WO2025226541A2

WO2025226541A2 - Klk2xcd3 antibody and an anti-cancer agent for treating prostate cancer

Info

Publication number: WO2025226541A2
Application number: PCT/US2025/025377
Authority: WO
Inventors: Victor Manuel VILLALOBOS; Daksh THAPER; Halley Mellor OYER; Vincent Lin
Original assignee: Janssen Biotech Inc
Current assignee: Janssen Biotech Inc
Priority date: 2024-04-26
Filing date: 2025-04-18
Publication date: 2025-10-30
Anticipated expiration: 2026-10-26
Also published as: WO2025226541A3

Abstract

The application describes the first-in-human study on using a anti-KLK2xCD3 bispecific antibody and another anti-cancer drug, in particular, in particular a taxane chemotherapy or Androgen Receptor Pathway Inhibitor (ARPI), to provide enhanced antitumor efficacy with a deeper and more durable clinical response.

Description

KLK2xCD3 ANTIBODY AND AN ANTI-CANCER AGENT FOR TREATING PROSTATE

CANCER

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Application No. 63/638,993, filed on April 26, 2024, and U.S. Provisional Application No. 63/682,774, filed on August 13, 2024 the disclosures of each of which are hereby incorporated by reference in their entireties.

SEQUENCE LISTING

[0002] The instant application contains a Sequence Listing which has been submitted electronically in XML format and is hereby incorporated by reference in its entirety. The XML copy, created on March 18, 2025, is named JBI6900PCT_SL.xml and is 58.4 KB in size.

TECHNICAL FIELD

[0003] Disclosed are methods of treating prostate cancers and therapeutics to potentiate T-cell activation.

BACKGROUND

[0004] Prostate cancer (PC) is the second most frequently diagnosed cancer and the sixth leading cause of cancer death in males, accounting for 14% (903,500) of the total new cancer cases and 6% (258,400) of the total cancer deaths in males worldwide. Historically, androgen depletion therapy (ADT) has been the standard of care for patients with metastatic prostate cancer. However, in the advanced form of prostate cancer, it becomes metastatic and spreads beyond the prostate to other parts of the body. With metastatic Castration-Resistant Prostate

Cancer (mCRPC), hormone therapy no longer stops cancer growth. End stage PC (castrationresistant prostate cancer) currently has no curative treatment option.

[0005] Antibody-based therapeutics have been used successfully to treat a variety of diseases, including cancer. One particular approach is to engineer a bispecific antibody with a first antigen binding domain that engages CD3 and a second antigen binding domain that engages an antigen associated with or upregulated on cancer cells so that the bispecific antibody redirects CD3⁺ T cells to destroy the cancer cells. Bispecific antibodies that bind specifically to kallikrein related peptidase 2 (KLK2, hK2) and CD3 (KLK2xCD3 bi-specific antibodies) and uses thereof for treating cancer have been described. See, e.g., WO2021019389. [0006] It is important for cancer therapy to enhance anti-tumor activity by specifically destroying tumor cells while minimizing peripheral toxicity. The tumor microenvironment, such as that in mCRPC, may lack a sufficient immune presence to allow for efficient immune- mediated cytotoxicity. In these so called “cold” tumors, T-cell redirection may be a particularly important approach to enhance immunoreactivity.

[0007] There remains a need for novel immune response enhancing therapies for the treatment of prostate cancer, particularly advanced prostate cancer, particularly mCRPC.

SUMMARY

[0008] The application describes the first-in-human study on using anti-KLK2xCD3 bispecific antibody and another anti-cancer agent, in particular a taxane chemotherapy or Androgen Receptor Pathway Inhibitor (ARPI) to treat prostate cancer.

[0009] Accordingly, in one general aspect, the application provides a method of treating prostate cancer in a subject, wherein the method comprises administering to the subject an anti- KLK2xCD3 antibody and another anti -cancer drug, wherein the other anti-cancer drug is an androgen receptor pathway inhibitor (ARPI) or an anti-cancer chemotherapeutic agent, wherein the anti-KLK2xCD3 antibody comprises a first antigen binding domain that binds specifically to KLK2, and a second antigen binding domain that binds specifically to CD3s, preferably, the first antigen binding domain comprises a first heavy chain complementarity determining region (HCDR) 1, a first HCDR2 and a first HCDR3 of a first heavy chain variable region (VH1), and a first light chain complementarity determining region (LCDR) 1, a first LCDR2, and a first LCDR3 of a first light chain variable region (VL1), wherein the VH1 and the VL1 comprise: i) the amino acid sequences of SEQ ID NO: 37 and SEQ ID NO: 38, respectively; ii) the amino acid sequences of SEQ ID NO: 39 and SEQ ID NO: 40, respectively; iii) the amino acid sequences of SEQ ID NO: 41 and SEQ ID NO: 42, respectively; or iv) the amino acid sequences of SEQ ID NO: 43 and SEQ ID NO: 44, respectively, wherein the first HCDR1, first HCDR2, first HCDR3, first LCDR1, first LCDR2 and first LCDR3 are defined by the Kabat, Chothia, IMGT or AbM numbering system.

[0010] In certain embodiments, the administering of the anti-KLK2xCD3 antibody and the other anti-cancer drug enhances immune cell function, such as enhances T cell function, as compared to the administration of each of the anti-KLK2xCD3 antibody and the other anti-cancer drug alone, preferably, the T cell function comprises T cell cytotoxicity (or T cell killing), T cell activation, and/or T cell proliferation, e.g., the T cell function is T cell cytotoxicity (or T cell killing), more preferably T cell killing of prostate cancer cells.

[0011] In certain embodiments, the administering of the anti-KLK2xCD3 antibody and the other anti-cancer drug prevents disease progression of the prostate cancer.

[0012] In certain embodiments, the administering of the anti-KLK2xCD3 antibody and the other anti-cancer drug does not increase the risk of a treatment related toxicity in a clinically significant way as compared to the administration of each of the anti-KLK2xCD3 antibody and the other anti-cancer drug alone (e.g., when assessed in a cohort of patients).

[0013] In certain embodiments, the administering of the anti-KLK2xCD3 antibody and the other anti-cancer drug provides a reduction in serum Prostate Specific Antigen (PSA), preferably an improved serum PSA reduction, as compared to the administration of each of the anti- KLK2xCD3 antibody and the other anti-cancer drug alone, without triggering a cytokine release syndrome (CRS) of grade 3 or higher according to the American Society for Transplantation and Cellular Therapy (ASTCT) guidelines.

[0014] In certain embodiments, the first HCDR1, first HCDR2, first HCDR3, first LCDR1, first LCDR2 and first LCDR3 comprises: i) the amino acid sequences of SEQ ID NOs: 1, 2, 3, 4, 5, and 6, respectively; ii) the amino acid sequences of SEQ ID NOs: 7, 8, 9, 10, 11, and 12, respectively; iii) the amino acid sequences of SEQ ID NOs: 13, 14, 15, 16, 17, and 18, respectively; or iv) the amino acid sequences of SEQ ID NOs: 19, 20, 21, 22, 23, and 24, respectively.

[0015] In certain embodiments, the VH1 and the VL1 comprise: i) amino acid sequences at least 90%, preferably 100%, identical to SEQ ID NO: 37 and

SEQ ID NO: 38, respectively, ii) amino acid sequences at least 90%, preferably 100%, identical to SEQ ID NO: 39 and SEQ ID NO: 40, respectively; iii) amino acid sequences at least 90%, preferably 100%, identical to SEQ ID NO: 41 and SEQ ID NO: 42, respectively; or iv) amino acid sequences at least 90%, preferably 100%, identical to SEQ ID NO: 43 and SEQ ID NO: 44, respectively.

[0016] In certain embodiments, the first binding domain comprises i) a first heavy chain (HC1) and a first light chain (LC1), and the HC1 and the LC1 comprise: a) amino acid sequences at least 90%, preferably 100%, identical to SEQ ID NO: 49 and

SEQ ID NO: 50, respectively; b) amino acid sequences at least 90%, preferably 100%, identical to SEQ ID NO: 53 and

SEQ ID NO: 54, respectively; or c) amino acid sequences at least 90%, preferably 100%, identical to SEQ ID NO: 55 and

SEQ ID NO: 50, respectively; or ii) a first single-chain variable fragment fused to a Fc (scFvl-Fc), and the scFvl-Fc comprises an amino acid sequence at least 90%, preferably 100%, identical to SEQ ID NO: 51 or 52.

[0017] In certain embodiments, the second antigen binding domain comprises a second HCDR1, second HCDR2 and a second HCDR3 of a second heavy chain variable region (VH2), and a second LCDR1, a second LCDR2, and a second LCDR3 of a second light chain variable region (VL2), wherein the VH2 and the VL2 comprise: i) the amino acid sequences of SEQ ID NO: 45 and SEQ ID NO: 46, respectively; or ii) the amino acid sequences of SEQ ID NO: 47 and SEQ ID NO: 48, respectively; wherein the second HCDR1, second HCDR2, second HCDR3, second LCDR1, second LCDR2 and second LCDR3 are defined by the Kabat, Chothia, IMGT or AbM numbering system. [0018] In certain embodiments, the second HCDR1, second HCDR2, second HCDR3, second LCDR1, second LCDR2 and second LCDR3 comprises: i) the amino acid sequences of SEQ ID NOs: 25, 26, 27, 28, 29, and 30, respectively; or ii) the amino acid sequences of SEQ ID NOs: 31, 32, 33, 34, 35, and 36, respectively.

In certain embodiments, the VH2 and the VL2 comprise: i) amino acid sequences at least 90%, preferably 100%, identical to SEQ ID NO: 45 and

SEQ ID NO: 46, respectively; or ii) amino acid sequences at least 90%, preferably 100%, identical to SEQ ID NO: 47 and SEQ ID NO: 48, respectively

In certain embodiments, the second binding domain comprises: i) a second heavy chain (HC2) and a second light chain (LC2), and the HC2 and the LC2 comprise: a) amino acid sequences at least 90%, preferably 100%, identical to SEQ ID NO: 57 and

SEQ ID NO: 58, respectively; or b) amino acid sequences at least 90%, preferably 100%, identical to SEQ ID NO: 59 and

SEQ ID NO: 60, respectively; or ii) a second single-chain variable fragment fused to a Fc(scFv2-Fc), and the scFv2-Fc comprises an amino acid sequence at least 90%, preferably 100%, identical to SEQ ID NO: 56 or 61.

[0019] In certain embodiments, the first HCDR1, first HCDR2, first HCDR3, first LCDR1, first LCDR2, first LCDR3, second HCDR1, second HCDR2, second HCDR3, second LCDR1, second LCDR2 and second LCDR3 comprise: i) the amino acid sequences of SEQ ID NOs: 1, 2, 3, 4, 5, 6, 25, 26, 27, 28, 29, and 30, respectively; ii) the amino acid sequences of SEQ ID NOs: 7, 8, 9, 10, 11, 12, 25, 26, 27, 28, 29, and

30, respectively; iii) the amino acid sequences of SEQ ID NOs: 13, 14, 15, 16, 17, 18, 31, 32, 33, 34, 35, and 36, respectively; or iv) the amino acid sequences of SEQ ID NOs: 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, and 30, respectively.

In certain embodiments, the VH1, VL1, VH2 and VL2 comprise: i) amino acid sequences at least 90%, preferably 100%, identical to SEQ ID NOs: 37, 38,

45, and 46, respectively; ii) amino acid sequences at least 90%, preferably 100%, identical to SEQ ID NOs: 39,

40, 45, and 46, respectively, iii) amino acid sequences at least 90%, preferably 100%, identical to SEQ ID NOs: 41,

42, 47, and 48, respectively, iv) amino acid sequences at least 90%, preferably 100%, identical to SEQ ID NOs: 43, 44, 45, and 46, respectively.

[0020] In certain embodiments, the first binding domain that binds specifically to KLK2 comprises the HC1 and LC1 comprising amino acid sequences at least 90%, preferably 100%, identical to SEQ ID NOs: 49 and 50, respectively, and the second binding domain that binds specifically to CD3s comprises the scFv2-Fc comprising an amino acid sequence at least 90%, preferably 100%, identical to SEQ ID NO: 56.

[0021] In certain embodiments, the first binding domain that binds specifically to KLK2 comprises the scFvl-Fc comprising an amino acid sequence at least 90%, preferably 100%, identical to SEQ ID NO: 51, and the second binding domain that binds specifically to CD3e comprises the HC2 and LC2 comprising amino acid sequences at least 90%, preferably 100%, identical to SEQ ID NOs: 57 and 58, respectively.

[0022] In certain embodiments, the first binding domain that binds specifically to KLK2 comprises the scFvl-Fc comprising an amino acid sequence at least 90%, preferably 100%, identical to SEQ ID NO: 52, and the second binding domain that binds specifically to CD3s comprises the HC2 and LC2 comprising amino acid sequences at least 90%, preferably 100%, identical to SEQ ID NOs: 59 and 60, respectively.

[0023] In certain embodiments, the first binding domain that binds specifically to KLK2 comprises the HC1 and LC1 comprising amino acid sequences at least 90%, preferably 100%, identical to SEQ ID NOs: 53 and 54, respectively, and the second binding domain that binds specifically to CD3s comprises the scFv2-Fc comprising an amino acid sequence at least 90%, preferably 100%, identical to SEQ ID NO: 56.

[0024] In certain embodiments, the first binding domain that binds specifically to KLK2 comprises the HC1 and LC1 comprising amino acid sequences at least 90%, preferably 100%, identical to SEQ ID NOs: 55 and 50, respectively, and the second binding domain that binds specifically to CD3s comprises the scFv2-Fc comprising an amino acid sequence at least 90%, preferably 100%, identical to SEQ ID NO: 61.

[0025] In certain embodiments, the anti-KLK2xCD3 antibody is administered to the subject subcutaneously. In other embodiments, the anti-KLK2xCD3 antibody is administered to the subject intravenously.

[0026] In certain embodiments, the anti-KLK2xCD3 antibody is administered once every 1-9 weeks, for example, once every 3 weeks, once every 6 weeks, or once every 9 weeks.

[0027] In certain embodiments, the administering of the anti-KLK2xCD3 antibody comprises the administering of more than one treatment dose, wherein the treatment doses are administered once every 1-9 weeks, for example, once every 3 weeks, once every 6 weeks, or once every 9 weeks, and wherein each treatment dose is at the same dose level. [0028] In certain embodiments, the other anti-cancer drug is administered simultaneously, sequentially or separately from the administering of the anti-KLK2xCD3 antibody, for example on the same day about 4 hours apart.

[0029] In certain embodiments, the anti-KLK2xCD3 antibody is administered at a treatment dose level of 100-2000 mg.

[0030] In certain embodiments, the method comprises administering the anti-KLK2xCD3 antibody at a step-up dose and at a treatment dose, wherein the level of the step-up dose is lower than the level of treatment dose, for example the level of the step-up dose is in the range of 0.1- 600mg per dose and the level of the treatment dose is the range of 100-2000 mg per dose.

[0031] In certain embodiments, the method comprises administering to the subject: i) a step-up dose of the anti-KLK2xCD3 antibody, and ii) a treatment dose of the anti-KLK2xCD3 antibody, wherein the step-up dose is administered once, and the treatment dose is administered at least twice (e.g., 2, 3, 4 or more times); and wherein the level of the step-up dose is lower than the level of the treatment dose.

[0032] In certain embodiments, the step-up dose is administered 2-15 days, such as 1 week, before the first administration of the treatment dose, and wherein the treatment dose is administered once every 1-9 weeks, for example, once every 3 weeks, once every 6 weeks, or once every 9 weeks.

In certain embodiments, the method comprises administering to the subject i) a first step-up dose of the anti-KLK2xCD3 antibody, ii) a second step-up dose of the anti-KLK2xCD3 antibody and iii) a treatment dose of the anti-KLK2xCD3 antibody, wherein the first step-up dose and the second step-up dose are each administered once, and the treatment dose is administered at least twice (e.g., 2, 3, 4 or more times); wherein the level of the first step-up dose is lower than the level of the second step-up dose, and wherein the level of the second step-up dose is lower than the level of the treatment dose level.

[0033] In certain embodiments, the other anti-cancer drug is the anti-cancer chemotherapeutic agent, preferably a taxane, preferably docetaxel or cabazitaxel. [0034] In certain embodiments, the anti -cancer chemotherapeutic agent is intravenously administered, such as via intravenous injection or infusion.

[0035] In certain embodiments, docetaxel or cabazitaxel is intravenously administered to the subject every 1-6 weeks, preferably every 3 weeks.

[0036] In certain embodiments, the other anti-cancer drug is docetaxel, preferably the other anticancer drug is docetaxel and is administered intravenously at a dose of 75 mg/m². In certain embodiments, the other anti -cancer drug is cabazitaxel, preferably the other anti-cancer drug is cabazitaxel and is administered intravenously at a dose of 20 mg/m². In certain embodiments, the other anti-cancer drug is a taxane, and wherein no prednisone, preferably no corticosteroid, is administered as a (pre)medication prior to the administration of taxane, or together with the administration of taxane.

[0037] In certain embodiments, the other anti-cancer drug is the ARPI, such as apatulamide, enzatulamide, darolutamide, or abiraterone acetate.

[0038] In certain embodiments, the ARPI is administered orally.

[0039] Inc certain embodiments, the other anti-cancer drug is apatulamide, preferably the other anti-cancer drug is apalutamide and is administered orally at a dose of 240 mg per day, preferably 240 mg once daily, preferably four tablets of 60 mg once daily. In certain embodiments, the method further comprises orally administering to the subject a pretreatment dose of apalutamide prior to the administration of apalutamide.

[0040] In certain embodiments, the other anti-cancer drug is enzatulamide, preferably the other anti-cancer drug is enzalutamide and is administered orally at a dose of 160 mg per day, preferably 160 mg once daily, preferably four capsules of 40 mg once a day.

[0041] In certain embodiments, the other anti-cancer drug is darolutamide, preferably the other anti-cancer drug is darolutamide and is administered orally at a dose of 1200 mg per day, preferably 600 mg twice daily, preferably two tablets of 300 mg twice daily.

[0042] In certain embodiments, the other anti-cancer drug is abiraterone acetate, preferably the other anti-cancer drug is abiraterone acetate and is administered orally at a dose of 1000 mg per day, preferably 1000 mg once daily, preferably four tablets of 250 mg once daily. In certain embodiments the method further comprises orally administering to the subject prednisone, preferably at a dose of 5 mg or 10 mg per day, preferably of 5 mg once or twice a day, such as one tablet of 5 mg once a day or one tablet of 5 mg twice a day. [0043] In certain embodiments, the prostate cancer is advanced prostate cancer, metastatic castration-sensitive prostate cancer (CSPC), metastatic castration-resistant prostate cancer (CRPC), non-metastatic CSPC, non-metastatic CRPC, or metastatic prostate cancer, preferably the prostate cancer is metastatic CRPC.

[0044] In certain embodiments, the method does not comprise the administration of an anti-PDl antibody at least 6 weeks prior to the first dose of anti-KLK2xCD3 antibody or other anti-cancer agent. In other embodiments, the method does not comprise the administration of an anti-PDl antibody.

[0045] In certain embodiments, the subject does not have one or more of the following:

1) active autoimmune disease within the 12 months that requires systemic immunosuppressive medications, prior to the initial administration of the anti- KLK2xCD3 antibody, except vitiligo and prior autoimmune thyroiditis that is currently euthyroid based on clinical symptoms and laboratory testing;

2) toxicity related to prior anti cancer therapy that has not returned to Grade <1 or baseline levels (except for alopecia, vitiligo, Grade <2 peripheral neuropathy);

3) solid organ or bone marrow transplantation;

4) known allergies or intolerance to any of the anti-KLK2xCD3 antibody, the anti-cancer chemotherapeutic agent and the androgen receptor pathway inhibitor (ARPI);

5) any of the following within 6 months prior to the initial administration of the anti-

KLK2xCD3 antibody: a. Myocardial infarction b. Severe or unstable angina c. Clinically significant ventricular arrhythmias d. Congestive heart failure (New York Heart Association [NYHA] class II to IV) e. Transient ischemic attack f Cerebrovascular accident

6) major surgery (e.g., requiring general anesthesia) within 2 weeks before the initial administration of the anti-KLK2xCD3 antibody or has not recovered from surgery;

7) active infection or condition that requires treatment with systemic antibiotics within 7 days prior to the initial administration of the anti-KLK2xCD3 antibody; ) venous thromboembolic events (e g., pulmonary embolism) within 1 month prior to the first dose of study treatment; uncomplicated (Grade <2) deep vein thrombosis is not considered exclusionary; ) clinically significant pulmonary compromise, particularly a requirement for supplemental oxygen use (>2 L/min by nasal cannula) to maintain adequate oxygenation; 0) active CNS involvement, except treated, stable and asymptomatic brain metastases requiring <10 mg prednisone or equivalent within 2 weeks prior to the first dose of study treatment are permitted; 1) prior treatment with KLK2-targeted therapy; 2) treatment with any anti-cancer or investigational agents within 28 days or 5-half-lives, whichever is shorter, prior to the initial administration of the anti-KLK2xCD3 antibody, such as,

• No restrictions on GnRH agonist/antagonists,

• Immune checkpoint inhibitors within 6 weeks prior to start of study treatment,

• Any T-cell redirecting treatment (e.g., CD3-directed bispecific or CAR-T therapy) within 90 days prior to the start of study treatment,

• External beam radiation therapy within 14 days prior to start of study treatment. However, if palliative focal radiation was used, the participant is eligible irrespective of the end date of radiotherapy,

• Radionuclide therapy within 6 weeks prior to start of study treatment, 3) received immunosuppressive doses of systemic medications, such as glucocorticoids (doses >10 mg/day prednisone or equivalent) within 7 days prior to the first dose of study treatment, provided that a single course of glucocorticoids is permitted as prophylaxis for imaging contrast (i.e., for participants with allergies to contrast); 4) received or plans to receive any live, attenuated vaccine within 4 weeks before the first dose of study treatment; and 5) active hepatitis B or C virus infection according to local laboratory range.

In certain embodiments, the subject is 18 years of age or older, such as i) a subject having metastatic CRPC (mCRPC), ii) a subject having prior orchiectomy, or the subject having not undergone orchiectomy and receives ongoing androgen deprivation therapy with a gonadotropin releasing hormone (GnRH) analog (agonist or antagonist) prior to the initial administration of the anti-KLK2xCD3 antibody and continue androgen deprivation therapy throughout the treatment phase, iii) a subject having microsatellite instability (MSI-H)/mismatch repair deficient (dMMR) disease not previously received and progressed on PD-(L)1 therapy, or iv) a subject having received at least 1 prior treatment with an ARPI (e.g., apalutamide, enzalutamide, darolutamide, or abiraterone acetate) and/or taxane (e.g., docetaxel or cabazitaxel) prior to the initial administration of the anti-KLK2xCD3 antibody.

[0046] In certain embodiments, the subject has not received immunosuppressive doses of systemic medications, such as glucocorticoids (doses >10 mg/day prednisone or equivalent) within 7 days prior to the first dose of study treatment, provided that a single course of glucocorticoids is permitted as prophylaxis for imaging contrast (i.e., for participants with allergies to contrast).

In certain embodiments, the subject is i) a subject having metastatic CRPC (mCRPC); ii) a subject having prior orchiectomy, or the subject having not undergone orchiectomy and receives ongoing androgen deprivation therapy with a gonadotropin releasing hormone (GnRH) analog (agonist or antagonist) prior to the initial administration of the anti-KLK2xCD3 antibody and continue androgen deprivation therapy throughout the treatment phase; iii) a subject having microsatellite instability (MSI-H)/mismatch repair deficient (dMMR) disease not previously received and progressed on PD-(L)1 therapy; iv) a subject having received at least 1 prior treatment with an ARPI (e.g., apalutamide, enzalutamide, darolutamide, or abiraterone acetate) and/or taxane (e.g., docetaxel or cabazitaxel) prior to the initial administration of the anti-KLK2xCD3 antibody; and/or v) a subject living with HIV; and wherein the subject preferably is 18 years of age or older.

[0047] The application also relates to the anti-KLK2xCD3 antibody, the taxane (e.g., docetaxel or cabazitaxel), the ARPI (e.g., apalutamide, enzalutamide, darolutamide, or abiraterone acetate), the combination of the anti-KLK2xCD3 antibody with the taxane (e.g., docetaxel or cabazitaxel), or the combination of the anti-KLK2xCD3 antibody with the ARPI (e g., apalutamide, enzalutamide, darolutamide, or abiraterone acetate) in a method of treating prostate cancer according to an embodiment of the application.

[0048] Further aspects, features and advantages of the present invention will be better appreciated upon a reading of the following detailed description of the invention and claims.

BRIEF DESCRIPTION OF THE DRAWINGS

[0049] The foregoing and other objects, aspects, features, and advantages of exemplary embodiments will become more apparent and may be better understood by referring to the following description taken in conjunction with the accompanying drawings.

[0050] FIG. 1 shows the reduction in surface expression of KLK2 in VCaP prostate cancer cells after treatment with apalutamide for 6 days.

[0051] FIG. 2A shows the total count of isolated CD3+ cells from donor whole blood. Each donor is represented by a single data point.

[0052] FIG. 2B shows the abundance of CD3+ cells from donor whole blood as a portion of the live, singlet cells. Each donor is represented by a single data point.

[0053] FIG. 3A shows the mean cytolysis AUC ± standard deviation of prostate cancer target cells treated with KLK2xCD3 bispecific antibody with and without apalutamide for healthy donors (n = 5). The horizontal dotted line shows the AUC cytolysis of prostate cancer target cells treated with apalutamide alone at 10 pM apalutamide for healthy donors.

[0054] FIG. 3B shows the mean cytolysis AUC ± standard deviation of prostate cancer target cells treated with KLK2xCD3 bispecific antibody with and without apalutamide for mCRPC donors (n = 7). The horizontal dotted line shows the AUC cytolysis of prostate cancer target cells with apalutamide alone at 10 pM apalutamide for mCRPC donors.

[0055] FIG. 4 shows the statistical comparison of the AUC of cytolysis with KLK2xCD3 bispecific antibody alone versus KLK2xCD3 bispecific antibody in combination with 10 pM apalutamide in lysed whole blood from healthy donors (n= 5) and mCRPC donors (n= 7). Each paired data point represents a unique donor. Two-tailed, paired t tests were used to compare mean AUCs for each donor at given doses of the KLK2xCD3 bispecific antibody. Results of the paired t test are shown for each plot. [0056] FIG. 5 shows the cytolysis AUC for each donor and ARPI at 1 .11 nM KLK2xCD3. Each data point represents a different donor. Height of bar denotes the mean cytolysis AUC at 1.11 nM and the error bars represent SEM.

[0057] FIG. 6 shows the schematic overview of the study of study KLK2xCD3 bispecific antibody in combination with a taxane or an Androgen Receptor Pathway Inhibitor (ARPI). *PK/PD cohorts: additional participants may be enrolled at one or more dose cohorts considered to be safe by the Study Evaluation Team for additional PK/PD sample collection. **Different treatment dose levels and schedules may be explored during dose escalation.

DETAILED DESCRIPTION OF THE INVENTION

[0058] The disclosed methods may be understood more readily by reference to the following detailed description taken in connection with the accompanying figures, which form a part of this disclosure. It is to be understood that the disclosed methods are not limited to the specific methods described and/or shown herein, and that the terminology used herein is for the purpose of describing particular embodiments by way of example only and is not intended to be limiting of the claimed methods. All patents, published patent applications, and publications cited herein are incorporated by reference as if set forth fully herein.

[0059] Various terms relating to aspects of the description are used throughout the specification and claims. Such terms are to be given their ordinary meaning in the art unless otherwise indicated. Other specifically defined terms are to be construed in a manner consistent with the definitions provided herein.

[0060] As used in this specification and the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the content clearly dictates otherwise. Thus, for example, reference to “a cell” includes a combination of two or more cells, and the like.

[0061] When a list is presented, unless stated otherwise, it is to be understood that each individual element of that list, and every combination of that list, is a separate embodiment. For example, a list of embodiments presented as “A, B, or C” is to be interpreted as including the embodiments, “A,” “B,” “C,” “A or B,” “A or C,” “B or C,” or “A, B, or C.”

[0062] Unless otherwise stated, any numerical values, such as a concentration or a concentration range described herein, are to be understood as being modified in all instances by the term “about.” Thus, a numerical value typically includes ± 10% of the recited value. For example, a concentration of 1 mg/mL includes 0.9 mg/mL to 1 .1 mg/mL. Likewise, a concentration range of 1% to 10% (w/v) includes 0.9% (w/v) to 11% (w/v). As used herein, the use of a numerical range expressly includes all possible subranges, all individual numerical values within that range, including integers within such ranges and fractions of the values unless the context clearly indicates otherwise.

[0063] Unless otherwise indicated, the term “at least” preceding a series of elements is to be understood to refer to every element in the series. Those skilled in the art will recognize or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Such equivalents are intended to be encompassed by the invention.

[0064] The transitional terms “comprising,” “consisting essentially of,” and “consisting of’ are intended to connote their generally accepted meanings in the patent vernacular; that is, (i) “comprising,” which is synonymous with “including,” “containing,” or “characterized by,” is inclusive or open-ended and does not exclude additional, unrecited elements or method steps; (ii) “consisting of’ excludes any element, step, or ingredient not specified in the claim; and (iii) “consisting essentially of’ limits the scope of a claim to the specified materials or steps “and those that do not materially affect the basic and novel character! stic(s)” of the claimed invention. Embodiments described in terms of the phrase “comprising” (or its equivalents) also provide as embodiments those independently described in terms of “consisting of’ and “consisting essentially of.”

[0065] It should also be understood that the terms “about,” “approximately,” “generally,” “substantially” and like terms, used herein when referring to a dimension or characteristic of a component of the preferred invention, indicate that the described dimension/ characteristic is not a strict boundary or parameter and does not exclude minor variations therefrom that are functionally the same or similar, as would be understood by one having ordinary skill in the art. At a minimum, such references that include a numerical parameter would include variations that, using mathematical and industrial principles accepted in the art (e g., rounding, measurement or other systematic errors, manufacturing tolerances, etc.), would not vary the least significant digit. [0066] The terms “identical” or percent “identity,” in the context of two or more nucleic acids or polypeptide sequences (e.g., anti-KLK2/anti-CD3 bispecific antibodies and polynucleotides that encode them, anti-KLK2/anti-CD3 bispecific antibodies and polynucleotides that encode them, KLK2 polypeptides and KLK2 polynucleotides that encode them, CD3 polypeptides and CD3 polynucleotides that encode them), refer to two or more sequences or subsequences that are the same or have a specified percentage of amino acid residues or nucleotides that are the same, when compared and aligned for maximum correspondence, as measured using one of the following sequence comparison algorithms or by visual inspection.

[0067] For sequence comparison, typically one sequence acts as a reference sequence, to which test sequences are compared. When using a sequence comparison algorithm, test and reference sequences are input into a computer, subsequence coordinates are designated, if necessary, and sequence algorithm program parameters are designated. The sequence comparison algorithm then calculates the percent sequence identity for the test sequence(s) relative to the reference sequence, based on the designated program parameters.

[0068] Optimal alignment of sequences for comparison can be conducted, e.g., by the local homology algorithm of Smith & Waterman, Adv. Appl. Math. 2:482 (1981), by the homology alignment algorithm of Needleman & Wunsch, J. Mol. Biol. 48:443 (1970), by the search for similarity method of Pearson & Lipman, Proc. Nat’L Acad. Sci. USA 85:2444 (1988), by computerized implementations of these algorithms (GAP, BESTFIT, FASTA, and TFASTA in the Wisconsin Genetics Software Package, Genetics Computer Group, 575 Science Dr., Madison, WI), or by visual inspection (see generally, Current Protocols in Molecular Biology, F.M. Ausubel et al., eds., Current Protocols, a joint venture between Greene Publishing Associates, Inc. and John Wiley & Sons, Inc., (1995 Supplement) (Ausubel)).

[0069] Examples of algorithms that are suitable for determining percent sequence identity and sequence similarity are the BLAST and BLAST 2.0 algorithms, which are described in Altschul et al. (1990) J. Mol. Biol. 215: 403-410 and Altschul et al. (1997) Nucleic Acids Res. 25: 3389- 3402, respectively.

[0070] A “host cell” refers to a vehicle that includes the necessary cellular components, e.g., organelles, needed to express the polypeptides and constructs described herein from their corresponding nucleic acids. The nucleic acids may be included in nucleic acid vectors that can be introduced into the host cell by conventional techniques known in the art (e.g., transformation, transfection, electroporation, calcium phosphate precipitation, direct microinjection, infection, etc.). The choice of nucleic acid vectors depends in part on the host cells to be used. Generally, host cells are of either prokaryotic (e.g., bacterial) or eukaryotic (e.g., mammalian) origin. [0071 ] “Antigen” refers to any molecule (e.g., protein, peptide, polysaccharide, glycoprotein, glycolipid, nucleic acid, portions thereof, or combinations thereof) capable of being bound by an antigen binding domain or a T-cell receptor capable of mediating an immune response. Exemplary immune responses include antibody production and activation of immune cells, such as T cells, B cells or NK cells. Antigens may be expressed by genes, synthetized, or purified from biological samples such as a tissue sample, a tumor sample, a cell or a fluid with other biological components, organisms, subunits of proteins/antigens, killed or inactivated whole cells or lysates.

[0072] “Antigen binding fragment” or “antigen binding domain” refers to a portion of the protein that binds an antigen. Antigen binding fragments may be synthetic, enzymatically obtainable or genetically engineered polypeptides and include portions of an immunoglobulin that bind an antigen, such as the VH, the VL, the VH and the VL, Fab, Fab', F(ab')2, Fd and Fv fragments, domain antibodies (dAb) consisting of one VH domain or one VL domain, shark variable IgNAR domains, camelized VH domains, VHH domains, minimal recognition units consisting of the amino acid residues that mimic the CDRs of an antibody, such as FR3-CDR3- FR4 portions, the HCDR1, the HCDR2 and/or the HCDR3 and the LCDR1, the LCDR2 and/or the LCDR3, alternative scaffolds that bind an antigen, and multispecific proteins comprising the antigen binding fragments. Antigen binding fragments (such as VH and VL) may be linked together via a synthetic linker to form various types of single antibody designs where the VH/VL domains may pair intramolecularly, or intermolecularly in those cases when the VH and VL domains are expressed by separate single chains, to form a monovalent antigen binding domain, such as single chain Fv (scFv) or diabody. Antigen binding fragments may also be conjugated to other antibodies, proteins, antigen binding fragments or alternative scaffolds which may be monospecific or multispecific to engineer bispecific and multispecific proteins.

[0073] “Antibodies” is meant in a broad sense and includes immunoglobulin molecules including monoclonal antibodies including murine, human, humanized and chimeric monoclonal antibodies, antigen binding fragments, multispecific antibodies, such as bispecific, trispecific, tetraspecific, dimeric, tetrameric or multimeric antibodies, single chain antibodies, domain antibodies and any other modified configuration of the immunoglobulin molecule that comprises an antigen binding site of the required specificity. “Full length antibodies” are comprised of two heavy chains (HC) and two light chains (LC) inter-connected by disulfide bonds as well as multimers thereof (e.g. IgM). Each heavy chain is comprised of a heavy chain variable region (VH) and a heavy chain constant region (comprised of domains CHI, hinge, CH2 and CH3). Each light chain is comprised of a light chain variable region (VL) and a light chain constant region (CL). The VH and the VL regions may be further subdivided into regions of hypervariability, termed complementarity determining regions (CDR), interspersed with framework regions (FR). Each VH and VL is composed of three CDRs and four FR segments, arranged from amino-to-carboxy-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3 and FR4. Immunoglobulins may be assigned to five major classes, IgA, IgD, IgE, IgG and IgM, depending on the heavy chain constant domain amino acid sequence. IgA and IgG are further sub-classified as the isotypes IgAl, IgA2, IgGl, IgG2, IgG3 and IgG4. Antibody light chains of any vertebrate species may be assigned to one of two clearly distinct types, namely kappa (K) and lambda (X), based on the amino acid sequences of their constant domains.

[0074] “Complementarity determining regions” (CDR) are antibody regions that bind an antigen. There are three CDRs in the VH (HCDR1, HCDR2, HCDR3) and three CDRs in the VL (LCDR1, LCDR2, LCDR3). CDRs may be defined using various delineations such as Kabat (Wu et al. (1970) J Exp Med 132: 211-50; Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md., 1991), Chothia (Chothia et al. (1987) J Mol Biol 196: 901-17), IMGT (Lefranc et al. (2003) Dev Comp Immunol 27: 55-77) and AbM (Martin and Thornton J Bmol Biol 263: 800-15, 1996). The correspondence between the various delineations and variable region numbering is described (see e g., Lefranc et al. (2003) Dev Comp Immunol 27: 55-77; Honegger and Pluckthun, J Mol Biol (2001) 309:657-70; International ImMunoGeneTics (IMGT) database). Available programs such as abYsis by UCL Business PLC may be used to delineate CDRs. The term “CDR”, “HCDR1”, “HCDR2”, “HCDR3”, “LCDR”, “LCDR2” and “LCDR3” as used herein includes CDRs defined by any of the methods described supra, Kabat, Chothia, IMGT or AbM, unless otherwise explicitly stated in the specification.

