on the treatment. A cycle refers to a period over which the necessary treatments can be repeated. This is a standard way of defining the duration of treatment by defining the timing of treatment administration. For example, an anti-STEAP1 antigen-binding protein (zalritamig) cycle may be every 27, 28, 29, 30, or 31 days.

[0072] This disclosure provides, in various embodiments, a method for administering an anti-STEAP1 antigen-binding protein (e.g., zalritamig) to a patient in need over a course of treatment comprising two or more cycles, each cycle optionally comprising 28 days. Cycle 1 comprises a three-stage dosing schedule in which the patient is administered doses of 0.1 mg zalritamig on day 1 (C1D1), 0.3 mg zalritamig on day 8 (C1D8), 1 mg zalritamig on day 15 (C1D15), and 1.5 mg zalritamig on day 22 (C1D22). In this scenario, 1.5 mg zalritamig is the "target dose." Following Cycle 1, one or more additional treatment cycles (i.e., Cycle 2, Cycle 3, etc.) are administered over a desired period of time. In various embodiments, Cycle 2 and subsequent cycles (i.e., each cycle following Cycle 1) include administration of 1.5 mg of zalritamig every two weeks; for example, 1.5 mg of zalritamig is administered on C2D1 and 1.5 mg of zalritamig is administered on C2D15. In alternative embodiments, Cycle 2 may include administration of zalritamig every three weeks (e.g., 1.5 mg of zalritamig is administered on Q3W) or every four weeks (e.g., 1.5 mg of zalritamig is administered on Q4W). Cycle 2 may be repeated one or more times. For example, Cycle 2 may be repeated five times if the patient's treatment spans six months. Alternatively, Cycle 2 may be repeated eleven times if the patient's treatment spans twelve months. In various embodiments, patients are administered 1000 mg abiraterone orally once daily, and prednisone at doses of 5 mg twice daily or 10 mg once daily. In various embodiments, patients are administered 500 mg abiraterone orally once daily, and prednisone at doses of 4 mg twice daily. In various embodiments, patients are administered 160 mg enzalutamide orally once daily.

[0073] The phrase "by a certain dose" means that a certain dose of a molecule (drug) may be administered to a patient at the same time (on the same day) as another different molecule, or sequentially (for example, at least one dose of the molecule administered to the patient is time-separated from at least one dose of another molecule administered to the patient). Furthermore, this specification intends that a dose of a molecule may be followed by at least one additional dose of the same molecule, and then at least one dose of a different molecule.

[0074] In general, intravenous (IV) drug therapies may be administered together on the same day. Oral drug therapies and IV drug therapies may also be administered on the same day. For example, zalritamig and abiraterone may be administered together on the same day. Drug therapies may also be administered on separate days.

[0075] As used synonymously herein, “treatment” and / or “treating” and / or “to treat” are intended to refer to all processes that may result in slowing, interrupting, inhibiting, controlling, stopping, or reversing the progression of the disorders described herein, but not necessarily indicating the complete disappearance of all disorder symptoms. Treatment includes the administration of anti-STEAP1 antigen-binding proteins for the treatment of diseases or conditions in humans that may benefit from the activity of anti-STEAP1 antigen-binding proteins, such as prostate cancer, and includes (a) inhibiting further progression of the disease; and / or (b) alleviating the disease, i.e., causing regression of the disease or disorder, or reducing its symptoms or complications.

[0076] This disclosure also provides an anti-STEAP1 antigen-binding protein for use in reducing the size of a patient's prostate tumor. In one embodiment, the tumor is reduced by 10%. In one embodiment, the tumor is reduced by 20%. In one embodiment, the tumor is reduced by 30%. In one embodiment, the tumor is reduced by 40%. In one embodiment, the tumor is reduced by 50%. In one embodiment, the tumor is reduced by 60%. In one embodiment, the tumor is reduced by 70%. In one embodiment, the tumor is reduced by 80%. In one embodiment, the tumor is reduced by 90%. In one embodiment, the tumor is no longer present.

[0077] This disclosure also provides an anti-STEAP1 antigen-binding protein for use in reducing a patient's PSA. This disclosure intends for the anti-STEAP1 antigen-binding protein to be used in slowing or stopping cancer cells from spreading to one or more different parts of a patient's body.

[0078] This disclosure concerns the present invention's method for reducing the size of a patient's prostate tumor. In one embodiment, the tumor is reduced by 10%. In one embodiment, the tumor is reduced by 20%. In one embodiment, the tumor is reduced by 30%. In one embodiment, the tumor is reduced by 40%. In one embodiment, the tumor is reduced by 50%. In one embodiment, the tumor is reduced by 60%. In one embodiment, the tumor is reduced by 70%. In one embodiment, the tumor is reduced by 80%. In one embodiment, the tumor is reduced by 90%. In one embodiment, the tumor is no longer present.

[0079] This disclosure envisions a method of the present invention used to reduce a patient's PSA. This disclosure envisions a method of the present invention used to slow or stop cancer cells from spreading to one or more other parts of a patient's body. This disclosure envisions the use of an anti-STEAP1 antigen-binding protein in the manufacture of a pharmaceutical of the present invention used to reduce the size of a patient's prostate tumor. In one embodiment, the tumor is reduced by 10%. In one embodiment, the tumor is reduced by 20%. In one embodiment, the tumor is reduced by 30%. In one embodiment, the tumor is reduced by 40%. In one embodiment, the tumor is reduced by 50%. In one embodiment, the tumor is reduced by 60%. In one embodiment, the tumor is reduced by 70%. In one embodiment, the tumor is reduced by 80%. In one embodiment, the tumor is reduced by 90%. In one embodiment, the tumor is no longer present.

[0080] This disclosure envisions the use of an anti-STEAP1 antigen-binding protein in the manufacture of a pharmaceutical product of the present invention used to reduce a patient's PSA. This disclosure envisions a method of the present invention used to slow or stop cancer cells from spreading to one or more different parts of a patient's body.