[0075] “Epitope” refers to a portion of an antigen to which an antibody specifically binds. Epitopes typically consist of chemically active (such as polar, non-polar or hydrophobic) surface groupings of moieties such as amino acids or polysaccharide side chains and may have specific three-dimensional structural characteristics, as well as specific charge characteristics. An epitope may be composed of contiguous and/or discontinuous amino acids that form a conformational spatial unit. For a discontinuous epitope, amino acids from differing portions of the linear sequence of the antigen come in close proximity in 3 -dimensional space through the folding of the protein molecule. Antibody “epitope” depends on the methodology used to identify the epitope.

[0076] “Specifically binds,” “specific binding,” “specifically binding” or “binds” refer to a proteinaceous molecule binding to an antigen or an epitope within the antigen with greater affinity than for other antigens. Typically, the proteinaceous molecule binds to the antigen or the epitope within the antigen with an equilibrium dissociation constant (KD) of about 1 x 10 ⁷ M or less, for example about 5/ 10 ^XM or less, about lx 10 ⁸ M or less, about I ^z 10 ⁹ M or less, about I / J O ¹⁰ M or less, about 1 10 ¹¹ M or less, or about I x l O ¹² M or less, typically with the KD that is at least one hundred fold less than its KD for binding to a non-specific antigen (e.g., BSA, casein). In the context of the prostate neoantigens described here, “specific binding” refers to binding of the proteinacous molecule to the prostate neoantigen without detectable binding to a wild-type protein the neoantigen is a variant of.

[0077] “dAb” or “dAb fragment” refers to an antibody fragment composed of a VH domain (Ward et al., Nature 341:544 546 (1989)).

[0078] “Fab” or “Fab fragment” refers to an antibody fragment composed of VH, CHI, VL and CL domains.

[0079] “F(ab')2” or “F(ab')2 fragment” refers to an antibody fragment containing two Fab fragments connected by a disulfide bridge in the hinge region.

[0080] “Fd” or “Fd fragment” refers to an antibody fragment composed of VH and CHI domains.

[0081] “Fv” or “Fv fragment” refers to an antibody fragment composed of the VH and the VL domains from a single arm of the antibody. Fv fragments lack the constant regions of Fab (CHI and CL) regions. The VH and VL in Fv fragments are held together by non-covalent interactions. [0082] “Fc” polypeptide” of a dimeric Fc refers to one of the two polypeptide forming the dimeric Fc domain. For example, an Fc polypeptide of a dimeric IgG FC comprises an IgG CH2 and an IgG CH3 constant domain sequence).

[0083] “Single chain Fv” or “scFv” refers to a fusion protein comprising at least one antibody fragment comprising a light chain variable region (VL) and at least one antibody fragment comprising a heavy chain variable region (VH), wherein the VL and the VH are contiguously linked via a polypeptide linker, and capable of being expressed as a single chain polypeptide. Unless specified, as used herein, a scFv may have the VL and VH variable regions in either order, e.g., with respect to the N-terminal and C-terminal ends of the polypeptide, the scFv may comprise VL-linker-VH or may comprise VH-linker-VL. The scFv can be fused to an Fc to create a scFv-Fc wherein the scFv is fused to the IgG CH2 and IgG CH3 domain of the Fc via the hinge domain.

[0084] “Stapled single chain Fv”, “stapled scFv” or “spFv” refers to a scFv that comprises one or more disulfide bonds between the VH and the linker or the VL and the linker. Typically, the spFv may comprise one disulfide bond between the VH and the linker, and one disulfide bond between the VL and the linker, or two disulfide bonds between the VH and the linker and the VL and the linker. The spFv can be fused to an Fc to create a spFv-Fc wherein the spFv is fused to the IgG CH2 and IgG CH3 domain of the Fc via the hinge domain.

[0085] “(scFv)2” or “tandem scFv” or “bis-scFv” fragments refers to a fusion protein comprising two light chain variable region (VL) and two heavy chain variable region (VH), wherein the two VL and the two VH regions are contiguously linked via polypeptide linkers, and capable of being expressed as a single chain polypeptide. The two VL and two VH regions fused by peptide linkers form a bivalent molecule VLA-linker-VHA-linker-VLB-linker-VHB to form two binding sites, capable of binding two different antigens or epitopes concurrently.

[0086] “Full length antibody” is comprised of two heavy chains (HC) and two light chains (LC) inter-connected by disulfide bonds as well as multimers thereof (e.g. IgM). Each heavy chain is comprised of a heavy chain variable domain (VH) and a heavy chain constant domain, the heavy chain constant domain comprised of subdomains CHI, hinge, CH2 and CH3. Each light chain is comprised of a light chain variable domain (VL) and a light chain constant domain (CL). The VH and the VL may be further subdivided into regions of hypervariability, termed complementarity determining regions (CDR), interspersed with framework regions (FR). Each VH and VL is composed of three CDRs and four FR segments, arranged from amino-to-carboxy- terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3 and FR4.

[0087] “Monoclonal antibody” refers to an antibody obtained from a substantially homogenous population of antibody molecules, i.e., the individual antibodies comprising the population are identical except for possible well-known alterations such as removal of C-terminal lysine from the antibody heavy chain or post-translational modifications such as amino acid isomerization or deamidation, methionine oxidation or asparagine or glutamine deamidation. Monoclonal antibodies typically bind one antigenic epitope. A bispecific monoclonal antibody binds two distinct antigenic epitopes. Monoclonal antibodies may have heterogeneous glycosylation within the antibody population. Monoclonal antibody may be monospecific or multispecific such as bispecific, monovalent, bivalent or multivalent.

[0088] “Multispecific” refers to a molecule, such as an antibody that specifically binds two or more distinct antigens or two or more distinct epitopes within the same antigen. Multispecific molecule may have cross-reactivity to other related antigens, for example to the same antigen from other species (homologs), such as human or monkey, for example Macaca fascicularis (cynomolgus, cyno) or Pan troglodytes, or may bind an epitope that is shared between two or more distinct antigens.

[0089] “Bispecific” refers to a molecule (such as an antibody) that specifically binds two distinct antigens or two distinct epitopes within the same antigen. The bispecific molecule may have cross-reactivity to other related antigens, for example to the same antigen from other species (homologs), such as human or monkey, for example Macaca cynomolgus (cynomolgus, cyno) or Pan troglodytes, or may bind an epitope that is shared between two or more distinct antigens. [0090] Unless indicated otherwise, the numbering of amino acid residues in the antibody constant region throughout the specification is according to the EU index as described in Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md. (1991), unless otherwise explicitly stated.

[0091] In some embodiments, antibodies described herein can comprise mutations (e.g., amino acid substitutions, additions, and/or deletions) outside of the CDRs (e.g., in framework regions (FRs) or constant regions). An amino acid substitution, addition, and/or deletion can be a substitution, addition, and/or deletion of one or more amino acids (e.g., 1, 2, 3, 4, 5, 6, 7, 8, or more). An amino acid substitution, addition, and/or deletion can be a substitution, addition, and/or deletion of eight or fewer, seven or fewer, six or fewer, five or fewer, four or fewer, three or fewer, or two or fewer single amino acids. In some embodiments, antibodies described herein may include amino acid substitutions, additions, and/or deletions in the constant regions (e.g., Fc region) of the antibody that, e.g., lead to decreased effector function, e.g., decreased complement-dependent cytolysis (CDC) antibody-dependent cell-mediated cytolysis (ADCC), antibody-dependent cell-mediated phagocytosis (ADCP), and/or decreased B-cell killing. For many applications of therapeutic antibodies, Fc-mediated effector functions are not part of the mechanism of action. These Fc-mediated effector functions can be detrimental and potentially pose a safety risk by causing off-mechanism toxicity. Modifying effector functions can be achieved by engineering the Fc regions to reduce their binding to FcgRs or the complement factors. The binding of IgG to the activating (FcgRI, FcgRIIa, FcgRIIIa and FcgRIIIb) and inhibitory (FcgRIIb) FcgRs or the first component of complement (Clq) depends on residues located in the hinge region and the CH2 domain. Mutations can be introduced in IgGl, IgG2 and IgG4 to reduce or silence Fc functionalities. Silencing mutations can include, but are not limited to IgGl AA (F234A, L235A), IgG4 PAA (S228P, F234A, L235A), IgG2 AA (V234A, G237A), IgGl FEA (L234F, L235E or D265A), IgGl AAS (L234A, L235A, and D265S), or IgGl FES (L234F/L235E/P331S). In some embodiments, the disclosed antibody or antigen-binding fragment thereof can contain the IgGl AA (L234A, L235A) mutations. In some embodiments, the disclosed antibody or antigen-binding fragment thereof can contain IgGl AAS (L234A, L235A, and D265S) mutations to eliminate effector function. The disclosed antibodies or antigen-binding fragments thereof can comprise an Fc region with one or more of the following properties: (a) reduced effector function when compared to the parent Fc; (b) reduced affinity to FcyRI, FcyRIIa, FcyRIIb, FcyRIIIb and/or FcyRIIIa; (c) reduced affinity to FcyRI; (d) reduced affinity to FcyRIIa; (e) reduced affinity to FcyRIIb; (f) reduced affinity to FcyRIIIb; or (g) reduced affinity to FcyRIIIa.

[0092] In some embodiment, one or more mutations can be introduced into the CH3 domain of two heavy chains to favor formation of the heterodimer during co-transfection.

“Heterodimerization” as used herein refers to an interaction of two heavy chains having nonidentical CH3 amino acid sequences. “Heterodimer” as used herein refers to an antibody having two heavy chains with non-identical CH3 amino acid sequences. The “knob-in-hole” strategy (see, e.g., PCT Publ. No. W02006/028936) can be used to generate full length bispecific antibodies. Briefly, selected amino acids forming the interface of the CH3 domains in human IgG can be mutated at positions affecting CH3 domain interactions to promote heterodimer formation. An amino acid with a small side chain (hole) is introduced into a heavy chain of an antibody specifically binding a first antigen and an amino acid with a large side chain (knob) is introduced into a heavy chain of an antibody specifically binding a second antigen. After coexpression of the two antibodies, a heterodimer is formed as a result of the preferential interaction of the heavy chain with a “hole” with the heavy chain with a “knob .” Exemplary CH3 substitution pairs forming a knob and a hole are (expressed as modified position in the first CH3 domain of the first heavy chain/modified position in the second CH3 domain of the second heavy chain): T366Y/F405A, T366W/F405W, F405W/Y407A, T394W/Y407T, T394S/Y407A, T366W/T394S, F405W/T394S and T366W/T366S_L368A_Y407V. For example, one heavy chain can feature a knob mutation: T366W while another heavy chain can feature the hole mutations: T366S, L368A, Y407V, and the knobs-into-holes mutations promote heterodimerization of the two heavy chains.

[0093] Other strategies such as promoting heavy chain heterodimerization using electrostatic interactions by substituting positively charged residues at one CH3 surface and negatively charged residues at a second CH3 surface can be used, as described in US Pat. Publ. No. US2010/0015133; US Pat. Publ. No. US2009/0182127; US Pat. Publ. No. US2010/028637; or US Pat. Publ. No. US2011/0123532. In other strategies, heterodimerization can be promoted by the following substitutions (expressed as modified position in the first CH3 domain of the first heavy chain/modified position in the second CH3 domain of the second heavy chain): L351 Y_F405AY407V/T394W, T3661_K392M_T394W/F405A_Y407V, T366L_K392M_T394W/F405A_Y407V, L351 Y_Y407A/T366A_K409F, L351Y_Y407A/T366V K409F Y407A/T366A_K409F, or T350V_L351Y_F405A Y407V/T350V_T366L_K392L_T394W as described in U.S. Pat. Publ. No. US2012/0149876 or U.S. Pat. Publ. No. US2013/0195849. For example, L351Y, F405A and Y407V mutations can be introduced into one immunoglobulin constant region, and T394W can be introduced into another immunoglobulin constant region, and the interaction of the L351Y, F405A and Y407V mutations in the first Ig constant region and T394W mutation in the second Ig constant region promotes heterodimerization of the two immunoglobulin constant regions.

[0094] “CD3” refers to an antigen which is expressed on T cells as part of the multimolecular T cell receptor (TCR) complex and which consists of a homodimer or heterodimer formed from the association of two or four receptor chains: CD3 epsilon, CD3 delta, CD3 zeta and CD3 gamma. All references to proteins, polypeptides and protein fragments herein are intended to refer to the human version of the respective protein, polypeptide or protein fragment unless explicitly specified as being from a non-human species. Thus, “CD3” means human CD3 unless specified as being from a non-human species, e g., “mouse CD3” or “monkey CD3,” etc. [0095] Throughout the specification, “CD3-specific” or “specifically binds CD3” or “anti-CD3 antibody” refers to antibodies that bind specifically to a CD3 -epsilon polypeptide, including antibodies that bind specifically to the CD3-epsilon extracellular domain (ECD). CD3-epsilon, together with CD3-gamma, -delta and -zeta, and the T-cell receptor alpha/beta and gamma/delta heterodimers, forms the T-cell receptor-CD3 complex. This complex plays an important role in coupling antigen recognition to several intracellular signal-transduction pathways. The CD3 complex mediates signal transduction, resulting in T cell activation and proliferation. CD3 is required for the immune response.

[0096] “Kallikrein related peptidase 2” or “KLK2” or “hK2” refers to a human protein which is also called kallikrein-2, grandular kallikrein 2, or HK2. hK2 is produced as a preproprotein and cleaved during proteolysis to generate active protease. All hK2 isoforms and variants are encompassed in “hK2”. The amino acid sequences of various isoforms are retrievable from public sources, such as GenBank accession numbers NP_005542.1, NP_001002231.1 and NP_001243009.

[0097] “Bispecific anti-hK2/anti-CD3 antibody”, “hk2/CD3 antibody”, “hk2xCD3 antibody,” “KLK2xCD3 antibody,” “anti-KLK2xCD3 antibody,” “anti-hK2/anti-CD3 protein,” and the like refer to an antibody that binds KLK2 and CD3 and that comprises at least one binding domain specifically binding KLK2 and at least one binding domain specifically binding CD3. The domains specifically binding hK2 and CD3 are typically VH/VL pairs. The bispecific anti- hk2xCD3 antibody may be monovalent in terms of its binding to either KLK2 or CD3.

[0098] “Decrease,” “lower,” “lessen,” “reduce,” or “abate” refers generally to the ability of a test molecule to mediate a reduced response (i.e., downstream effect) when compared to the response mediated by a control or a vehicle. Decrease may be a statistically significant difference in the measured response between the test molecule and the control (or the vehicle), or a decrease in the measured response, such as a decrease of about 1.1, 1.2, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20 or 30 fold or more, such as 500, 600, 700, 800, 900 or 1000 fold or more (including all integers and decimal points in between and above 1, e.g., 1.5, 1.6, 1.7, 1.8, etc.).

[0099] “Enhance,” “promote,” “increase,” “expand” or “improve” refers generally to the ability of a test molecule to mediate a greater response (i.e., downstream effect) when compared to the response mediated by a control or a vehicle. Enhance may be a statistically significant difference in the measured response between the test molecule and control (or vehicle), or an increase in the measured response, such as an increase of about 1.1, 1.2, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 , 20 or 30 fold or more, such as 500, 600, 700, 800, 900 or 1000 fold or more (including all integers and decimal points in between and above 1, e.g., 1.5, 1.6, 1.7, 1.8, etc.).

[0100] “Enhanced immune cell function” can be enhanced function of any type of immune cells, for example of T and/or NK cells, for example of T cells. The term function is understood in accordance with its ordinary meaning in the art. More particularly, it refers to:

[0101] - tumor cell killing induced or mediated by immune cells (e.g., by T cells and/or NK cells, e.g., by T cells);

[0102] - cytotoxicity induced or mediated by immune cells (e.g., by T cells and/or NK cells, e.g., by T cells);

[0103] - activation of immune cells (e.g., of T cells and/or NK cells, e.g., of T cells); and [0104] - proliferation of immune cells (e.g., of T cells and/or NK cells, e.g., of T cells);

[0105] preferably tumor cell killing induced or mediated by immune cells (e.g., by T cells and/or NK cells, e.g., by T cells).

[0106] “Combination” refers to a functional unity comprising two or more ingredients for simultaneous, sequential, or separate administration.

[0107] “Pharmaceutical composition” refers to a composition that results from combining an active ingredient and a pharmaceutically acceptable carrier.

[0108] “Pharmaceutically acceptable carrier” or “excipient” refers to an ingredient in a pharmaceutical composition, other than the active ingredient, which is nontoxic to a subject. Exemplary pharmaceutically acceptable carriers are a buffer, stabilizer or preservative.

[0109] “Treat,” “treating” or “treatment” of a disease or disorder such as cancer refers to accomplishing one or more of the following: reducing the severity and/or duration of the disorder, inhibiting worsening of symptoms characteristic of the disorder being treated, limiting or preventing recurrence of the disorder in subjects that have previously had the disorder, or limiting or preventing recurrence of symptoms in subjects that were previously symptomatic for the disorder.

[0110] “Prevent,” “preventing,” “prevention,” or “prophylaxis” of a disease or disorder means preventing that a disorder occurs in a subject.

[0111] “Relapsed” refers to the return of a disease or the signs and symptoms of a disease after a period of improvement after prior treatment with a therapeutic. [0112] “Refractory” refers to a disease that does not respond to a treatment. A refractory disease can be resistant to a treatment before or at the beginning of the treatment, or a refractory disease can become resistant during a treatment.

[0113] “Therapeutically effective amount” or “effective amount” used interchangeably herein, refers to an amount effective, at dosages and for periods of time necessary, to achieve a desired therapeutic result. A therapeutically effective amount may vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of a therapeutic or a combination of therapeutics to elicit a desired response in the individual. Example indicators of an effective therapeutic or combination of therapeutics that include, for example, improved wellbeing of the patient, reduction of a tumor burden, arrested or slowed growth of a tumor, and/or absence of metastasis of cancer cells to other locations in the body. An “effective amount” can be a “combination dose”, a dosage amount of a drug product to be used when the drug product is administered to a subject with another drug product.

[0114] “Subject” includes any human or nonhuman animal. “Nonhuman animal” includes all vertebrates, e.g., mammals and non-mammals, such as nonhuman primates, sheep, dogs, cats, horses, cows, chickens, amphibians, reptiles, etc. The terms “subject” and “patient” can be used interchangeably herein.

[0115] “Cancer” refers to a broad group of various diseases characterized by the uncontrolled growth of abnormal cells in the body. Unregulated cell division and growth results in the formation of malignant tumors that invade neighboring tissues and may also metastasize to distant parts of the body through the lymphatic system or bloodstream. A “cancer” or “cancer tissue” can include a tumor.

[0116] “Tumor cell” or a “cancer cell” refers to a cancerous, pre-cancerous or transformed cell, either in vivo, ex vivo, or in tissue culture, that has spontaneous or induced phenotypic changes. These changes do not necessarily involve the uptake of new genetic material. Although transformation may arise from infection with a transforming virus and incorporation of new genomic nucleic acid, uptake of exogenous nucleic acid or it can also arise spontaneously or following exposure to a carcinogen, thereby mutating an endogenous gene.

Transformation/cancer is exemplified by morphological changes, immortalization of cells, aberrant growth control, foci formation, proliferation, malignancy, modulation of tumor specific marker levels, invasiveness, tumor growth in suitable animal hosts such as nude mice, and the like, in vitro, in vivo, and ex vivo.

[0117] As used herein, the term “adverse event” (AE) refers to any untoward medical occurrence in a patient administered a pharmaceutical product and which does not necessarily have a causal relationship with the treatment. According to embodiments of the invention, AEs are rated on a 3-point scale of increasing severity using the following definitions: mild (grade 1), referring to an AE that is easily tolerated by the subject, which causes minimal discomfort and does not interfere with everyday activities; moderate (grade 2), referring to an AE that is sufficiently discomforting to interfere with normal everyday activities and intervention may be needed; severe (grade 3), referring to an AE that prevents normal everyday activities, and treatment or other intervention is usually needed. Adverse events include cytokine release syndrome (CRS), immune effector cell associated neurotoxicity syndrome (ICANS), systemic administration related reactions (sARRs), immune-related adverse events (irAEs).

[0118] A serious AE (SAE) can be any AE occurring at any dose that results in any of the following outcomes: death, where death is an outcome, not an event; life-threatening, referring to an event in which the patient is at risk of death at the time of the event; it does not refer to an event which could hypothetically have caused death had it been more severe; in patient hospitalization, i.e., an unplanned, overnight hospitalization, or prolongation of an existing hospitalization; persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions; congenital anomaly/birth defect; important medical event (as deemed by the investigator) that may jeopardize the patients or may require medical or surgical intervention to prevent one of the other outcomes listed above (e.g., intensive treatment in an emergency room or at home for allergic bronchospasm or blood dyscrasias or convulsions that do not result in hospitalization). Hospitalization is official admission to a hospital.

Hospitalization or prolongation of a hospitalization constitutes criteria for an AE to be serious; however, it is not in itself considered an SAE. In the absence of an AE, hospitalization or prolongation of hospitalization should not be reported as a SAE by the participating investigator. This can be the case, in the following situations: the hospitalization or prolongation of hospitalization is needed for a procedure required by the protocol; or the hospitalization or prolongation of hospitalization is a part of a routine procedure followed by the center (e.g., stent removal after surgery). This should be recorded in the study file. Hospitalization for elective treatment of a pre-existing condition that did not worsen during the study is not considered an AE. Complications that occur during hospitalization are AEs. If a complication prolongs hospitalization, or meets any of the other SAE criteria, then the event is an SAE.

[0119] “Flat dose” refers to a dose that is administered to a subject without correction for the subject’s specific body weight or body surface area. A flat dose, sometimes referred to as a fixed dose, is therefore provided as an absolute amount of the agent (e.g., mg drug), and not as a weight-based amount that accounts for the subject’s specific weight (e.g. pg/kg or pg drug per kg body weight). For example, a subject weighing 65kg may be administered the same flat dose in milligrams as a subject weighing 85kg. A flat dose may be administered according to a predefined class or category of body weight, but is not modified according to the subject’s specific weight. For example, a “Flat Dose A” may be administered if a patient is greater than a predefined threshold weight, whereas a different “Flat Dose B” may be administered if the patent is less than the pre-defined threshold weight.

“Weight-based dose” refers to when a dose, such as a treatment dose or a step-up dose, is determined using the body weight of the subject. Such dosages can, for example, be based on the mg/kg dosages provided above according to the following: dose (mg/kg) x body weight (e.g., 50 - 100 kg).

[0120] In one general aspect, the application relates to a method of treating prostate cancer in a subject, wherein the method comprises administering to the subject an anti-KLK2xCD3 antibody and another anti-cancer drug, wherein the other anti-cancer drug an androgen receptor pathway inhibitor (ARPI) or an anti -cancer chemotherapeutic agent.

[0121] In certain embodiments, the administering of the anti-KLK2xCD3 antibody and the other anti-cancer drug enhances immune cell function, such as enhances T cell function, as compared to the administration of each of the anti-KLK2xCD3 antibody and the other anti-cancer drug alone, preferably, the T cell function comprises T cell cytotoxicity (or T cell killing), T cell activation, and/or T cell proliferation, e.g., the T cell function is T cell cytotoxicity (or T cell killing), more preferably T cell killing of prostate cancer cells.

[0122] In certain embodiments, the administering of the anti-KLK2xCD3 antibody and the other anti-cancer drug prevents disease progression of the prostate cancer. [0123] In certain embodiments, the administering of the anti-KLK2xCD3 antibody and the other anti-cancer drug does not increase the risk of a treatment emergent adverse event as compared to the administration of each of the anti-KLK2xCD3 antibody and the other anti-cancer drug alone. [0124] In certain embodiments, the administering of the anti-KLK2xCD3 antibody and the other anti-cancer drug provides a reduction in serum Prostate Specific Antigen (PSA), preferably an improved serum PSA reduction, as compared to the administration of each of the anti- KLK2xCD3 antibody and the other anti-cancer drug alone, without triggering a cytokine release syndrome (CRS) of grade 3 or higher according to the American Society for Transplantation and Cellular Therapy (ASTCT) guidelines.

[0125] In certain embodiments, the anti-KLK2xCD3 antibody comprises a first antigen binding domain that binds specifically to KLK2, and a second antigen binding domain that binds specifically to CD3s.

[0126] In certain embodiments, the first antigen binding domain that binds specifically to KLK2 comprises a first heavy chain complementarity determining region (HCDR) 1, a first HCDR2 and a first HCDR3 of a first heavy chain variable region (VH1), and a first light chain complementarity determining region (LCDR) 1, a first LCDR2, and a first LCDR3 of a first light chain variable region (VL1), wherein the VH1 and the VL1 comprise i) the amino acid sequences of SEQ ID NO: 37 and SEQ ID NO: 38, respectively; ii) the amino acid sequences of SEQ ID NO: 39 and SEQ ID NO: 40, respectively; iii) the amino acid sequences of SEQ ID NO: 41 and SEQ ID NO: 42, respectively; or iv) the amino acid sequences of SEQ ID NO: 43 and SEQ ID NO: 44, respectively, wherein the first HCDR1, first HCDR2, first HCDR3, first LCDR1, first LCDR2 and first LCDR3 are defined by the Kabat, Chothia, IMGT or AbM numbering system.

[0127] In certain embodiments, the first HCDR1, first HCDR2, first HCDR3, first LCDR1, first LCDR2 and first LCDR3 that bind specifically to KLK2 comprises: i) the amino acid sequences of SEQ ID NOs: 1, 2, 3, 4, 5, and 6, respectively; ii) the amino acid sequences of SEQ ID NOs: 7, 8, 9, 10, 11, and 12, respectively; iii) the amino acid sequences of SEQ ID NOs: 13, 14, 15, 16, 17, and 18, respectively; or iv) the amino acid sequences of SEQ ID NOs: 19, 20, 21, 22, 23, and 24, respectively.

[0128] In certain embodiments, the VH1 and the VL1 comprise: i) amino acid sequences at least 90%, preferably 100%, identical to SEQ ID NO: 37 and SEQ ID NO: 38, respectively; ii) amino acid sequences at least 90%, preferably 100%, identical to SEQ ID NO: 39 and SEQ ID NO: 40, respectively; iii) amino acid sequences at least 90%, preferably 100%, identical to SEQ ID NO: 41 and SEQ ID NO: 42, respectively; or iv) amino acid sequences at least 90%, preferably 100%, identical to SEQ ID NO: 43 and SEQ ID NO: 44, respectively.

[0129] In certain embodiments, the first binding domain that binds specifically to KLK2 comprises a first heavy chain (HC1) and a first light chain (LC1), and the HC1 and the LC1 comprise amino acid sequences at least 90%, preferably 100%, identical to SEQ ID NO: 49 and SEQ ID NO: 50, respectively. In certain embodiments, the first binding domain that binds specifically to KLK2 comprises a first heavy chain (HC1) and a first light chain (LC1), and the HC1 and the LC1 comprise amino acid sequences at least 90%, preferably 100%, identical to SEQ ID NO: 53 and SEQ ID NO: 54, respectively.

[0130] In certain embodiments, the first binding domain that binds specifically to KLK2 comprises a first single-chain variable fragment fused to an Fc (scFvl-Fc), and the scFvl-Fc comprises an amino acid sequence at least 90%, preferably 100%, identical to SEQ ID NO: 51. In certain embodiments, the first binding domain that binds specifically to KLK2 comprises a first single-chain variable fragment fused to an Fc (scFvl-Fc), and the scFvl-Fc comprises an amino acid sequence at least 90%, preferably 100%, identical to SEQ ID NO: 52.

[0131] In certain embodiments, the second antigen binding domain that binds specifically to CD3s comprises a second HCDR1, a second HCDR2 and a second HCDR3 of a second heavy chain variable region (VH2), and a second LCDR1, a second LCDR2, and a second LCDR3 of a second light chain variable region (VL2), wherein the VH2 and the VL2 comprise the amino acid sequences of SEQ ID NO: 45 and SEQ ID NO: 46, respectively. In certain embodiments, the second antigen binding domain that binds specifically to CD3E comprises a second HCDR1, a second HCDR2 and a second HCDR3 of a second heavy chain variable region (VH2), and a second LCDR1, a second LCDR2, and a second LCDR3 of a second light chain variable region (VL2), wherein the VH2 and the VL2 comprise the amino acid sequences of SEQ ID NO: 47 and SEQ ID NO: 48, respectively, wherein the second HCDR1, second HCDR2, second HCDR3, second LCDR1, second LCDR2 and second LCDR3 are defined by the Kabat, Chothia, IM GT or AbM numbering system.

[0132] In certain embodiments, the second HCDR1, second HCDR2, second HCDR3, second LCDR1, second LCDR2 and second LCDR3 comprises: i) the amino acid sequences of SEQ ID NOs: 25, 26, 27, 28, 29, and 30, respectively; or ii) the amino acid sequences of SEQ ID NOs: 31, 32, 33, 34, 35, and 36, respectively.

[0133] In certain embodiments, the VH2 and the VL2 that bind specifically to CD3s comprise amino acid sequences at least 90%, preferably 100%, identical to SEQ ID NO: 45 and SEQ ID NO: 46, respectively. In certain embodiments, VH2 and the VL2 that bind specifically to CD3s comprise amino acid sequences at least 90%, preferably 100%, identical to SEQ ID NO: 47 and SEQ ID NO: 48, respectively.

[0134] In certain embodiments, the second binding domain that binds specifically to CD3s comprises a second heavy chain (HC2) and a second light chain (LC2), and the HC2 and the LC2 comprise amino acid sequences at least 90%, preferably 100%, identical to SEQ ID NO: 57 and SEQ ID NO: 58, respectively. In certain embodiments, the second binding domain that binds specifically to CD3s comprises a second heavy chain (HC2) and a second light chain (LC2), and the HC2 and the LC2 comprise amino acid sequences at least 90%, preferably 100%, identical to SEQ ID NO: 59 and SEQ ID NO: 60, respectively. In certain embodiments, the second binding domain that binds specifically to CD3s comprises a second single-chain variable fragment fused to an Fc (scFv2-Fc), and the scFv2-Fc comprises an amino acid sequence at least 90%, preferably 100%, identical to SEQ ID NO: 56. In certain embodiments, the second binding domain that binds specifically to CD3e comprises a second single-chain variable fragment fused to a Fc (scFv2-Fc), and the scFv2-Fc comprises an amino acid sequence at least 90%, preferably 100%, identical to SEQ ID NO: 61.

[0135] In certain embodiments, the first HCDR1, first HCDR2, first HCDR3, first LCDR1, first LCDR2, first LCDR3, second HCDR1, second HCDR2, second HCDR3, second LCDR1, second LCDR2 and second LCDR3 comprise the amino acid sequences of SEQ ID NOs: 1, 2, 3, 4, 5, 6, 25, 26, 27, 28, 29, and 30, respectively. In certain embodiments, the first HCDR1, first HCDR2, first HCDR3, first LCDR1, first LCDR2, first LCDR3, second HCDR1, second HCDR2, second HCDR3, second LCDR1, second LCDR2 and second LCDR3 comprise the amino acid sequences of SEQ ID NOs: 7, 8, 9, 10, 11, 12, 25, 26, 27, 28, 29, and 30, respectively. In certain embodiments, the first HCDR1, first HCDR2, first HCDR3, first LCDR1, first LCDR2, first LCDR3, second HCDR1, second HCDR2, second HCDR3, second LCDR1, second LCDR2 and second LCDR3 comprise the amino acid sequences of SEQ ID NOs: : 13, 14, 15, 16, 17, 18, 31, 32, 33, 34, 35, and 36, respectively. In certain embodiments, the first HCDR1 , first HCDR2, first HCDR3, first LCDR1 , first LCDR2, first LCDR3, second HCDR1 , second HCDR2, second HCDR3, second LCDR1, second LCDR2 and second LCDR3 comprise the amino acid sequences of SEQ ID NOs: 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, and 30, respectively.

[0136] In certain embodiments, the VH1, VL1, VH2 and VL2 comprise amino acid sequences at least 90%, preferably 100%, identical to SEQ ID NOs: 37, 38, 45, and 46, respectively. In certain embodiments, the VH1, VL1, VH2 and VL2 comprise amino acid sequences at least 90%, preferably 100%, identical to SEQ ID NOs: 39, 40, 45, and 46, respectively. In certain embodiments, the VH1, VL1, VH2 and VL2 comprise amino acid sequences at least 90%, preferably 100%, identical to SEQ ID NOs: 41, 42, 47, and 48, respectively. In certain, embodiments, the VH1, VL1, VH2 and VL2 comprise amino acid sequences at least 90%, preferably 100%, identical to SEQ ID NOs: 43, 44, 45, and 46, respectively.

[0137] In certain embodiments, the first binding domain that binds specifically to KLK2 comprises the HC1 and LC1 comprising amino acid sequences at least 90%, preferably 100%, identical to SEQ ID NOs: 49 and 50, respectively, and the second binding domain that binds specifically to CD3s comprises the scFv2-Fc comprising an amino acid sequence at least 90%, preferably 100%, identical to SEQ ID NO: 56.

[0138] In certain embodiments, the first binding domain that binds specifically to KLK2 comprises the scFvl-Fc comprising an amino acid sequence at least 90%, preferably 100%, identical to SEQ ID NO: 51, and the second binding domain that binds specifically to CD3s comprises the HC2 and LC2 comprising amino acid sequences at least 90%, preferably 100%, identical to SEQ ID NOs: 57 and 58, respectively.

[0139] In certain embodiments, the first binding domain that binds specifically to KLK2 comprises the scFvl-Fc comprising an amino acid sequence at least 90%, preferably 100%, identical to SEQ ID NO: 52, and the second binding domain that binds specifically to CD3s comprises the HC2 and LC2 comprising amino acid sequences at least 90%, preferably 100%, identical to SEQ ID NOs: 59 and 60, respectively.

[0140] In certain embodiments, the first binding domain that binds specifically to KLK2 comprises the HC1 and LC1 comprising amino acid sequences at least 90%, preferably 100%, identical to SEQ ID NOs: 53 and 54, respectively, and the second binding domain that binds specifically to CD3s comprises the scFv2-Fc comprising an amino acid sequence at least 90%, preferably 100%, identical to SEQ ID NO: 56.

[0141] In certain embodiments, the first binding domain that binds specifically to KLK2 comprises the HC1 and LC1 comprising amino acid sequences at least 90%, preferably 100%, identical to SEQ ID NOs: 55 and 50, respectively, and the second binding domain comprises the scFv2-Fc comprising an amino acid sequence at least 90%, preferably 100%, identical to SEQ ID NO: 61.

[0142] In certain embodiments, the anti-KLK2xCD3 antibody comprises sequences as shown in Tables 1, 2, 3, and 4.

Table 1. HCDR sequences of KLK2xCD3 bispecific antibodies

Table 2. LCDR sequences of KLK2xCD3 bispecific antibodies

Table 3. VH and VL sequences of KLK2xCD3 bispecific antibodies

Table 4. HC and LC sequences of KLK2xCD3 bispecific antibodies. NA = Not Applicable

[0143] The antibodies disclosed herein can be administered in pharmaceutical compositions that include an effective amount of the antibody, and one or more pharmaceutically acceptable carriers or excipients, which can be formulated by methods known to those skilled in the art. [0144] Acceptable carriers and excipients in the pharmaceutical compositions are nontoxic to recipients at the dosages and concentrations employed. Acceptable carriers and excipients may include buffers, antioxidants, preservatives, polymers, amino acids, and carbohydrates.

Pharmaceutical compositions can be administered parenterally in the form of an injectable formulation. Pharmaceutical compositions for injection can be formulated using a sterile solution or any pharmaceutically acceptable liquid as a vehicle. Pharmaceutically acceptable vehicles include, but are not limited to, sterile water, physiological saline, and cell culture media (e.g., Dulbecco’s Modified Eagle Medium (DMEM), a-Modified Eagles Medium (a-MEM), F-12 medium). Formulation methods are known in the art, see e.g., Banga (ed.) Therapeutic Peptides and Proteins: Formulation, Processing and Delivery Systems (2^nd ed.) Taylor & Francis Group, CRC Press (2006).

[0145] In some embodiments, antibodies and other anti-cancer drugs useful for a method of the application can be packaged in one or more kits, which can optionally contain instructions for use.

[0146] In certain embodiments, the anti-KLK2xCD3 antibody is administered to the subject subcutaneously. In certain embodiments, the anti-KLK2xCD3 antibody is administered to the subject intravenously.

[0147] In certain embodiments, the anti-KLK2xCD3 antibody is administered once every 1-9 weeks, for example, once every 3 weeks, once every 6 weeks, or once every 9 weeks.

[0148] In certain embodiments, the administering of the anti-KLK2xCD3 antibody comprises the administering of more than one treatment dose, wherein the treatment doses are administered once every 1-9 weeks, for example, once every 3 weeks, once every 6 weeks, or once every 9 weeks, and wherein each treatment dose is at the same dose level.

[0149] In certain embodiments, the other anti-cancer drug is administered simultaneously, sequentially or separately from the administering of the anti-KLK2xCD3 antibody, for example on the same day about 4 hours apart.

[0150] In certain embodiments, the anti-KLK2xCD3 antibody is administered at a treatment dose level of 100-2000 mg.

[0151] In certain embodiments, the method comprises administering the anti-KLK2xCD3 antibody at a step-up dose and at a treatment dose, wherein the level of the step-up dose is lower than the level of treatment dose, for example the level of the step-up dose is in the range of 0.1- 600mg per dose and the level of the treatment dose is the range of 100-2000 mg per dose.

[0152] In certain embodiments, the method comprises administering to the subject: i) a step-up dose of the anti-KLK2xCD3 antibody, and ii) a treatment dose of the anti-KLK2xCD3 antibody, wherein the step-up dose is administered once, and the treatment dose is administered at least twice (e.g., 2, 3, 4 or more times); and wherein the level of the step-up dose is lower than the level of the treatment dose.

In certain embodiments, the method comprises administering to the subject: i) a first step-up dose of the anti-KLK2xCD3 antibody, ii) a second step-up dose of the anti-KLK2xCD3 antibody and iii) a treatment dose of the anti-KLK2xCD3 antibody, wherein the first step-up dose and the second step-up dose are each administered once, and the treatment dose is administered at least twice (e.g., 2, 3, 4 or more times); wherein the level of the first step-up dose is lower than the level of the second step-up dose, and wherein the level of the second step-up dose is lower than the level of the treatment dose level. [0153] In certain embodiments, the step-up dose is administered 2-15 days, such as 1 week, before the first administration of the treatment dose, and wherein the treatment dose is administered once every 1-9 weeks, for example, once every 3 weeks, once every 6 weeks, or once every 9 weeks.

Administration of the anti-KLK2xCD3 bispecific antibody by intravenous infusion

[0154] In some embodiments, the anti-KLK2xCD3 antibody is administered to the subject by intravenous (IV) infusion at a treatment dose.

[0155] Accordingly, the invention also provides a method of treating prostate cancer in a subject, wherein the method comprises administering to the subject an anti-KLK2xCD3 antibody and another anti-cancer drug, wherein the anti-KLK2xCD3 antibody is administered by intravenous infusion at a treatment dose, wherein the other anti-cancer drug is an androgen receptor pathway inhibitor (ARPI) or an anti -cancer chemotherapeutic agent, wherein the anti-KLK2xCD3 antibody comprises a first antigen binding domain that binds specifically to KLK2, and a second antigen binding domain that binds specifically to CD3s, preferably, the first antigen binding domain comprises a first heavy chain complementarity determining region (HCDR) 1, a first HCDR2 and a first HCDR3 of a first heavy chain variable region (VH1), and a first light chain complementarity determining region (LCDR) 1, a first LCDR2, and a first LCDR3 of a first light chain variable region (VL1), wherein the VH1 and the VL1 comprise: i) the amino acid sequences of SEQ ID NO: 37 and SEQ ID NO: 38, respectively; ii) the amino acid sequences of SEQ ID NO: 39 and SEQ ID NO: 40, respectively; iii) the amino acid sequences of SEQ ID NO: 41 and SEQ ID NO: 42, respectively; or iv) the amino acid sequences of SEQ ID NO: 43 and SEQ ID NO: 44, respectively wherein the first HCDR1, first HCDR2, first HCDR3, first LCDR1, first LCDR2 and first LCDR3 are defined by the Kabat, Chothia, IMGT or AbM numbering system.

[0156] The methods of administering the anti-KLK2xCD3 antibody by intravenous infusion described in the follow subsections on intravenous infusion may be used in any of the methods disclosed herein in which the anti-KLK2xCD3 antibody is administered with another anti -cancer drug.

[0157] An intravenous infusion of the anti-KLK2xCD3 antibody may be administered over several minutes to several hours. The inventors have found that administration of an initial dose of an anti-KLK2xCD3 antibody over a period of one hour followed by administration of subsequent infusions over a period of 30 minutes are suitable timings for administration. Accordingly, in some embodiments, the treatment dose is administered by intravenous (IV) infusion over a period of at least one hour. In certain such embodiments, the treatment dose is administered by intravenous (IV) infusion over a period of about one hour.

[0158] In some embodiments, the treatment dose is administered by intravenous (IV) infusion over a period of at least 30 minutes. In certain such embodiments, the treatment dose is administered by intravenous (IV) infusion over a period of about 30 minutes.

[0159] In some embodiments, the first treatment dose is administered by intravenous infusion over a period of at least one hour (for example over a period of about one hour) and any subsequent treatment dose is administered by intravenous infusion over a period of at least 30 minutes (for example over a period of about 30 minutes).

Intravenous infusion dosing of anti-KLK2xCD3 antibody

[0160] The anti-KLK2xCD3 antibody is administered by intravenous infusion at a treatment dose, with another anti-cancer drug as defined elsewhere herein, to treat prostate cancer in a subject.

[0161] In some embodiments, the treatment dose is at least about 75 mg per administrations. [0162] In some embodiments, the treatment dose is between about 75 mg and about 900 mg per administration, for example about 75 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, or about 900 mg per administration.

[0163] In some embodiments, the treatment dose is between about 75 mg and about 600 mg per administration, for example about 75 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 400 mg, about 500 mg, or about 600 mg per administration.

[0164] In some embodiments, the treatment dose is between about 75 mg and about 300 mg per administration, for example about 75 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, or about 300 mg per administration.

[0165] In some embodiments, the treatment dose is between about 75 mg and about 250 mg per administration, for example about 75 mg, about 100 mg, about 150 mg, about 200 mg, or about 250 mg per administration.

[0166] In some embodiments, the treatment dose is between about 75 mg and about 200 mg per administration, for example about 75 mg, about 100 mg, about 150 mg, or about 200 mg, per administration.

[0167] In some embodiments, the treatment dose is between about 75 mg and about 150 mg per administration, for example about 75 mg, about 100 mg, or about 150 mg per administration. [0168] In a particular embodiment, the treatment dose is about 75 mg per administration.

[0169] In some embodiments, the treatment dose is at least about 150 mg per administration.

[0170] In some embodiments, the treatment dose is between about 150 mg to about 900 mg, for example about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg or about 900 mg per administration.

[0171] In some embodiments, the treatment dose is between about 150 mg to about 600 mg, for example about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 400 mg, about 500 mg, or about 600 mg per administration.

[0172] In some embodiments, the treatment dose is between about 150 mg to about 300 mg, for example about 150 mg, about 200 mg, about 250 mg, or about 300 mg per administration.

[0173] In some embodiments, the treatment dose is between about 150 mg to about 250 mg, for example about 150 mg, about 200 mg, or about 250 mg per administration. [0174] In some embodiments, the treatment dose is about 150 mg to about 200 mg, for example about 150 mg, or about 200 mg per administration.

[0175] In a particular embodiment, the treatment dose is about 150 mg per administration.

[0176] In some embodiments, the treatment dose is at least about 200 mg per administration.

[0177] In some embodiments, the treatment dose is between about 200 mg to about 900 mg, for example about 200 mg, about 250 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg or about 900 mg per administration.

[0178] In some embodiments, the treatment dose is between about 200 mg to about 600 mg, for example about 200 mg, about 250 mg, about 300 mg, about 400 mg, about 500 mg, or about 600 mg per administration.

[0179] In some embodiments, the treatment dose is between about 200 mg to about 300 mg, for example about 200 mg, about 250 mg, or about 300 mg per administration.

[0180] In some embodiments, the treatment dose is between about 200 mg to about 250 mg, for example about 200 mg, or about 250 mg per administration.

[0181] In a particular embodiment, the treatment dose is about 200 mg per administration.

[0182] In some embodiments, the treatment dose is at least about 250 mg per administration.

[0183] In some embodiments, the treatment dose is between about 250 mg to about 900 mg, for example about 250 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg or about 900 mg per administration.

[0184] In some embodiments, the treatment dose is between about 250 mg to about 600 mg, for example about 250 mg, about 300 mg, about 400 mg, about 500 mg, or about 600 mg per administration.

[0185] In some embodiments, the treatment dose is between about 250 mg to about 300 mg, for example about 250 mg, or about 300 mg per administration.

[0186] In a particular embodiment, the treatment dose is about 250 mg per administration.

[0187] In some embodiments, the treatment dose is at least about 300 mg per administration.

[0188] In some embodiments, the treatment dose is between about 300 to about 900 mg per administration, for example about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg or about 900 mg per administration.

[0189] In some embodiments, the treatment dose is between about 300 mg to about 600 mg, for example about 300 mg, about 400 mg, about 500 mg, or about 600 mg per administration. [0190] In a particular embodiment, the treatment dose is about 300 mg per administration. [0191] In some embodiments, the treatment dose is at least about 600 mg per administration. [0192] In some embodiments, the treatment dose is between about 600 to about 900 mg per administration, for example about 600 mg, about 700 mg, about 800 mg or about 900 mg per administration.

[0193] In a particular embodiment, the treatment dose is about 600 mg per administration. [0194] In a particular embodiment, the treatment dose is about 900 mg per administration. [0195] The treatment dose of the anti-KLK2xCD3 antibody may be a flat dose, as defined herein. Flat dosing may provide advantages compared to dosing according to body weight, such as reduced preparation time, and simpler administration and manufacturing.

[0196] In some embodiments, the treatment dose is a flat dose of at least about 75 mg per administrations.

[0197] In some embodiments, the treatment dose is a flat dose of between about 75 mg and about 900 mg per administration, for example a flat dose of about 75 mg, a flat dose of about 100 mg, a flat dose of about 150 mg, a flat dose of about 200 mg, a flat dose of about 250 mg, a flat dose of about 300 mg, a flat dose of about 400 mg, a flat dose of about 500 mg, a flat dose of about 600 mg, a flat dose of about 700 mg, a flat dose of about 800 mg, or a flat dose of about 900 mg per administration.

[0198] In some embodiments, the treatment dose is a flat dose of between about 75 mg and about 600 mg per administration, for example a flat dose of about 75 mg, a flat dose of about 100 mg, a flat dose of about 150 mg, a flat dose of about 200 mg, a flat dose of about 250 mg, a flat dose of about 300 mg, a flat dose of about 400 mg, a flat dose of about 500 mg, or a flat dose of about 600 mg per administration.

[0199] In some embodiments, the treatment dose is a flat dose of between about 75 mg and about 300 mg per administration, for example a flat dose of about 75 mg, a flat dose of about 100 mg, a flat dose of about 150 mg, a flat dose of about 200 mg, a flat dose of about 250 mg, or a flat dose of about 300 mg per administration.

[0200] In some embodiments, the treatment dose is a flat dose of between about 75 mg and about 250 mg per administration, for example a flat dose of about 75 mg, a flat dose of about 100 mg, a flat dose of about 150 mg, a flat dose of about 200 mg, or a flat dose of about 250 mg per administration. [0201 ] In some embodiments, the treatment dose is a flat dose of between about 75 mg and about 200 mg per administration, for example a flat dose of about 75 mg, a flat dose of about 100 mg, a flat dose of about 150 mg, or a flat dose of about 200 mg, per administration.

[0202] In some embodiments, the treatment dose is a flat dose of between about 75 mg and about 150 mg per administration, for example a flat dose of about 75 mg, a flat dose of about 100 mg, or a flat dose of about 150 mg per administration.

[0203] In a particular embodiment, the treatment dose is a flat dose of about 75 mg per administration.

[0204] In some embodiments, the treatment dose is a flat dose of at least about 150 mg per administration.

[0205] In some embodiments, the treatment dose is a flat dose of between about 150 mg to about 900 mg, for example a flat dose of about 150 mg, a flat dose of about 200 mg, a flat dose of about 250 mg, a flat dose of about 300 mg, a flat dose of about 400 mg, a flat dose of about 500 mg, a flat dose of about 600 mg, a flat dose of about 700 mg, a flat dose of about 800 mg or a flat dose of about 900 mg per administration.

[0206] In some embodiments, the treatment dose is a flat dose of between about 150 mg to about 600 mg, for example a flat dose of about 150 mg, a flat dose of about 200 mg, a flat dose of about 250 mg, a flat dose of about 300 mg, a flat dose of about 400 mg, a flat dose of about 500 mg, or a flat dose of about 600 mg per administration.

[0207] In some embodiments, the treatment dose is a flat dose of between about 150 mg to about 300 mg, for example a flat dose of about 150 mg, a flat dose of about 200 mg, a flat dose of about 250 mg, or a flat dose of about 300 mg per administration.

[0208] In some embodiments, the treatment dose is a flat dose of between about 150 mg to about 250 mg, for example a flat dose of about 150 mg, a flat dose of about 200 mg, or a flat dose of about 250 mg per administration.

[0209] In some embodiments, the treatment dose is a flat dose of about 150 mg to about 200 mg, for example a flat dose of about 150 mg, or a flat dose of about 200 mg per administration.

[0210] In a particular embodiment, the treatment dose is a flat dose of about 150 mg per administration.

[0211] In some embodiments, the treatment dose is a flat dose of at least about 200 mg per administration. [0212] In some embodiments, the treatment dose is a flat dose of between about 200 mg to about 900 mg, for example a flat dose of about 200 mg, a flat dose of about 250 mg, a flat dose of about 300 mg, a flat dose of about 400 mg, a flat dose of about 500 mg, a flat dose of about 600 mg, a flat dose of about 700 mg, a flat dose of about 800 mg or a flat dose of about 900 mg per administration.

[0213] In some embodiments, the treatment dose is a flat dose of between about 200 mg to about 600 mg, for example a flat dose of about 200 mg, a flat dose of about 250 mg, a flat dose of about 300 mg, a flat dose of about 400 mg, a flat dose of about 500 mg, or a flat dose of about 600 mg per administration.

[0214] In some embodiments, the treatment dose is a flat dose of between about 200 mg to about 300 mg, for example a flat dose of about 200 mg, a flat dose of about 250 mg, or a flat dose of about 300 mg per administration.

[0215] In some embodiments, the treatment dose is a flat dose of between about 200 mg to about 250 mg, for example a flat dose of about 200 mg, or a flat dose of about 250 mg per administration.

[0216] In a particular embodiment, the treatment dose is a flat dose of about 200 mg per administration.

[0217] In some embodiments, the treatment dose is a flat dose of at least about 250 mg per administration.

[0218] In some embodiments, the treatment dose is a flat dose of between about 250 mg to about 900 mg, for example a flat dose of about 250 mg, a flat dose of about 300 mg, a flat dose of about 400 mg, a flat dose of about 500 mg, a flat dose of about 600 mg, a flat dose of about 700 mg, a flat dose of about 800 mg or a flat dose of about 900 mg per administration.

[0219] In some embodiments, the treatment dose is a flat dose of between about 250 mg to about 600 mg, for example a flat dose of about 250 mg, a flat dose of about 300 mg, a flat dose of about 400 mg, a flat dose of about 500 mg, or a flat dose of about 600 mg per administration.

[0220] In some embodiments, the treatment dose is a flat dose of between about 250 mg to about 300 mg, for example a flat dose of about 250 mg, or a flat dose of about 300 mg per administration.

[0221] In a particular embodiment, the treatment dose is a flat dose of about 250 mg per administration. [0222] In some embodiments, the treatment dose is a flat dose of at least about 300 mg per administration.

[0223] In some embodiments, the treatment dose is a flat dose of between about 300 to about 900 mg per administration, for example a flat dose of about 300 mg, a flat dose of about 400 mg, a flat dose of about 500 mg, a flat dose of about 600 mg, a flat dose of about 700 mg, a flat dose of about 800 mg or a flat dose of about 900 mg per administration.

[0224] In some embodiments, the treatment dose is a flat dose of between about 300 mg to about 600 mg, for example a flat dose of about 300 mg, a flat dose of about 400 mg, a flat dose of about 500 mg, or a flat dose of about 600 mg per administration.

[0225] In a particular embodiment, the treatment dose is a flat dose of about 300 mg per administration.

[0226] In some embodiments, the treatment dose is a flat dose of at least about 600 mg per administration.

[0227] In some embodiments, the treatment dose is a flat dose of between about 600 to about 900 mg per administration, for example a flat dose of about 600 mg, a flat dose of about 700 mg, a flat dose of about 800 mg or a flat dose of about 900 mg per administration.

[0228] In a particular embodiment, the treatment dose is a flat dose of about 600 mg per administration.

[0229] In a particular embodiment, the treatment dose is a flat dose of about 900 mg per administration.

[0230] The treatment dose of the anti-KLK2xCD3 antibody may be a weight-based dose. Therefore, in some embodiments of the invention, the treatment dose is a weight-based dose. Such dosages can, for example, be based on the mg/kg dosages provided above according to the following: dose (mg/kg)x body weight (e.g., 50 - 100 kg).

Administration frequency of intravenous infusion of anti-KLK2xCD3 antibody [0231] In some embodiments, the treatment dose of the anti-KLK2xCD3 antibody is administered every one to six weeks, for example, once a week, once every two weeks, once every three weeks, once every four weeks, once every five week or once every six weeks. [0232] In a particular embodiment, the treatment dose is administered once every three weeks. [0233] In a particular embodiment, the treatment dose is administered once every six weeks. [0234] In some embodiments, the treatment dose is at least about 75 mg per administration (for example a flat dose of at least about 75 mg per administration) and is administered once every three weeks.

[0235] In some embodiments, the treatment dose is between about 75 mg and about 900 mg per administration (for example a flat dose of between about 75 mg and 900 mg per administration) and is administered once every three weeks. In some embodiments, the treatment dose is between about 75 mg and about 600 mg per administration (for example a flat dose of between about 75 mg and 600 mg per administration) and is administered once every three weeks. In some embodiments, the treatment dose is between about 75 mg and about 300 mg per administration (for example a flat dose of between about 75 mg and 300 mg per administration) and is administered once every three weeks. In some embodiments, the treatment dose is between about 75 mg and about 250 mg per administration (for example a flat dose of between about 75 mg and 250 mg per administration) and is administered once every three weeks. In some embodiments, the treatment dose is between about 75 mg and about 200 mg per administration (for example a flat dose of between about 75 mg and 200 mg per administration) and is administered once every three weeks. In some embodiments, the treatment dose is between about 75 mg and about 150 mg per administration (for example a flat dose of between about 75 mg and 150 mg per administration) and is administered once every three weeks.

[0236] In a particular embodiment, the treatment dose is about 75 mg per administration (for example a flat dose of about 75 mg per administration) administered once every three weeks. [0237] In some embodiments, the treatment dose is at least about 150 mg per administration (for example a flat dose of about 150 mg per administration) administered once every three weeks. [0238] In some embodiments, the treatment dose is between about 150 mg to about 900 mg per administration (for example a flat dose of between about 150 mg and 900 mg per administration) and is administered once every three weeks. In some embodiments, the treatment dose is between about 150 mg to about 600 mg per administration (for example a flat dose of between about 150 mg and 600 mg per administration) and is administered once every three weeks. In some embodiments, the treatment dose is between about 150 mg to about 300 mg per administration (for example a flat dose of between about 150 mg and 300 mg per administration) and is administered once every three weeks. In some embodiments, the treatment dose is between about 150 mg to about 250 mg per administration (for example a flat dose of between about 150 mg and 250 mg per administration) and is administered once every three weeks. In some embodiments, the treatment dose is about 150 mg to about 200 mg per administration (for example a flat dose of between about 150 mg and 200 mg per administration) and is administered once every three weeks.

[0239] In a particular embodiment, the treatment dose is about 150 mg per administration (for example a flat dose of about 150 mg per administration) administered once every three weeks. [0240] In some embodiments, the treatment dose is at least about 200 mg per administration (for example a flat dose of at least about 200 mg per administration) administered once every three weeks.

[0241] In some embodiments, the treatment dose is between about 200 mg to about 900 mg per administration (for example a flat dose of between about 200 mg and 900 mg per administration) and is administered once every three weeks. In some embodiments, the treatment dose is between about 200 mg to about 600 mg per administration (for example a flat dose of between about 200 mg and 600 mg per administration) and is administered once every three weeks. In some embodiments, the treatment dose is between about 200 mg to about 300 mg per administration (for example a flat dose of between about 200 mg and 300 mg per administration) and is administered once every three weeks.

[0242] In some embodiments, the treatment dose is between about 200 mg to about 250 mg per administration (for example a flat dose of between about 200 mg and 250 mg per administration) and is administered once every three weeks.

[0243] In a particular embodiment, the treatment dose is about 200 mg per administration (for example a flat dose of about 200 mg per administration) administered once every three weeks. [0244] In some embodiments, the treatment dose is at least about 250 mg per administration (for example a flat dose of at least about 250 mg per administration) administered once every three weeks.

[0245] In some embodiments, the treatment dose is between about 250 mg to about 900 mg per administration (for example a flat dose of between about 250 mg and 900 mg per administration) and is administered once every three weeks. In some embodiments, the treatment dose is between about 250 mg to about 600 mg (for example a flat dose of between about 250 mg and 600 mg per administration) and is administered once every three weeks. In some embodiments, the treatment dose is between about 250 mg to about 300 mg (for example a flat dose of between about 250 mg and 300 mg per administration) and is administered once every three weeks. [0246] In a particular embodiment, the treatment dose is about 250 mg per administration (for example a flat dose of about 250 mg per administration) administered once every three weeks [0247] In some embodiments, the treatment dose is at least about 300 mg per administration (for example a flat dose of about 300 mg per administration) administered once every three weeks. [0248] In some embodiments, the treatment dose is between about 300 mg to about 900 mg per administration (for example between about 300 mg to about 900 mg per administration) administered once every three weeks. In some embodiments, the treatment dose is between about 300 mg to about 600 mg per administration (for example a flat dose of between about 300 mg to about 600 mg per administration) administered once every three weeks.

[0249] In a particular embodiment, the treatment dose is about 300 mg per administration (for example a flat dose of about 300 mg per administration) administered once every three weeks. [0250] In some embodiments, the treatment dose is at least about 300 mg per administration (for example a flat dose of about 300 mg per administration) administered once every six weeks. [0251] In some embodiments, the treatment dose is between about 300 mg to about 900 mg per administration (for example between about 300 mg to about 900 mg per administration) administered once every six weeks. In some embodiments, the treatment dose is between about 300 mg to about 600 mg per administration (for example a flat dose of between about 300 mg to about 600 mg per administration) administered once every six weeks.

[0252] In a particular embodiment, the treatment dose is about 300 mg per administration (for example a flat dose of about 300 mg per administration) administered once every six weeks. [0253] In some embodiments, the treatment dose is at least about 600 mg per administration (for example a flat dose of at least about 600 mg per administration) and is administered once every six weeks.

[0254] In some embodiments, the treatment dose is between about 600 mg to about 900 mg per administration (for example a flat dose between about 600 mg to about 900 mg per administration) and is administered once every six weeks.

[0255] In a particular embodiment, the treatment dose is about 600 mg per administration (for example a flat dose of about 600 mg per administration) and is administered once every six weeks. [0256] In a particular embodiment, the treatment dose is about 900 mg per administration (for example a flat dose of about 900 mg per administration) and is administered once every six weeks.

[0257] In some embodiments, the methods of the invention comprise administering a treatment dose of an anti-KLK2xCD3 antibody to the subject with another anti-cancer drug as defined elsewhere herein, to treat prostate cancer. One or more treatment doses may be administered to the subject and typically several treatment doses are administered to the subject in the course of the treatment. The administration of several treatment doses of the anti-KLK2xCD3 antibody may be defined according to a number of cycles of administration. For instance, a treatment dose may be administered once every three weeks over a twelve-week period. In this case, the treatment dose is administered four times in a twelve-week period and the treatment dose is therefore administered for four cycles (i.e. there are four three week cycles). As another example, a treatment dose may be administered one every six weeks over a twelve week period. In this case, the treatment dose is administered twice in a twelve week period and the treatment dose is therefore administered for two cycles (i.e. there are two six week cycles).

[0258] Accordingly, the treatment dose may be administered in one or more cycles. In some embodiments, the treatment dose is administered for at least two cycles, for example, two, three, four, five, ten, fifteen, twenty or more cycles. Any of the treatment doses described elsewhere herein may be administered in the one or more cycles (for example, two, three, four, five, ten, fifteen, twenty or more cycles). The treatment dose that is administered in each cycle may be administered at the same dose in each cycle.

[0259] In some embodiments, the treatment dose of the anti-KLK2xCD3 antibody is administered every one to six weeks, for example, once a week, once every two weeks, once every three weeks, once every four weeks, once every five weeks or once every six weeks for at least two cycles (for example, two, three, four, five, ten, fifteen, twenty or more cycles).

[0260] In a particular embodiment, the treatment dose is administered once every three weeks for at least two cycles (for example, two, three, four, five, ten, fifteen, twenty or more cycles). [0261] In some embodiments, the treatment dose is administered once every three weeks for at least two cycles. In some embodiments, the treatment dose is administered once every three weeks for at least three cycles. In some embodiments, the treatment dose is administered once every three weeks for at least four cycles. In some embodiments, the treatment dose is administered once every three weeks for at least five cycles. In some embodiments, the treatment dose is administered once every three weeks for at least ten cycles. In some embodiments, the treatment dose is administered once every three weeks for at least fifteen cycles. In some embodiments, the treatment dose is administered once every three weeks for at least twenty cycles.

[0262] In some embodiments, the treatment dose is administered once every six weeks for at least two cycles. In some embodiments, the treatment dose is administered once every six weeks for at least three cycles. In some embodiments, the treatment dose is administered once every six weeks for at least four cycles. In some embodiments, the treatment dose is administered once every six weeks for at least five cycles. In some embodiments, the treatment dose is administered once every six weeks for at least ten cycles. In some embodiments, the treatment dose is administered once every six weeks for at least fifteen cycles. In some embodiments, the treatment dose is administered once every six weeks for at least twenty or more cycles.

[0263] In some embodiments, the treatment dose is administered for at least a year.

[0264] In some embodiments, the treatment dose is administered throughout the lifespan of the patient.

Step-up dosing prior to intravenous infusion of anti-KLK2xCD3 antibody

[0265] The anti-KLK2xCD3 antibody that is administered by intravenous infusion may be administered with or without step-up dosing. Administration of step-up doses prior to treatment doses may prevent or lessen certain adverse events or side-effects that can be associated with administration of bispecific CD3 antibodies, such as cytokine release syndrome (CRS). The step-up doses are not higher than the treatment dose and thus may function as priming doses that prevent or lessen adverse events.

[0266] Accordingly, in some embodiments, the method comprises administering to the human subject one or more one step-up doses of the anti-KLK2xCD3 antibody, wherein the one or more step-up does are administered prior to the treatment dose of the anti-KLK2xCD3 antibody and wherein the one or more step-up doses are not higher than the treatment dose.

[0267] In some embodiments, one step-up dose of the anti-KLK2xCD3 antibody is administered. [0268] In some embodiments, two step-up doses of the anti-KLK2xCD3 antibody are administered. [0269] In some embodiments, the method comprises administering to the subject a step-up dose of between about 2 mg to about 5 mg per administration. In certain embodiments, the step-up dose is about 2 mg per administration. In other embodiments, the step-up dose is about 2.5 mg per administration. In other embodiments, the step-up dose is about 3 mg per administration. In other embodiments, the step-up dose is about 3.5 mg per administration. In other embodiments, the step-up dose is about 4 mg per administration. In other embodiments, the step-up dose is about 4.5 mg per administration. In other embodiments, the step-up dose is about 5 mg per administration.

[0270] In a particular embodiment, the step-up dose is about 3.5mg per administration.

[0271] In some embodiments, the method comprises administering to the subject a step-up dose of between about 5 mg to about 15 mg per administration. In certain embodiments, the step-up dose is about 5 mg per administration. In other embodiments, the step-up dose is about 10 mg per administration. In other embodiments, the step-up dose is about 15 mg per administration. [0272] In a particular embodiment, the step-up dose is about 10 mg per administration.

[0273] In some embodiments, the method comprises administering to the subject a step-up dose of between about 15 mg to about 25 mg per administration. In certain embodiments, the step-up dose is about 15 mg per administration. In other embodiments, the step-up dose is about 16 mg per administration. In other embodiments, the step-up dose is about 17 mg per administration. In other embodiments, the step-up dose is about 18 mg per administration. In other embodiments, the step-up dose is about 19 mg per administration. In other embodiments, the step-up dose is about 20 mg per administration. In other embodiments, the step-up dose is about 21 mg per administration. In other embodiments, the step-up dose is about 22 mg per administration. In other embodiments, the step-up dose is about 23 mg per administration. In other embodiments, the step-up dose is about 24 mg per administration. In other embodiments, the step-up dose is about 25 mg per administration.

[0274] In a particular embodiment, the step-up dose is about 18 mg per administration.

[0275] In some embodiments, the method comprises administering to the subject a step-up dose of between about 200 mg to about 400 mg per administration. In certain embodiments, the step- up dose is about 200 mg per administration. In other embodiments, the step-up dose is about 300 mg per administration. In other embodiments, the step-up dose is about 400 mg per administration. [0276] In a particular embodiment, the step-up dose is about 300 mg per administration. [0277] The step-up dose of the anti-KLK2xCD3 antibody may be administered as a flat dose. [0278] In some embodiments, the method comprises administering to the subject a step-up dose at a flat dose of between about 2 mg to about 5 mg per administration. In certain embodiments, the step-up dose is a flat dose of about 2 mg per administration. In other embodiments, the step- up dose is a flat dose of about 2.5 mg per administration. In other embodiments, the step-up dose is a flat dose of about 3 mg per administration. In other embodiments, the step-up dose is a flat dose of about 3.5 mg per administration. In other embodiments, the step-up dose is a flat dose of about 4 mg per administration. In other embodiments, the step-up dose is a flat dose of about 4.5 mg per administration. In other embodiments, the step-up dose is a flat dose of about 5 mg per administration.

[0279] In a particular embodiment, the step-up dose is a flat dose of about 3.5mg per administration.

[0280] In some embodiments, the method comprises administering to the subject a step-up dose at a flat dose of between about 5 mg to about 15 mg per administration. In certain embodiments, the step-up dose is a flat dose of about 5 mg per administration. In other embodiments, the step- up dose is a flat dose of about 10 mg per administration. In other embodiments, the step-up dose is about a flat dose of 15 mg per administration.

[0281] In a particular embodiment, the step-up dose is a flat dose of about 10 mg per administration.

[0282] In some embodiments, the method comprises administering to the subject a step-up dose at a flat dose of between about 15 mg to about 25 mg per administration. In certain embodiments, the step-up dose is a flat dose of about 15 mg per administration. In other embodiments, the step-up dose is a flat dose of about 16 mg per administration. In other embodiments, the step-up dose is a flat dose of about 17 mg per administration. In other embodiments, the step-up dose is a flat dose of about 18 mg per administration. In other embodiments, the step-up dose is a flat dose of about 19 mg per administration. In other embodiments, the step-up dose is a flat dose of about 20 mg per administration. In other embodiments, the step-up dose is a flat dose of about 21 mg per administration. In other embodiments, the step-up dose is a flat dose of about 22 mg per administration. In other embodiments, the step-up dose is a flat dose of about 23 mg per administration. In other embodiments, the step-up dose is a flat dose of about 24 mg per administration. In other embodiments, the step-up dose is a flat dose of about 25 mg per administration.

[0283] In a particular embodiment, the step-up dose is a flat dose of about 18 mg per administration.

[0284] In some embodiments, the method comprises administering to the subject a step-up dose at a flat dose of between about 200 mg to about 400 mg per administration. In certain embodiments, the step-up dose is a flat dose of about 200 mg per administration. In other embodiments, the step-up dose is a flat dose of about 300 mg per administration. In other embodiments, the step-up dose is a flat dose of about 400 mg per administration.

[0285] In a particular embodiment, the step-up dose is a flat dose of about 300 mg per administration.

[0286] The step-up dose of the anti-KLK2xCD3 antibody may be a weight-based dose. Therefore, in some embodiments of the invention, the step-up dose is a weight-based dose. Such dosages can, for example, be based on the mg/kg dosages provided above according to the following: dose (mg/kg) x body weight (e.g., 50 - 100 kg).

[0287] In some embodiments, the step-up dose of the anti-KLK2xCD3 antibody is administered 3 days to 8 days prior to the administration of the treatment dose. In certain embodiments, the step-up dose is administered 3 days prior to the administration of the treatment dose. In other embodiments, the step-up dose is administered 4 days prior to the administration of the treatment dose. In other embodiments, the step-up dose is administered 5 days prior to the administration of the treatment dose. In other embodiments, the step-up dose is administered 6 days prior to the administration of the treatment dose. In other embodiments, the step-up dose is administered 7 days prior to the administration of the treatment dose. In other embodiments, the step-up dose is administered 8 days prior to the administration of the treatment dose.

[0288] In a particular embodiment, the step-up dose of the anti-KLK2xCD3 antibody is administered 3 days prior to the administration of the treatment dose.

[0289] In some embodiments, the method comprises administering to the subject a step-up dose of between about 2 mg to about 5 mg per administration (for example a flat dose of between about 2 mg to about 5 mg per administration) and the administration of the step-up dose is 3 days prior to the administration of the treatment dose. [0290] In a particular embodiment, the step-up dose is about 3.5 mg per administration (for example a flat dose of about 3.5 mg per administration) and the administration of the step-up dose is 3 days prior to the administration of the treatment dose.

[0291] In some embodiments, the method comprises administering to the subject a step-up dose of between about 5 mg to about 15 mg per administration (for example a flat dose of between about 5 mg to about 15 mg per administration) and the administration of the step-up dose is 3 days prior to the administration of the treatment dose.

[0292] In a particular embodiment, the step-up dose is about 10 mg per administration (for example a flat dose of about 10 mg per administration) and the administration of the step-up dose is 3 days prior to the administration of the treatment dose.

[0293] In some embodiments, the method comprises administering to the subject a step-up dose of between about 15 mg to about 25 mg per administration (for example a flat dose of between about 15 mg to about 25 mg per administration) and the administration of the step-up dose is 3 days prior to the administration of the treatment dose.

[0294] In a particular embodiment, the step-up dose is about 18 mg per administration (for example a flat dose of about 18 mg per administration) and the administration of the step-up dose is 3 days prior to the administration of the treatment dose.

[0295] In some embodiments, the method comprises administering to the subject a step-up dose of between about 200 mg to about 400 mg per administration (for example a flat dose of between about 200 mg to about 400 mg per administration) and the administration of the step-up dose is 3 days prior to the administration of the treatment dose.

[0296] In a particular embodiment, the step-up dose is about 300 mg per administration (for example a flat dose of about 300 mg per administration) and the administration of the step-up dose is 3 days prior to the administration of the treatment dose.

[0297] In a particular embodiment, the step-up dose of the anti-KLK2xCD3 antibody is administered 7 days prior to the administration of the treatment dose.

[0298] In some embodiments, the method comprises administering to the subject a step-up dose of between about 2 mg to about 5 mg per administration (for example a flat dose of between about 2 mg to about 5 mg per administration) and the administration of the step-up dose is 7 days prior to the administration of the treatment dose. In a particular embodiment, the step-up dose is about 3.5 mg per administration (for example a flat dose of about 3.5 mg per administration) and the administration of the step-up dose is 7 days prior to the administration of the treatment dose. [0299] In some embodiments, the method comprises administering to the subject a step-up dose of between about 5 mg to about 15 mg per administration (for example a flat dose of between about 5 mg to about 15 mg per administration) and the administration of the step-up dose is 7 days prior to the administration of the treatment dose. In a particular embodiment, the step-up dose is about 10 mg per administration (for example a flat dose of about 10 mg per administration) and the administration of the step-up dose is 7 days prior to the administration of the treatment dose.

[0300] In some embodiments, the method comprises administering to the subject a step-up dose of between about 15 mg to about 25 mg per administration (for example a flat dose of between about 15 mg to about 25 mg per administration) and the administration of the step-up dose is 7 days prior to the administration of the treatment dose. In a particular embodiment, the step-up dose is about 18 mg per administration (for example a flat dose of 18 mg per administration) and the administration of the step-up dose is 7 days prior to the administration of the treatment dose. [0301] In some embodiments, the method comprises administering to the subject a step-up dose of between about 200 mg to about 400 mg per administration (for example a flat dose of between about 200 mg to about 400 mg per administration) and the administration of the step-up dose is 7 days prior to the administration of the treatment dose. In a particular embodiment, the step-up dose is about 300 mg per administration (for example a flat dose of 300 mg per administration) and the administration of the step-up dose is 7 days prior to the administration of the treatment dose.

[0302] In some embodiments the method may comprise administering to the subject a step-up dose of the anti-KLK2xCD3 antibody; and a treatment dose of the anti-KLK2xCD3 antibody, wherein the step-up dose is administered once.

[0303] The inventors have found that administration by intravenous infusion may be advantageous in reducing the likelihood of adverse events following administration of bispecific antibodies. The step-up doses may therefore be administered by intravenous infusion. Accordingly, in some embodiments the step-up dose of the anti-KLK2xCD3 antibody is administered by intravenous (IV) infusion. [0304] An intravenous infusion of the anti-KLK2xCD3 antibody may be administered over several minutes to several hours. The inventors have found that administration of the step-up dose of an anti-KLK2xCD3 antibody over a period of one hour followed by administration of subsequent infusions of the treatment dose over a period of 30 minutes are suitable timings for administration. Accordingly, in some embodiments, the step-up dose is administered by intravenous (IV) infusion over a period of at least one hour. In certain such embodiments, the step-up dose is administered by intravenous (IV) infusion over a period of about one hour. [0305] In some embodiments, the step-up dose is administered by intravenous infusion over a period of at least one hour (for example over a period of about one hour) and any subsequent treatment dose is administered by intravenous infusion over a period of at least 30 minutes (for example over a period of about 30 minutes).

[0306] The methods of the invention may also involve administering two step up doses prior to the treatment dose. Typically, the second step up dose is greater than the first step up dose and the treatment dose is greater than the second step up dose.

[0307] Accordingly, in some embodiments the method comprises administering to the subject a first step-up dose and a second step-up dose of the anti-KLK2xCD3 antibody, wherein the first step up dose is administered prior to the second step-up dose, and the second step up dose is administered prior to the treatment dose.