[0081] The size of a patient's prostate (and / or metastatic lesions) can be determined by methods known in the art. Such methods include computed tomography (CT), MRI, and / or bone scans. PSA can be determined by blood tests known in the art.

[0082] This invention aims to provide a stepwise administration method for anti-STEAP1 antigen-binding protein to reduce cytokine release syndrome (CRS) that may occur with T-cell engager therapy (compared to treatment with anti-STEAP1 antigen-binding protein without a stepwise administration method). Since cytokine release syndrome can occur with bystander immunity and activation of non-immune cells, comorbidities may occur. CRS can be graded according to Lee et al. ASTCT Consensus Grading for Cytokine Release Syndrome and Neurologic Toxicity Associated with Immune Effector Cells. Biol Blood Marrow Transplant. 2019;25(4):625 638.

[0083] The term "approximately" refers to a value that falls within a range of plus or minus 10% of the reference value. [Examples]

[0084] Example 1: Phase 1 Clinical Study Design This study (NCT04221542) was designed to evaluate the safety, tolerability, pharmacokinetics (PK), and antitumor activity of zalritamig as monotherapy or in combination with mCRPC in patients with mCRPC (pt) to determine the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D). Parts 1-3 will evaluate various dosing schedules and target doses of monotherapy and SC administration. Part 4 will evaluate combinations with established standard treatments for mCRPC: zalritamig + abiraterone acetate (4A) or zalritamig + enzalutamide (4B), in patients previously treated with 0, 1, or 2 NHTs and up to 1 taxane (hormone-sensitive prostate cancer (HSPC) only) in 4A and 4B. Part 5 will involve dose expansion in an outpatient setting based on efficacy and toxicity from the dose exploration in Part 1. The primary endpoints include dose-limiting toxicities, treatment-related adverse events occurring during the study treatment, and changes in clinical and laboratory parameters. Key secondary endpoints include PK, objective response by RECIST 1.1, prostate-specific antigen response, progression-free survival by radiographic assessment by PCWG3, and overall survival. Key inclusion criteria are males with pathologically confirmed mCRPC, evidence of disease progression, and an ECOG performance status of 0 or 1. Key exclusion criteria include a history or present-day small cell or neuroendocrine prostate cancer, untreated CNS metastases or leptomeningeal disease, and autoimmune disease or any disease requiring chronic immunosuppressive therapy. In Part 1, dose escalation will be guided by a Bayesian logistic regression model. In Parts 2 and 4, the AMG 509 dose will be based on data from the monotherapy part, and dose exploration will be guided by an mTPI-2 design. Study sites are located in North America, Australia, Asia, and Europe.

[0085] This is an open-label, escalation-based, multi-dose, phase 1, multi-cohort study evaluating zalritamig in patients with mCRPC. Up to 441 patients will be enrolled in this study. This study includes the following parts: Part 1: Zarritamig monotherapy is administered intravenously to patients with a history of NHT and 1-2 prior taxane treatments; Part 2: Zarritamig monotherapy is administered via SC injection to patients with a history of NHT and 1-2 prior taxane treatments (Part 2 is complete); Part 3: Zarritamig monotherapy is administered intravenously to patients with no prior history of NHT treatment or one prior treatment (which may have been given for hormone-sensitive prostate cancer [HSPC], and no prior taxane treatment); Part 4: Zarritamig is administered intravenously in combination with abiraterone acetate (Part 4A) or enzalutamide (Part 4B), administered to patients with no prior history of NHT treatment or one prior treatment (for hormone-sensitive or castration-resistant disease) in Parts 4A and 4B, and to patients with 0-2 prior taxane treatments for hormone-sensitive disease in Parts 4A and 4B. In Part 4A, zalritamig is administered intravenously, and abiraterone is administered starting on day 1 of cycle 1, according to the abiraterone instructions. In Part 4B, zalritamig is administered intravenously, and enzalutamide is administered starting one week after zalritamig reaches the target dose, according to the enzalutamide instructions (or an alternative schedule based on newly obtained safety data). Part 5: In an outpatient setting, zalritamig monotherapy is administered intravenously to patients with a history of 1-2 NHTs and 1-2 prior taxane treatments.

[0086] In Parts 1, 3, 4, and 5, zalritamig will be administered weekly (QW) or Q2W as a short intravenous infusion (approximately 60 minutes), with the possibility of exploring Q3W or Q4W schedules based on newly obtained data and DLRT recommendations. The dosing regimens and schedules for Parts 3 and 4 will be adjusted to follow the regimens and schedules explored in Part 1, based on newly obtained data and DLRT recommendations. The dosing regimens and schedules for Part 5 will be selected based on newly obtained data and DLRT recommendations, which may include stepwise dosing. In Part 2, zalritamig was administered as deep subcutaneous injection in either QW or Q2W. Dose escalation of zalritamig IV monotherapy will be performed in conjunction with combination and SC dose escalation, and two or more dose regimens may be evaluated in parallel. The dose for Part 3 will be the MTD or RP2D determined in Part 1 dose exploration or expansion. Throughout the entire treatment cycle, patients are required to continue ADT while continuing treatment with AMG 509.

[0087] The Part 1 dose exploration phase will enroll up to 100 mCRPC patients. Dose exploration will be conducted in two stages: one or more single-patient cohorts followed by one or more multi-patient cohorts (2-4 patients per cohort). Planned dose levels are 0.001, 0.003, 0.01, 0.03, 0.1, 0.3, 1, 1.5, and 2 mg IV administered quarterly (QW). A 2-week schedule (Q2W) may be introduced early, starting from Cycle 2, and DLRT may further recommend exploring 3-week (Q3W) or 4-week (Q4W) schedules.

[0088] [Table 1]

[0089] The decision to increase or decrease the dose in Part 1 will be guided by the BLRM model of dose toxicity. The BLRM MTD is the dose level at which the probability of a DLT rate within the target interval of 20% to 33% is most likely, provided that overdose control is maintained. To control the risk of overdose, the MTD must have a predicted overdose probability of less than 40% (DLT rate > 33%).

[0090] The MTDs for Parts 2 and 4 are the dose levels that are most likely to result in a DLT rate within the target interval range of 30% to 40%.

[0091] The primary endpoints include dose-limiting toxicity, adverse events occurring during the study treatment, treatment-related adverse events, and changes in vital signs, ECG, and laboratory tests.

[0092] Secondary endpoints include, but are not limited to, PK parameters including peak serum concentration (Cmax), time to peak concentration (Tmax), minimum serum concentration (Cmin), area under the concentration-time curve (AUC) over the dosing interval, accumulated volume after multiple doses, and, where feasible, half-life (t1 / 2); objective response rate (OR) according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1; prostate-specific antigen (PSA) response rate (30%, 50%, 70%, and 90%); PSA50 response rate at 12 weeks, duration of response (DOR) according to RECIST 1.1; and PSA50-based PSA DOR; progression-free survival (X-ray and PSA); progression-free survival (PFS) (X-ray and PSA); 6-month X-ray PFS 1, 2, and 3-year overall survival (OS); circulating tumor cell (CTC) response (CTC0) and CTC conversion rate; and other PCWG3 recommended endpoints (time to symptomatic skeletal events, alkaline phosphatase [whole, bone], lactate dehydrogenase [LDH], hemoglobin, neutrophil-to-lymphocyte ratio, urinary N-telopeptide).

[0093] Once a MTD is identified, enrollment will be initiated in a dose expansion phase to assess safety and tolerability by evaluating three alternative dosing regimens, and to further evaluate PD and antitumor activity to select the optimal dose and schedule. These dosing regimens will be explored in parallel during expansion and will include different dose levels and / or schedules as shown in Table 2.

[0094] [Table 2]

[0095] Patients will be randomized in a 1:1:1 ratio to different expanded cohorts. Each expanded cohort is expected to enroll up to 50 patients (pt).

[0096] As of March 23, 2023, 97 patients had received one or more doses of zalritamig across 15 dose levels / schedules (DLs) (28 patients [28.3%] received treatment for more than 6 months); 25 patients were continuing treatment. The median age (range) was 67 (40-86) years; 67 patients (69.1%) had a history of more than three lines of prior treatment. 100% of patients reported a therapeutic adverse event (TEAE) during the study treatment (grade ≥3, 74.2%). The most common AE was cytokine release syndrome (CRS; 72.2%), which was mainly grade 1 / 2 (cycle 1), although one case was grade 3 (no grade 4 / 5 CRS). In the 2 mg TD cohort, DLT was observed in 3 / 6 DLT-evaluable patients, and 1.5 mg was defined as the MTD. Treatment-related TEAEs leading to discontinuation occurred in 17.5% of patients. Overall, 89 patients were PSA evaluable; 66 patients were RECIST evaluable. 42 patients (47.2%) achieved a PSA 50 response (a decrease of 50% or more in PSA); and 24 patients (27.0%) achieved a PSA 90 response. Higher DL (0.75 mg to 2 mg) was associated with a higher PSA response rate compared to lower DL (0.001 to 0.3 mg): ≥90% (34.8% vs. 18.6%) and ≥50% (54.3% vs. 39.5%). RECIST responses included 15 confirmed PRs (22.7%) and 30 stable disease (45.5%). In patients with high DL, 14 patients (38.9%) were confirmed PRs and 12 patients (33.3%) were stable disease. Preliminary PK studies showed a dose-proportional increase in exposure in the range of 0.003 mg to 1.5 mg, with an average terminal phase half-life of approximately 3 to 4 days.

[0097] Patients were initially enrolled in a fixed (non-graded) dose regimen administered weekly (QW) intravenously (IV) to 0.001 (n=2), 0.003 (n=4), 0.01 (n=4), 0.03 (n=4), 0.1 (n=10), and 0.3 (n=6) mg in cohorts 1-6, respectively. In cohort 6, dose-limiting toxicity (DLT) of grade 3 CRS / encephalopathy and back pain was observed in 2 out of 6 patients at 0.3 mg, and this dose level was determined to be unacceptable, exceeding the maximum tolerable dose (MTD) on day 1 of cycle 1. After adjustment of premedication, the starting dose of 0.3 mg (cohort 8) was still determined to be unacceptable, and the MTD for the initial dose (priming dose) was confirmed to be 0.1 mg.

[0098] The stepwise dosing method involved starting with 0.1 mg on day 1 and reaching the target dose by days 8, 15, or 22, using one step (increasing on day 8), two steps (increasing on days 8 and 15), or three steps (increasing on days 8, 15, and 22).

[0099] In cohorts 7a and 10, the one-step dosing regimen consisted of 0.1 to 0.3 mg or 0.1 to 1.0 mg. The 0.1 to 0.3 mg regimen (cohort 7a) was tolerable, but as the dose increase from 0.1 to 1.0 mg increased (cohort 10), it became intolerable due to DLTs (Disorderly Tolerable Therapies) in 3 out of 4 patients, consisting of grade 3 atrial fibrillation / QT interval prolongation, grade 3 fasciitis / pharyngitis, and grade 3 arthralgia (one patient each). Based on the findings of the one-step dosing regimen, two-step dosing regimens consisting of a priming dose of 0.1 mg, an 8-day dose of 0.3 mg, and a 15-day dose of 0.75 or 1.0 mg were evaluated in cohorts 7b, 7c, and 9; all were determined to be tolerable.