[0308] In some embodiments, the second step-up dose is greater than the first step-up dose. [0309] In some embodiments, the method comprises administering to the subject a first step-up dose of between about 2 mg to about 5 mg per administration. In certain embodiments, the first step-up dose is about 2 mg per administration. In other embodiments, the first step-up dose is about 2.5 mg per administration. In other embodiments, the first step-up dose is about 3 mg per administration. In other embodiments, the first step-up dose is about 3.5 mg per administration. In other embodiments, the first step-up dose is about 4 mg per administration. In other embodiments, the first step-up dose is about 4.5 mg per administration. In other embodiments, the first step-up dose is about 5 mg per administration.

[0310] In a particular embodiment, the first step-up dose is about 3.5mg per administration.

[0311] In some embodiments, the method comprises administering to the subject a first step-up dose of between about 5 mg to about 15 mg per administration. In certain embodiments, the first step-up dose is about 5 mg per administration. In other embodiments, the first step-up dose is about 10 mg per administration. In other embodiments, the first step-up dose is about 15 mg per administration.

[0312] In a particular embodiment, the first step-up dose is about 10 mg per administration. [0313] In some embodiments, the method comprises administering to the subject a second step- up dose of between about 5 mg to about 15 mg per administration. In certain embodiments, the second step-up dose is about 5 mg per administration. In other embodiments, the second step-up dose is about 10 mg per administration. In other embodiments, the second step-up dose is about 15 mg per administration.

[0314] In a particular embodiment, the second step-up dose is about 10 mg per administration. [0315] In some embodiments, the method comprises administering to the subject a second step- up dose of between about 15 mg to about 25 mg per administration. In certain embodiments, the second step-up dose is about 15 mg per administration. In other embodiments, the second step-up dose is about 16 mg per administration. In other embodiments, the second step-up dose is about 17 mg per administration. In other embodiments, the second step-up dose is about 18 mg per administration. In other embodiments, the second step-up dose is about 19 mg per administration. In other embodiments, the second step-up dose is about 20 mg per administration. In other embodiments, the second step-up dose is about 21 mg per administration. In other embodiments, the second step-up dose is about 22 mg per administration. In other embodiments, the second step-up dose is about 23 mg per administration. In other embodiments, the second step-up dose is about 24 mg per administration. In other embodiments, the second step-up dose is about 25 mg per administration.

[0316] In a particular embodiment, the second step-up dose is about 18 mg per administration. [0317] In some embodiments, the method comprises administering to the subject a second step- up dose of between about 200 mg to about 400 mg per administration. In certain embodiments, the second step-up dose is about 200 mg per administration. In other embodiments the second step-up dose is about 300 mg per administration. In other embodiments the second step-up dose is about 400 mg per administration.

[0318] In a particular embodiment, the second step-up dose is about 300 mg per administration. [0319] The first step-up dose and the second step-up dose of the anti-KLK2xCD3 antibody may be a flat dose. [0320] Accordingly, in some embodiments, the method comprises administering to the subject a first step-up dose at a flat dose of between about 2 mg to about 5 mg per administration. In certain embodiments, the first step-up dose is a flat dose of about 2 mg per administration. In other embodiments, the first step-up dose is a flat dose of about 2.5 mg per administration. In other embodiments, the first step-up dose is a flat dose of about 3 mg per administration. In other embodiments, the first step-up dose is a flat dose of about 3.5 mg per administration. In other embodiments, the first step-up dose is a flat dose of about 4 mg per administration. In other embodiments, the first step-up dose is a flat dose of about 4.5 mg per administration. In other embodiments, the first step-up dose is a flat dose of about 5 mg per administration.

[0321] In a particular embodiment, the first step-up dose is a flat dose of about 3.5mg per administration.

[0322] In some embodiments, the method comprises administering to the subject a first step-up dose at a flat dose of between about 5 mg to about 15 mg per administration. In certain embodiments, the first step-up dose is a flat dose of about 5 mg per administration. In other embodiments, the first step-up dose is a flat dose of about 10 mg per administration. In other embodiments, the first step-up dose is a flat dose of about 15 mg per administration.

[0323] In a particular embodiment, the first step-up dose is a flat dose of about 10 mg per administration.

[0324] In some embodiments, the method comprises administering to the subject a second step- up dose at a flat dose of between about 5 mg to about 15 mg per administration. In certain embodiments, the second step-up dose is a flat dose of about 5 mg per administration. In other embodiments, the second step-up dose is a flat dose of about 10 mg per administration. In other embodiments, the second step-up dose is a flat dose of about 15 mg per administration.

[0325] In a particular embodiment, the second step-up dose is a flat dose of about 10 mg per administration.

[0326] In some embodiments, the method comprises administering to the subject a second step- up dose at a flat dose of between about 15 mg to about 25 mg per administration. In certain embodiments, the second step-up dose is a flat dose of about 15 mg per administration. In other embodiments, the second step-up dose is a flat dose of about 16 mg per administration. In other embodiments, the second step-up dose is a flat dose of about 17 mg per administration. In other embodiments, the second step-up dose is a flat dose of about 18 mg per administration. In other embodiments, the second step-up dose is a flat dose of about 19 mg per administration. In other embodiments, the second step-up dose is a flat dose of about 20 mg per administration. In other embodiments, the second step-up dose is a flat dose of about 21 mg per administration. In other embodiments, the second step-up dose is a flat dose of about 22 mg per administration. In other embodiments, the second step-up dose is a flat dose of about 23 mg per administration. In other embodiments, the second step-up dose is a flat dose of about 24 mg per administration. In other embodiments, the second step-up dose is a flat dose of about 25 mg per administration.

[0327] In a particular embodiment, the second step-up dose is a flat dose of about 18 mg per administration.

[0328] In some embodiments, the method comprises administering to the subject a second step- up dose at a flat dose of between about 200 mg to about 400 mg per administration. In certain embodiments, the second step-up dose is a flat dose of about 200 mg per administration. In other embodiments the second step-up dose is a flat dose of about 300 mg per administration. In other embodiments the second step-up dose is a flat dose of about 400 mg per administration.

[0329] In a particular embodiment, the second step-up dose is a flat dose of about 300 mg per administration.

[0330] The first step-up dose and the second step-up dose of the anti-KLK2xCD3 antibody may be a weight-based dose. Therefore, in some embodiments of the invention, the first step-up dose and the second step-up dose are weight-based doses. Such dosages can, for example, be based on the mg/kg dosages provided above according to the following: dose (mg/kg) x body weight (e g., 50 - 100 kg).

[0331] In some embodiments, the first step-up dose of the anti-KLK2xCD3 antibody is administered 3 days to 8 days prior to the administration of the second step-up dose. In certain embodiments, the first step-up dose is administered 3 days prior to the administration of the second step-up dose. In other embodiments, the first step-up dose is administered 4 days prior to the administration of the second step-up dose. In other embodiments, the first step-up dose is administered 5 days prior to the administration of the second step-up dose. In other embodiments, the first step-up dose is administered 6 days prior to the administration of the second step-up dose. In other embodiments, the first step-up dose is administered 7 days prior to the administration of the second step-up dose. In other embodiments, the first step-up dose is administered 8 days prior to the administration of the second step-up dose. [0332] In a particular embodiment, the first step-up dose of the anti-KLK2xCD3 antibody is administered 3 days prior to the administration of the second step-up dose.

[0333] In some embodiments, the method comprises administering to the subject a first step-up dose of between about 2 mg to about 5 mg per administration (for example a flat dose of about 2 mg to about 5 mg per administration) and the first step-up dose is administered 3 days prior to the administration of the second step up dose. In a particular embodiment, the first step-up dose is about 3.5 mg per administration (for example a flat dose of about 3.5 mg per administration) and the first step-up dose is administered 3 days prior to the administration of the second step up dose.

[0334] In some embodiments, the method comprises administering to the subject a first step-up dose of between about 5 mg to about 15 mg per administration (for example a flat dose of between about 5 mg to about 15 mg per administration) and the first step-up dose is administered 3 days prior to the administration of the second step up dose. In a particular embodiment, the first step-up dose is about 10 mg per administration (for example a flat dose of about 10 mg per administration) and the first step-up dose is administered 3 days prior to the administration of the second step up dose.

[0335] In a particular embodiment, the first step-up dose of the anti-KLK2xCD3 antibody is administered 7 days prior to the administration of the second step-up dose.

[0336] In some embodiments, the method comprises administering to the subject a first step-up dose of between about 2 mg to about 5 mg per administration (for example a flat dose of between about 2 mg to about 5 mg per administration) and the first step-up dose is administered 7 days prior to the administration of the second step up dose. In a particular embodiment, the first step- up dose is about 3.5 mg per administration (for example a flat dose of about 3.5 mg per administration) and the first step-up dose is administered 7 days prior to the administration of the second step-up dose.

[0337] In some embodiments, the method comprises administering to the subject a first step-up dose of between about 5 mg to about 15 mg per administration (for example a flat dose of between about 5 mg to about 15 mg per administration) and the first step-up dose is administered 7 days prior to the administration of the second step up dose. In a particular embodiment, the first step-up dose is about 10 mg per administration (for example a flat dose of about 10 mg per administration) and the first step-up dose is administered 7 days prior to the administration of the second step up dose.

[0338] In some embodiments, the second step-up dose of the anti-KLK2xCD3 antibody is administered 3 days to 8 days prior to the administration of the treatment dose. In certain embodiments, the second step-up dose is administered 3 days prior to the administration of the treatment dose. In other embodiments, the second step-up dose is administered 4 days prior to the administration of the treatment dose. In other embodiments, the second step-up dose is administered 5 days prior to the administration of the treatment dose. In other embodiments, the second step-up dose is administered 6 days prior to the administration of the treatment dose. In other embodiments, the second step-up dose is administered 7 days prior to the administration of the treatment dose. In other embodiments, the second step-up dose is administered 8 days prior to the administration of the treatment dose.

[0339] In a particular embodiment, the second step-up dose of the anti-KLK2xCD3 antibody is administered 3 days prior to the administration of the treatment dose.

[0340] In some embodiments, the method comprises administering to the subject a second step- up dose of between about 5 mg to about 15 mg per administration (for example a flat dose of between about 5 mg to about 15 mg per administration) and the second step-up dose is administered 3 days prior to the administration of the treatment dose. In a particular embodiment, the second step-up dose is about 10 mg per administration (for example a flat dose of about 10 mg per administration) and the second step-up dose is administered 3 days prior to the administration of the treatment dose.

[0341] In some embodiments, the method comprises administering to the subject a second step- up dose of between about 15 mg to about 25 mg per administration (for example a flat dose of between about 15 mg to about 25 mg per administration) and the second step-up dose is administered 3 days prior to the administration of the treatment dose. In a particular embodiment, the second step-up dose is about 18 mg per administration (for example a flat dose of about 18 mg per administration) and the second step-up dose is administered 3 days prior to the administration of the treatment dose.

[0342] In some embodiments, the method comprises administering to the subject a second step- up dose of between about 200 mg to about 400 mg per administration (for example a flat dose of between about 200 mg to about 400 mg per administration) and the second step-up dose is administered 3 days prior to the administration of the treatment dose. In a particular embodiment, the second step-up dose is about 300 mg per administration (for example a flat dose of about 300 mg per administration) and the second step-up dose is administered 3 days prior to the administration of the treatment dose.

[0343] In a particular embodiment, the second step-up dose of the anti-KLK2xCD3 antibody is administered 7 days prior to the administration of the treatment dose.

[0344] In some embodiments, the method comprises administering to the subject a second step- up dose of between about 5 mg to about 15 mg per administration (for example a flat dose of between about 5 mg to about 15 mg per administration) and the second step-up dose is administered 7 days prior to the administration of the treatment dose. In a particular embodiment, the second step-up dose is about 10 mg per administration (for example a flat dose of about 10 mg per administration) and the second step-up dose is administered 7 days prior to the administration of the treatment dose.

[0345] In some embodiments, the method comprises administering to the subject a second step- up dose of between about 15 mg to about 25 mg per administration (for example a flat dose of between about 15 mg to about 25 mg per administration) and the second step-up dose is administered 7 days prior to the administration of the treatment dose. In a particular embodiment, the second step-up dose is about 18 mg per administration (for example a flat dose of about 18 mg per administration) and the second step-up dose is administered 7 days prior to the administration of the treatment dose.

[0346] In some embodiments, the method comprises administering to the subject a second step- up dose of between about 200 mg to about 400 mg per administration (for example a flat dose of between about 200 mg to about 400 mg per administration) and the second step-up dose is administered 7 days prior to the administration of the treatment dose. In a particular embodiment, the second step-up dose is about 300 mg per administration (for example a flat dose of about 300 mg per administration) and the second step-up dose is administered 7 days prior to the administration of the treatment dose.

[0347] In embodiments that involve the administration of two step-up doses, the method may comprise administering to the subject: a first step-up dose of the anti-KLK2xCD3 antibody; a second step-up dose of the anti-KLK2xCD3 antibody; and a treatment dose of the anti- KLK2xCD3 antibody, wherein the first step-up dose is administered once, and the second step up dose is administered once.

[0348] In some embodiments, the first step-up dose of the anti-KLK2xCD3 antibody is administered, via IV infusion, 3 days to 8 days prior to the administration of the second step-up dose.

[0349] In a particular embodiment, the first step-up dose of the anti-KLK2xCD3 antibody is administered, via IV infusion, 3 days prior to the administration of the second step-up dose. [0350] In some embodiments, the method comprises administering to the subject a first step-up dose of between about 2 mg to about 5 mg per administration (for example a flat dose of between about 2 mg to about 5 mg per administration) and the first step-up dose is administered, via IV infusion, 3 days prior to the administration of the second step up dose. In a particular embodiment, the first step-up dose is about 3.5 mg per administration (for example a flat dose of about 3.5 mg per administration) and the first step-up dose is administered, via IV infusion, 3 days prior to the administration of the second step up dose.

[0351] In some embodiments, the method comprises administering to the subject a first step-up dose of between about 5 mg to about 15 mg per administration (for example a flat dose of between about 5 mg to about 15 mg per administration) and the first step-up dose is administered, via IV infusion, 3 days prior to the administration of the second step up dose. In a particular embodiment, the first step-up dose is about 10 mg per administration (for example a flat dose of about 10 mg per administration) and the first step-up dose is administered, via IV infusion, 3 days prior to the administration of the second step up dose.

[0352] In a particular embodiment, the first step-up dose of the anti-KLK2xCD3 antibody is administered, via IV infusion, 7 days prior to the administration of the second step-up dose. [0353] In some embodiments, the method comprises administering to the subject a first step-up dose of between about 2 mg to about 5 mg per administration (for example a flat dose of between about 2 mg to about 5 mg per administration) and the first step-up dose is administered, via IV infusion, 7 days prior to the administration of the second step up dose. In a particular embodiment, the first step-up dose is about 3.5 mg per administration (for example a flat dose of about 3.5 mg per administration) and the first step-up dose is administered, via IV infusion, 7 days prior to the administration of the second step up dose. [0354] In some embodiments, the method comprises administering to the subject a first step-up dose of between about 5 mg to about 15 mg per administration (for example a flat dose of between about 5 mg to about 15 mg per administration) and the first step-up dose is administered, via IV infusion, 7 days prior to the administration of the second step up dose. In a particular embodiment, the first step-up dose is about 10 mg per administration (for example a flat dose of about 10 mg per administration) and the first step-up dose is administered, via IV infusion, 7 days prior to the administration of the second step up dose.

[0355] In some embodiments, the second step-up dose of the anti-KLK2xCD3 antibody is administered, via IV infusion, 3 days to 8 days prior to the administration of the treatment dose. In certain embodiments, the second step-up dose is administered, via IV infusion, 3 days prior to the administration of the treatment dose.

[0356] In a particular embodiment, the second step-up dose of the anti-KLK2xCD3 antibody is administered, via IV infusion, 3 days prior to the administration of the treatment dose.

[0357] In some embodiments, the method comprises administering to the subject a second step- up dose of between about 5 mg to about 15 mg per administration (for example a flat dose of between about 5 mg to about 15 mg per administration) and the second step-up dose is administered, via IV infusion, 3 days prior to the administration of the treatment dose. In a particular embodiment, the second step-up dose is about 10 mg per administration (for example a flat dose of about 10 mg per administration) and the second step-up dose is administered, via IV infusion, 3 days prior to the administration of the treatment dose.

[0358] In some embodiments, the method comprises administering to the subject a second step- up dose of between about 15 mg to about 25 mg per administration (for example a flat dose of between about 15 mg to about 25 mg per administration) and the second step-up dose is administered, via IV infusion, 3 days prior to the administration of the treatment dose. In a particular embodiment, the second step-up dose is about 18 mg per administration (for example a flat dose of about 18 mg per administration) and the second step-up dose is administered, via IV infusion, 3 days prior to the administration of the treatment dose.

[0359] In some embodiments, the method comprises administering to the subject a second step- up dose of between about 200 mg to about 400 mg per administration (for example a flat dose of between about 200 mg to about 400 mg per administration) and the second step-up dose is administered, via IV infusion, 3 days prior to the administration of the treatment dose. In a particular embodiment, the second step-up dose is about 300 mg per administration (for example a flat dose of about 300 mg per administration) and the second step-up dose is administered, via IV infusion, 3 days prior to the administration of the treatment dose.

[0360] In a particular embodiment, the second step-up dose of the anti-KLK2xCD3 antibody is administered, via IV infusion, 7 days prior to the administration of the treatment dose.

[0361] In some embodiments, the method comprises administering to the subject a second step- up dose of between about 5 mg to about 15 mg per administration (for example a flat dose of between about 5 mg to about 15 mg per administration) and the second step-up dose is administered, via IV infusion, 7 days prior to the administration of the treatment dose. In a particular embodiment, the second step-up dose is about 10 mg per administration (for example a flat dose of about 10 mg per administration) and the second step-up dose is administered, via IV infusion, 7 days prior to the administration of the treatment dose.

[0362] In some embodiments, the method comprises administering to the subject a second step- up dose of between about 15 mg to about 25 mg per administration (for example a flat dose of between about 15 mg to about 25 mg per administration) and the second step-up dose is administered, via IV infusion, 7 days prior to the administration of the treatment dose. In a particular embodiment, the second step-up dose is about 18 mg per administration (for example a flat dose of about 18 mg per administration) and the second step-up dose is administered, via IV infusion, 7 days prior to the administration of the treatment dose.

[0363] In some embodiments, the method comprises administering to the subject a second step- up dose of between about 200 mg to about 400 mg per administration (for example a flat dose of between about 200 mg to about 400 mg per administration) and the second step-up dose is administered, via IV infusion, 7 days prior to the administration of the treatment dose. In a particular embodiment, the second step-up dose is about 300 mg per administration (for example a flat dose of about 300 mg per administration) and the second step-up dose is administered, via IV infusion, 7 days prior to the administration of the treatment dose.

[0364] The inventors have found that administration by intravenous infusion may be advantageous in reducing the likelihood of adverse events following administration of bispecific antibodies. The step-up doses may therefore also be administered by intravenous infusion. Accordingly, in some embodiments, the first step-up dose of the anti-KLK2xCD3 antibody is administered via intravenous (IV) infusion. In some embodiments, the second step-up dose of the anti-KLK2xCD3 antibody is administered via IV infusion. In some embodiments, the first step-up dose and the second step up dose of the anti-KLK2xCD3 antibody is administered via intravenous (IV) infusion.

[0365] In some embodiments the method comprises administering to the subject a first step-up dose of the anti-KLK2xCD3 antibody administered by intravenous (IV) infusion. In some embodiments, the method comprises administering to the subject a second step-up dose of the anti-KLK2xCD3 antibody administered by intravenous (IV) infusion. In some embodiments, the method comprises administering to the subject a first step-up dose of the anti-KLK2xCD3 antibody administered by intravenous (IV) infusion and a second step-up dose the anti- KLK2xCD3 antibody administered by intravenous (IV) infusion

[0366] An intravenous infusion of the anti-KLK2xCD3 antibody may be administered over several minutes to several hours. The inventors have found that administration of the first step- up dose of an anti-KLK2xCD3 antibody over a period of one hour followed by administration of subsequent infusions of the treatment dose over a period of 30 minutes are suitable timings for administration. Accordingly, in some embodiments, the first step-up dose is administered by intravenous (IV) infusion over a period of at least about one hour. In certain such embodiments, the first step-up dose is administered by intravenous (IV) infusion over a period of about one hour.

[0367] In some embodiments, the second step-up dose is administered by intravenous (IV) infusion over a period of at least about 30 minutes. In certain such embodiments, the second step-up dose is administered by intravenous (IV) infusion over a period of about 30 minutes. [0368] In some embodiments, the treatment dose is administered by intravenous (IV) infusion over a period of at least about 30 minutes. In certain such embodiments, the treatment dose is administered by intravenous (IV) infusion over a period of about 30 minutes.

[0369] In some embodiments, the first step-up dose is administered by intravenous infusion over a period of at least one hour (for example over a period of about one hour); the second step-up dose is administered by intravenous infusion over a period of at least 30 minutes (for example over a period of about 30 minutes); and any subsequent treatment dose is administered by intravenous infusion over a period of at least 30 minutes (for example over a period of about 30 minutes). Dosing regimens for intravenous infusion of anti-KLK2xCD3 antibody

[0370] The inventors have found that certain dosing regimens may be particularly suitable for the treatment of prostate cancer, as described elsewhere herein.

[0371] Accordingly, in some embodiments, the method of treating prostate cancer in a subject comprises administering to the subject an anti-KLK2xCD3 antibody and another anti-cancer drug, wherein the other anti -cancer drug is an androgen receptor pathway inhibitor (ARPI) or an anti-cancer chemotherapeutic agent, wherein the anti-KLK2xCD3 antibody is administered by intravenous (IV) infusion at a treatment dose, wherein the method comprises administering to the subject: i) a step-up dose of the anti-KLK2xCD3 antibody; and ii) the treatment dose of the anti- KLK2xCD3 antibody, wherein the step-up dose is administered once, and wherein the anti- KLK2xCD3 antibody comprises a first antigen binding domain that binds specifically to KLK2, and a second antigen binding domain that binds specifically to CD3e, preferably, the first antigen binding domain comprises a first heavy chain complementarity determining region (HCDR) 1, a first HCDR2 and a first HCDR3 of a first heavy chain variable region (VH1), and a first light chain complementarity determining region (LCDR) 1, a first LCDR2, and a first LCDR3 of a first light chain variable region (VL1), wherein the VH1 and the VL1 comprise: i) the amino acid sequences of SEQ ID NO: 37 and SEQ ID NO: 38, respectively; ii) the amino acid sequences of SEQ ID NO: 39 and SEQ ID NO: 40, respectively; iii) the amino acid sequences of SEQ ID NO: 41 and SEQ ID NO: 42, respectively; or iv) the amino acid sequences of SEQ ID NO: 43 and SEQ ID NO: 44, respectively wherein the first HCDR1, first HCDR2, first HCDR3, first LCDR1, first LCDR2 and first

LCDR3 are defined by the Kabat, Chothia, IMGT or AbM numbering system.

[0372] In certain embodiments, the step-up dose is administered prior to the treatment dose, the step-up dose is about 10 mg (for example a flat dose of about 10 mg) and the treatment dose is about 300 mg (for example a flat dose of about 300 mg).

[0373] In certain embodiments, the step-up dose is administered 7 days prior to the treatment dose.

[0374] In a particular embodiment, the method comprises administering to the subject a step-up dose of the anti-KLK2xCD3 antibody, wherein the step-up dose is about 10 mg (for example a flat dose of about 10 mg) is administered 7 days prior to the treatment dose, and the treatment dose is about 300 mg per administration (for example a flat dose of about 300 mg). [0375] In certain embodiments, the treatment dose is administered once every six weeks.

[0376] In a particular embodiment, the method comprises administering to the subject a step-up dose of the anti-KLK2xCD3 antibody, wherein the step-up dose is about 10 mg (for example a flat dose of about 10 mg) and is administered prior to the treatment dose, and the treatment dose is about 300 mg (for example a flat dose of about 300 mg) and is administered once every six weeks.

[0377] In a particular embodiment, the method comprises administering to the subject a step-up dose of the anti-KLK2xCD3 antibody, wherein the step-up dose is about 10 mg (for example a flat dose of about 10 mg) and is administered 7 days prior to the treatment dose, and the treatment dose is about 300 mg (for example a flat dose of about 300 mg) and is administered once every six weeks.

[0378] In certain embodiments, the treatment dose is administered once every three weeks.

[0379] In a particular embodiment, the method comprises administering to the subject a step-up dose of the anti-KLK2xCD3 antibody, wherein the step-up dose is about 10 mg (for example a flat dose of about 10 mg) and is administered prior to the treatment dose, and the treatment dose is about 300 mg (for example a flat dose of about 300 mg) and is administered once every three weeks.

[0380] In a particular embodiment, the method comprises administering to the subject a step-up dose of the anti-KLK2xCD3 antibody, wherein the step-up dose is about 10 mg (for example a flat dose of about 10 mg) and is administered 7 days prior to the treatment dose, and the treatment dose is about 300 mg (for example a flat dose of about 300 mg) and is administered once every three weeks.

[0381] In some embodiments, the method of treating prostate cancer in a subject comprises administering to the subject an anti-KLK2xCD3 antibody and another anti-cancer drug, wherein the other anti-cancer drug is an androgen receptor pathway inhibitor (ARPI) or an anti-cancer chemotherapeutic agent, wherein the anti-KLK2xCD3 antibody is administered by intravenous (IV) infusion at a treatment dose, wherein the method comprises administering to the subject: i) a step-up dose of the anti-KLK2xCD3 antibody; and ii) the treatment dose of the anti-KLK2xCD3 antibody, and wherein the step-up dose is administered once, wherein the anti-KLK2xCD3 antibody comprises a first antigen binding domain that binds specifically to KLK2, and a second antigen binding domain that binds specifically to CD3s, preferably, the first antigen binding domain comprises a first heavy chain complementarity determining region (HCDR) 1 , a first HCDR2 and a first HCDR3 of a first heavy chain variable region (VH1), and a first light chain complementarity determining region (LCDR) 1, a first LCDR2, and a first LCDR3 of a first light chain variable region (VL1), wherein the VH1 and the VL1 comprise: i) the amino acid sequences of SEQ ID NO: 37 and SEQ ID NO: 38, respectively; ii) the amino acid sequences of SEQ ID NO: 39 and SEQ ID NO: 40, respectively; iii) the amino acid sequences of SEQ ID NO: 41 and SEQ ID NO: 42, respectively; or iv) the amino acid sequences of SEQ ID NO: 43 and SEQ ID NO: 44, respectively wherein the first HCDR1, first HCDR2, first HCDR3, first LCDR1, first LCDR2 and first

LCDR3 are defined by the Kabat, Chothia, IMGT or AbM numbering system.

[0382] In certain embodiments, the step-up dose is administered prior to the treatment dose, the step-up dose is about 10 mg (for example a flat dose of about 10 mg) and the treatment dose is about 600 mg (for example a flat dose of about 600 mg).

[0383] In certain embodiments, the step-up dose is administered 7 days prior to the treatment dose.

[0384] In a particular embodiment, the method comprises administering to the subject a step-up dose of the anti-KLK2xCD3 antibody, wherein the step-up dose is administered 7 days prior to the treatment dose, wherein the step-up dose is about 10 mg (for example a flat dose of about 10 mg) and the treatment dose is about 600 mg (for example a flat dose of about 600 mg) .

[0385] In certain embodiments, the treatment dose is administered once every six weeks.

[0386] In a particular embodiment, the method comprises administering to the subject a step-up dose of the anti-KLK2xCD3 antibody, wherein the step-up dose is administered prior to the treatment dose, wherein the step-up dose is about 10 mg (for example a flat dose of about 10 mg) and the treatment dose is about 600 mg (for example a flat dose of about 600 mg) and the treatment dose is administered once every six weeks.

[0387] In a particular embodiment, the method comprises administering to the subject a step-up dose of the anti-KLK2xCD3 antibody, wherein the step-up dose is administered 7 days prior to the treatment dose, wherein the step-up dose is 10 mg (for example a flat dose of about 10 mg) and the treatment dose is 600 mg (for example a flat dose of about 600 mg) and the treatment dose is administered once every six weeks.

[0388] In certain embodiments, the treatment dose is administered once every three weeks. [0389] In a particular embodiment, the method comprises administering to the subject a step-up dose of the anti-KLK2xCD3 antibody , wherein the step-up dose is administered prior to the treatment dose, wherein the step-up dose is about 10 mg (for example a flat dose of about 10 mg) and the treatment dose is about 600 mg (for example a flat dose of about 600 mg) and the treatment dose is administered once every three weeks.

[0390] In a particular embodiment, the method comprises administering to the subject a step-up dose of the anti-KLK2xCD3 antibody , wherein the step-up dose is administered 7 days prior to the treatment dose, wherein the step-up dose is 10 mg (for example a flat dose of about 10 mg) and the treatment dose is 600 mg (for example a flat dose of about 600 mg) and the treatment dose is administered once every three weeks.

[0391] In some embodiments, the method of treating prostate cancer in a subject comprises administering to the subject an anti-KLK2xCD3 antibody and another anti-cancer drug, wherein the other anti-cancer drug is an androgen receptor pathway inhibitor (ARPI) or an anti-cancer chemotherapeutic agent, wherein the anti-KLK2xCD3 antibody is administered by intravenous (IV) infusion at a treatment dose, wherein the method comprises administering to the subject i) a first step-up dose of the anti-KLK2xCD3 antibody; ii) a second step-up dose of the anti- KLK2xCD3 antibody; and iii) the treatment dose of the anti-KLK2xCD3 antibody, wherein the first step-up dose and the second step-up doses are administered once, wherein the anti- KLK2xCD3 antibody comprises a first antigen binding domain that binds specifically to KLK2, and a second antigen binding domain that binds specifically to CD3e, preferably, the first antigen binding domain comprises a first heavy chain complementarity determining region (HCDR) 1, a first HCDR2 and a first HCDR3 of a first heavy chain variable region (VH1), and a first light chain complementarity determining region (LCDR) 1, a first LCDR2, and a first LCDR3 of a first light chain variable region (VL1), wherein the VH1 and the VL1 comprise: i) the amino acid sequences of SEQ ID NO: 37 and SEQ ID NO: 38, respectively; ii) the amino acid sequences of SEQ ID NO: 39 and SEQ ID NO: 40, respectively; iii) the amino acid sequences of SEQ ID NO: 41 and SEQ ID NO: 42, respectively; or iv) the amino acid sequences of SEQ ID NO: 43 and SEQ ID NO: 44, respectively wherein the first HCDR1, first HCDR2, first HCDR3, first LCDR1, first LCDR2 and first

LCDR3 are defined by the Kabat, Chothia, IMGT or AbM numbering system. [0392] In certain embodiments, the first step up dose is administered prior to the second step-up dose, and the second step-up dose is administered prior to the treatment dose, wherein the first step-up dose is about 3.5 mg (for example a flat dose of about 3.5 mg), the second step up dose is 18 mg (for example a flat dose of about 18 mg), and the treatment dose is 300 mg (for example a flat dose of about 300mg).

[0393] In certain embodiments, the first step-up dose is administered 7 days prior to the second step up dose.

[0394] In certain embodiments, the second step up dose is administered 7 days prior to the treatment dose.

[0395] In a particular embodiment, the method comprises administering to the subject a first step-up dose and a second step-up dose of the anti-KLK2xCD3 antibody, wherein the first step up dose is administered 7 days prior to the second step-up dose, the second step-up dose is administered 7 days prior to the treatment dose, the first step-up dose is about 3.5 mg (for example a flat dose of about 3.5 mg), the second step up dose is about 18 mg (for example a flat dose of about 18 mg), and the treatment dose is about 300 mg per administration (for example a flat dose of about 300 mg).

[0396] In certain embodiments, the treatment dose is administered once every six weeks.

[0397] In a particular embodiment, the method comprises administering to the subject a first step-up dose and a second step-up dose of the anti-KLK2xCD3 antibody , wherein the first step up dose is administered prior to the second step-up dose, the second step-up dose is administered prior to the treatment dose, the first step-up dose is about 3.5 mg (for example a flat dose of about 3.5 mg), the second step up dose is about 18 mg (for example a flat dose of about 18 mg), the treatment dose is 300 mg per administration (for example a flat dose of about 300 mg per administration) and the treatment dose is administered once every six weeks.

[0398] In a particular embodiment, the method comprises administering to the subject a first step-up dose and a second step-up dose of the anti-KLK2xCD3 antibody, wherein the first step up dose is administered 7 days prior to the second step-up dose, the second step-up dose is administered 7 days prior to the treatment dose, the first step-up dose is about 3.5 mg (for example a flat dose of about 3.5 mg), the second step up dose is about 18 mg (for example a flat dose of about 18 mg), the treatment dose is about 300 mg per administration (for example a flat dose of about 300 mg per administration) and the treatment dose is administered once every six weeks.

[0399] In certain embodiments, the treatment dose is administered once every three weeks. [0400] In a particular embodiment, the method comprises administering to the subject a first step-up dose and a second step-up dose of the anti-KLK2xCD3 antibody , wherein the first step up dose is administered prior to the second step-up dose, the second step-up dose is administered prior to the treatment dose, the first step-up dose is about 3.5 mg (for example a flat dose of about 3.5 mg), the second step up dose is about 18 mg (for example a flat dose of about 18 mg), the treatment dose is 300 mg per administration (for example a flat dose of about 300 mg per administration) and the treatment dose is administered once every three weeks.

[0401] In a particular embodiment, the method comprises administering to the subject a first step-up dose and a second step-up dose of the anti-KLK2xCD3 antibody , wherein the first step up dose is administered 7 days prior to the second step-up dose, the second step-up dose is administered 7 days prior to the treatment dose, the first step-up dose is about 3.5 mg (for example a flat dose of about 3.5 mg), the second step up dose is about 18 mg (for example a flat dose of about 18 mg), the treatment dose is about 300 mg per administration (for example a flat dose of about 300 mg per administration) and the treatment dose is administered once every three weeks.

[0402] In some embodiments, the method of treating prostate cancer in a subject comprises administering to the subject an anti-KLK2xCD3 antibody and another anti-cancer drug, wherein the other anti-cancer drug is an androgen receptor pathway inhibitor (ARPI) or an anti-cancer chemotherapeutic agent, wherein the anti-KLK2xCD3 antibody is administered by intravenous (IV) infusion at a treatment dose, wherein the method comprises administering to the subject i) a first step-up dose of the anti-KLK2xCD3 antibody; ii) a second step-up dose of the anti- KLK2xCD3 antibody; and iii) the treatment dose of the anti-KLK2xCD3 antibody, wherein the first step-up dose and the second step-up doses are administered once, wherein the anti- KLK2xCD3 antibody comprises a first antigen binding domain that binds specifically to KLK2, and a second antigen binding domain that binds specifically to CD3e, preferably, the first antigen binding domain comprises a first heavy chain complementarity determining region (HCDR) 1, a first HCDR2 and a first HCDR3 of a first heavy chain variable region (VH1), and a first light chain complementarity determining region (LCDR) 1, a first LCDR2, and a first LCDR3 of a first light chain variable region (VL1), wherein the VH1 and the VL1 comprise: i) the amino acid sequences of SEQ ID NO: 37 and SEQ ID NO: 38, respectively; ii) the amino acid sequences of SEQ ID NO: 39 and SEQ ID NO: 40, respectively; iii) the amino acid sequences of SEQ ID NO: 41 and SEQ ID NO: 42, respectively; or iv) the amino acid sequences of SEQ ID NO: 43 and SEQ ID NO: 44, respectively wherein the first HCDR1, first HCDR2, first HCDR3, first LCDR1, first LCDR2 and first LCDR3 are defined by the Kabat, Chothia, IMGT or AbM numbering system.

[0403] In certain embodiments, the first step up dose is administered prior to the second step-up dose, the second step-up dose is administered prior to the treatment dose, the first step-up dose is about 3.5 mg (for example a flat dose of about 3.5 mg), the second step up dose is 18 mg (for example a flat dose of about 18 mg), and the treatment dose is 600 mg (for example a flat dose of about 600mg).

[0404] In certain embodiments, the first step-up dose is administered 7 days prior to the second step up dose.

[0405] In certain embodiments, the second step up dose is administered 7 days prior to the treatment dose.

[0406] In a particular embodiment, the method comprises administering to the subject a first step-up dose and a second step-up dose of the anti-KLK2xCD3 antibody, wherein the first step up dose is administered 7 days prior to the second step-up dose, the second step-up dose is administered 7 days prior to the treatment dose, the first step-up dose is about 3.5 mg (for example a flat dose of about 3.5 mg), the second step up dose is about 18 mg (for example a flat dose of about 18 mg), and the treatment dose is about 600 mg per administration (for example a flat dose of about 600 mg).

[0407] In certain embodiments, the treatment dose is administered once every six weeks.

[0408] In a particular embodiment, the method comprises administering to the subject a first step-up dose and a second step-up dose of the anti-KLK2xCD3 antibody, wherein the first step up dose is administered prior to the second step-up dose, the second step-up dose is administered prior to the treatment dose, the first step-up dose is about 3.5 mg (for example a flat dose of about 3.5 mg), the second step up dose is about 18 mg (for example a flat dose of about 18 mg), the treatment dose is 600 mg per administration (for example a flat dose of about 600 mg per administration ) and the treatment dose is administered once every six weeks.

[0409] In a particular embodiment, the method comprises administering to the subject a first step-up dose and a second step-up dose of the anti-KLK2xCD3 antibody , wherein the first step up dose is administered 7 days prior to the second step-up dose, the second step-up dose is administered 7 days prior to the treatment dose, the first step-up dose is about 3.5 mg (for example a flat dose of about 3.5 mg), the second step up dose is about 18 mg (for example a flat dose of about 18 mg), the treatment dose is about 600 mg per administration (for example a flat dose of about 600 mg per administration) and the treatment dose is administered once every 6 weeks.