[0100] Based on findings from the two-step dosing regimen, a three-step dosing regimen consisting of a priming dose of 0.1 mg, an 8-day dose of 0.3 mg, a 15-day dose of either 0.75 mg or 1.0 mg, and a 22-day dose of either 1.5 mg or 2 mg was evaluated in cohorts 11, 12, and 13. In cohorts 11 (15-day dose of 0.75 mg) and 12 (15-day dose of 1.0 mg), the target dose for 22 days was 1.5 mg, and both were determined to be tolerable. In cohort 13, the highest 22-day dose of 2.0 mg was tested, but it was deemed untolerable because 3 out of 4 evaluable patients had DLTs (grade 3 myalgia [n=2]; grade 3 back pain and arthralgia [n=1]).

[0101] In summary, the maximum priming dose tolerated in the complete prophylaxis regimen was 0.1 mg, and a three-step dosing regimen consisting of 0.3 mg on day 8, 1.0 mg on day 15, and 1.5 mg IV QW from day 22 onward was determined to be the MTD (Main Treatment Dosage).

[0102] Zarritamig has been well-tolerated in low-grade CRS (primarily cycle 1) and has shown promising preliminary clinical efficacy in pt in mCRPC with a history of severe treatment.

[0103] Preliminary efficacy, measured by both PSA and RECIST, was promising in the mCRPC population with a history of severe treatment, and responses occurred more frequently in higher-dose cohorts. Consistent with PD markers of T cell activity, a decrease in PSA was observed starting with 0.1 mg zalritamig, and many patients achieved confirmed PSA 50 and PSA 90 responses. At higher doses, this led to an OR, with a response rate of 50% observed in RECIST-evaluable patients.

[0104] The maximum tolerated dose was determined to be 1.5 mg once a week using a three-stage schedule (0.1 mg on day 1 of cycle 1 / 0.3 mg on day 8 of cycle 1 / 1 mg on day 15 of cycle 1 / 1.5 mg on day 22 of cycle 1). For dose expansion, a second dosing schedule of 0.75 mg once a week using a two-stage schedule (0.1 mg on day 1 of cycle 1 / 0.3 mg on day 8 of cycle 1 / 0.75 mg on day 15 of cycle 1) will be explored. A dosing method of 1.5 mg once every two weeks (Q2W) will also be explored. This schedule will use the three-stage schedule. From cycle 2 onward, the target dose of 1.5 mg will be administered Q2W.

[0105] In this study, early signs of clinical efficacy based on PSA reduction were observed at zalritamig target dose levels of 0.1 mg or higher, with one OR observed in the 0.3 mg target dose cohort. Higher OR rates were particularly observed among patients in the high-dose cohort (QW administration, target doses above 0.3 mg considered safe and tolerable). Among the 67 patients with RECIST-evaluable disease, 16 patients (24%) achieved confirmed partial response (PR); 32 patients (48%) achieved stable disease (SD); 13 patients (19%) experienced disease progression (PD); and 6 patients (9%) were unevaluable (Figure 2; Table 3). RECIST OR was higher at higher doses, with 10 patients (50%) achieving confirmed PR. Responses were typically achieved within the first two cycles of treatment, and the duration of response in the high-dose cohort remains immature. During this study, early clinical benefits, including a reduction in bone lesions and imaging-based responses according to RECIST version 1.1, were observed among patients with a wide range of disease burdens.

[0106] [Table 3]

[0107] In the PSA-evaluable analysis population (N=87), a confirmed PSA50 response rate was reported in 43 patients (49%), and a confirmed PSA90 response was reported in 24 patients (28%) (Figure 3). In the low-dose cohort (n=43 evaluable patients) and high-dose cohort (n=44 patients), a confirmed PSA50 response was reported in 17 patients (40%) and 26 patients (59%), respectively, while a confirmed PSA90 response occurred in 8 patients (19%) and 16 patients (36%), respectively. One patient was a 65-year-old male initially diagnosed with stage IV prostate adenocarcinoma (Gleason score 9). This patient was undergoing androgen deprivation therapy, and prior treatments included bicalutamide, abiraterone, docetaxel, cabazitaxel, and carboplatin. In patients receiving IV zalritamig with a three-stage target dose of 1.5 mg, a confirmed PSA 50 response was demonstrated, with a maximum PSA reduction of 99% from baseline on day 1 of cycle 7. CT scans showed three target lesions and multiple non-target lesions during screening. Post-treatment images after two cycles showed lesion reduction consistent with a PR (37.3% reduction in target lesions) according to RECIST 1.1 criteria, which was confirmed at 16 weeks and maintained at 24 weeks (Figures 4 and 5). AEs during the initial treatment cycle were grade 2 or lower and included recurrent CRS, rash, exacerbation of back pain, and tinea masculinum. During subsequent treatment cycles, grade 2 or higher AEs such as rash, myalgia, and hyperkalemia were reported.

[0108] In preliminary PK studies, dose-proportional increases in exposure were observed across the explored dose levels, with a mean terminal phase half-life of approximately 3–4 days. Based on preclinical studies, the black dashed horizontal lines below and above represent the 90% effective concentration (EC90) (74 ng / mL) in the in vitro mediated cytotoxicity assay and the half-inhibitory inhibitory concentration (IC50) (259 ng / mL) in the xenograph PK / PD model, respectively. Starting from Cohort 5 (0.1 mg QW), observed pre-administration (C trough The concentrations are close to the predicted minimum effective exposure levels, suggesting that these doses may lead to clinical responses.

[0109] A rapid decrease in peripheral T cell count was observed after the initial zalritamig infusion. Transient expression of the T cell activation marker CD69 facilitated lymphocyte redistribution. Serum cytokine levels, including IFN-γ, IL-2, IL-6, and TNF-α, increased from baseline after zalritamig infusion. Cytokine concentrations peaked within 6–24 hours and returned to baseline before the next infusion. T cell periphery, T cell activation, and cytokine induction were all dose-dependent, and FDR-adjusted p-values ​​reached significance at multiple post-infusion time points.

[0110] The overall incidence of ADA in the study treatment was 49 out of 90 evaluable patients (54%), of which 8 patients had a transient antibody response. The median time to the onset of bound ADA was day 1 of cycle 2. In patients positive for bound ADA, the impact of ADA on drug activity, exposure, and association with safety events was evaluated. The observed ADA was not associated with adverse events. Some patients positive for bound ADA were determined to have an impact on neutralization and / or exposure.

[0111] The safety profile in this trial consisted mostly of clinically manageable Grade 1 and 2 adverse events, with no Grade 5 events associated with zalritamig. Nineteen percent of patients discontinued treatment due to TRAEs, but some of these were due to limited treatment interruption periods.

[0112] The most frequent TRAE was low-grade CRS, primarily occurring in cycle 1. CRS was anticipated in this study due to the biological mechanism of zalritamig and clinical experience with other TCEs (11). Three cases (3%) of grade 3 CRS were reported, one of which later decreased to grade 1 after the data cutoff. Grade 3 events (cohorts 6 and 7a) occurred before the addition of a second pre-administration of dexamethasone and post-administration IV hydration initiated in the subsequent cohort. Almost all CRS events presented as hypotension, tachycardia, and, rarely, fever with or without hypoxia. There were no grade 4 or 5 CRS events. Overall, all CRS events resolved with standard management using acetaminophen, intravenous tocilizumab, and / or corticosteroids.

[0113] A favorable and predictable dose-exposure relationship was observed after zalritamig administration. The preliminary terminal phase half-life was approximately 3-4 days, which supports the QW dose schedule. PK suggested that when the patient's target dose was 0.75 mg or higher, trough concentrations could be reached with the minimum effective exposure based on preclinical studies. This allows for further analysis to evaluate clinical outcomes in low-dose (<0.75 mg) and high-dose (≥0.75 mg) cohorts.

[0114] In mCRPC patients, additional analyses were conducted during dose escalation phases in a 1:1:1 randomized population to receive target doses of IV zalritamig at 0.75 mg QW, 1.5 mg QW, or 1.5 mg Q2W using a two-step or three-step dosing method in cycle 1. The results are provided in the table below.

[0115] [Table 4]

[0116] Both doses were effective, but in this randomized dose-expansion / optimization study of severely treated mCRPC patients, the target dose of 1.5 mg improved the efficacy of zalritamig compared to 0.75 mg, while maintaining a manageable side effect profile. The higher target dose of 1.5 mg tended to demonstrate superior efficacy and similar safety compared to 0.75 mg.

[0117] PSA50 0.75mg:36%, 1.5mg:53%~60%

[0118] PSA90 0.75mg:21%, 1.5mg:30%~34%

[0119] ORR 0.75mg:15%, 1.5mg:19%~29%

[0120] Most Grade 3 adverse events were transient, manageable, and reversible, and most patients were able to continue treatment. There were a few discontinuations due to musculoskeletal inflammatory events or cytokine release syndrome (CRS), but most Grade 3 CRS events occurred in Cycle 1 (there were no Grade 4 / 5 CRS). The Q2W dosing schedule demonstrated an improvement in the adverse event profile, with a reduced overall incidence of treatment-related musculoskeletal inflammatory events (69% vs. 74% and 86% in the QW schedule) and a lower number of high-grade events (Grade 2 / 3: 22% / 33% vs. 31% / 37% and 34% / 43%).

[0121] [Table 5]

[0122] [Table 6]

[0123] [Table 7]

[0124] Table 8

[0125] Table 9

Claims

1. A method for treating a patient having prostate cancer, comprising administering to the patient a pharmaceutical composition containing an anti-STEAP1 antigen-binding protein in a dose of about 0.1 mg to about 2.0 mg.

2. The method according to claim 1, wherein the dose is approximately 0.1 mg.

3. The method according to claim 1, wherein the dose is approximately 0.3 mg.

4. The method according to claim 1, wherein the dose is approximately 0.75 mg.

5. The method according to claim 1, wherein the dose is approximately 1 mg.

6. The method according to claim 1, wherein the dose is approximately 1.5 mg.

7. The method according to claim 1, wherein the dose is 1.5 mg.

8. The method according to any one of claims 1 to 7, wherein the aforementioned dose is administered once a week.

9. The method according to any one of claims 1 to 7, wherein the aforementioned dose is administered once every two weeks.

10. The method according to any one of claims 1 to 9, wherein the aforementioned dose is administered by intravenous administration.

11. The method according to any one of claims 1 to 10, comprising administering to the patient a pharmaceutical composition containing an anti-STEAP1 antigen-binding protein in a dose of approximately 0.1 mg to approximately 1.5 mg, further comprising administering to the patient a certain dose of abiraterone.

12. The method according to claim 11, wherein the dose of abiraterone is approximately 1000 mg.

13. The method according to claim 11 or 12, wherein the aforementioned dose of abiraterone is administered orally.

14. The method according to any one of claims 11 to 13, wherein the patient is administered approximately 5 mg of prednisone twice a day.

15. The method according to any one of claims 11 to 13, wherein the patient is administered approximately 10 mg of prednisone once daily.

16. The method according to any one of claims 11 to 15, wherein the dose of the anti-STEAP1 antigen-binding protein is about 0.75 mg to about 2.0 mg.

17. The method according to any one of claims 1 to 10, comprising administering to the patient a pharmaceutical composition containing an anti-STEAP1 antigen-binding protein in a dose of approximately 0.1 mg to approximately 1.5 mg, further comprising administering to the patient a certain dose of enzalutamide.

18. The method according to claim 17, wherein the dose of enzalutamide is about 160 mg.

19. The method according to claim 17 or 18, wherein the dose of enzalutamide is administered orally.

20. The method according to any one of claims 17 to 19, wherein the dose of the anti-STEAP1 antigen-binding protein is about 0.75 mg to about 2.0 mg.