[0410] In certain embodiments, the treatment dose is administered once every three weeks. [0411] In a particular embodiment, the method comprises administering to the subject a first step-up dose and a second step-up dose of the anti-KLK2xCD3 antibody , wherein the first step up dose is administered prior to the second step-up dose, the second step-up dose is administered prior to the treatment dose, the first step-up dose is about 3.5 mg (for example a flat dose of about 3.5 mg), the second step up dose is about 18 mg (for example a flat dose of about 18 mg), the treatment dose is 600 mg per administration (for example a flat dose of about 600 mg per administration) and the treatment dose is administered once every three weeks.

[0412] In a particular embodiment, the method comprises administering to the subject a first step-up dose and a second step-up dose of the anti-KLK2xCD3 antibody, wherein the first step up dose is administered 7 days prior to the second step-up dose, the second step-up dose is administered 7 days prior to the treatment dose, the first step-up dose is about 3.5 mg (for example a flat dose of about 3.5 mg), the second step up dose is about 18 mg (for example a flat dose of about 18 mg), the treatment dose is about 600 mg per administration (for example a flat dose of about 600 mg per administration) and the treatment dose is administered once every three weeks.

[0413] In some embodiments, the method of treating prostate cancer in a subject comprises administering to the subject an anti-KLK2xCD3 antibody and another anti-cancer drug, wherein the other anti-cancer drug is an androgen receptor pathway inhibitor (ARPI) or an anti-cancer chemotherapeutic agent, wherein the anti-KLK2xCD3 antibody is administered by intravenous (IV) infusion at a treatment dose, wherein the method comprises administering to the subject i) a first step-up dose of the anti-KLK2xCD3 antibody; ii) a second step-up dose of the anti- KLK2xCD3 antibody; and iii) the treatment dose of the anti-KLK2xCD3 antibody, wherein the first step-up dose and the second step-up doses are administered once, wherein the anti- KLK2xCD3 antibody comprises a first antigen binding domain that binds specifically to KLK2, and a second antigen binding domain that binds specifically to CD3s, preferably, the first antigen binding domain comprises a first heavy chain complementarity determining region (HCDR) 1, a first HCDR2 and a first HCDR3 of a first heavy chain variable region (VH1), and a first light chain complementarity determining region (LCDR) 1, a first LCDR2, and a first LCDR3 of a first light chain variable region (VL1), wherein the VH1 and the VL1 comprise: i) the amino acid sequences of SEQ ID NO: 37 and SEQ ID NO: 38, respectively; ii) the amino acid sequences of SEQ ID NO: 39 and SEQ ID NO: 40, respectively; iii) the amino acid sequences of SEQ ID NO: 41 and SEQ ID NO: 42, respectively; or iv) the amino acid sequences of SEQ ID NO: 43 and SEQ ID NO: 44, respectively wherein the first HCDR1, first HCDR2, first HCDR3, first LCDR1, first LCDR2 and first LCDR3 are defined by the Kabat, Chothia, IMGT or AbM numbering system.

[0414] In certain embodiments, the first step up dose is administered prior to the second step-up dose, the second step-up dose is administered prior to the treatment dose, the first step-up dose is about 10 mg (for example a flat dose of about 10 mg), the second step up dose is 300 mg (for example a flat dose of about 300 mg) and the treatment dose is 900 mg (for example a flat dose of about 900mg).

[0415] In certain embodiments, the first step-up dose is administered 7 days prior to the second step up dose.

[0416] In certain embodiments, the second step up dose is administered 7 days prior to the treatment dose.

[0417] In a particular embodiment, the method comprises administering to the subject a first step-up dose and a second step-up dose of the anti-KLK2xCD3 antibody , wherein the first step up dose is administered 7 days prior to the second step-up dose, the second step-up dose is administered 7 days prior to the treatment dose, the first step-up dose is about 10 mg (for example a flat dose of about 10 mg), the second step up dose is about 300 mg (for example a flat dose of about 300 mg) and the treatment dose is about 900 mg per administration (for example a flat dose of about 900 mg). [0418] In certain embodiments, the treatment dose is administered once every six weeks. [0419] In a particular embodiment, the method comprises administering to the subject a first step-up dose and a second step-up dose of the anti-KLK2xCD3 antibody , wherein the first step- up dose is administered prior to the second step-up dose, the second step-up dose is administered prior to the treatment dose, the first step-up dose is about 10 mg (for example a flat dose of about 10 mg), the second step-up dose is about 300 mg (for example a flat dose of about 300 mg), the treatment dose is 900 mg per administration (for example a flat dose of about 900 mg per administration ) and the treatment dose is administered once every six weeks.

[0420] In a particular embodiment, the method comprises administering to the subject a first step-up dose and a second step-up dose of the anti-KLK2xCD3 antibody, wherein the first step up dose is administered 7 days prior to the second step-up dose, the second step-up dose is administered 7 days prior to the treatment dose, the first step-up dose is about 10 mg (for example a flat dose of about 10 mg), the second step up dose is about 300 mg (for example a flat dose of about 300 mg), the treatment dose is about 900 mg per administration (for example a flat dose of about 900 mg per administration) and the treatment dose is administered once every six weeks.

[0421] In some embodiments, the method of treating prostate cancer in a subject comprises administering to the subject an anti-KLK2xCD3 antibody and another anti-cancer drug, wherein the other anti-cancer drug is an androgen receptor pathway inhibitor (ARPI) or an anti-cancer chemotherapeutic agent, wherein the anti-KLK2xCD3 antibody is administered by intravenous (IV) infusion at a treatment dose, wherein the method comprises administering to the subject i) a first step-up dose of the anti-KLK2xCD3 antibody; ii) a second step-up dose of the anti- KLK2xCD3 antibody; and iii) the treatment dose of the anti-KLK2xCD3 antibody, wherein the first step-up dose and the second step-up doses are administered once, wherein the anti- KLK2xCD3 antibody comprises a first antigen binding domain that binds specifically to KLK2, and a second antigen binding domain that binds specifically to CD3e, preferably, the first antigen binding domain comprises a first heavy chain complementarity determining region (HCDR) 1, a first HCDR2 and a first HCDR3 of a first heavy chain variable region (VH1), and a first light chain complementarity determining region (LCDR) 1, a first LCDR2, and a first LCDR3 of a first light chain variable region (VL1), wherein the VH1 and the VL1 comprise: i) the amino acid sequences of SEQ ID NO: 37 and SEQ ID NO: 38, respectively; ii) the amino acid sequences of SEQ ID NO: 39 and SEQ ID NO: 40, respectively; iii) the amino acid sequences of SEQ ID NO: 41 and SEQ ID NO: 42, respectively; or iv) the amino acid sequences of SEQ ID NO: 43 and SEQ ID NO: 44, respectively wherein the first HCDR1, first HCDR2, first HCDR3, first LCDR1, first LCDR2 and first LCDR3 are defined by the Kabat, Chothia, IMGT or AbM numbering system.

[0422] In certain embodiments, the first step up dose is administered prior to the second step-up dose and the second step-up dose is administered prior to the treatment dose, wherein the first step-up dose is about 10 mg (for example a flat dose of about 10 mg), the second step up dose is 300 mg (for example a flat dose of about 300 mg), and the treatment dose is 600 mg (for example a flat dose of about 600mg).

[0423] In certain embodiments, the first step-up dose is administered 7 days prior to the second step up dose.

[0424] In certain embodiments, the second step-up dose is administered 7 days prior to the treatment dose.

[0425] In a particular embodiment, the method comprises administering to the subject a first step-up dose and a second step-up dose of the anti-KLK2xCD3 antibody, wherein the first step up dose is administered 7 days prior to the second step-up dose, the second step-up dose is administered 7 days prior to the treatment dose, wherein the first step-up dose is about 10 mg (for example a flat dose of about 10 mg), the second step up dose is about 300 mg (for example a flat dose of about 300 mg), the treatment dose is about 600 mg per administration (for example a flat dose of about 600 mg).

[0426] In certain embodiments, the treatment dose is administered once every six weeks.

[0427] In a particular embodiment, the method comprises administering to the subject a first step-up dose and a second step-up dose of the anti-KLK2xCD3 antibody , wherein the first step up dose is administered prior to the second step-up dose, the second step-up dose is administered prior to the treatment dose, the first step-up dose is about 10 mg (for example a flat dose of about 10 mg), the second step up dose is about 300 mg (for example a flat dose of about 300 mg), the treatment dose is 600 mg per administration (for example a flat dose of about 600 mg per administration ) and the treatment dose is administered once every six weeks.

[0428] In a particular embodiment, the method comprises administering to the subject a first step-up dose and a second step-up dose of the anti-KLK2xCD3 antibody , wherein the first step up dose is administered 7 days prior to the second step-up dose, the second step-up dose is administered 7 days prior to the treatment dose, the first step-up dose is about 10 mg (for example a flat dose of about 10 mg), the second step up dose is about 300 mg (for example a flat dose of about 300 mg), the treatment dose is about 600 mg per administration (for example a flat dose of about 600 mg per administration) and the treatment dose is administered once every six weeks.

[0429] In any of the dosing regimen embodiments described in the preceding paragraphs, the anti-KLK2xCD3 antibody may comprise a HC1 of SEQ ID NO: 55, a LC1 of SEQ ID NO: 50 and a HC2 of SEQ ID NO: 61.

[0430] In certain embodiments, the other anti-cancer drug is an anti-cancer chemotherapeutic agent. In certain embodiments, the anti-cancer chemotherapeutic is a taxane. Taxanes are widely- used chemotherapy agents for treating various solid malignancies and work as microtubule inhibitors resulting cell cycle inhibition during the G2/M phase activates the cellular apoptosis pathways. Taxanes include paclitaxel, docetaxel, cabazitaxel, and albumin-bound paclitaxel. In preferred embodiments, the taxane is docetaxel or cabazitaxel.

[0431] In certain embodiments, the anti-cancer chemotherapeutic agent is intravenously administered, such as via intravenous injection or infusion. In certain embodiments, docetaxel or cabazitaxel is intravenously administered to the subject every 1-6 weeks, preferably every 3 weeks.

[0432] In certain embodiments, the other anti-cancer drug is docetaxel, preferably the other anticancer drug is docetaxel and is administered intravenously at a dose of 75 mg/m². In certain embodiments, the other anti -cancer drug is cabazitaxel, preferably the other anti-cancer drug is cabazitaxel and is administered intravenously at a dose of 20 mg/m².

[0433] In certain embodiments, the other anti-cancer drug is a taxane, and wherein no prednisone, preferably no corticosteroid, is administered as a (pre)medi cation prior to the administration of taxane, or together with the administration of taxane.

[0434] Early-stage and castration-sensitive prostate cancer growth is solely mediated by androgen signaling pathways. As used herein, “androgen-receptor signaling inhibitors,” or “ARSIs, “androgen-receptor pathway inhibitors,” or “ARPIs” are used interchangeably. ARPIs include androgen synthesis inhibitor-abiraterone and androgen receptor antagonists- enzalutamide, apalutamide, and darolutamide. In certain embodiments, the other anti-cancer drug is an ARPT. In certain embodiments the ARPI is apatulamide, enzatulamide, darolutamide, or abiraterone acetate.

[0435] In certain embodiments, the ARPI is administered orally.

[0436] In certain embodiments, the other anti-cancer drug is apatulamide, preferably the other anti-cancer drug is apalutamide and is administered orally at a dose of 240 mg per day, preferably 240 mg once daily, preferably four tablets of 60 mg once daily. In certain embodiments, the other anti -cancer drug is enzatulamide, preferably the other anti-cancer drug is enzalutamide and is administered orally at a dose of 160 mg per day, preferably 160 mg once daily, preferably four capsules of 40mg once a day. In certain embodiments, the other anti-cancer drug is darolutamide, preferably the other anti-cancer drug is darolutamide and is administered orally at a dose of 1200 mg per day, preferably 600 mg twice daily, preferably two tablets of 300 mg twice daily. In certain embodiments, the other anti-cancer drug is abiraterone acetate, preferably the other anti-cancer drug is abiraterone acetate and is administered orally at a dose of 1000 mg per day, preferably 1000 mg once daily, preferably four tablets of 250 mg once daily. [0437] In certain embodiments, the method further comprises orally administering to the subject prednisone, preferably at a dose of 5 mg or 10 mg per day, preferably of 5 mg once or twice a day, such as one tablet of 5 mg once a day or one tablet of 5 mg twice a day.

[0438] In certain embodiments, the method does not comprise the administration of an anti-PDl antibody at least 6 weeks prior to the first dose of anti-KLK2xCD3 antibody or other anti-cancer agent. In other embodiments, the method does not comprise the administration of an anti-PDl antibody.

[0439] In certain embodiments, the prostate cancer is advanced prostate cancer, metastatic castration-sensitive prostate cancer (CSPC), metastatic castration-resistant prostate cancer (CRPC), non-metastatic CSPC, non-metastatic CRPC, or metastatic prostate cancer, preferably the prostate cancer is metastatic CRPC.

[0440] In certain embodiments, the subject does not have one or more of the following:

1) active autoimmune disease within the 12 months that requires systemic immunosuppressive medications, prior to the initial administration of the anti- KLK2xCD3 antibody, except vitiligo and prior autoimmune thyroiditis that is currently euthyroid based on clinical symptoms and laboratory testing; ) toxicity related to prior anti cancer therapy that has not returned to Grade <1 or baseline levels (except for alopecia, vitiligo, Grade <2 peripheral neuropathy); ) solid organ or bone marrow transplantation; ) known allergies or intolerance to any of the anti-KLK2xCD3 antibody, the anti-cancer chemotherapeutic agent and the androgen receptor pathway inhibitor (ARPI); ) any of the following within 6 months prior to the initial administration of the anti-

KLK2xCD3 antibody: a. Myocardial infarction b. Severe or unstable angina c. Clinically significant ventricular arrhythmias d. Congestive heart failure (New York Heart Association [NYHA] class II to IV) e. Transient ischemic attack f. Cerebrovascular accident ) major surgery (e.g., requiring general anesthesia) within 2 weeks before the initial administration of the anti-KLK2xCD3 antibody or has not recovered from surgery; ) active infection or condition that requires treatment with systemic antibiotics within 7 days prior to the initial administration of the anti-KLK2xCD3 antibody; ) venous thromboembolic events (e.g., pulmonary embolism) within 1 month prior to the first dose of study treatment; uncomplicated (Grade <2) deep vein thrombosis is not considered exclusionary; ) clinically significant pulmonary compromise, particularly a requirement for supplemental oxygen use (>2 L/min by nasal cannula) to maintain adequate oxygenation; 0) active CNS involvement, except treated, stable and asymptomatic brain metastases requiring <10 mg prednisone or equivalent within 2 weeks prior to the first dose of study treatment are permitted; 1) prior treatment with KLK2-targeted therapy; 2) treatment with any anti-cancer or investigational agents within 28 days or 5-half-lives, whichever is shorter, prior to the initial administration of the anti-KLK2xCD3 antibody, such as,

No restrictions on GnRH agonist/antagonists,

Immune checkpoint inhibitors within 6 weeks prior to start of study treatment, • Any T-cell redirecting treatment (e.g., CD3-directed bispecific or CAR-T therapy) within 90 days prior to the start of study treatment,

• Radionuclide therapy within 6 weeks prior to start of study treatment,

13) received immunosuppressive doses of systemic medications, such as glucocorticoids (doses >10 mg/day prednisone or equivalent) within 7 days prior to the first dose of study treatment, provided that a single course of glucocorticoids is permitted as prophylaxis for imaging contrast (i.e., for participants with allergies to contrast);

14) received or plans to receive any live, attenuated vaccine within 4 weeks before the first dose of study treatment; and

15) active hepatitis B or C virus infection according to local laboratory range.

In certain embodiments, the subject is 18 years of age or older, such as: i) a subject having metastatic CRPC (mCRPC), ii) a subject having prior orchiectomy, or the subject having not undergone orchiectomy and receives ongoing androgen deprivation therapy with a gonadotropin releasing hormone (GnRH) analog (agonist or antagonist) prior to the initial administration of the anti-KLK2xCD3 antibody and continue androgen deprivation therapy throughout the treatment phase, iii) a subject having microsatellite instability (MSI-H)/mismatch repair deficient (dMMR) disease not previously received and progressed on PD-(L)1 therapy, or iv) a subject having received at least 1 prior treatment with an ARPI (e.g., apalutamide, enzalutamide, darolutamide, or abiraterone acetate) and/or taxane (e.g., docetaxel or cabazitaxel) prior to the initial administration of the anti-KLK2xCD3 antibody.

[0441] In certain embodiments, the subject is: i) a subject having metastatic CRPC (mCRPC); ii) a subject having prior orchiectomy, or the subject having not undergone orchiectomy and receives ongoing androgen deprivation therapy with a gonadotropin releasing hormone (GnRH) analog (agonist or antagonist) prior to the initial administration of the anti-KLK2xCD3 antibody and continue androgen deprivation therapy throughout the treatment phase; iii) a subject having microsatellite instability (MSI-H)/mismatch repair deficient (dMMR) disease not previously received and progressed on PD-(L)1 therapy; iv) a subject having received at least 1 prior treatment with an ARPI (e.g., apalutamide, enzalutamide, darolutamide, or abiraterone acetate) and/or taxane (e.g., docetaxel or cabazitaxel) prior to the initial administration of the anti-KLK2xCD3 antibody; and/or v) a subject living with HIV; and wherein the subject preferably is 18 years of age or older.

[0442] In certain embodiments, the subject has not received immunosuppressive doses of systemic medications, such as glucocorticoids (doses >10 mg/day prednisone or equivalent) within 7 days prior to the first dose of study treatment, provided that a single course of glucocorticoids is permitted as prophylaxis for imaging contrast (i.e., for participants with allergies to contrast).

SUBJECT MATTER DESCRIBED IN THE APPLICATION

1 . A method of treating prostate cancer in a subject, wherein the method comprises administering to the subject an anti-KLK2xCD3 antibody and another anti-cancer drug, wherein the other anti-cancer drug an androgen receptor pathway inhibitor (ARPI) or an anticancer chemotherapeutic agent, wherein the anti-KLK2xCD3 antibody comprises a first antigen binding domain that binds specifically to KLK2, and a second antigen binding domain that binds specifically to CD3s, preferably, the first antigen binding domain comprises a first heavy chain complementarity determining region (HCDR) 1, a first HCDR2 and a first HCDR3 of a first heavy chain variable region (VH1), and a first light chain complementarity determining region (LCDR) 1, a first LCDR2, and a first LCDR3 of a first light chain variable region (VL1), wherein the VH1 and the VL1 comprise: i) the amino acid sequences of SEQ ID NO: 37 and SEQ ID NO: 38, respectively; ii) the amino acid sequences of SEQ ID NO: 39 and SEQ ID NO: 40, respectively; iii) the amino acid sequences of SEQ ID NO: 41 and SEQ ID NO: 42, respectively; or iv) the amino acid sequences of SEQ ID NO: 43 and SEQ ID NO: 44, respectively wherein the first HCDR1, first HCDR2, first HCDR3, first LCDR1, first LCDR2 and first LCDR3 are defined by the Kabat, Chothia, IMGT or AbM numbering system. he method of embodiment 1, wherein the administering of the anti-KLK2xCD3 antibody and the other anti-cancer drug enhances immune cell function, such as enhances T cell function, as compared to the administration of each of the anti-KLK2xCD3 antibody and the other anti-cancer drug alone, preferably, the T cell function comprises T cell cytotoxicity (or T cell killing), T cell activation, and/or T cell proliferation, e.g., the T cell function is T cell cytotoxicity (or T cell killing), more preferably T cell killing of prostate cancer cells. he method of any of the foregoing embodiments, wherein the administering of the anti-

KLK2xCD3 antibody and the other anti-cancer drug prevents disease progression of the prostate cancer. he method of any of the foregoing embodiments, wherein the administering of the anti- KLK2xCD3 antibody and the other anti-cancer drug does not increase the risk of a treatment related toxicity in a clinically significant way as compared to the administration of each of the anti-KLK2xCD3 antibody and the other anti-cancer drug alone (e.g., when assessed in a cohort of patients). he method of any of the foregoing embodiments, wherein the administering of the anti-

KLK2xCD3 antibody and the other anti-cancer drug provides a reduction in serum Prostate Specific Antigen (PSA), preferably an improved serum PSA reduction, as compared to the administration of each of the anti-KLK2xCD3 antibody and the other anti-cancer drug alone, without triggering a cytokine release syndrome (CRS) of grade 3 or higher according to the American Society for Transplantation and Cellular Therapy (ASTCT) guidelines. he method of any of the foregoing embodiments, wherein the first HCDR1, first HCDR2, first HCDR3, first LCDR1, first LCDR2 and first LCDR3 comprises: i) the amino acid sequences of SEQ ID NOs: 1, 2, 3, 4, 5, and 6, respectively; ii) the amino acid sequences of SEQ ID NOs: 7, 8, 9, 10, 1 1, and 12, respectively; iii) the amino acid sequences of SEQ ID NOs: 13, 14, 15, 16, 17, and 18, respectively; or iv) the amino acid sequences of SEQ ID NOs: 19, 20, 21, 22, 23, and 24, respectively. he method of any of the foregoing embodiments, wherein the VH1 and the VL1 comprise: i) amino acid sequences at least 90%, preferably 100%, identical to SEQ ID NO: 37 and

SEQ ID NO: 38, respectively, ii) amino acid sequences at least 90%, preferably 100%, identical to SEQ ID NO: 39 and SEQ ID NO: 40, respectively; iii) amino acid sequences at least 90%, preferably 100%, identical to SEQ ID NO: 41 and SEQ ID NO: 42, respectively; or iv) amino acid sequences at least 90%, preferably 100%, identical to SEQ ID NO: 43 and SEQ ID NO: 44, respectively. he method of embodiment 8, wherein the first binding domain comprises i) a first heavy chain (HC1) and a first light chain (LC1), and the HC1 and the LC1 comprise: a) amino acid sequences at least 90%, preferably 100%, identical to SEQ ID NO: 49 and

SEQ ID NO: 50, respectively; or ii) a first single-chain variable fragment fused to a Fc (scFvl-Fc), and the scFvl-Fc comprises an amino acid sequence at least 90%, preferably 100%, identical to SEQ ID NO: 51 or 52. he method of any of the foregoing embodiments, wherein the second antigen binding domain comprises a second HCDR1, a second HCDR2 and a second HCDR3 of a second heavy chain variable region (VH2), and a second LCDR1, a second LCDR2, and a second LCDR3 of a second light chain variable region (VL2), wherein the VH2 and the VL2 comprise: i) the amino acid sequences of SEQ ID NO: 45 and SEQ ID NO: 46, respectively; or ii) the amino acid sequences of SEQ ID NO: 47 and SEQ ID NO: 48, respectively wherein the second HCDR1, second HCDR2, second HCDR3, second LCDR1, second LCDR2 and second LCDR3 are defined by the Kabat, Chothia, IMGT or AbM numbering system.

10. The method of embodiment 9, wherein the second HCDR1, second HCDR2, second HCDR3, second LCDR1, second LCDR2 and second LCDR3 comprises: i) the amino acid sequences of SEQ ID NOs: 25, 26, 27, 28, 29, and 30, respectively; or ii) the amino acid sequences of SEQ ID NOs: 31, 32, 33, 34, 35, and 36, respectively.

11. The method of embodiment 10, wherein the VH2 and the VL2 comprise: i) amino acid sequences at least 90%, preferably 100%, identical to SEQ ID NO: 45 and

SEQ ID NO: 46, respectively; or ii) amino acid sequences at least 90%, preferably 100%, identical to SEQ ID NO: 47 and SEQ ID NO: 48, respectively.

12. The method of embodiment 11, wherein the second binding domain comprises: i) a second heavy chain (HC2) and a second light chain (LC2), and the HC2 and the LC2 comprise: a) amino acid sequences at least 90%, preferably 100%, identical to SEQ ID NO: 57 and

SEQ ID NO: 60, respectively; or ii) a second single-chain variable fragment fused to a Fc (scFv2-Fc), and the scFv2-Fc comprises an amino acid sequence at least 90%, preferably 100%, identical to SEQ ID NO: 56 or 61.

13. The method of embodiment 10, wherein the first HCDR1, first HCDR2, first HCDR3, first LCDR1, first LCDR2, first LCDR3, second HCDR1, second HCDR2, second HCDR3, second LCDR1, second LCDR2 and second LCDR3 comprise: i) the amino acid sequences of SEQ ID NOs: 1, 2, 3, 4, 5, 6, 25, 26, 27, 28, 29, and 30, respectively; ii) the amino acid sequences of SEQ ID NOs: 7, 8, 9, 10, 11, 12, 25, 26, 27, 28, 29, and

30, respectively; iii) the amino acid sequences of SEQ ID NOs: 13, 14, 15, 16, 17, 18, 31, 32, 33, 34, 35, and 36, respectively; or iv) the amino acid sequences of SEQ ID NOs: 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, and 30, respectively. method of embodiment 13, wherein the VH1, VL1, VH2 and VL2 comprise: i) amino acid sequences at least 90%, preferably 100%, identical to SEQ ID NOs: 37, 38,

45, and 46, respectively; ii) amino acid sequences at least 90%, preferably 100%, identical to SEQ ID NOs: 39, 40, 45, and 46, respectively, iii) amino acid sequences at least 90%, preferably 100%, identical to SEQ ID NOs: 41, 42, 47, and 48, respectively, iv) amino acid sequences at least 90%, preferably 100%, identical to SEQ ID NOs: 43, 44, 45, and 46, respectively. method of embodiment 14, wherein i) the first binding domain comprises the HC1 and LC1 comprising amino acid sequences at least 90%, preferably 100%, identical to SEQ ID NOs: 49 and 50, respectively, and the second binding domain comprises the scFv2-Fc comprising an amino acid sequence at least 90%, preferably 100%, identical to SEQ ID NO: 56; ii) the first binding domain comprises the scFvl-Fc comprising an amino acid sequence at least 90%, preferably 100%, identical to SEQ ID NO: 51, and the second binding domain comprises the HC2 and LC2 comprising amino acid sequences at least 90%, preferably 100%, identical to SEQ ID NOs: 57 and 58, respectively; iii) the first binding domain comprises the scFvl-Fc comprising an amino acid sequence at least 90%, preferably 100%, identical to SEQ ID NO: 52, and the second binding domain comprises the HC2 and LC2 comprising amino acid sequences at least 90%, preferably 100%, identical to SEQ ID NOs: 59 and 60, respectively, iv) the first binding domain comprises the HC1 and LC1 comprising amino acid sequences at least 90%, preferably 100%, identical to SEQ ID NOs: 53 and 54, respectively, and the second binding domain comprises the scFv2-Fc comprising an amino acid sequence at least 90%, preferably 100%, identical to SEQ ID NO: 56; or v) the first binding domain comprises the HC1 and LC1 comprising amino acid sequences at least 90%, preferably 100%, identical to SEQ ID NOs: 55 and 50, respectively, and the second binding domain comprises the scFv2-Fc comprising an amino acid sequence at least 90%, preferably 100%, identical to SEQ ID NO: 61.

16. The method of any one of embodiments 1-15, wherein the anti-KLK2xCD3 antibody is administered to the subject subcutaneously.

17. The method of any one of embodiments 1-15, wherein the anti-KLK2xCD3 antibody is administered to the subject intravenously.

18. The method of embodiment 16 or 17, wherein the anti-KLK2xCD3 antibody is administered once every 1-9 weeks, for example, once every 3 weeks, once every 6 weeks, or once every 9 weeks.

19. The method of any one of the preceding embodiments, wherein the administering of the anti- KLK2xCD3 antibody comprises the administering of more than one treatment dose, wherein the treatment doses are administered once every 1-9 weeks, for example, once every 3 weeks, once every 6 weeks, or once every 9 weeks, and wherein each treatment dose is at the same dose level.

20. The method of any one of the preceding embodiments, wherein the other anti-cancer drug is administered simultaneously, sequentially or separately from the administering of the anti- KLK2xCD3 antibody, for example on the same day about 4 hours apart. 21 . The method of any one of the preceding embodiments, wherein the anti-KLK2xCD3 antibody is administered at a treatment dose level of 100-2000 mg.

22. The method of any one of embodiments 1-21, which comprises administering the anti- KLK2xCD3 antibody at a step-up dose and at a treatment dose, wherein the level of the step-up dose is lower than the level of treatment dose, for example the level of the step-up dose is in the range of 0.1-600mg per dose and the level of the treatment dose is the range of 100-2000 mg per dose.

23. The method of embodiment 22, comprising administering to the subject i) a step-up dose of the anti-KLK2xCD3 antibody, and ii) a treatment dose of the anti-KLK2xCD3 antibody, wherein the step-up dose is administered once, and the treatment dose is administered at least twice (e.g., 2, 3, 4 or more times); and wherein the level of the step-up dose is lower than the level of the treatment dose.

24. The method of embodiment 22 or 23, wherein the step-up dose is administered 2-15 days, such as 1 week, before the first administration of the treatment dose, and wherein the treatment dose is administered once every 1-9 weeks, for example, once every 3 weeks, once every 6 weeks, or once every 9 weeks.

25. The method of embodiment 22, comprising administering to the subject i) a first step-up dose of the anti-KLK2xCD3 antibody, ii) a second step-up dose of the anti-KLK2xCD3 antibody and iii) a treatment dose of the anti-KLK2xCD3 antibody, wherein the first step-up dose and the second step-up dose are each administered once, and the treatment dose is administered at least twice (e g., 2, 3, 4 or more times); wherein the level of the first step-up dose is lower than the level of the second step-up dose, and wherein the level of the second step-up dose is lower than the level of the treatment dose level 26. The method of embodiment 25, wherein the first step-up dose is administered 2-15 days, such as 1 week, before the second step-up dose; wherein the second step-up dose is administered 2-15 days, such as 1 week before the first administration of the treatment dose; and wherein the treatment dose is administered once every 1-9 weeks, for example, once every 3 weeks, once every 6 weeks, or once every 9 weeks.

27. The method of embodiment 17, wherein the anti-KLK2xCD3 antibody is administered to the subject by intravenous (IV) infusion.

28. The method of embodiment 27, wherein the treatment dose is at least about 75 mg per administration.

29. The method of embodiment 28, wherein the treatment dose is between about 75 mg and about 900 mg per administration, for example about 75 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, or about 900 mg per administration.

30. The method of embodiment 28 or embodiment 29, wherein the treatment dose is about 75 mg per administration.

31. The method of any one of embodiments 27-29, wherein the treatment dose is at least about 150 mg per administration.

32. The method of embodiment 31, wherein the treatment dose is between about 150 mg and about 900 mg per administration, for example about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, or about 900 mg per administration.

33. The method of embodiment 31 or embodiment 32, wherein the treatment dose is about 150 mg per administration. 34. The method of any one of embodiments 27-29, and 31-32, wherein the treatment dose is at least about 200 mg per administration.

35. The method of embodiment 34, wherein the treatment dose is between about 200 mg and about 900 mg per administration, for example about 200 mg, about 250 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg or about 900 mg per administration.

36. The method of embodiment 34 or embodiment 35, wherein the treatment dose is about 200 mg per administration.

37. The method of embodiment 34 or embodiment 35 wherein the treatment dose is about 250 mg per administration.

38. The method of any one of embodiments 27-29, 31-32, and 34-35, wherein the treatment dose is at least about 300 mg per administration.

39. The method of embodiment 38, wherein the treatment dose is between about 300 mg and about 900 mg per administration, for example about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg or about 900 mg per administration.

40. The method of embodiment 38 or embodiment 39, wherein the treatment dose is about 300 mg per administration.

41. The method of any one of embodiments 27-29, 31-32, 34-35, and 38-39, wherein the treatment dose is at least about 600 mg per administration.

42. The method of embodiment 41, wherein the treatment dose is between about 600 mg and about 900 mg per administration, for example, about 600 mg, about 700 mg, about 800 mg or about 900 mg per administration. 43. The method of embodiment 42, wherein the treatment dose is about 600 mg per administration.

44. The method of embodiment 42, wherein the treatment dose is about 900 mg per administration.

45. The method of any one of embodiments 27-44, wherein the treatment dose is administered at a flat dose.

46. The method of any one of embodiments 27-45, wherein the treatment dose is administered once every 1 to 6 weeks, such as once every 1, 2, 3, 4, 5, or 6 weeks.

47. The method of any one of embodiments 46, wherein the treatment dose is administered once every three weeks.

48. The method of any one of embodiments 46, wherein the treatment dose is administered once every six weeks.

49. The method of any one of embodiments 27-48, wherein the treatment dose is administered for at least two cycles (for example, two, three, four, five, ten, fifteen, twenty or more cycles).

50. The method of embodiment 49, wherein the treatment dose is administered for at least a year, or throughout the lifespan of the subject.

51. The method of any one of embodiments 27-50, wherein the treatment dose is administered by intravenous (IV) infusion over a period of at least about one hour, for example wherein the treatment dose is administered by IV infusion over a period of about one hour. 52. The method of any one of embodiments 27-50, wherein the treatment dose is administered by intravenous (IV) infusion over a period of at least about 30 minutes, for example wherein the treatment dose is administered by IV infusion over a period of about 30 minutes.

53. The method of any one of embodiments 27-52, wherein the first treatment dose is administered by intravenous (IV) infusion over a period of at least about one hour, for example wherein the treatment dose is administered by IV infusion over a period of about one hour and any subsequent treatment dose is administered by intravenous (IV) infusion over a period of at least about 30 minutes, for example wherein the treatment dose is administered by IV infusion over a period of about 30 minutes.

54. The method of any one of embodiments 27-53, wherein the method does not comprise administering a step-up dose prior to the administration of the treatment dose.

55. The method of any one of embodiments 27-54, wherein the method comprises administering to the human subject one or more step-up doses (for example, one or two step-up doses) of the anti-KLK2xCD3 antibody, wherein the one or more step-up doses are administered prior to the treatment dose and wherein the one or more step-up doses are not higher than the treatment dose.

56. The method of embodiment 55, wherein the method comprises administering to the subject a step-up dose of between about 2 mg and about5 mg per administration, for example about 2 mg, about 2.5 mg, about 3 mg, about 3.5 mg, about 4 mg, about 4.5 mg or about 5 mg per administration, prior to the treatment dose.

57. The method of embodiment 56, wherein the step-up dose is about 3.5 mg per administration.

58. The method of any one of embodiments 55-57, wherein the method comprises administering to the subject a step-up dose of between about 5 mg and aboutl5 mg per administration, for example about 5 mg, about 10 mg, or about 15 mg per administration, prior to the treatment dose. 59. The method of embodiment 58, wherein the step-up dose is about 10 mg per administration.

60. The method of any one of embodiments 27-59, wherein the method comprises administering to the subject a step-up dose of between about 15 mg and about 25 mg per administration, for example about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, about 21 mg, about 22 mg, about 23 mg, about 24 mg, or about 25 mg per administration, prior to the treatment dose.

61. The method of embodiment 60, wherein the step-up dose is about 18 mg per administration.

62. The method of any one of embodiments 55-61, wherein the method comprises administering to the subject a step-up dose of between about 200 and about 400 mg per administration, for example about 200 mg, about 300 mg or about 400 mg per administration, prior to the treatment dose.

63. The method of embodiment 62, wherein the step-up dose is about 300 mg per administration.

64. The method of any one of embodiments 55-63, wherein the step-up dose is administered 3-8 days, for example 3, 4, 5, 6, 7 or 8 days prior to the administration of the treatment dose.

65. The method of embodiment 64, wherein the administration of the step-up dose is 3 days prior to the administration of the treatment dose.

66. The method of embodiment 65, wherein the administration of the step-up dose is 7 days prior to the administration of the treatment dose.

67. The method of any one of embodiments 55-66, wherein the one or more step-up doses are administered via intravenous (IV) infusion.

68. The method of any one of embodiments 55-67, wherein the one or more step-up doses are administered at a flat dose. 69. The method of any one of embodiments 27-53 and 55-68, wherein the method comprises administering to the subject:

(i) a step-up dose of the anti-KLK2xCD3 antibody; and

(ii) a treatment dose of the anti-KLK2xCD3 antibody, wherein the step-up dose is administered once.

70. The method of any one of embodiments 27-53 and 55-68, wherein the method comprises administering to the subject a first step-up dose and a second step-up dose of the anti- KLK2xCD3 antibody, wherein the first step up dose is administered prior to the second step-up dose, and the second step up dose is administered prior to the treatment dose.

71. The method of embodiment 70, wherein the second step-up dose is greater than the first step- up dose.

72. The method of embodiment 70 or embodiment 71, wherein the first step-up dose is between about 2 mg and about5 mg per administration, for example about 2 mg, about 2.5 mg, about 3 mg, about 3.5 mg, about 4 mg, about 4.5 mg or about 5 mg per administration.

73. The method of embodiment 72, wherein the first step-up dose is about 3.5 mg per administration.

74. The method of embodiment 70 or embodiment 71, wherein the first step-up dose is between about 5 mg and about 15 mg per administration, for example about 5 mg, about 10 mg, or about 15 mg per administration.

75. The method of embodiment 74, wherein the first step-up dose is about 10 mg per administration. 76. The method of any one of embodiments 70-75, wherein the second step-up dose is between about 5 mg and about 15 mg per administration, for example about 5 mg, about 10 mg, or about 15 mg per administration.

77. The method of embodiment 76, wherein the second step-up dose is about 10 mg per administration.

78. The method of any one of embodiments 70-75, wherein the second step-up dose is between about 15 mg and about25 mg per administration, for example about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, about 21 mg, about 22 mg, about 23 mg, about 24 mg, or about 25 mg per administration.

79. The method of embodiment 78, wherein the second step-up dose is about 18 mg per administration.

80. The method of any one of embodiments 70-75, wherein the second step-up dose is between about 200 mg and about 400 mg per administration, for example about 200 mg, about 300 mg or about 400 mg per administration.

81. The method of embodiment 78, wherein the second step-up dose is about 300 mg per administration.

82. The method of any one of embodiments 70-81, wherein the first step-up dose is administered 3-8 days, for example 3, 4, 5, 6, 7 or 8 days prior to the administration of the second step-up dose.

83. The method of embodiment 82, wherein the first step-up dose is administered 3 days prior to the administration of the second step-up dose.

84. The method of embodiment 82, wherein the first step-up dose is administered 7 days prior to the administration of the second step-up dose. 85. The method of any one of embodiments 70-84, wherein the second step-up dose is administered 3-8 days, for example 3, 4, 5, 6, 7 or 8 days prior to the administration of the treatment dose.

86. The method of embodiment 85, wherein the second step-up dose is administered 3 days prior to the administration of the treatment dose.

87. The method of embodiment 85, wherein the second step-up dose is administered 7 days prior to the administration of the treatment dose.

88. The method of any one of embodiments 70-87, wherein the method comprises administering to the subject:

(i) a first step-up dose of the anti-KLK2xCD3 antibody,

(ii) a second step-up dose of the anti-KLK2xCD3 antibody; and

(iii) a treatment dose of the anti-KLK2xCD3 antibody, wherein the first step-up dose is administered once, and the second step up dose is administered once.

89. The method of any one of embodiments 55-88, wherein the first step-up dose is administered via intravenous (IV) infusion.

90. The method of any one of embodiments 70-89, wherein the second step-up dose is administered via intravenous (IV) infusion.

91. The method of any one of embodiments 55-90, wherein the first step-up dose is administered at a flat dose.

92. The method of any one of embodiments 55-91, wherein the second step-up dose is administered at a flat dose. 93. The method of any one of embodiments 55-92, wherein the first step-up dose is administered by intravenous (IV) infusion over a period of at least about one hour, for example wherein the treatment dose is administered by IV infusion over a period of about one hour.

94. The method of any one of embodiments 70-93, wherein the second step-up dose is administered by intravenous (IV) infusion over a period of at least about 30 minutes, for example wherein the treatment dose is administered by IV infusion over a period of about 30 minutes.

95. The method of any one of embodiment 93 or embodiment 94, wherein the treatment dose is administered by intravenous (IV) infusion over a period of at least about 30 minutes, for example wherein the treatment dose is administered by IV infusion over a period of about 30 minutes.

96. The method of any one of embodiments 70 and 82-95, wherein the method comprises administering to the subject a first step-up dose and a second step-up dose of the anti- KLK2xCD3 antibody, wherein the first step up dose is administered prior to the second step-up dose, and wherein the second step-up dose is administered prior to the treatment dose, wherein:

(i) the first step-up dose is about 3.5 mg;

(ii) the second step up dose is about 18 mg; and

(iii) the treatment dose is about 300 mg.

97. The method of embodiment 96, wherein the first step-up dose is administered 7 days prior to the second step-up dose.

98. The method of embodiment 96 or embodiment 97, wherein the second step up dose is administered 7 days prior to the treatment dose.

99. The method any one of embodiments 96-98, wherein the treatment dose is administered once every 6 weeks.

100. The method of any one of embodiments 96-98, wherein the treatment dose is administered once every 3 weeks. 101. The method of any one of embodiments 70 and 82-95, wherein the method comprises administering to the subject a first step-up dose and a second step-up dose of the anti- KLK2xCD3 antibody, wherein the first step up dose is administered prior to the second step-up dose, and wherein the second step-up dose is administered prior to the treatment dose, wherein:

(i) the first step-up dose is about 3.5 mg;

(ii) the second step up dose is about 18 mg; and

(iii) the treatment dose is about 600 mg.

102. The method of embodiment 101, wherein the first step-up dose is administered about 7 days prior to the second step-up dose.

103. The method of embodiment 101 or embodiment 102, wherein the second step up dose is administered about 7 days prior to the treatment dose.

104. The method of any one of embodiments 101-103, wherein the treatment dose is administered once every 6 weeks.

105. The method of any one of embodiments 101-104, wherein the treatment dose is administered once every 3 weeks.

106. The method of any one of embodiments 55 and 64-69, wherein the method comprises administering to the subject a step-up dose of the anti-KLK2xCD3 antibody, wherein the step-up dose is administered prior to the treatment dose, wherein:

(i) the step-up dose is about 10 mg; and

(ii) the treatment dose is about 300mg.

107. The method of embodiment 106, wherein the first step-up dose is administered 7 days prior to the treatment dose. 108. The method of embodiment 106 or embodiment 107, wherein the treatment dose is administered once every 6 weeks.

109. The method of any one of embodiments 106-108, wherein the treatment dose is administered once every 3 weeks.

110. The method of any one of embodiments 55 and 64-69, wherein the method comprises administering to the subject a step-up dose of the anti-KLK2xCD3 antibody, wherein the step-up dose is administered prior to the treatment dose, wherein:

(i) the step-up dose is about 10 mg; and

(ii) the treatment dose is about 600mg.

111. The method of embodiment 110, wherein the first step-up dose is administered about 7 days prior to the treatment dose.

112. The method of embodiment 110 or embodiment 111, wherein the treatment dose is administered once every 6 weeks.

113. The method of any one of embodiments 110-112, wherein the treatment dose is administered once about every 3 weeks.

114. The method of any one of embodiments 70 and 82-95, wherein the method comprises administering to the subject a first step-up dose and a second step-up dose of the anti- KLK2xCD3 antibody, wherein the first step up dose is administered prior to the second step-up dose, and wherein the second step-up dose is administered prior to the treatment dose, wherein:

(i) the first step-up dose is aboutlO mg;

(ii) the second step up dose is about 300 mg; and

(iii) the treatment dose is about 900 mg.

115. The method of embodiment 114, wherein the first step-up dose is administered 7 days prior to the second step-up dose. 116. The method of embodiment 114 or embodiment 115, wherein the second step up dose is administered 7 days prior to the treatment dose.

117. The method of any one of embodiments 114-116, wherein the treatment dose is administered once every 6 weeks.

118. The method of any one of embodiments 70 and 82-95, wherein the method comprises administering to the subject a first step-up dose and a second step-up dose of the anti- KLK2xCD3 antibody, wherein the first step up dose is administered prior to the second step-up dose, and wherein the second step-up dose is administered prior to the treatment dose, wherein:

(i) the first step-up dose is about 10 mg;

(ii) the second step up dose is about 300 mg; and

(iii) the treatment dose is about 600 mg.

119. The method of embodiment 118, wherein the first step-up dose is administered 7 days prior to the second step-up dose.

120. The method of embodiment 118 or embodiment 119, wherein the second step up dose is administered 7 days prior to the treatment dose.

121. The method of any one of embodiments 118-120, wherein the treatment dose is administered once every 6 weeks.

122. The method of any one of embodiments 27-118, wherein the other anti-cancer drug is administered simultaneously, sequentially or separately from the administering of the anti- KLK2xCD3 antibody, for example on the same day about 4 hours apart.

123. The method of any of the foregoing embodiments, wherein the other anti-cancer drug is the anti-cancer chemotherapeutic agent, preferably a taxane, preferably docetaxel or cabazitaxel. 124. The method of embodiment 123, wherein the anti-cancer chemotherapeutic agent is intravenously administered, such as via intravenous injection or infusion.

125. The method of embodiment 123, wherein docetaxel or cabazitaxel is intravenously administered to the subject every 1-6 weeks, preferably every 3 weeks.

126. The method of embodiment 125, wherein the other anti-cancer drug is docetaxel, preferably the other anti-cancer drug is docetaxel and is administered intravenously at a dose of 75 mg/m².

127. The method of embodiment 125, wherein the other anti-cancer drug is cabazitaxel, preferably the other anti-cancer drug is cabazitaxel and is administered intravenously at a dose of 20 mg/m².

128. The method of any one of embodiments 123-127, wherein the other anti-cancer drug is a taxane, and wherein no prednisone, preferably no corticosteroid, is administered as a (pre)medication prior to the administration of taxane, or together with the administration of taxane.

129. The method of any one of embodiments 1-128, wherein the other anti-cancer drug is the ARPI, such as apatulamide, enzatulamide, darolutamide, or abiraterone acetate.

130. The method of embodiment 129, wherein the ARPI is administered orally.

131. The method of embodiment 130, wherein the other anti-cancer drug is apatulamide, preferably the other anti-cancer drug is apalutamide and is administered orally at a dose of 240 mg per day, preferably 240 mg once daily, preferably four tablets of 60 mg once daily.

132. The method of embodiment 130, wherein the other anti-cancer drug is enzatulamide, preferably the other anti-cancer drug is enzalutamide and is administered orally at a dose of 160 mg per day, preferably 160 mg once daily, preferably four capsules of 40 mg once a day. 133. The method of embodiment 130, wherein the other anti-cancer drug is darolutamide, preferably the other anti-cancer drug is darolutamide and is administered orally at a dose of 1200 mg per day, preferably 600 mg twice daily, preferably two tablets of 300 mg twice daily.

134. The method of embodiment 130, wherein the other anti-cancer drug is abiraterone acetate, preferably the other anti-cancer drug is abiraterone acetate and is administered orally at a dose of 1000 mg per day, preferably 1000 mg once daily, preferably four tablets of 250 mg once daily.

135. The method of embodiment 134, further comprising orally administering to the subject prednisone, preferably at a dose of 5 mg or 10 mg per day, preferably of 5 mg once or twice a day, preferably one tablet of 5 mg once a day or one tablet of 5 mg twice a day.

136. The method any of the foregoing embodiments, wherein the prostate cancer is locally advanced prostate cancer, metastatic castration-sensitive prostate cancer (CSPC), metastatic castration-resistant prostate cancer (CRPC), non-metastatic CSPC, non-metastatic CRPC, or metastatic prostate cancer, preferably the prostate cancer is metastatic CRPC.

137. The method any of the foregoing embodiments, which does not comprise the administration of an anti-PDl antibody at least 6 weeks prior to the first dose of anti-KLK2xCD3 antibody or other anti-cancer agent.

138. The method any of the foregoing embodiments, which does not comprise the administration of an anti-PDl antibody.

139. The method of any of the foregoing embodiments, wherein the subject does not have one or more of the following:

KLK2xCD3 antibody: a. Myocardial infarction b . S evere or un stab 1 e angi na c. Clinically significant ventricular arrhythmias d. Congestive heart failure (New York Heart Association [NYHA] class II to IV) e. Transient ischemic attack f. Cerebrovascular accident ) major surgery (e.g., requiring general anesthesia) within 2 weeks before the initial administration of the anti-KLK2xCD3 antibody or has not recovered from surgery; ) active infection or condition that requires treatment with systemic antibiotics within 7 days prior to the initial administration of the anti-KLK2xCD3 antibody; ) venous thromboembolic events (e.g., pulmonary embolism) within 1 month prior to the first dose of study treatment; uncomplicated (Grade <2) deep vein thrombosis is not considered exclusionary; ) clinically significant pulmonary compromise, particularly a requirement for supplemental oxygen use (>2 L/min by nasal cannula) to maintain adequate oxygenation; 0) active CNS involvement, except treated, stable and asymptomatic brain metastases requiring <10 mg prednisone or equivalent within 2 weeks prior to the first dose of study treatment are permitted; 1) prior treatment with KLK2-targeted therapy; 2) treatment with any anti-cancer or investigational agents within 28 days or 5-half-lives, whichever is shorter, prior to the initial administration of the anti-KLK2xCD3 antibody, such as,

No restrictions on GnRH agonist/antagonists,

• Radionuclide therapy within 6 weeks prior to start of study treatment,

140. The method of any of the foregoing embodiments, wherein the subject has not received immunosuppressive doses of systemic medications, such as glucocorticoids (doses >10 mg/day prednisone or equivalent) within 7 days prior to the first dose of study treatment, provided that a single course of glucocorticoids is permitted as prophylaxis for imaging contrast (i.e., for participants with allergies to contrast).

141. The method of any of the foregoing embodiments, wherein the subject is i) a subject having metastatic CRPC (mCRPC); ii) a subject having prior orchiectomy, or the subject having not undergone orchiectomy and receives ongoing androgen deprivation therapy with a gonadotropin releasing hormone (GnRH) analog (agonist or antagonist) prior to the initial administration of the anti-KLK2xCD3 antibody and continue androgen deprivation therapy throughout the treatment phase; iii) a subject having microsatellite instability (MSI-H)/mismatch repair deficient (dMMR) disease not previously received and progressed on PD-(L)1 therapy; iv) a subject having received at least 1 prior treatment with an ARPI (e.g., apalutamide, enzalutamide, darolutamide, or abiraterone acetate) and/or taxane (e.g., docetaxel or

I l l cabazitaxel) prior to the initial administration of the anti-KLK2xCD3 antibody; and/or v) a subject living with HIV; and wherein the subject preferably is 18 years of age or older.

142. The method of any one of the foregoing embodiments, wherein the prostate cancer is metastatic prostate cancer.

143. The method of any one of the foregoing embodiments, wherein the prostate cancer is metastatic castration -resistant prostate cancer.

144. The method of any one of the foregoing embodiments, wherein the subject has metastatic castration-resistant prostate cancer and is taxane naive (or chemotherapy-naive) (prior to being administered the treatment of the application).

145. The method of any one of embodiments 1-142, wherein the prostate cancer is metastatic hormone-sensitive prostate cancer.

146. The method of embodiment 145, wherein the prostate cancer is oligometastatic hormonesensitive prostate cancer (a subject, who has an oligometastatic hormone-sensitive prostate cancer, typically has no more than five total lesions on imaging, for example up to five lesions PSMA-PET or no more than three lesions by conventional imaging).

147. The method of any one of the preceding embodiments, wherein the anti-KLK2xCD3 antibody is pasritamig.

148. The anti-KLK2xCD3 antibody for use in the method of any one of the foregoing embodiments.

149. The taxane for use in the method of any one of embodiments 1-128 and 136-147. 150. Docetaxel for use in the method of any one of claims 1-126, 128 and 136-147.

151. Cabazitaxel for use in the method of any one of embodiments 1-125, 127 and 136-147.

152. The ARPI for use in the method of any one of embodiments 1-124, and 129-147.

153. Apalutamide for use in the method of any one of embodiments 1-124, 129-131 and 136- 147.

154. Enzalutamide for use in the method of any one of embodiments 1-124, 129-130, 132 and 136-147.

155. Darolutamide for use in the method of any one of embodiments 1-124, 129-130, 133 and 136-147.

156. Abiraterone acetate for use in the method of any one of embodiments 1-124, 129-130 and 134-147.

157. A combination of the anti-KLK2xCD3 and the anti -cancer chemotherapeutic agent or the ARPI for use in the method of any one of embodiments 1-147.

158. A combination of the anti-KLK2xCD3 and the taxane for use in the method of any one of embodiments 1-128 and 136-147.

159. A combination of the anti-KLK2xCD3 and docetaxel for use in the method of any one of embodiments 1-28, 126 and 136-147.

160. A combination of the anti-KLK2xCD3 and cabazitaxel for use in the method of any one of embodiments 1-125, 26, 123 and 136-147. 161 . A combination of the anti-KLK2xCD3 and the ARPI for use in the method of any one of embodiments 1-26, and 129-147.

162. A combination of the anti-KLK2xCD3 and apalutamide for use in the method of any one of embodiments 1-26, 129-131 and 136-147.

163. A combination of the anti-KLK2xCD3 and enzalutamide for use in the method of any one of embodiments 1-26, 129-125, 128 and 136-147.

164. A combination of the anti-KLK2xCD3 and darolutamide for use in the method of any one of embodiments 1-26, 129-130, 132 and 136-147.

165. A combination of the anti-KLK2xCD3 and abiraterone acetate for use in the method of any one of embodiments 1-26, 129-130 and 134-147.

[0443] Various embodiments or subject matter have been described. It will be understood that various modifications may be made without departing from the spirit and scope of the invention. Accordingly, the following examples are intended to illustrate but not limit the scope of inventions described in the claims.

EXAMPLES

[0444] The following examples are provided to further describe some of the embodiments disclosed herein. The examples are intended to illustrate, not to limit, the disclosed embodiments.

Example 1. T-cell killing activity of KLK2xCD3 bispecific antibody ± apalutamide in whole blood from healthy donors and mCRPC donors

[0445] This study looked at the T-cell killing activity of a KLK2xCD3 bispecific antibody alone or with apalutamide in healthy and mCRPC donors. The KLK2xCD3 bispecific antibody is a bispecific antibody of the application that simultaneously binds to the CD3 receptor complex on T cells and to KLK2 on prostate cancer cells. Evaluation of KLK2 expression on VCaP cells

[0446] VCaP cells were cultured in DMEM (Gibco) and 15% HI FBS (Gibco) and 0.25% trypsin was used for splitting them. VCaP cells were seeded into poly-L-lysine (Sigma Aldrich) coated 10 cm plates in culture media containing DMSO (Sigma Aldrich) or 10 pM apalutamide (SelleckChem). After culturing for 6 days, VCaP cells were harvested using enzyme-free dissociation buffer (Corning) and stained for KLK2 and an isotype control (1ST) for analysis by flow cytometry. Receptor density was calculated using Bangs Beads (Bangs Laboratories) and normalized against the signal from the 1ST. This data confirms the findings from the literature that KLK2 is positively regulated by AR signaling such that treatment with apalutamide reduces KLK2 expression (FIG. 1).

Whole Blood Collection and Processing

[0447] Blood from 7 male mCRPC and 5 age-matched healthy male donors were obtained through Discovery Life Sciences. Whole blood was pooled and processed using Red Blood Cell Lysing reagent and protocol (Miltenyi) and Erythrocyte Depletion Kit (Miltenyi) to obtain a population of lysed, whole blood. Cells were stored in RPMI (Gibco 11835-030) with 10% HI FBS (Gibco) at room temperature for no longer than 90 minutes while plate was being prepared.

CD3 Quantification

[0448] Small sample of lysed whole blood was analyzed by flow cytometry to quantify the total count of CD3+ cells isolated and abundance of CD3+ cells as a portion of the live, singlet cells. CD3+ cells were successfully isolated from donor whole blood. The CD3+ portion of the material was quantified using CD3 staining (BioLegend) with Live/Dead Near-IR (Invitrogen). FIG. 2A shows the total count of CD3+ cells isolated and FIG. 2B shows the abundance of CD3+ cells as a portion of the live, singlet cells. The frequency of CD3+ cells expressed as a portion of the live cells was used to accurately plate an E:T ratio of 1 : 1 during the T cell killing assay.

T Cell Killing Assay

[0449] LNCaP-KLK2-NLR cells (LNCaP cells overexpressing KLK2 and NucLightRed) were cultured in RPMI 1640 (Thermo) with 10% HI FBS (Gibco). 25,000 LNCaP -KLK2-NLR cells were seeded into 96-well IncuCyte plates (Costar) in 100 pl of RPMT 1640 (Gibco 1 1835-030) + 10% HI FBS (Gibco) and allowed to adhere overnight.

[0450] Dilutions of KLK2xCD3 bispecific antibody and apalutamide were prepared fresh on the day of the assay. Dilutions of the KLK2xCD3 bispecific antibody were prepared to generate final concentrations of 30 nM to 41 pM of KLK2xCD3 bispecific antibody with 3-fold serial dilutions. 30 nM of NullxCD3 controls were also prepared. The dilutions of the KLK2xCD3 bispecific antibody were prepared in RPMI 1640 (Gibco) + 10% FBS alone or in combination with apalutamide (SelleckChem). The final concentration of apalutamide in the treatment well was 10 pM. A 50 pl volume of the treatment solutions was applied to the previously plated target cells.

[0451] On the day of the assay, lysed whole blood was seeded at an E:T ratio of 1 : 1 normalized to CD3+ cells. The effector cells were applied in a volume of 50 pl to the previously seeded target cells and treatments. An IncuCyte cytolysis assay was started with 4 images per well being collected every 3 to 6 hours for the 5- to 6-day duration of the assay.

[0452] Target cells were quantified using an IncuCyte analysis definition optimized to detect NLR positive cells. The percent cytolysis was calculated at each time point using the following equation:

% Cytolysis — 100 100

[0453] For wells containing KLK2xCD3 bispecific antibody alone, the control cells were LNCaP-KLK2-NLR target cells with lysed whole blood. For wells containing KLK2xCD3 bispecific antibody with 10 pM apalutamide, the control cells were LNCaP-KLK2-NLR target cells with lysed whole blood plus 10 pM apalutamide.

[0454] To account for slight differences in seeding density, the cytolysis calculations were normalized to time point of Oh using this following equation:

% Normalized Cytolysis_t=x = % Cytolysis_t=x — average(% Cytolysis_t=oh [0455] The % Normalized Cytolysis was plotted against treatment time to generate an area under the curve (AUC) for each treatment. As shorthand throughout this document, data is presented as % Cytolysis and AUC of % Cytolysis.

Statistical Comparisons

[0456] Two-tailed, paired t tests were used to compare mean AUCs for each donor at given doses of the KLK2xCD3 bispecific antibody.

T Cell Killing Results for KLK2xCD3 bispecific antibody ± apalutamide

[0457] Increasing concentrations of KLK2xCD3 bispecific antibody caused a dose dependent increase in cytolysis (FIG. 3A and FIG. 3B). Cytolysis with KLK2xCD3 bispecific antibody alone was roughly equivalent between healthy and mCRPC lysed whole blood (FIG. 3A and FIG. 3B). The performance of apalutamide alone (horizontal dotted line) was better in healthy donor lysed whole blood (FIG. 3A) compared to mCRPC lysed whole blood (FIG. 3B). This observed difference may result from effector cells from mCRPC patients having been previously exposed to androgen deprivation therapy. Independent of the observed difference in apalutamide monotherapy efficacy, the combination between KLK2xCD3 and apalutamide improved cytolysis in both healthy and mCRPC donors.

[0458] To directly compare the effects of apalutamide combination on KLK2xCD3 -induced cell killing, two doses of the bi specific antibody were analyzed, 0.1 nM and 10 nM for healthy donors and mCRPC donors. For both donor cohorts and at both doses of KLK2xCD3 bispecific molecule tested, the addition of apalutamide resulted in statistically significant increases in target cell cytolysis (FIG. 4). The combination of KLK2XCD3 bispecific antibody and apalutamide resulted in an unexpected, improved immune cell mediated killing activity (activation and proliferation).

Example 2. T-cell killing activity of KLK2xCD3 bispecific antibody ± ARPI in PBMC from healthy donors

[0459] This study looks at the T-cell killing activity of a KLK2xCD3 bispecific antibody alone or with an Androgen Receptor Pathway Inhibitor (ARPI) in healthy donors. The KLK2xCD3 bispecific antibody is a bispecific antibody of the application that simultaneously binds to the CD3 receptor complex on T cells and to KLK2 on prostate cancer cells. ARPI can e.g., be enzalutamide, darolutamide or abiraterone acetate (abiraterone acetate optionally with prednisone).

Leukopak Collection and Processing

[0460] Leukopaks for healthy male donors are purchased from StemExpress and shipped at room temperature prior to processing for PBMC and T cell isolation. Briefly, PBMCs and T cells are isolated using MultiMACS following MACS isolation kit as per manufacturer directions for each cell population. Cells are resuspended in CryoStor (Biolife Systems) for freezing, aliquoted and transferred to liquid nitrogen for further storage until used in the assays described below.

T Cell Killing Assay

[0461] LNCaP-KLK2-NLR cells (LNCaP cells overexpressing KLK2 and NucLightRed) and LNCaP-NLR cells (LNCaP cells expressing NucLightRed) are cultured in RPMI 1640 (Thermo) with 10% HI FBS (Gibco). VCaP-NLR cells (VCaP cells expressing NucLightRed) are cultured in DMEM (Gibco 10567-014) with (15% HI FBS (Gibco). Tumor cells are pre-treated with ARPI or vehicle for 6 days. Following pre-treatment, the control (vehicle) and ARPI treated tumor cells are seeded into 96-well IncuCyte plates (Costar) in 100 pl culture media at a density of 25,000 cells/well and allowed to adhere overnight. After seeding, the vehicle and ARPI treated cells receive vehicle or ARPI, respectively, as a continued treatment for an additional 7 days thus creating scenarios whereby prostate cancer cells are either naive or pre-exposed to ARPI when receiving KLK2xCD3.

[0462] Dilutions of KLK2xCD3 bispecific antibody and ARPI are prepared fresh on the day of the assay. Dilutions of the KLK2xCD3 bispecific antibody are prepared to generate final concentrations of 30 nM to 41 pM of KLK2xCD3 bispecific antibody with 3-fold serial dilutions. 30 nM of NullxCD3 controls are also prepared. The dilutions of the KLK2xCD3 bispecific antibody are prepared in RPMI 1640 (Gibco) + 10% FBS alone or in combination with ARPI. A 50 pl volume of the treatment solutions was applied to the previously plated target cells.

[0463] On the day of the assay, pan T cells are seeded at an E:T ratio of 3 : 1. The effector cells are applied in a volume of 50 pl to the previously seeded target cells and treatment solutions. An IncuCyte cytolysis assay is started with 4 images per well being collected every 3 to 6 hours for the 7-day duration of the assay.

[0464] Target cells are quantified using an IncuCyte analysis definition optimized to detect NLR positive cells. The percent cytolysis is calculated at each time point using the following equation:

% Cytolysis = 100

[0465] For wells containing KLK2xCD3 bispecific antibody alone, the control cells are tumor cells with pan T cells. For wells containing KLK2xCD3 bispecific antibody with ARPI, the control cells are tumor cells with pan T cells plus ARPI.

T cell activation assay

[0466] T cells from male donors are thawed and plated for T cell activation assay by flow cytometry at an E:T ratio of 3: 1 with 275,000 LNCaP-KLK2 clone H3E10 cells/well that have been either pre-treated for 7 days with DMSO or ARPI and then seeded into a 6-well dish in RPMI 1640 (ThermoFisher) with 10% HI FBS (Gibco) with 10 nM of KLK2xCD3 plus DMSO or ARPI. Cells are kept for 3, 6, or 10 days in co-culture followed by flow cytometry analysis. Supernatant and cells are collected at each day for subsequent analysis.

T cell staining by flow cytometry

[0467] At each end point of the T cell activation assay cells are harvested for T cell staining. Fluorescently labeled chemokine receptor antibodies are added to cells and incubated at 37°C in the dark for 30 min. Cells are then incubated with Fixable Live/Dead stain (ThermoFisher) for 10 min at 4°C. Antibody mix containing the rest of the surface antibodies are added directly to cells and incubated for 60 min at RT in the dark. Following surface staining, cells are washed once with FACS buffer and resuspended in 100 pl FOXP3 fixation/permeabilization solution (Invitrogen) and incubated at 4°C for 30 min in the dark. Cells are then washed twice with permeabilization buffer and stained with intracellular and intranuclear antibodies overnight at 4°C in the dark. After staining, cells are washed twice with permeabilization buffer and resuspended in APC-Cy7 fixative (BD). All samples are acquired on a BD spectral Symphony A5. A list of antibodies used in this panel can be found in Table 5.

Table 5: Flow cytometry antibodies Example 3. T-cell killing activity of KLK2xCD3 bispecific antibody ± Taxane in PBMC from healthy donors

[0468] This study looks at the T-cell killing activity of a KLK2xCD3 bispecific antibody alone or with Taxane in healthy donors. The KLK2xCD3 bispecific antibody is a bispecific antibody of the application that simultaneously binds to the CD3 receptor complex on T cells and to KLK2 on prostate cancer cells.

Leukopak Collection and Processing

[0469] Leukopaks for healthy male donors are purchased from StemExpress and shipped at room temperature prior to processing for PBMC and T cell isolation. Briefly, PBMCs and T cells are isolated using MultiMACS following MACS isolation kit as per manufacturer directions for each cell population. Cells are resuspended in CryoStor (Biolife Systems) for freezing, aliquoted and transferred to liquid nitrogen for further storage until used in the assays described below.

T Cell Killing Assay

[0470] LNCaP-KLK2-NLR cells (LNCaP cells overexpressing KLK2 and NucLightRed) and LNCaP-NLR cells (LNCaP cells expressing NucLightRed) are cultured in RPMI 1640 (Thermo) with 10% HI FBS (Gibco). VCaP-NLR cells (VCaP cells expressing NucLightRed) are cultured in DMEM (Gibco 10567-014) with (15% HI FBS (Gibco). Tumor cells are seeded into 96-well IncuCyte plates (Costar) in 100 pl culture media at a density of 25,000 cells/well and allowed to adhere overnight.

[0471] Dilutions of KLK2xCD3 bispecific antibody and taxane are prepared fresh on the day of the assay. Dilutions of the KLK2xCD3 bispecific antibody are prepared to generate final concentrations of 30 nM to 41 pM of KLK2xCD3 bispecific antibody with 3-fold serial dilutions. 30 nM of NullxCD3 controls are also prepared. The dilutions of the KLK2xCD3 bispecific antibody are prepared in RPMI 1640 (Gibco) + 10% FBS alone or in combination with taxane. A 50 pl volume of the treatment solutions is applied to the previously plated target cells. [0472] On the day of the assay, pan T cells are seeded at an E:T ratio of 1 : 1 or 3 : 1. The effector cells are applied in a volume of 50 pl to the previously seeded target cells and treatment solutions. An IncuCyte cytolysis assay is started with 4 images per well being collected every 3 to 6 hours for the 7-day duration of the assay. [0473] Target cells are quantified using an IncuCyte analysis definition optimized to detect NLR positive cells. The percent cytolysis is calculated at each time point using the following equation:

% Cytolysis = 100

[0474] For wells containing KLK2xCD3 bispecific antibody alone, the control cells are tumor cells with pan T cells. For wells containing KLK2xCD3 bispecific antibody with taxane, the control cells are tumor cells with pan T cells plus taxane.

Example 4. T-cell killing activity of KLK2xCD3 bispecific antibody in combination with Apalutamide and other ARPI in PBMC from healthy donors

Cell lines, cell culture, and maintenance

[0475] LNCaP cells were grown in RPMI 1640 with L-glutamine (Gibco 11875-085) + 10% FBS (Gibco A56708-01) on poly-L-lysine coated plasticware (Sigma P1274). LNCaP cells (ATCC) were engineered to constitutively express KLK2 (NM_005551.5) driven by a CMV promoter with a C-terminal 3X FLAG tag. Cloning and lentiviral particles were provided by Vectorbuilder (pLV[Exp]-Bsd-CMV>hKLK2[NM_005551.5]/3xFLAG [Vector ID:VB230215- 1719twt]). Cells were selected with 5 pg/mL blasticidin, then LNCaP -KLK2 cells were transduced with IncuCyte Nuclight Red Lentivirus (NLR; EFla; Bleo, Sartorius Item 4478) and selected with 100 pg/ml Zeocin to produce LNCaP-KLK2-NLR cells for visualization by IncuCyte assay.

Leukopak collection and processing

[0476] Healthy male, donor leukopaks were purchased from StemExpress. Informed consent was obtained and leukapheresis was performed. Leukopaks were shipped at room temperature prior to processing for PBMC isolation. Briefly, PBMCs from the leukopaks were isolated using a manual Ficoll process. Cells from each leukopak were centrifuged for 10 minutes at 200 x g at room temperature. Cells were washed with PBS/0.5% BSA buffer and centrifuged for 10 minutes at 200 x g. Cells were resuspended with 25 ml PBS/0.5% BSA and then cells were carefully under layered with 15 ml Ficoll. Cells were centrifuged for 20 minutes at 2,000 rpm at room temperature. The upper buffer layer was carefully removed (-5-10 ml) at buffer to Ficoll interface, taking care not to remove too much Ficoll with cells. Cell suspension was diluted in PBS/0.5% BSA buffer and mixed well. Cells were centrifuged 6 minutes at 1,500 rpm at 4°C. Cells were then resuspended in CryoStor (Biolife Systems) for freezing, aliquoted and transferred to liquid nitrogen for further storage until used in the assays described below. All blood products were handled in a BSL-2 laboratory with the use of appropriate personal protective equipment and safety precautions.

[0477] Isolated PBMCs were quantified for %CD3⁺ using 8-color Immunophenotyping Kit (Miltenyi Biotec) and live/dead fixable aqua dead cell stain kit (Invitrogen) on a MACSQuant 10 Analyzer. This information was used to normalize the amount of PBMCs used in T cell killing assays to achieve consistent E:T ratios across donors.

T cell killing assay

[0478] 25,000 LNCaP-KLK2-NLR cells were seeded into 96-well IncuCyte plates in 100 pl of RPMI 1640 (Gibco) + 10% FBS and allowed to adhere overnight. Dilutions of KLK2xCD3 bispecific antibody and apalutamide were prepared fresh on the day of the assay. Dilutions of KLK2xCD3 bispecific antibody were prepared to generate final concentrations of 30 nM to 14 pM with 3 -fold serial dilutions. The dilutions of KLK2xCD3 bispecific antibody and control were prepared in RPMI 1640 (Gibco) + 10% HI FBS (Gibco) in combination with apalutamide (SelleckChem), enzalutamide (SelleckChem), darolutamide (SelleckChem) or ARV-110 (SelleckChem) or DMSO (Invitrogen). The final concentration of apalutamide, enzalutamide, and darolutamide was 10 pM. An equivalent volume of DMSO was used to generate a vehicle control solution. The final concentration of ARV-110 was 0.05 pM. A 50 pl volume of the treatment solution was applied to the previously plated target cells

[0479] On the day of the assay, PBMC cells were seeded at a normalized E:T ratio of 1 : 1 adjusted for % CD3+ cells for each donor. The effector cells were applied in a volume of 50 pl to the previously seeded target cells and treatment solutions. An IncuCyte cytolysis assay was started with 4 images per well being collected every 6 hours for the 6-day duration of the assay. [0480] Target cells were quantified using an IncuCyte analysis definition optimized to detect NLR positive cells. The percent cytolysis was calculated at each time point using the following equation:

% Cytolysis = 100 100

[0481] For each ARPI, the KLK2xCD3 -containing wells were normalized against wells containing only the ARPI. For example, the wells containing LNCaP-KLK2-NLR cells, PBMCs, KLK2xCD3, and apalutamide were normalized to wells containing LNCaP-KLK2-NLR cells, PBMCs, and apalutamide only.

[0482] To account for slight differences in seeding density, the cytolysis calculations were normalized to time point of 0 hours using this following equation:

% Normalized Cytolysis_t=x = % Cytolysis_t=x — average(% Cytolysls_t=oh)

[0483] The % Normalized Cytolysis can be plotted against treatment time to generate an area under the curve (AUC) for each treatment. As shorthand throughout this document, data is presented as % Cytolysis and AUC of % Cytolysis.

Statistical analysis

[0484] Data and statistical analyses were done in Microsoft Excel and GraphPad Prism 8.4. Two-tailed, paired t tests were used to compare means in the flow cytometry analysis. Significance of p values was noted with * for/? < 0.05, ** for/? < 0.01, *** for/? < 0.001, and **** for /? < 0.0001. ECso values were calculated using the cytolysis AUC for each dose of KLK2xCD3 and each ARPI using a non-linear regression. A sigmoidal 4 parameter logistic model was applied [0485] Where x is the dose of KLK2xCD3 (nM), y is the response (cytolysis AUC), Top and Bottom are plateaus of response (cytolysis AUC), ECso is in the same unit as response and Hill Slope is the slope factor (unitless)

Efficacy of KLK2xCD3 in Healthy Donors

[0486] ECso values on an individual donor basis and as a compilation of all donors were compared (ECso values in Table 6, fold change values in Table 7).

Table 6. Summary of KLK2xCD3 ECso values for each donor and ARPI

Table 7: Summary of fold change differences in KLK2xCD3 ECso values for each donor and

ARPI.

[0487] A reduction in ECso was observed for all combinations of KLK2xCD3 with ARPIs tested in each donor compared to the KLK2xCD3 with DMSO control. A reduction in ECso for the ARPI combinations indicates that KLK2xCD3 has a greater efficacy when combined with an ARPI, than KLK2xCD3 with DMSO. The addition of apalutamide, enzalutamide, darolutamide or ARV-110 increases the efficacy of KLK2xCD3.

[0488] The increased performance of KLK2xCD3 with each ARPI molecule is exemplified using the 1.11 nM KLK2xCD3 dosage (FIG. 5). Addition of apalutamide, enzalutamide, darolutamide, or ARV-110 to 1.11 nM KLK2xCD3 produced a statistically significant increase (p = 0.0113,/? = 0.0165,/? = 0.0049, and /? = 0.0467, respectively) in T cell killing as shown by increased cytolysis AUC compared to the DMSO control.

Example 5. A phase 1 study of an anti-KLK2xCD3 bispecific antibody and Androgen Receptor Pathway Inhibitors (ARPI) and Taxanes for the treatment of advanced prostate cancer

[0489] This is an open-label, multicenter, Phase lb study to evaluate the safety, tolerability, and preliminary antitumor activity of an anti-KLK2xCD3 bispecific antibody (“study KLK2xCD3 bispecific antibody”) and taxane chemotherapy, or Androgen Receptor Pathway Inhibitors (ARPIs) administered to adult participants with mCRPC following at least 1 prior line of therapy. The study is composed of 2 parts: dose escalation (Part 1) and dose expansion (Part 2). Part 1 will explore study KLK2xCD3 bispecific antibody and cabazitaxel (Part IB), docetaxel (Part 1C), apalutamide (Part ID), enzalutamide (Part IE), darolutamide (Part IF), or abiraterone acetate + prednisone (AAP) (Part 1G). During the study, safety will be monitored by the Study Evaluation Team (SET) at each dose escalation step and at regular intervals during dose expansion. More than one RP2R may be explored in Part 2.