21. The method according to any one of claims 1 to 20, wherein the anti-STEAP1 antigen-binding protein is first administered by a stepwise administration method.

22. The method according to claim 21, wherein the anti-STEAP1 antigen-binding protein is administered by a two-step or three-step stepwise administration method.

23. The method according to claim 21, wherein the anti-STEAP1 antigen-binding protein is administered in a stepwise manner at a dose of 0.1 mg on day 1, 0.3 mg on day 8, 1.0 mg on day 15, and 1.5 mg on day 22.

24. The method according to claim 21, wherein the anti-STEAP1 antigen-binding protein is administered in a stepwise manner at a dose of 0.1 mg on day 1, 0.3 mg on day 8, 0.75 mg on day 15, and 0.75 mg on day 22.

25. The method according to any one of claims 21 to 24, further comprising administering the anti-STEAP1 antigen-binding protein according to any one of claims 1 to 10 to the patient once a week, once every two weeks, once every three weeks, or once every four weeks after administration of the stepwise administration method.

26. The method according to claim 25, further comprising administering the anti-STEAP1 antigen-binding protein at a dose of 1.5 mg once every two weeks after the stepwise administration method described above.

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

14.

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

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

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

14.

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

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

6.

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

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

8.

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

8.

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

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

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

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

18.

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

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

42. Use of an anti-STEAP1 antigen-binding protein for the preparation of a therapeutic drug for prostate cancer, wherein the drug is formulated to be administered in a dose of approximately 0.1 mg to approximately 2.0 mg.

43. The use according to claim 42, wherein the dose is approximately 0.1 mg.

44. The use according to claim 42, wherein the dose is approximately 0.3 mg.

45. The use according to claim 42, wherein the aforementioned dose is approximately 0.75 mg.

46. The use according to claim 42, wherein the dose is approximately 1 mg.

47. The use according to claim 42, wherein the dose is approximately 1.5 mg.

48. The use according to claim 42, wherein the dose is 1.5 mg.

49. The use according to any one of claims 42 to 48, wherein the aforementioned dose is administered once a week.

50. The use according to any one of claims 42 to 48, wherein the aforementioned dose is administered once every two weeks.

51. The use according to any one of claims 42 to 50, wherein the aforementioned dose is administered by intravenous administration.

52. A use according to any one of claims 42 to 51, comprising administering to the patient a certain dose of a pharmaceutical composition containing an anti-STEAP1 antigen-binding protein in a dose of approximately 0.1 mg to approximately 2.0 mg, further comprising administering to the patient a certain dose of abiraterone.

53. The use according to claim 52, wherein the dose of abiraterone is approximately 1000 mg.

54. The use according to claim 52 or 53, wherein the aforementioned dose of abiraterone is administered orally.

55. The use according to any one of claims 52 to 54, wherein the patient is administered approximately 5 mg of prednisone twice a day.

56. The use according to any one of claims 52 to 54, wherein the patient is administered approximately 10 mg of prednisone once daily.

57. The use according to any one of claims 52 to 55, wherein the dose of the anti-STEAP1 antigen-binding protein is about 0.75 mg to about 2.0 mg.

58. A use according to any one of claims 42 to 51, comprising administering to the patient a certain dose of a pharmaceutical composition containing an anti-STEAP1 antigen-binding protein in a dose of approximately 0.1 mg to approximately 1.5 mg, wherein the method further comprises administering to the patient a certain dose of enzalutamide.

59. The use according to claim 58, wherein the dose of enzalutamide is about 160 mg.

60. The use according to claim 58 or 59, wherein the dose of enzalutamide is administered orally.

61. The use according to any one of claims 58 to 60, wherein the dose of the anti-STEAP1 antigen-binding protein is about 0.75 mg to about 2.0 mg.

62. The use according to any one of claims 42 to 61, wherein the anti-STEAP1 antigen-binding protein is first administered by a stepwise administration method.

63. The use according to claim 62, wherein the anti-STEAP1 antigen-binding protein is administered by a two-step or three-step stepwise administration method.

64. The use according to claim 62, wherein the anti-STEAP1 antigen-binding protein is administered in a stepwise manner: 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.

65. The use according to claim 62, wherein the anti-STEAP1 antigen-binding protein is administered in a stepwise manner: 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.

66. The use according to any one of claims 62 to 65, further comprising administering the anti-STEAP1 antigen-binding protein according to any one of claims 52 to 61 to the patient once a week, once every two weeks, once every three weeks, or once every four weeks after administration of the stepwise administration method.

67. The use according to any one of claims 42 to 66, wherein the anti-STEAP1 antigen-binding protein comprises two Fab-binding domains, each Fab-binding domain being bound to STEAP1, each Fab-binding domain comprising a variable heavy chain domain, a variable light chain domain, a CH1 domain, and a constant light chain domain, the variable heavy chain domain comprising HCDR1 containing SEQ ID NO: 9, HCDR2 containing SEQ ID NO: 10, and HCDR3 containing SEQ ID NO: 11; and the variable light chain domain comprising LCDR1 containing SEQ ID NO: 12, LCDR2 containing SEQ ID NO: 13, and LCDR3 containing SEQ ID NO:

14.

68. The use according to any one of claims 42 to 67, wherein the anti-STEAP1 antigen-binding protein comprises two Fab domains that bind to STEAP1 and one scFv domain that binds to CD3.

69. The use according to any one of claims 42 to 68, wherein the anti-STEAP1 antigen-binding protein comprises two Fab-binding domains, each Fab-binding domain binding to STEAP1.