[0490] Study KLK2xCD3 bispecific antibody is a bispecific antibody of the application that simultaneously binds to the CD3 receptor complex on T cells and to cell surface KLK2 on prostate cancer cells.

[0491] The primary objective of this study is to determine the RP2R(s), based on the safety, including DLTs, and tolerability of study KLK2xCD3 bispecific antibody administered with a fixed dose of taxane chemotherapy, or ARPIs. A key secondary objective is to characterize the preliminary antitumor activity of the study KLK2xCD3 bi specific antibody and taxane chemotherapy, or ARPI combinations. Study population.

[0492] Screening for eligible participants will be performed within 30 days before administration of the study treatment.

Inclusion criteria

[0493] Each potential participant must satisfy all of the following criteria to be enrolled in this study:

(1) Be >18 years of age (or the legal age of majority in the jurisdiction in which the study is taking place, whichever is greater) at the time of informed consent.

(2) Have metastatic Castration Resistant Prostate Cancer (mCRPC): Histologically confirmed adenocarcinoma of the prostate as defined by Prostate Cancer Working Group 3 (PCWG3). Adenocarcinoma with small cell or neuroendocrine (NE) features is permitted. However, small cell carcinoma, carcinoid tumor, mixed NE carcinoma, or large cell NE carcinoma is disallowed.

(3) Measurable or evaluable disease.

(4) Can have a prior or concurrent second malignancy (other than the disease under study) whose natural history or treatment is unlikely to interfere with any study endpoints of safety or the efficacy of the study treatment(s).

(5) Prior therapy requirements a. Part 1C: Study KLK2xCD3 bispecific antibody + docetaxel, Part ID: Study KLK2xCD3 bispecific antibody + apalutamide, Part IE: Study KLK2xCD3 bispecific antibody + enzalutamide, Part IF: Study KLK2xCD3 bispecific antibody + darolutamide, and Part 1G: Study KLK2xCD3 bispecific antibody + abiraterone acetate + prednisone : Prior treatment with at least 1 prior ARPI (ie, apalutamide, enzalutamide, darolutamide, or abiraterone acetate,). b. Part IB: Study KLK2xCD3 bispecific antibody + cabazitaxel : Prior treatment with at least 1 prior ARPI (ie, abiraterone acetate, apalutamide, enzalutamide, darolutamide) and docetaxel.

(6) Prior orchiectomy; or, for participants who have not undergone orchiectomy, must be receiving ongoing androgen deprivation therapy with a gonadotropin releasing hormone (GnRH) analog (agonist or antagonist) prior to the first dose of study treatment and must continue this therapy throughout the treatment phase. (7) Have an ECOG performance status of 0 or 1 .

(8) Have an estimated glomerular filtration rate (eGFR) >40 mL/min, based on the Modified Diet in Renal Disease (MDRD) 4-variable formula.

(9) Participants are eligible if they have the hepatic function: a. Part ID (apalutamide), Part IE (enzalutamide): i. ALT and AST <2.5 x ULN (or <4 x ULN for participants with hepatic metastases) ii. Serum albumin >3.0 g/dL iii. Serum total bilirubin <1.5 x ULN; participants with congenital nonhemolytic hyperbilirubinemia, such as Gilbert’s syndrome, may enroll if conjugated bilirubin is within normal range. b. Part IB (cabazitaxel), Part 1C (docetaxel), Part IF (darolutamide), and Part 1G (abiraterone acetate + prednisone [AAP]): i. ALT (alanine aminotransferase) and AST (aspartate aminotransferase) <1.5 x ULN (or <3 x ULN for participants with hepatic metastases) ii. Serum albumin >3.0 g/dL iii. Serum total bilirubin < 1 x ULN; participants with congenital nonhemolytic hyperbilirubinemia, such as Gilbert’s syndrome, may enroll if conjugated bilirubin is within normal range.

(10) Participants are eligible if they have the hematologic values: a. Part ID (apalutamide), Part IE (enzalutamide), Part IF (darolutamide), and Part 1G (abiraterone acetate + prednisone [AAP]): i. Hematology laboratory parameters within the following ranges, independent of transfusion within 7 days, or growth factors within 3 weeks prior to first dose of study treatment: ii. Hemoglobin> 9.0 g/dL iii. Absolute neutrophil count >1.5*109/L (except for participants with benign ethnic neutropenia who may be enrolled with ANC >1.0 x 109/L) iv. Platelets >75* 109/L. b. Part IB (cabazitaxel) and Part 1C (docetaxel) i. Hematology laboratory parameters within the following ranges, independent of transfusion within 7 days, or growth factors within 3 weeks prior to first dose of study treatment: ii. Hemoglobin> 10.0 g/dL iii. Absolute neutrophil count >1.5*109/L (except for participants with benign ethnic neutropenia who may be enrolled with ANC >1.0 x 109/L) iv. Platelets >100x 109/L.

(11) Human immunodeficiency virus-positive participants are eligible if they meet all of the following: a. No detectable viral load (ie, <50 copies/mL) at screening b. CD4+ count >300 cells/mm3 at screening c. No acquired immunodeficiency syndrome (AIDS)-defining opportunistic infection within 6 months of screening d. Receiving highly active antiretroviral therapy (HAART). Any changes in HAART due to resistance/progression should occur at least 3 months prior to screening. A change in HAART due to toxicity is allowed up to 4 weeks prior to screening. HAART that could interfere with study treatment is excluded (consult the sponsor for a review of medications prior to enrollment).

Exclusion Criteria

[0494] Any potential participant who meets any of the following exclusion criteria for the study will be excluded from participating in the study:

(1) Active autoimmune disease within the 12 months prior to signing consent that requires systemic immunosuppressive medications. EXCEPTIONS: Participants with vitiligo and prior autoimmune thyroiditis that is currently euthyroid based on clinical symptoms and laboratory testing.

(2) Toxicity related to prior anticancer therapy that has not returned to Grade <1 or baseline levels (except for alopecia, vitiligo, Grade <2 peripheral neuropathy).

(3) Solid organ or bone marrow transplantation.

(4) Known allergies or intolerance to any of the components (eg, excipients) of study KLK2xCD3 bispecific antibody, cabazitaxel, (Part IB), docetaxel (Part 1C), apalutamide (Part ID), enzalutamide (Part IE), darolutamide (Part IF), or abiraterone acetate + prednisone (AAP) (Part 1G) (refer to the IBs or local product labeling).

(5) Any of the following within 6 months prior to signature of informed consent: a. Myocardial infarction b. Severe or unstable angina c. Clinically significant ventricular arrhythmias d. Congestive heart failure (New York Heart Association [NYHA] class II to IV) e. Transient ischemic attack f. Cerebrovascular accident

(6) Had major surgery (eg, requiring general anesthesia) within 2 weeks before first dose of study treatment or has not recovered from surgery. Must not have major surgery planned during the time the participant is receiving study treatment. Participants with recent or planned surgical procedures utilizing only local anesthesia may participate.

(7) Active infection or condition that requires treatment with systemic antibiotics within 7 days prior to the first dose of study treatment.

(8) Venous thromboembolic events (eg, pulmonary embolism) within 1 month prior to the first dose of study treatment; uncomplicated (Grade <2) deep vein thrombosis is not considered exclusionary.

(9) Clinically significant pulmonary compromise, particularly a requirement for supplemental oxygen use (>2 L/min by nasal cannula) to maintain adequate oxygenation.

(10) Active CNS involvement. Exception: Treated, stable and asymptomatic brain metastases requiring <10 mg prednisone or equivalent within 2 weeks prior to the first dose of study treatment are permitted.

(11) Prior treatment with KLK2-targeted therapy .

(12) Treatment with any anti-cancer or investigational agents within 28 days or 5-half- lives, whichever is shorter, prior to the first dose of study treatment; specific requirements for certain anti-cancer therapies are as follows: a. No restrictions on GnRH agonist/antagonists. b. Immune checkpoint inhibitors within 6 weeks prior to start of study treatment. c. Any T-cell redirecting treatment (eg, CD3-directed bispecific or CAR-T therapy) within 90 days prior to the start of study treatment. d. External beam radiation therapy within 14 days prior to start of study treatment. However, if palliative focal radiation was used, the participant is eligible irrespective of the end date of radiotherapy. e. Radionuclide therapy within 6 weeks prior to start of study treatment.

(13) Received immunosuppressive doses of systemic medications, such as glucocorticoids (doses >10 mg/day prednisone or equivalent) within 7 days prior to the first dose of study treatment. A single course of glucocorticoids is permitted as prophylaxis for imaging contrast (ie, for participants with allergies to contrast).

(14) Received or plans to receive any live, attenuated vaccine within 4 weeks before the first dose of study treatment. Live, attenuated influenza vaccines are permitted as late as 7 days before the study treatment. Non-live or non-replication-competent vaccines approved or authorized for emergency use (eg, COVID-19) by local health authorities are allowed.

(15) Active hepatitis B or C virus infection according to local laboratory range.

(16) Any serious underlying medical conditions or other issue that would impair the ability of the participant to receive or tolerate the planned treatment at the investigational site, to understand the informed consent, or any condition for which, in the opinion of the investigator, participation would not be in the best interest of the participant (eg, compromise the well-being) or that could prevent, limit, or confound the protocol-specified assessments.

(17) For Part ID (apalutamide), Part IE (enzalutamide), Part IF (darolutamide), and Part 1G (abiraterone acetate + prednisone): History of seizure or condition that may predispose to seizure (including but not limited to prior cerebrovascular accident, TIA, or loss of consciousness within the last 12 months, brain AVM, brain metastases, or the use of concomitant medications).

(18) For Part 1C (cabazitaxel) and Part ID (docetaxel): History of a Grade >3 hypersensitivity or infusion related reaction to prior taxane. Study design

[0495] The study is composed of 2 parts: Dose Escalation (Part 1) and Dose Expansion (Part 2). Approximately 165 participants in Part 1 (up to 25 participants in each Part 1B-1G cohort) and up to 30 participants for each putative RP2R selected for expansion. A schematic overview of the study is shown in FIG. 6.

[0496] Part 1 (Dose Escalation). Part 1 (dose escalation) of the study is designed to select the recommended Phase 2 regimen(s) RP2R(s) of study KLK2xCD3 bispecific antibody and combination agent in participants with mCRPC:

(1) Taxane chemotherapy (Continuous oral daily prednisone will not be administered): a. Part IB: The dose of study KLK2xCD3 bispecific antibody will be escalated to the RP2R with cabazitaxel guided by BOIN design. Cabazitaxel will be a fixed dose at 20 mg/m2 IV, Q3W. b. Part 1C: The dose of study KLK2xCD3 bispecific antibody will be escalated to the RP2R with docetaxel guided by BOIN design. Docetaxel will be a fixed dose at 75 mg/m2 IV, Q3W.

(2) ARPIs: a. Part ID: The dose of study KLK2xCD3 bispecific antibody will be escalated to the RP2R with apalutamide guided by BOIN design. Apalutamide will be a fixed dose at 240 mg QD PO. b. Part IE: The dose of study KLK2xCD3 bispecific antibody will be escalated to the RP2R with enzalutamide guided by BOIN design. Enzalutamide will be a fixed dose at 160 mg QD PO. c. Part IF: The dose of study KLK2xCD3 bispecific antibody will be escalated to the RP2R with darolutamide guided by BOIN design. Darolutamide will be a fixed dose at 600 mg BID PO. d. Part 1G: The dose of study KLK2xCD3 bispecific antibody will be escalated to the RP2R with AAP guided by BOIN design. Abiraterone acetate will be a fixed dose at 1000 mg QD PO. Prednisone will be administered at a fixed dose of 5 mg QD PO.

[0497] Dosing of study KLK2xCD3 bispecific antibody will be initiated with 2 step-up doses followed by the first treatment dose of study KLK2xCD3 bispecific antibody. Step-up dose strategies have been effective in mitigating cytokine-mediated toxi cities in the study KLK2xCD3 bispecific antibody monotherapy study. Alternative step-up dose levels and schedules may be explored based on evaluation of the totality of clinical and supportive data by the Study Evaluation Team. In Part 1B-1G, study KLK2xCD3 bispecific antibody will be administered with taxane chemotherapy or ARPIs.

[0498] Dose levels are subject to change based on emerging data. Intermediate dose-level increments are possible to ensure the safety of study participants.

[0499] Part 2 (Dose Expansion). In Part 2, the putative RP2R(s) of study KLK2xCD3 bispecific antibody and combination agent will be administered to additional participants with mCRPC to confirm the safety and assess preliminary anti-tumor activity of study KLK2xCD3 bispecific antibody and combination agent. More than one putative RP2R may be explored.

[0500] The study treatment is summarized in Table 8.

Table 8.

Dose Limiting Toxicity (DLT)

[0501] Dose Limiting Toxicity (DLT) will be assessed. For Part 1B-G a DLT is an Adverse Event (AE) that meets the toxicity the criteria listed below and occurs in the DLT evaluation period, defined as the first 21 days following the initial combination dose of study treatment (ie, Cycle 1) for the participants in dose escalation. Participants who experience toxicity meeting criteria occurring with single agent study KLK2xCD3 bispecific antibody in the step-up period will not be eligible to go on to receive the combination therapy.

[0502] Criteria for DLT are outlined below:

(1) Hematologic toxicity a. Neutrophil count decreased: Febrile neutropenia and Neutropenia: Grade 4 for >7 days b. Platelet count decreased: Grade 3 thrombocytopenia with clinically significant bleeding or any Grade 4 thrombocytopenia with duration >7 days

(2) Non-Hematological Toxicity a. Alanine Aminotransferase (ALT) or Aspartate Aminotransferase (AST) elevation: any occurrence >8x upper limit of normal or >5x upper limit of normal lasting >14 days or criteria for Hy’s law are met b. Any non-hematological toxicity of Grade >3, with the following exceptions: i. Grade 3 fatigue, asthenia, fever, or constipation, lasting <7 days with best supportive care ii. Grade 3 nausea/vomiting or diarrhea lasting <72 hours with adequate antiemetic and other supportive care iii. Grade >3 hypertension that can be controlled by medical management in <7 days iv. Isolated Grade >3 alkaline phosphatase or GGT increase that returns to Grade <1 or baseline within 7 days

Grade >3 lipase or amylase increase not associated with clinical or radiological evidence of pancreatitis v. Grade >3 electrolyte abnormalitiesc that last up to 72 hours, are not clinically complicated, and either resolve spontaneously or respond to conventional medical interventions vi. Any Grade 3 AE of tumor flare (defined as pain at sites of known or suspected tumor) that resolves to Grade <1 in <7 days vii. Grade 3 or Grade 4 immune-related endocrine disorder (thyroid, pituitary, and/or adrenal insufficiency) that is managed with or without systemic glucocorticoid therapy and/or hormone replacement therapy leading to asymptomatic control viii. First occurrence of Grade 3 sARR/IRR

(3) Other DLT criteria: a. Any death not clearly due to the underlying disease or extraneous causes. b. Any delay in dosing due to study treatment-related toxicity of >14 days in duration.

Efficacy evaluation

[0503] Efficacy evaluations include radiographic disease assessments: whole-body bone scans (^99mTc), and CT scan or MRI according to RECIST vl .1 (Overall Response Rate (ORR), Duration of Response (DoR)) and according to Prostate Cancer Working Group 3 (PCWG3) criteria.

Radiographic Image Assessment (CT or MRI)

[0504] Baseline disease burden will be assessed using Computed Tomography (CT) scans of the chest, abdomen, and pelvis, plus other areas of known disease involvement as appropriate, with IV contrast. Participants who are intolerant of IV contrast agents may have CT scans performed with oral contrast and the reason for not using IV contrast will be documented in source documents. Subsequent efficacy evaluations during the study will include radiographic imaging of all disease sites documented at baseline.

[0505] Magnetic resonance imaging (MRI) may be used to evaluate sites of disease that cannot be adequately imaged using CT scan. In any case, where an MRI is desirable, it must be the imaging technique used to assess disease at baseline and at all subsequent response evaluations. For all other sites of disease, MRI assessments do not replace the required chest, abdomen, and pelvic CT scans, unless CT scan is contraindicated. Brain MRI is required only if clinically indicated. CT scan of the head can be used if MRI is contraindicated.

[0506] Progression of soft tissue lesions will be measured by CT or MRI as defined in RECIST, vl. l.

Assessment of Bone Lesions.

[0507] Bone disease will be evaluated according to PCWG3 criteria.

[0508] Progression of bone lesions observed by bone scan. According to the PCWG3 criteria, bone progression must be confirmed by a subsequent scan >6 weeks later. The first posttreatment scan should be used as the reference scan to which all subsequent scans are compared with, to determine progression. Bone progression is defined as one of the following:

(1) Posttreatment scan is observed to have >2 new bone lesions compared with baseline scan. A confirmatory scan performed >6 weeks later is required and would fall into one of the 2 categories below: a. Confirmatory scan (which is performed >6 weeks later) shows >2 new lesions compared with the post-treatment scan (ie, a total of >4 new lesions compared with baseline scan) will be considered bone scan progression at the first posttreatment scan. b. Confirmatory scan does not show >2 new lesions compared with the posttreatment scan will not be considered bone scan progression at that time. The post-treatment scan will be considered as the reference scan to which subsequent scans are compared.

(2) Posttreatment scan does not show >2 new bone lesions compared with baseline scan; the first scan timepoint that shows >2 new lesions compared with the first posttreatment scan will be considered as the bone scan progression timepoint if these new lesions are confirmed (as above) by a subsequent scan >6 weeks later. Assessment of Disease Response and Progressive Disease.

[0509] Participants with objective response per RECIST vl.l will have a confirmatory scan performed at least 4 weeks later. If a participant is assessed with partial response (PR) or complete response (CR) anytime during study treatment but without confirmation >4 weeks later, the participant’s best response will be classified as stable disease/progressive disease/not evaluable depending on the participant’s next immediate assessments. During the study, disease response will be assessed using CT or MRI scans of the locations of known lesions.

Endpoints

[0510] The objectives and endpoints of the study are listed in Table 9.

Table 9. Objectives and endpoints of the study [0511 ] A further Phase 1 study was conducted to evaluate the recommended phase 2 dose(s) (RP2Ds) of the KLK2xCD3 bispecific antibody in Part 1 (Dose Escalation) and the safety at the RP2Ds in Part 2 (Dose Expansion) in patients with (advanced) prostate cancer (mCRPC patients). The study provides the number of participants with Adverse Events when receiving the KLK2xCD3 bispecific antibody by IV administration or by SC administration.

Example 6. A phase 1 study of an anti-KLK2xCD3 bispecific antibody and Androgen Receptor Pathway Inhibitors (ARPI) and Taxanes for the treatment of advanced prostate cancer

[0512] This is an open-label, multicenter, Phase lb study to evaluate the safety, tolerability, and preliminary antitumor activity of an anti-KLK2xCD3 bispecific antibody (“study KLK2xCD3 bispecific antibody”) in combination with taxane chemotherapy, or Androgen Receptor Pathway Inhibitors (ARPIs) administered to adult participants with metastatic castration-resistant prostate cancer (mCRPC) following at least 1 prior line of therapy or with metastatic hormone-sensitive prostate cancer (mHSPC). The study is composed of 2 parts: dose escalation (Part 1) and dose expansion (Part 2). Part 1 is explore study KLK2xCD3 bispecific antibody in combination with cabazitaxel (Part IB), docetaxel (Part 1C), apalutamide (Part ID), enzalutamide (Part IE), darolutamide (Part IF), or abiraterone acetate + prednisone (AAP) (Part 1G). During the study, safety is monitored at each dose escalation step and at regular intervals during dose expansion. More than one RP2R may be explored in Part 2.

[0513] Study KLK2xCD3 bispecific antibody is a bispecific antibody of the application that simultaneously binds to the CD3 receptor complex on T cells and to cell surface KLK2 on prostate cancer cells.

[0514] The primary objective of this study is to determine the RP2R(s) of study KLK2xCD3 bispecific antibody and combination agents, based on the safety, including DLTs, and tolerability of study KLK2xCD3 bispecific antibody administered with a fixed dose of taxane chemotherapy, or ARPIs. A key secondary objective is to characterize the preliminary antitumor activity of the study KLK2xCD3 bispecific antibody and taxane chemotherapy, or ARPI combinations.

Study population.

[0515] Screening for eligible participants is performed within 30 days before administration of the study treatment. Inclusion criteria

[0516] Each potential participant must satisfy all of the following criteria to be enrolled in the study:

(1) Be >18 years of age (or the legal age of majority in the jurisdiction in which the study is taking place, whichever is greater) at the time of informed consent

(2) Disease criteria:

(a) Parts 1B-G (all combination treatments) and Parts 2B-C (cabazitaxel, docetaxel): Have metastatic Castration Resistant Prostate Cancer (mCRPC) : Histologically confirmed adenocarcinoma of the prostate as defined by PCWG3. Adenocarcinoma with small cell or NE features is permitted. However, small cell carcinoma, carcinoid tumor, mixed NE carcinoma, or large cell NE carcinoma is disallowed

(b) Parts 2D-G (apalutamide, enzalutamide, darolutamide, AAP): Have metastatic Castration Resistant Prostate Cancer (mCRPC): Histologically confirmed adenocarcinoma of the prostate as defined by PCWG3, with a minimum PSA of

2 ng/mL. Adenocarcinoma with small cell or NE features is permitted. However, small cell carcinoma, carcinoid tumor, mixed NE carcinoma, or large cell NE carcinoma is disallowed

(c) Part 2H (apalutamide):

(i) Have metastatic hormone-sensitive prostate cancer (mHSPC) with non-castrate levels of testosterone (>150 ng/dL) and a minimum PSA of 2 ng/mL

(ii) Have metastatic disease documented by >1 bone lesion(s) on "^mTc bone scan. No definitive evidence of metastatic visceral disease

(3) Measurable or evaluable disease.

(4) Can have a prior or concurrent second malignancy (other than the disease under study) whose natural history or treatment is unlikely to interfere with any study endpoints of safety or the efficacy of the study treatment(s) (see Section 10.6, Appendix 6 on Allowed Recent Second or Prior Malignancies for details)

(5) Prior Therapy Requirements a. Parts 1C & 2C (docetaxel), Part ID (apalutamide), Parts IE & 2E (enzalutamide), Parts IF & 2F (darolutamide), and Parts 1G & 2G (AAP) - Prior treatment with at least 1 prior ARPI (ie, apalutamide, enzalutamide, darolutamide, or abiraterone acetate) b. Parts IB & 2B (cabazitaxel) - Prior treatment with at least 1 prior ARPI (ie, abiraterone acetate, apalutamide, enzalutamide, darolutamide) and docetaxel c. Part 2D (apalutamide) - Prior treatment with at least 1 prior ARPI (ie, apalutamide, enzalutamide, darolutamide, or abiraterone acetate). Participant must not have received prior cytotoxic chemotherapy for mCRPC (ie, docetaxel, cabazitaxel, carboplatin, etoposide, etc.). Prior docetaxel is allowed in the mHSPC setting unless disease progressed during docetaxel therapy d. Part 2H (apalutamide) - Participant must not have received prior cytotoxic chemotherapy (ie, docetaxel, cabazitaxel, carboplatin, etoposide, etc.)

(6) Androgen Deprivation Therapy (ADT) a. Parts 1B-G and Parts 2B-G (all combination treatments): Prior orchiectomy; or, for participants who have not undergone orchiectomy, must be receiving ongoing ADT with a GnRH analog (agonist or antagonist) prior to the first dose of study treatment and must continue this therapy throughout the treatment phase b. Part 2H (apalutamide): ADT must start at the initiation of Study KLK2xCD3 bispecific antibody full treatment dose, ie, C1D1

(7) Have an ECOG performance status of 0 or 1 (see Section 10.8, Appendix 8).

(8) Have an estimated glomerular filtration rate (eGFR) >40 mL/min, based on the MDRD 4 variable formula

(9) Participants are eligible if they have the hepatic function: a. Parts ID & 2D and Part 2H (apalutamide), Parts IE & 2E (enzalutamide):

(i) ALT and AST <2.5><ULN (or <4*ULN for participants with hepatic metastases)

(ii) Serum albumin >3.0 g/dL

(iii) Serum total bilirubin <L5*ULN; participants with congenital nonhemolytic hyperbilirubinemia, such as Gilbert’s syndrome, may enroll if conjugated bilirubin is within normal range b. Parts IB & 2B (cabazitaxel), Parts 1C & 2C (docetaxel), Parts IF & 2F (darolutamide), and Parts 1G & 2G (AAP):

(i) ALT and AST <1.5*ULN (or <3*ULN for participants with hepatic metastases) (ii) Serum albumin >3.0 g/dL

(iii) Serum total bilirubin <1 *ULN; participants with congenital nonhemolytic hyperbilirubinemia, such as Gilbert’s syndrome, may enroll if conjugated bilirubin is within normal range

(10) Participants are eligible if they have the hematologic values: a. Parts ID & 2D and Part 2H (apalutamide), Parts IE & 2E (enzalutamide), Parts IF

& 2F (darolutamide), and Parts 1G & 2G (AAP):

Hematology laboratory parameters within the following ranges, independent of transfusion within 7 days, or growth factors within 3 weeks prior to first dose of study treatment:

(i) Hemoglobin >9.0 g/dL

(ii) ANC >1.5xl09/L (except for participants with benign ethnic neutropenia who may be enrolled with ANC >1. Ox 109/L)

(iii) Platelets >75 x 109/L b. Parts IB & 2B (cabazitaxel) and Parts 1C & 2C (docetaxel)

(i) Hemoglobin> 10.0 g/dL

(ii) ANC >1.5xl09/L (except for participants with benign ethnic neutropenia who may be enrolled with ANC >1 ,0x 109/L)

(iii) Platelets > 100 x 109/L

(11) Human immunodeficiency virus-positive participants are eligible if they meet all of the following: a. No detectable viral load (ie, <50 copies/mL) at screening b. CD4+ count >300 cells/mm3 at screening c. No acquired immunodeficiency syndrome (AIDS)-defining opportunistic infection within 6 months of screening d. Receiving highly active antiretroviral therapy (HAART). Any changes in HAART due to resistance/progression should occur at least 3 months prior to screening. A change in HAART due to toxicity is allowed up to 4 weeks prior to screening. HAART that could interfere with study treatment is excluded (consult the sponsor for a review of medications prior to enrollment)

Exclusion Criteria

[0517] Any potential participant who meets any of the following exclusion criteria for the study may be excluded from participating in the study:

(1) Active autoimmune disease within the 12 months prior to signing consent that requires systemic immunosuppressive medications. EXCEPTIONS: Participants with vitiligo and prior autoimmune thyroiditis that is currently euthyroid based on clinical symptoms and laboratory testing

(2) Toxicity related to prior anticancer therapy that has not returned to Grade <1 or baseline levels (except for alopecia, vitiligo, Grade <2 peripheral neuropathy)

(3) Solid organ or bone marrow transplantation

(4) Known allergies or intolerance to any of the components (eg, excipients) of study KLK2xCD3 bispecific antibody, cabazitaxel (Parts IB & 2B), docetaxel (Parts 1C & 2C), apalutamide (Parts ID & 2D and Part 2H), enzalutamide (Parts IE & 2E), darolutamide (Parts IF & 2F), or AAP (Parts 1G & 2G)

(5) Any of the following within 6 months prior to signature of informed consent: a. Myocardial infarction b. Severe or unstable angina c. Clinically significant ventricular arrhythmias d. Congestive heart failure (New York Heart Association class II to IV) e. Transient ischemic attack f. Cerebrovascular accident

(6) Had major surgery (eg, requiring general anesthesia) within 2 weeks before first dose of study treatment or has not recovered from surgery. Must not have major surgery planned during the time the participant is receiving study treatment. Participants with recent or planned surgical procedures utilizing only local anesthesia may participate

(7) Active infection or condition that requires treatment with systemic antibiotics within 7 days prior to the first dose of study treatment (8) Venous thromboembolic events (eg, pulmonary embolism) within 1 month prior to the first dose of study treatment; uncomplicated (Grade <2) deep vein thrombosis is not considered exclusionary

(9) Clinically significant pulmonary compromise, particularly a requirement for supplemental oxygen use (>2 L/min by nasal cannula) to maintain adequate oxygenation

(10) Disease Characteristics a. Parts 1B-G and Parts 2B-G (all combination treatments): Active CNS involvement. Exception: Treated, stable and asymptomatic brain metastases requiring <10 mg prednisone or equivalent within 2 weeks prior to the first dose of study treatment are permitted b. Part 2H (apalutamide):

(i) Evidence of castration resistance, defined as having undergone bilateral orchiectomy or progressed while castrated on prior Androgen Deprivation Therapy (ADT)

(ii) Initiation of treatment with a bisphosphonate or denosumab for the management of bone metastasis <28 days prior to first dose of study treatment

(11) Prior treatment with KLK2 -targeted therapy

(12) Treatment with any anti-cancer or investigational agents within 28 days or 5-half- lives, whichever is shorter, prior to the first dose of study treatment; specific requirements for certain anti-cancer therapies are as follows: a. No restrictions on GnRH agonist/antagonists b. Immune checkpoint inhibitors within 6 weeks prior to start of study treatment. c. Any T-cell redirecting treatment (eg, CD3-directed bispecific or CAR-T therapy) within 90 days prior to the start of study treatment d. External beam radiation therapy within 14 days prior to start of study treatment. However, if palliative focal radiation was used, the participant is eligible irrespective of the end date of radiotherapy e. Radionuclide therapy within 6 weeks prior to start of study treatment (13) Patient having received immunosuppressive doses of systemic medications, such as glucocorticoids (doses >10 mg/day prednisone or equivalent) within 7 days prior to the first dose of study treatment. A single course of glucocorticoids is permitted as prophylaxis for imaging contrast (ie, for participants with allergies to contrast)

(14) Patient having received or plans to receive any live, attenuated vaccine within 4 weeks before the first dose of study treatment. Live, attenuated influenza vaccines are permitted as late as 7 days before the study treatment. Nondive or nonreplication-competent vaccines approved or authorized for emergency use (eg, COVID-19) by local health authorities are allowed

Viral Hepatitis Assessments

(15) Active hepatitis B or C virus infection according to local laboratory range

(16) Any serious underlying medical conditions or other issue that would impair the ability of the participant to receive or tolerate the planned treatment at the investigational site, to understand the informed consent, or any condition for which, in the opinion of the investigator, participation would not be in the best interest of the participant (eg, compromise the well-being) or that could prevent, limit, or confound the protocol -specified assessments

(17) For Parts ID & 2D and Part 2H (apalutamide), Parts IE & 2E (enzalutamide), Parts IF & 2F (darolutamide), and Parts 1G & 2G (AAP): History of seizure or condition that may predispose to seizure (including but not limited to prior cerebrovascular accident, TIA, or loss of consciousness within the last 12 months, brain AVM, brain metastases, or the use of concomitant medications)

(18) For Parts IB & 2B (cabazitaxel) and Parts 1C & 2C (docetaxel): History of a Grade >3 hypersensitivity or IRR to prior taxane

Study Design

[0518] The study is composed of 2 parts: Dose Escalation (Part 1) and Dose Expansion (Part 2). Approximately 165 participants in Part 1 (up to approximately 15 participants in Part 1A and up to approximately 25 participants each in Parts 1B-G) and up to 30 participants for each putative RP2R selected for expansion in Part 2 are being treated. In addition, Part 2H enrolls up to approximately 50 participants with mHSPC at the putative RP2R of study KLK2xCD3 bispecific antibody in combination with apalutamide determined in Part ID. However, the actual sample size depends on the number of cohorts explored, the number of participants enrolled, and the number of RP2Rs selected for dose expansion cohorts(s).

[0519] Part 1 (dose escalation) of the study is designed to select the RP2R(s) of study KLK2xCD3 bispecific antibody and combination agent.

(1) Taxane chemotherapy (Continuous oral daily prednisone is not administered): a. Part IB: The dose of study KLK2xCD3 bispecific antibody is escalated to the RP2R in combination with cabazitaxel guided by BOIN design. Cabazitaxel is a fixed dose at 20 mg/m² IV, Q3W. b. Part 1C: The dose of study KLK2xCD3 bispecific antibody is escalated to the RP2R in combination with docetaxel guided by BOIN design. Docetaxel is a fixed dose at 75 mg/m IV, Q3W.

(2) ARPIs: a. Part ID: The dose of study KLK2xCD3 bispecific antibody is escalated to the RP2R in combination with apalutamide guided by BOIN design. Apalutamide is a fixed dose at 240 mg once daily PO. b. Part IE: The dose of study KLK2xCD3 bispecific antibody is escalated to the RP2R in combination with enzalutamide guided by BOIN design. Enzalutamide is a fixed dose at 160 mg once daily PO. c. Part IF: The dose of study KLK2xCD3 bispecific antibody is escalated to the RP2R in combination with darolutamide guided by BOIN design. Darolutamide is a fixed dose at 600 mg twice daily PO. d. Part 1G: The dose of study KLK2xCD3 bispecific antibody is escalated to the RP2R in combination with AAP guided by BOIN design. Abiraterone acetate is a fixed dose at 1000 mg once daily PO. Prednisone is administered at a dose of 5 mg once daily PO.

[0520] Dosing is initiated with 2 step-up doses of study KLK2xCD3 bispecific antibody followed by a treatment dose of study KLK2xCD3 bispecific antibody.

[0521] In Part 2, the putative RP2R(s) of study KLK2xCD3 bispecific antibody and combination agent determined in Part 1 is administered to additional participants with mCRPC in Parts 2B-G to confirm the safety and assess preliminary anti-tumor activity of study KLK2xCD3 bispecific antibody and combination agent. In addition, Part 2H enrolls up to approximately 50 participants with mHSPC at the putative RP2R of study KLK2xCD3 bispecific antibody in combination with apalutamide determined in Part ID. More than one putative RP2R may be explored.

[0522] Study KLK2xCD3 bispecific antibody administered via IV infusion at 300 mg Q6W by IV infusion, with step-up doses of 3.5 mg and 18 mg (Day 1 step-up dose of 3.3mg; day 8 step- up dose of 18mg; Day 15; first treatment dose of 300mg; and then 300mg Q6W as of Day 15; IV infusion).

[0523] A BOIN design is implemented to support dose escalation. In this study, the target DLT rate is 30%; the optimal boundaries for dose escalation and de-escalation are 24.0% and 36.0%.

Table 10: Taxane/ARPI Dosing

Dose Limiting Toxicity (DLT)

[0524] Dose Limiting Toxicity (DLT) is being assessed. For Part 1B-G a DLT is an Adverse Event (AE) that meets the toxicity the criteria listed below and occurs in the DLT evaluation period, defined as the first 21 days following the initial combination dose of study treatment (ie, Cycle 1) for the participants in dose escalation. Participants who experience toxicity meeting criteria occurring with single agent study KLK2xCD3 bispecific antibody in the step-up period are not eligible to go on to receive the combination therapy.

Criteria for DLT are outlined below:

Grade >3 lipase or amylase increase not associated with clinical or radiological evidence of pancreatitis v. Grade >3 electrolyte abnormalities that last up to 72 hours, are not clinically complicated, and either resolve spontaneously or respond to conventional medical interventions vi. Any Grade 3 AE of tumor flare (defined as pain at sites of known or suspected tumor) that resolves to Grade <1 in <7 days vii. Grade 3 or Grade 4 immune-related endocrine disorder (thyroid, pituitary, and/or adrenal insufficiency) that is managed with or without systemic glucocorticoid therapy and/or hormone replacement therapy leading to asymptomatic control viii. First occurrence of Grade 3 sARR/IRR

Efficacy evaluation

[0525] Efficacy evaluations include radiographic disease assessments: whole-body bone scans (^99mTc), and CT scan or MRI according to RECIST vl .1 (Overall Response Rate (ORR), Duration of Response (DoR)) and according to Prostate Cancer Working Group 3 (PCWG3) criteria.

Radiographic Image Assessment (CT or MRI)

[0526] Baseline disease burden are assessed using Computed Tomography (CT) scans of the chest, abdomen, and pelvis, plus other areas of known disease involvement as appropriate, with IV contrast. Participants who are intolerant of IV contrast agents may have CT scans performed with oral contrast and the reason for not using IV contrast are documented in source documents. Subsequent efficacy evaluations during the study include radiographic imaging of all disease sites documented at baseline.

[0527] Magnetic resonance imaging (MRI) may be used to evaluate sites of disease that cannot be adequately imaged using CT scan. In any case, where an MRI is desirable, it must be the imaging technique used to assess disease at baseline and at all subsequent response evaluations. For all other sites of disease, MRI assessments do not replace the required chest, abdomen, and pelvic CT scans, unless CT scan is contraindicated. Brain MRI is required only if clinically indicated. CT scan of the head can be used if MRI is contraindicated.

[0528] Progression of soft tissue lesions is measured by CT or MRI as defined in RECIST, vl.l.

Assessment of Bone Lesions.

[0529] Bone disease is evaluated according to PCWG3 criteria.