70. The use according to any one of claims 52 to 69, wherein the anti-STEAP1 antigen-binding protein comprises two Fab-binding domains, each Fab-binding domain being bound to STEAP1, and each Fab-binding domain comprises a variable heavy chain domain, a variable light chain domain, a CH1 domain, and a constant light chain domain, the variable heavy chain domain comprising HCDR1 containing SEQ ID NO: 9, HCDR2 containing SEQ ID NO: 10, and HCDR3 containing SEQ ID NO: 11; and the variable light chain domain comprising LCDR1 containing SEQ ID NO: 12, LCDR2 containing SEQ ID NO: 13, and LCDR3 containing SEQ ID NO:

14.

71. The use according to any one of claims 42 to 70, wherein the anti-STEAP1 antigen-binding protein comprises an scFv-binding domain that binds to CD3.

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

6.

73. The use according to any one of claims 42 to 72, wherein the anti-STEAP1 antigen-binding protein comprises a first Fc domain and a second Fc domain.

74. The use according to any one of claims 71 to 73, wherein each Fab variable heavy chain domain contains an amino acid sequence that is at least 90% identical to SEQ ID NO: 15; each Fab variable light chain domain contains an amino acid sequence that is at least 90% identical to SEQ ID NO: 16; and the scFv variable heavy chain domain contains an amino acid sequence that is at least 90% identical to SEQ ID NO: 7; and the scFv variable light chain domain contains an amino acid sequence that is at least 90% identical to SEQ ID NO:

8.

75. The use according to any one of claims 71 to 74, wherein each Fab variable heavy chain domain includes SEQ ID NO: 15; each Fab variable light chain domain includes SEQ ID NO: 16; the scFv variable heavy chain domain includes SEQ ID NO: 7; and the scFv variable light chain domain includes SEQ ID NO:

8.

76. The use according to any one of claims 71 to 75, wherein the scFv binding domain that binds to CD3 includes an scFv linker.

77. The use according to any one of claims 73 to 76, 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.

78. The use according to any one of claims 73 to 77, wherein the first Fc domain and the second Fc domain each contain a deletion at position 234.

79. The use according to any one of claims 42 to 78, wherein the anti-STEAP1 antigen-binding protein comprises an HC containing SEQ ID NO: 17, an HC into which CD3 scFv containing SEQ ID NO: 19 is inserted, and two light chains, each containing SEQ ID NO:

18.

80. The use according to any one of claims 42 to 79, wherein the anti-STEAP1 antigen-binding protein is zalritamig.

81. The use according to any one of claims 42 to 80, wherein the patient has metastatic castration-resistant prostate cancer.

82. An anti-STEAP1 antigen-binding protein for use in the treatment of prostate cancer, wherein the antigen-binding protein is formulated to be administered in a dose of approximately 0.1 mg to approximately 2.0 mg.

83. The anti-STEAP1 antigen-binding protein according to claim 82, wherein the dose is approximately 0.1 mg.

84. The anti-STEAP1 antigen-binding protein according to claim 82, wherein the aforementioned dose is approximately 0.3 mg.

85. The anti-STEAP1 antigen-binding protein according to claim 82, wherein the aforementioned dose is approximately 0.75 mg.

86. The anti-STEAP1 antigen-binding protein according to claim 82, wherein the dose is approximately 1 mg.

87. The anti-STEAP1 antigen-binding protein according to claim 82, wherein the dose is approximately 1.5 mg.

88. The anti-STEAP1 antigen-binding protein according to claim 82, wherein the dose is 1.5 mg.

89. The anti-STEAP1 antigen-binding protein according to any one of claims 82 to 88, wherein the aforementioned dose is administered once a week.

90. The anti-STEAP1 antigen-binding protein according to any one of claims 82 to 88, wherein the aforementioned dose is administered once every two weeks.

91. The anti-STEAP1 antigen-binding protein according to any one of claims 82 to 90, wherein the aforementioned dose is administered by intravenous administration.

92. The use of an anti-STEAP1 antigen-binding protein according to any one of claims 82 to 91, comprising administering to the patient a certain dose of a pharmaceutical composition containing an anti-STEAP1 antigen-binding protein in a dose of approximately 0.1 mg to approximately 2.0 mg, the use further comprising administering to the patient a certain dose of abiraterone.

93. The anti-STEAP1 antigen-binding protein according to claim 92, wherein the dose of abiraterone is approximately 1000 mg.

94. The anti-STEAP1 antigen-binding protein according to claim 92 or 93, wherein the aforementioned dose of abiraterone is administered orally.

95. The anti-STEAP1 antigen-binding protein according to any one of claims 92 to 94, wherein the patient is administered approximately 5 mg of prednisone twice daily.

96. The anti-STEAP1 antigen-binding protein according to any one of claims 92 to 95, wherein the patient is administered approximately 10 mg of prednisone once daily.

97. The anti-STEAP1 antigen-binding protein according to any one of claims 82 to 96, wherein the dose of the anti-STEAP1 antigen-binding protein is about 0.75 mg to about 2.0 mg.

98. The method comprises administering to the patient a certain dose of a pharmaceutical composition containing an anti-STEAP1 antigen-binding protein in a dose of approximately 0.1 mg to approximately 2.0 mg, further comprising administering to the patient a certain dose of enzalutamide, according to any one of claims 82 to 97.

99. The anti-STEAP1 antigen-binding protein according to claim 98, wherein the dose of enzalutamide is approximately 160 mg.

100. The anti-STEAP1 antigen-binding protein according to claim 98 or 99, wherein the aforementioned dose of enzalutamide is administered orally.

101. The anti-STEAP1 antigen-binding protein according to any one of claims 98 to 100, wherein the dose of the anti-STEAP1 antigen-binding protein is about 0.75 mg to about 2.0 mg.

102. The anti-STEAP1 antigen-binding protein according to any one of claims 82 to 101, wherein the anti-STEAP1 antigen-binding protein is first administered by a stepwise administration method.

103. The anti-STEAP1 antigen-binding protein according to claim 102, wherein the anti-STEAP1 antigen-binding protein is administered by a two-step or three-step stepwise administration method.

104. The anti-STEAP1 antigen-binding protein according to claim 103, wherein the anti-STEAP1 antigen-binding protein is administered in a stepwise manner at a dose of 0.1 mg on day 1, 0.3 mg on day 8, 1.0 mg on day 15, and 1.5 mg on day 22.

105. The anti-STEAP1 antigen-binding protein according to claim 103, wherein the anti-STEAP1 antigen-binding protein is administered in a stepwise manner at a dose of 0.1 mg on day 1, 0.3 mg on day 8, 0.75 mg on day 15, and 0.75 mg on day 22.

106. The anti-STEAP1 antigen-binding protein according to any one of claims 102 to 105, further comprising administering the anti-STEAP1 antigen-binding protein to the patient once a week, once every two weeks, once every three weeks, or once every four weeks after administration of the stepwise administration method.

107. The anti-STEAP1 antigen-binding protein according to any one of claims 82 to 106, wherein the anti-STEAP1 antigen-binding protein comprises two Fab-binding domains, each Fab-binding domain being bound to STEAP1, and each Fab-binding domain comprising a variable heavy chain domain, a variable light chain domain, a CH1 domain, and a constant light chain domain, the variable heavy chain domain comprising HCDR1 containing SEQ ID NO: 9, HCDR2 containing SEQ ID NO: 10, and HCDR3 containing SEQ ID NO: 11; and the variable light chain domain comprising LCDR1 containing SEQ ID NO: 12, LCDR2 containing SEQ ID NO: 13, and LCDR3 containing SEQ ID NO:

14.

108. The anti-STEAP1 antigen-binding protein according to any one of claims 82 to 107, wherein the anti-STEAP1 antigen-binding protein is an XmAb® 2+1 molecule, each comprising two Fab domains that bind to STEAP1 and one scFv domain that binds to CD3.

109. The anti-STEAP1 antigen-binding protein according to any one of claims 82 to 108, wherein the anti-STEAP1 antigen-binding protein comprises two Fab-binding domains, each Fab-binding domain binding to STEAP1.

110. The anti-STEAP1 antigen-binding protein according to any one of claims 82 to 109, wherein the anti-STEAP1 antigen-binding protein comprises two Fab-binding domains, each Fab-binding domain being bound to STEAP1, and each Fab-binding domain comprising a variable heavy chain domain, a variable light chain domain, a CH1 domain, and a constant light chain domain, wherein the variable heavy chain domain comprises HCDR1 containing SEQ ID NO: 9, HCDR2 containing SEQ ID NO: 10, and HCDR3 containing SEQ ID NO: 11; and the variable light chain domain comprises LCDR1 containing SEQ ID NO: 12, LCDR2 containing SEQ ID NO: 13, and LCDR3 containing SEQ ID NO:

14.

111. The anti-STEAP1 antigen-binding protein according to any one of claims 82 to 110, wherein the anti-STEAP1 antigen-binding protein comprises an scFv-binding domain that binds to CD3.

112. The anti-STEAP1 antigen-binding protein according to any one of claims 82 to 111, wherein the anti-STEAP1 antigen-binding protein comprises an scFv-binding domain that binds to CD3, and the scFv variable heavy chain domain comprises HCDR1 containing SEQ ID NO: 1, HCDR2 containing SEQ ID NO: 2, and HCDR3 containing SEQ ID NO: 3; an scFv linker; and an scFv variable light chain domain, wherein the scFv variable light chain domain comprises LCDR1 containing SEQ ID NO: 4, LCDR2 containing SEQ ID NO: 5, and LCDR3 containing SEQ ID NO:

6.

113. The anti-STEAP1 antigen-binding protein according to any one of claims 82 to 112, wherein the anti-STEAP1 antigen-binding protein comprises a first Fc domain and a second Fc domain.

114. The anti-STEAP1 antigen-binding protein according to any one of claims 111 to 113, wherein each Fab variable heavy chain domain comprises an amino acid sequence identical to at least 90% of SEQ ID NO: 15; each Fab variable light chain domain comprises an amino acid sequence identical to at least 90% of SEQ ID NO: 16; and the scFv variable heavy chain domain comprises an amino acid sequence identical to at least 90% of SEQ ID NO: 7; and the scFv variable light chain domain comprises an amino acid sequence identical to at least 90% of SEQ ID NO:

8.

115. The anti-STEAP1 antigen-binding protein according to any one of claims 111 to 114, wherein each Fab variable heavy chain domain comprises SEQ ID NO: 15; each Fab variable light chain domain comprises SEQ ID NO: 16; the scFv variable heavy chain domain comprises SEQ ID NO: 7; and the scFv variable light chain domain comprises SEQ ID NO:

8.

116. The anti-STEAP1 antigen-binding protein according to any one of claims 111 to 115, wherein the scFv-binding domain that binds to CD3 includes an scFv linker.

117. The anti-STEAP1 antigen-binding protein according to any one of claims 111 to 116, 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.

118. The anti-STEAP1 antigen-binding protein according to any one of claims 111 to 116, wherein the first Fc domain and the second Fc domain each contain a deletion at position 234.

119. The anti-STEAP1 antigen-binding protein according to any one of claims 82 to 118, wherein the anti-STEAP1 antigen-binding protein comprises an HC containing SEQ ID NO: 17, an HC into which CD3 scFv containing SEQ ID NO: 19 is inserted, and two light chains, each containing SEQ ID NO:

18.

120. The anti-STEAP1 antigen-binding protein according to any one of claims 82 to 119, wherein the anti-STEAP1 antigen-binding protein is zalritamig.

121. The anti-STEAP1 antigen-binding protein according to any one of claims 82 to 120, wherein the patient has metastatic castration-resistant prostate cancer.

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