[0530] Progression of bone lesions observed by bone scan. According to the PCWG3 criteria, bone progression must be confirmed by a subsequent scan >6 weeks later. The first posttreatment scan should be used as the reference scan to which all subsequent scans are compared with, to determine progression. Bone progression is defined as one of the following:

(1) Posttreatment scan is observed to have >2 new bone lesions compared with baseline scan. A confirmatory scan performed >6 weeks later is required and would fall into one of the 2 categories below: a. Confirmatory scan (which is performed >6 weeks later) shows >2 new lesions compared with the post-treatment scan (ie, a total of >4 new lesions compared with baseline scan) is considered bone scan progression at the first posttreatment scan. b. Confirmatory scan does not show >2 new lesions compared with the posttreatment scan is not considered bone scan progression at that time. The post- treatment scan is considered as the reference scan to which subsequent scans are compared.

(2) Posttreatment scan does not show >2 new bone lesions compared with baseline scan; the first scan timepoint that shows >2 new lesions compared with the first posttreatment scan is considered as the bone scan progression timepoint if these new lesions are confirmed (as above) by a subsequent scan >6 weeks later.

Assessment of Disease Response and Progressive Disease.

[0531] Participants with objective response per RECIST vl .1 have a confirmatory scan performed at least 4 weeks later. If a participant is assessed with partial response (PR) or complete response (CR) anytime during study treatment but without confirmation >4 weeks later, the participant’s best response is classified as stable disease/progressive disease/not evaluable depending on the participant’s next immediate assessments. During the study, disease response is assessed using CT or MRI scans of the locations of known lesions.

Endpoints

[0532] The objectives and endpoints of the study are summarized in Table 11 Table 11. Objectives and endpoints of the study

Outcome measures

Primary outcome measure

[0533] Parti : Number of participants with dose limiting toxicity (DLT) - Time frame: up to 21 days after first dose of combination agent. DLT are specific adverse events and are define as any of the following: high grade non-hematologic toxicity or hematologic toxicity.

[0534] Parti and Part 2: Number of participants with adverse events (AEs) by severity - Time frame; up to 2 years 11 months. An AE is any untoward medical occurrence in a participant participating in a clinical study that does not necessarily have a causal relationship with the pharmaceutical/biological agent under study. Severity is graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0 with the exception of cytokine release syndrome (CRS) and immune effector cell -associated neurotoxicity syndrome events, which is graded by American Society for Transplantation and Cellular Therapy (ASTCT) guidelines. Severity scale ranges from grade 1 (mild) to grade 5 (death). Grade 1 = mild, Grade 2 = moderate, Grade 3 = severe, Grade 4 = life-threatening and Grade 5 = death related to adverse event.

Secondary Outcome Measures

1. Overall Response Rate (ORR) - Time frame: up to 2 years 11 months. ORR is defined as the percentage of participants who have a partial response (RR) or better without evidence of bone progression according to Prostate Cancer Working Group 4 (PCWG3) criteria.

2. Prostate Specific Antigen (PSA) Response rate - Time frame: up to 2 years 11 months. PSA response rate is defined as the percentage of participants with a confirmed decline of PSA of 50 percent (%) or more form baseline 3. Radiographic Progression-free Survival (rPFS) - Time frame: up to 2 years 1 1 months. rPFS is define time from the date of first dose of KLK2xCD3 bispecific antibody until the date of objective disease progression or death, whichever comes first.

4. Time to Response (TTR) - Time frame: up to 2 years 11 months. TTR is defined for the responders as the time from the date of first dose to the time of first dose documented response that is subsequently confirmed.

5. Duration of Response (DOR) - Time frame: up to 2 years 11 months. DOR is defined for participants who achieved response (PR or better) as the time between the date of initial documentation of response (PR or better) to the date of first documented evidence of progressive disease, as defined in the PCWG3, or death due to any cause, whichever occurs first.

As of April 8, 2025, most frequently reported TRAEs (>10%) in 43 patients were alopecia, fatigue, nausea, diarrhoea, oedema peripheral, and myalgia; no patient discontinued study treatment due to TRAE; and the PSA50 rate was 55.8%.

Example 7. A Phase 3 Randomized, Open-label Study of KLK2xCD3 bispecific antibody, a T Cell -redirecting agent targeting Human Kallikrein 2, with Docetaxel Versus Docetaxel for chemo-naive Metastatic Castration-Resistant Prostate Cancer

Overall Design

[0535] This is a randomized, controlled, open-label international Phase 3 study in adult participants with mCRPC who are taxane naive. The study aims to enroll a participant population that is geographically reflective of the overall incidence/prevalence of this disease.

Approximately 844 participants are randomly assigned in a 1 : 1 ratio to receive the combination of an anti-KLK2xCD3 bispecific antibody (“study KLK2xCD3 bispecific antibody”; pasritamig) with docetaxel vs docetaxel alone. All participants must be receiving background androgen deprivation therapy (ADT) or have had prior orchiectomy. Randomization is stratified by sites of metastases (bone, LN or both, visceral) and prior use of radioligand therapy (Y/N).

[0536] The study includes a screening phase, a treatment phase, post-treatment EOT visit, and a follow-up phase. The screening phase begins up to 28 days prior to randomization. [0537] The treatment phase continues until a radiation progression free survival (rPFS) event, intolerable toxicity, withdrawal of consent, or end of the study, whichever occurs first. Docetaxel may be administered up to 10 doses or until requirements for docetaxel discontinuation are met. Once docetaxel treatment is discontinued participants remain under observation and return to the site every 6 weeks until the end of treatment (EOT) criteria are met. In study KLK2xCD3 bispecific antibody + docetaxel arm, participants continue with study KLK2xCD3 bispecific antibody when docetaxel stopped.

Background: Non-Clinical and Clinical Studies

[0538] Study KLK2xCD3 bispecific antibody has been studied in a first-in-human, doseescalation Phase 1 trial to evaluate its safety, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity in mCRPC, both as a single agent and in combination with taxane chemotherapy, ARPIs, and immunotherapy (Example 5).

[0539] As of 7 October 2024, 174 participants with mCRPC have been treated (102 via SC administration and 72 via IV administration) in the ongoing monotherapy study. A recommended phase 2 dose (RP2D) of 300 mg Q6W dose by IV administration, with 2 step doses of 3.5 mg on Day 1 and 18 mg on Day 8, was selected and expanded.

[0540] In total, 33 participants treated with target dose of 300 IV Q6W were grouped together as the RP2D-efficacy population. A total of 42.4% achieved a PSA50 response and 36.4% had a confirmed PSA50 response. Median rPFS was 6.77 months. The most common TRAEs at the RP2D dose level were fatigue (15.6%) and infusion-related reaction (22.2%), all of which were Grade 2 or lower. No participants discontinued study treatment due to AEs and only 4 (8.9%) participants reported CRS, all of which were Grade 1.

Justification of dose - Study KLK2xCD3 bispecific antibody

[0541] Dosing of study KLK2xCD3 bispecific antibody consists of 2 step-up doses (3.5 mg and 18 mg) followed by the fixed target dose of 300 mg Q6W by IV administration.

[0542] Note that data presented below represent data cutoffs of 7 October 2024.

[0543] At the dose level of 300 mg IV (Q3W or Q6W), with step-up doses of 3.5 mg and 18 mg, there were no dose-limiting toxicities, nor any related treatment-emergent adverse events (TEAEs) leading to treatment discontinuation. The rate of cytokine release syndrome (CRS) observed was 8.9% (4/45 participants), all of which were Grade 1 . The safety profile at 300 mg IV dose was similar to the lower dose/exposure.

[0544] Among the participants treated at the recommended phase 2 dose (RP2D), PSA50 response rate was 42.4%, confirmed PSA50 response was 36.4%, and the median rPFS was 6.77 months, with 39.4% participants still on treatment at time of data cutoff. The efficacy (based on confirmed PSA50 response) was close to plateau at RP2D with no further increase of efficacy at higher dose/exposure. Pharmacodynamics data also support this regimen with induction of cytokines and T-cell activation following study KLK2xCD3 bispecific dosing, indicative of the mechanism of action.

Dose justification - Docetaxel

[0545] Docetaxel is dosed per approved label as follows:

[0546] Docetaxel is a fixed dose at 75mg/m², Q3 weeks

[0547] The treatment label for docetaxel utilizes concomitant daily prednisone, but oral daily prednisone is not administered in this study for the study KLK2xCD3 bispecific antibody plus docetaxel treatment arm.

Objectives and endpoints

[0548] Objectives and endpoints are summarized in Table 12.

Table 12. Objectives and endpoints

Study population

Inclusion criteria

[0549] Each potential participant must satisfy all of the following criteria to be enrolled in the study:

(1) be >18 years of age

(2) Have histologically confirmed adenocarcinoma of the prostate. Primary (or documented evidence of conversion to) small cell carcinoma, carcinoid tumor, mixed NE carcinoma, large cell neuroendocrine (NE) carcinoma, or sarcoma of the prostate is excluded.

(3) Have progressive metastatic castrate-resistant disease defined as at least one of the following: PSA level > 2 ng/mL that has increased on at least 2 successive occasions at least 1 week apart; progressive disease or new lesion(s) in the lymph nodes, bones, or viscera as defined by RECIST 1.1 and/or in bone scan as per Prostate cancer working group 3 (PCWG3) while on medical or surgical castration

(4) Disease that is metastatic at the time of the screening.

(5) Prior Therapy Restrictions or Requirements:

Serum testosterone <50 ng/dL (<1.73 nmol/L) at screening.

Receiving ongoing Androgen deprivation therapy (ADT) with a GnRH analog (agonist or antagonist) or have had prior orchiectomy. Must continue this therapy throughout the treatment phase.

Prior ARPIs (ex. abiraterone acetate, apalutamide, enzalutamide, darolutamide) for any stage of disease are allowed until randomization.

(6) Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.

(7) Have an estimated Glomerular Filtration Rate (eGFR), calculated with the CKD-epi formula of >30 ml/min during the screening period. Participants with obstructive uropathy should have treatment prior to randomization (eg, foley catheter, nephrostomy tubes, etc).

(8) Participants are eligible if they have the following lab values during the screening period

Table 13.

(9) Participants must have hemoglobin >10.0 g/dL, without transfusion or growth factors within 28 days of the randomization.

(10) Participants must have neutrophils >1.5 x l O’/uL, without growth factors within 14 days of randomization

(11) Participants must have platelets >100 x 10³/pL, without transfusion and growth factors within 14 days of randomization.

Exclusion criteria

[0550] Any potential participant who meets any of the following criteria may be excluded from participating in the study:

(1) Known history of either brain or leptomingeal prostate cancer metastases.

(2) Known BRCA 1/2 mutations

(3) Suspected or known allergies, hypersensitivity, or intolerance to KLK2 bispecific antibody excipients or docetaxel excipients.

(4) Must be sufficiently recovered from any recent surgery

(5) Solid organ or bone marrow transplantation

(6) Any of the following within 6 months prior to first dose of study treatment: severe or unstable angina, myocardial infarction, major thromboembolic events (eg, pulmonary embolism, cerebrovascular accident), clinically significant ventricular arrhythmias or heart failure New York Heart Association functional classification Class II to IV.

Uncomplicated deep vein thrombosis is not considered exclusionary.

(7) Participant has a prior or concurrent second malignancy (other than the disease under study) the natural history or treatment of which could likely interfere with any study endpoints of safety or the efficacy of the study treatment(s)

(8) Participant received cytotoxic chemotherapy for prostate cancer (eg docetaxel, cabazitaxel)

(9) Participant received prior treatment with KLK-2 directed therapies

(10) Participant received prior treatment with:

(a) CD-3 redirected therapies

(b) Radiopharmaceutical agents

(c) Immunotherapy agents for prostate cancer (eg, Sipuleucel T, PD-1 inhibitors, T cell redirectors, costimulatory agents).

(11) Participants who are human immunodeficiency virus-positive and meet any of the following:

(a) Detectable viral load (ie, >50 copies/mL) at screening

(b) CD4⁺ count <300 cells/mm³ at screening

(c) Acquired immunodeficiency syndrome (AIDS)-defining opportunistic infection within 6 months of screening

(d) Receive treatment other than continued highly active antiretroviral therapy (HAART).

(12) Active hepatitis of infectious origin.

(a) Seropositive for hepatitis B: defined by a positive test for hepatitis B surface antigen (HBsAg).

(b) Known hepatitis C infection or positive serologic testing for hepatitis C virus (anti-HCV) antibody.

(c) Other clinically active liver disease of infectious origin.

(13) Received or plans to receive any live, attenuated vaccine within 4 weeks before the first dose of study drug. Non-live and non-replicati on-competent vaccines are allowed. (14) Received immunosuppressive doses of systemic medications, such as glucocorticoids (doses >10 mg/day prednisone or equivalent) within 3 days prior to the first dose of study drug. A single course of glucocorticoids is permitted as prophylaxis for imaging contrast (ie, for participants with allergies to contrast). If glucocorticoids were used to treat immune-related adverse events associated with prior therapy, >7 days must have elapsed since the last dose of corticosteroid.

(15) Any condition which, in the opinion of the investigator, would not be in the best interest of the participant (eg, compromise the well-being) or that could prevent, limit, or confound the protocol-specified assessments.

SEQUENCE LISTING

Claims

CLAIMS We claim:

1. A method of treating prostate cancer in a subject, wherein the method comprises administering to the subject an anti-KLK2xCD3 antibody and another anti-cancer drug, wherein the other anti-cancer drug an androgen receptor pathway inhibitor (ARP I) or an anticancer chemotherapeutic agent, wherein the anti-KLK2xCD3 antibody comprises a first antigen binding domain that binds specifically to KLK2, and a second antigen binding domain that binds specifically to CD3a, preferably, the first antigen binding domain comprises a first heavy chain complementarity determining region (HCDR) 1, a first HCDR2 and a first HCDR3 of a first heavy chain variable region (VH1), and a first light chain complementarity determining region (LCDR) 1, a first LCDR2, and a first LCDR3 of a first light chain variable region (VL1), wherein the VH1 and the VL1 comprise: i) the amino acid sequences of SEQ ID NO: 37 and SEQ ID NO: 38, respectively; ii) the amino acid sequences of SEQ ID NO: 39 and SEQ ID NO: 40, respectively; iii) the amino acid sequences of SEQ ID NO: 41 and SEQ ID NO: 42, respectively; or iv) the amino acid sequences of SEQ ID NO: 43 and SEQ ID NO: 44, respectively wherein the first HCDR1, first HCDR2, first HCDR3, first LCDR1, first LCDR2 and first LCDR3 are defined by the Kabat, Chothia, IMGT or AbM numbering system.

2. The method of claim 1, wherein the administering of the anti-KLK2xCD3 antibody and the other anti-cancer drug enhances immune cell function, such as enhances T cell function, as compared to the administration of each of the anti-KLK2xCD3 antibody and the other anticancer drug alone, preferably, the T cell function comprises T cell cytotoxicity (or T cell killing), T cell activation, and/or T cell proliferation, e.g., the T cell function is T cell cytotoxicity (or T cell killing), more preferably T cell killing of prostate cancer cells.

3. The method of any of the foregoing claims, wherein the administering of the anti-KLK2xCD3 antibody and the other anti-cancer drug prevents disease progression of the prostate cancer.

4. The method of any of the foregoing claims, wherein the administering of the anti-KLK2xCD3 antibody and the other anti-cancer drug does not increase the risk of a treatment related toxicity in a clinically significant way as compared to the administration of each of the anti- KLK2xCD3 antibody and the other anti-cancer drug alone (e.g., when assessed in a cohort of patients).

5. The method of any of the foregoing claims, wherein the administering of the anti-KLK2xCD3 antibody and the other anti-cancer drug provides a reduction in serum Prostate Specific Antigen (PSA), preferably an improved serum PSA reduction, as compared to the administration of each of the anti-KLK2xCD3 antibody and the other anti-cancer drug alone, without triggering a cytokine release syndrome (CRS) of grade 3 or higher according to the American Society for Transplantation and Cellular Therapy (ASTCT) guidelines.

6. The method of any of the foregoing claims, wherein the first HCDR1, first HCDR2, first

HCDR3, first LCDR1, first LCDR2 and first LCDR3 comprises: i) the amino acid sequences of SEQ ID NOs: 1, 2, 3, 4, 5, and 6, respectively; ii) the amino acid sequences of SEQ ID NOs: 7, 8, 9, 10, 11, and 12, respectively; iii) the amino acid sequences of SEQ ID NOs: 13, 14, 15, 16, 17, and 18, respectively; or iv) the amino acid sequences of SEQ ID NOs: 19, 20, 21, 22, 23, and 24, respectively.

7. The method of any of the foregoing claims, wherein the VH1 and the VL1 comprise: i) amino acid sequences at least 90%, preferably 100%, identical to SEQ ID NO: 37 and

8. The method of claim 8, wherein the first binding domain comprises i) a first heavy chain (HC1) and a first light chain (LC1), and the HC1 and the LC1 comprise: a) amino acid sequences at least 90%, preferably 100%, identical to SEQ ID NO: 49 and SEQ ID NO: 50, respectively; b) amino acid sequences at least 90%, preferably 100%, identical to SEQ ID NO: 53 and

9. The method of any of the foregoing claims, wherein the second antigen binding domain comprises a second HCDR1, a second HCDR2 and a second HCDR3 of a second heavy chain variable region (VH2), and a second LCDR1, a second LCDR2, and a second LCDR3 of a second light chain variable region (VL2), wherein the VH2 and the VL2 comprise: i) the amino acid sequences of SEQ ID NO: 45 and SEQ ID NO: 46, respectively; or ii) the amino acid sequences of SEQ ID NO: 47 and SEQ ID NO: 48, respectively wherein the second HCDR1, second HCDR2, second HCDR3, second LCDR1, second LCDR2 and second LCDR3 are defined by the Kabat, Chothia, IMGT or AbM numbering system.

10. The method of claim 9, wherein the second HCDR1, second HCDR2, second HCDR3, second LCDR1, second LCDR2 and second LCDR3 comprises: i) the amino acid sequences of SEQ ID NOs: 25, 26, 27, 28, 29, and 30, respectively; or ii) the amino acid sequences of SEQ ID NOs: 31, 32, 33, 34, 35, and 36, respectively.

11. The method of claim 10, wherein the VH2 and the VL2 comprise: i) amino acid sequences at least 90%, preferably 100%, identical to SEQ ID NO: 45 and

12. The method of claim 11, wherein the second binding domain comprises: i) a second heavy chain (HC2) and a second light chain (LC2), and the HC2 and the LC2 comprise: a) amino acid sequences at least 90%, preferably 100%, identical to SEQ ID NO: 57 and

13. The method of claim 10, wherein the first HCDR1, first HCDR2, first HCDR3, first LCDR1, first LCDR2, first LCDR3, second HCDR1, second HCDR2, second HCDR3, second LCDR1, second LCDR2 and second LCDR3 comprise: i) the amino acid sequences of SEQ ID NOs: 1, 2, 3, 4, 5, 6, 25, 26, 27, 28, 29, and 30, respectively; ii) the amino acid sequences of SEQ ID NOs: 7, 8, 9, 10, 11, 12, 25, 26, 27, 28, 29, and

14. The method of claim 13, wherein the VH1, VL1, VH2 and VL2 comprise: i) amino acid sequences at least 90%, preferably 100%, identical to SEQ ID NOs: 37, 38,

45, and 46, respectively; ii) amino acid sequences at least 90%, preferably 100%, identical to SEQ ID NOs: 39, 40, 45, and 46, respectively, iii) amino acid sequences at least 90%, preferably 100%, identical to SEQ ID NOs: 41,

15. The method of claim 14, wherein i) the first binding domain comprises the HC1 and LC1 comprising amino acid sequences at least 90%, preferably 100%, identical to SEQ ID NOs: 49 and 50, respectively, and the second binding domain comprises the scFv2-Fc comprising an amino acid sequence at least 90%, preferably 100%, identical to SEQ ID NO: 56; ii) the first binding domain comprises the scFvl-Fc comprising an amino acid sequence at least 90%, preferably 100%, identical to SEQ ID NO: 51, and the second binding domain comprises the HC2 and LC2 comprising amino acid sequences at least 90%, preferably 100%, identical to SEQ ID NOs: 57 and 58, respectively; iii) the first binding domain comprises the scFvl-Fc comprising an amino acid sequence at least 90%, preferably 100%, identical to SEQ ID NO: 52, and the second binding domain comprises the HC2 and LC2 comprising amino acid sequences at least 90%, preferably 100%, identical to SEQ ID NOs: 59 and 60, respectively, iv) the first binding domain comprises the HC1 and LC1 comprising amino acid sequences at least 90%, preferably 100%, identical to SEQ ID NOs: 53 and 54, respectively, and the second binding domain comprises the scFv2-Fc comprising an amino acid sequence at least 90%, preferably 100%, identical to SEQ ID NO: 56; or v) the first binding domain comprises the HC1 and LC1 comprising amino acid sequences at least 90%, preferably 100%, identical to SEQ ID NOs: 55 and 50, respectively, and the second binding domain comprises the scFv2-Fc comprising an amino acid sequence at least 90%, preferably 100%, identical to SEQ ID NO: 61.

16. The method of any one of claims 1-15, wherein the anti-KLK2xCD3 antibody is administered to the subject subcutaneously.

17. The method of any one of claims 1-15, wherein the anti-KLK2xCD3 antibody is administered to the subject intravenously.

18. The method of claim 16 or 17, wherein the anti-KLK2xCD3 antibody is administered once every 1-9 weeks, for example, once every 3 weeks, once every 6 weeks, or once every 9 weeks.

19. The method of any one of the preceding claims, wherein the administering of the anti- KLK2xCD3 antibody comprises the administering of more than one treatment dose, wherein the treatment doses are administered once every 1-9 weeks, for example, once every 3 weeks, once every 6 weeks, or once every 9 weeks, and wherein each treatment dose is at the same dose level.

20. The method of any one of the preceding claims, wherein the other anti-cancer drug is administered simultaneously, sequentially or separately from the administering of the anti- KLK2xCD3 antibody, for example on the same day about 4 hours apart.

21. The method of any one of the preceding claims, wherein the anti-KLK2xCD3 antibody is administered at a treatment dose level of 100-2000 mg.

22. The method of any one of claims 1-21, which comprises administering the anti-KLK2xCD3 antibody at a step-up dose and at a treatment dose, wherein the level of the step-up dose is lower than the level of treatment dose, for example the level of the step-up dose is in the range of 0.1- 600mg per dose and the level of the treatment dose is the range of 100-2000 mg per dose.

23. The method of claim 22, comprising administering to the subject i) a step-up dose of the anti-KLK2xCD3 antibody, and ii) a treatment dose of the anti-KLK2xCD3 antibody, wherein the step-up dose is administered once, and the treatment dose is administered at least twice (e.g., 2, 3, 4 or more times); and wherein the level of the step-up dose is lower than the level of the treatment dose.

24. The method of claim 22 or 23, wherein the step-up dose is administered 2-15 days, such as 1 week, before the first administration of the treatment dose, and wherein the treatment dose is administered once every 1-9 weeks, for example, once every 3 weeks, once every 6 weeks, or once every 9 weeks.

25. The method of claim 22, comprising administering to the subject i) a first step-up dose of the anti-KLK2xCD3 antibody, ii) a second step-up dose of the anti-KLK2xCD3 antibody and iii) a treatment dose of the anti-KLK2xCD3 antibody, wherein the first step-up dose and the second step-up dose are each administered once, and the treatment dose is administered at least twice (e.g., 2, 3, 4 or more times); wherein the level of the first step-up dose is lower than the level of the second step-up dose, and wherein the level of the second step-up dose is lower than the level of the treatment dose level.

26. The method of claim 25, wherein the first step-up dose is administered 2-15 days, such as 1 week, before the second step-up dose; wherein the second step-up dose is administered 2-15 days, such as 1 week before the first administration of the treatment dose; and wherein the treatment dose is administered once every 1-9 weeks, for example, once every 3 weeks, once every 6 weeks, or once every 9 weeks.

27. The method of claim 17, wherein the anti-KLK2xCD3 antibody is administered to the subject by intravenous (IV) infusion.

28. The method of claim 27, wherein the treatment dose is at least about 75 mg per administration.

29. The method of claim 28, wherein the treatment dose is between about 75 mg and about 900 mg per administration, for example about 75 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, or about 900 mg per administration.

30. The method of claim 28 or claim 29, wherein the treatment dose is about 75 mg per administration.

31. The method of any one of claims 27-29, wherein the treatment dose is at least about 150 mg per administration.

32. The method of claim 31 , wherein the treatment dose is between about 150 mg and about 900 mg per administration, for example about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, or about 900 mg per administration.

33. The method of claim 31 or claim 32, wherein the treatment dose is about 150 mg per administration.

34. The method of any one of claims 27-29, and 31-32, wherein the treatment dose is at least about 200 mg per administration.

35. The method of claim 34, wherein the treatment dose is between about 200 mg and about 900 mg per administration, for example about 200 mg, about 250 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg or about 900 mg per administration.

36. The method of claim 34 or claim 35, wherein the treatment dose is about 200 mg per administration.

37. The method of claim 34 or claim 35 wherein the treatment dose is about 250 mg per administration.

38. The method of any one of claims 27-29, 31-32, and 34-35, wherein the treatment dose is at least about 300 mg per administration.

39. The method of claim 38, wherein the treatment dose is between about 300 mg and about 900 mg per administration, for example about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg or about 900 mg per administration.

40. The method of claim 38 or claim 39, wherein the treatment dose is about 300 mg per administration.

41 . The method of any one of claims 27-29, 31-32, 34-35, and 38-39, wherein the treatment dose is at least about 600 mg per administration.

42. The method of claim 41, wherein the treatment dose is between about 600 mg and about 900 mg per administration, for example, about 600 mg, about 700 mg, about 800 mg or about 900 mg per administration.

43. The method of claim 42, wherein the treatment dose is about 600 mg per administration.

44. The method of claim 42, wherein the treatment dose is about 900 mg per administration.

45. The method of any one of claims 27-44, wherein the treatment dose is administered at a flat dose.

46. The method of any one of claims 27-45, wherein the treatment dose is administered once every 1 to 6 weeks, such as once every 1, 2, 3, 4, 5, or 6 weeks.

47. The method of any one of claims 46, wherein the treatment dose is administered once every three weeks.

48. The method of any one of claims 46, wherein the treatment dose is administered once every six weeks.

49. The method of any one of claims 27-48, wherein the treatment dose is administered for at least two cycles (for example, two, three, four, five, ten, fifteen, twenty or more cycles).

50. The method of claim 49, wherein the treatment dose is administered for at least a year, or throughout the lifespan of the subject.

51 . The method of any one of claims 27-50, wherein the treatment dose is administered by intravenous (IV) infusion over a period of at least about one hour, for example wherein the treatment dose is administered by IV infusion over a period of about one hour.

52. The method of any one of claims 27-50, wherein the treatment dose is administered by intravenous (IV) infusion over a period of at least about 30 minutes, for example wherein the treatment dose is administered by IV infusion over a period of about 30 minutes.

53. The method of any one of claims 27-52, wherein the first treatment dose is administered by intravenous (IV) infusion over a period of at least about one hour, for example wherein the treatment dose is administered by IV infusion over a period of about one hour and any subsequent treatment dose is administered by intravenous (IV) infusion over a period of at least about 30 minutes, for example wherein the treatment dose is administered by IV infusion over a period of about 30 minutes.

54. The method of any one of claims 27-53, wherein the method does not comprise administering a step-up dose prior to the administration of the treatment dose.

55. The method of any one of claims 27-54, wherein the method comprises administering to the human subject one or more step-up doses (for example, one or two step-up doses) of the anti- KLK2xCD3 antibody, wherein the one or more step-up doses are administered prior to the treatment dose and wherein the one or more step-up doses are not higher than the treatment dose.

56. The method of claim 55, wherein the method comprises administering to the subject a step- up dose of between about 2 mg and about5 mg per administration, for example about 2 mg, about 2.5 mg, about 3 mg, about 3.5 mg, about 4 mg, about 4.5 mg or about 5 mg per administration, prior to the treatment dose.

57. The method of claim 56, wherein the step-up dose is about 3.5 mg per administration.

58. The method of any one of claims 55-57, wherein the method comprises administering to the subject a step-up dose of between about 5 mg and aboutl5 mg per administration, for example about 5 mg, about 10 mg, or about 15 mg per administration, prior to the treatment dose.

59. The method of claim 58, wherein the step-up dose is about 10 mg per administration.

60. The method of any one of claims 27-59, wherein the method comprises administering to the subject a step-up dose of between about 15 mg and about 25 mg per administration, for example about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, about 21 mg, about 22 mg, about 23 mg, about 24 mg, or about 25 mg per administration, prior to the treatment dose.

61. The method of claim 60, wherein the step-up dose is about 18 mg per administration.

62. The method of any one of claims 55-61, wherein the method comprises administering to the subject a step-up dose of between about 200 and about 400 mg per administration, for example about 200 mg, about 300 mg or about 400 mg per administration, prior to the treatment dose.

63. The method of claim 62, wherein the step-up dose is about 300 mg per administration.

64. The method of any one of claims 55-63, wherein the step-up dose is administered 3-8 days, for example 3, 4, 5, 6, 7 or 8 days prior to the administration of the treatment dose.

65. The method of claim 64, wherein the administration of the step-up dose is 3 days prior to the administration of the treatment dose.

66. The method of claim 65, wherein the administration of the step-up dose is 7 days prior to the administration of the treatment dose.

67. The method of any one of claims 55-66, wherein the one or more step-up doses are administered via intravenous (IV) infusion.

68. The method of any one of claims 55-67, wherein the one or more step-up doses are administered at a flat dose.

69. The method of any one of claims 27-53 and 55-68, wherein the method comprises administering to the subject:

(i) a step-up dose of the anti-KLK2xCD3 antibody; and

70. The method of any one of claims 27-53 and 55-68, wherein the method comprises administering to the subject a first step-up dose and a second step-up dose of the anti- KLK2xCD3 antibody, wherein the first step up dose is administered prior to the second step-up dose, and the second step up dose is administered prior to the treatment dose.

71. The method of claim 70, wherein the second step-up dose is greater than the first step-up dose.

72. The method of claim 70 or claim 71, wherein the first step-up dose is between about 2 mg and about5 mg per administration, for example about 2 mg, about 2.5 mg, about 3 mg, about 3.5 mg, about 4 mg, about 4.5 mg or about 5 mg per administration.

73. The method of claim 72, wherein the first step-up dose is about 3.5 mg per administration.

74. The method of claim 70 or claim 71, wherein the first step-up dose is between about 5 mg and about 15 mg per administration, for example about 5 mg, about 10 mg, or about 15 mg per administration.

75. The method of claim 74, wherein the first step-up dose is about 10 mg per administration.

76. The method of any one of claims 70-75, wherein the second step-up dose is between about 5 mg and about 15 mg per administration, for example about 5 mg, about 10 mg, or about 15 mg per administration.

77. The method of claim 76, wherein the second step-up dose is about 10 mg per administration.

78. The method of any one of claims 70-75, wherein the second step-up dose is between about 15 mg and about25 mg per administration, for example about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, about 21 mg, about 22 mg, about 23 mg, about 24 mg, or about 25 mg per administration.

79. The method of claim 78, wherein the second step-up dose is about 18 mg per administration.

80. The method of any one of claims 70-75, wherein the second step-up dose is between about 200 mg and about 400 mg per administration, for example about 200 mg, about 300 mg or about 400 mg per administration.

81. The method of claim 78, wherein the second step-up dose is about 300 mg per administration.

82. The method of any one of claims 70-81, wherein the first step-up dose is administered 3-8 days, for example 3, 4, 5, 6, 7 or 8 days prior to the administration of the second step-up dose.

83. The method of claim 82, wherein the first step-up dose is administered 3 days prior to the administration of the second step-up dose.

84. The method of claim 82, wherein the first step-up dose is administered 7 days prior to the administration of the second step-up dose.

85. The method of any one of claims 70-84, wherein the second step-up dose is administered 3-8 days, for example 3, 4, 5, 6, 7 or 8 days prior to the administration of the treatment dose.

86. The method of claim 85, wherein the second step-up dose is administered 3 days prior to the administration of the treatment dose.

87. The method of claim 85, wherein the second step-up dose is administered 7 days prior to the administration of the treatment dose.

88. The method of any one of claims 70-87, wherein the method comprises administering to the subject:

(i) a first step-up dose of the anti-KLK2xCD3 antibody,

(ii) a second step-up dose of the anti-KLK2xCD3 antibody; and

89. The method of any one of claims 55-88, wherein the first step-up dose is administered via intravenous (IV) infusion.

90. The method of any one of claims 70-89, wherein the second step-up dose is administered via intravenous (IV) infusion.

91. The method of any one of claims 55-90, wherein the first step-up dose is administered at a flat dose.

92. The method of any one of claims 55-91, wherein the second step-up dose is administered at a flat dose.

93. The method of any one of claims 55-92, wherein the first step-up dose is administered by intravenous (IV) infusion over a period of at least about one hour, for example wherein the treatment dose is administered by IV infusion over a period of about one hour.

94. The method of any one of claims 70-93, wherein the second step-up dose is administered by intravenous (IV) infusion over a period of at least about 30 minutes, for example wherein the treatment dose is administered by IV infusion over a period of about 30 minutes.

95. The method of any one of claim 93 or claim 94, wherein the treatment dose is administered by intravenous (IV) infusion over a period of at least about 30 minutes, for example wherein the treatment dose is administered by IV infusion over a period of about 30 minutes.

96. The method of any one of claims 70 and 82-95, wherein the method comprises administering to the subject a first step-up dose and a second step-up dose of the anti-KLK2xCD3 antibody, wherein the first step up dose is administered prior to the second step-up dose, and wherein the second step-up dose is administered prior to the treatment dose, wherein:

(i) the first step-up dose is about 3.5 mg;

(ii) the second step up dose is about 18 mg; and

(iii) the treatment dose is about 300 mg.

97. The method of claim 96, wherein the first step-up dose is administered 7 days prior to the second step-up dose.

98. The method of claim 96 or claim 97, wherein the second step up dose is administered 7 days prior to the treatment dose.

99. The method any one of claims 96-98, wherein the treatment dose is administered once every 6 weeks.

100. The method of any one of claims 96-98, wherein the treatment dose is administered once every 3 weeks.

101. The method of any one of claims 70 and 82-95, wherein the method comprises administering to the subject a first step-up dose and a second step-up dose of the anti- KLK2xCD3 antibody, wherein the first step up dose is administered prior to the second step-up dose, and wherein the second step-up dose is administered prior to the treatment dose, wherein:

(i) the first step-up dose is about 3.5 mg;

(ii) the second step up dose is about 18 mg; and

(iii) the treatment dose is about 600 mg.

102. The method of claim 101, wherein the first step-up dose is administered about 7 days prior to the second step-up dose.

103. The method of claim 101 or claim 102, wherein the second step up dose is administered about 7 days prior to the treatment dose.

104. The method of any one of claims 101-103, wherein the treatment dose is administered once every 6 weeks.

105. The method of any one of claims 101-104, wherein the treatment dose is administered once every 3 weeks.

106. The method of any one of claims 55 and 64-69, wherein the method comprises administering to the subject a step-up dose of the anti-KLK2xCD3 antibody, wherein the step-up dose is administered prior to the treatment dose, wherein:

(i) the step-up dose is about 10 mg; and

(ii) the treatment dose is about 300mg.

107. The method of claim 106, wherein the first step-up dose is administered 7 days prior to the treatment dose.

108. The method of claim 106 or claim 107, wherein the treatment dose is administered once every 6 weeks.

109. The method of any one of claims 106-108, wherein the treatment dose is administered once every 3 weeks.

110. The method of any one of claims 55 and 64-69, wherein the method comprises administering to the subject a step-up dose of the anti-KLK2xCD3 antibody, wherein the step-up dose is administered prior to the treatment dose, wherein:

(i) the step-up dose is about 10 mg; and

(ii) the treatment dose is about 600mg.

111. The method of claim 110, wherein the first step-up dose is administered about 7 days prior to the treatment dose.

112. The method of claim 110 or claim 111, wherein the treatment dose is administered once every 6 weeks.

113. The method of any one of claims 110-112, wherein the treatment dose is administered once about every 3 weeks.

114. The method of any one of claims 70 and 82-95, wherein the method comprises administering to the subject a first step-up dose and a second step-up dose of the anti- KLK2xCD3 antibody, wherein the first step up dose is administered prior to the second step-up dose, and wherein the second step-up dose is administered prior to the treatment dose, wherein:

(i) the first step-up dose is aboutlO mg;

(ii) the second step up dose is about 300 mg; and

(iii) the treatment dose is about 900 mg.

115. The method of claim 114, wherein the first step-up dose is administered 7 days prior to the second step-up dose.

116. The method of claim 114 or claim 115, wherein the second step up dose is administered 7 days prior to the treatment dose.

117. The method of any one of claims 114-116, wherein the treatment dose is administered once every 6 weeks.

118. The method of any one of claims 70 and 82-95, wherein the method comprises administering to the subject a first step-up dose and a second step-up dose of the anti- KLK2xCD3 antibody, wherein the first step up dose is administered prior to the second step-up dose, and wherein the second step-up dose is administered prior to the treatment dose, wherein:

(i) the first step-up dose is about 10 mg;

(ii) the second step up dose is about 300 mg; and

(iii) the treatment dose is about 600 mg.

119. The method of claim 118, wherein the first step-up dose is administered 7 days prior to the second step-up dose.

120. The method of claim 118 or claim 119, wherein the second step up dose is administered 7 days prior to the treatment dose.

121. The method of any one of claims 118-120, wherein the treatment dose is administered once every 6 weeks.

122. The method of any one of claims 27-118, wherein the other anti-cancer drug is administered simultaneously, sequentially or separately from the administering of the anti-KLK2xCD3 antibody, for example on the same day about 4 hours apart.

123. The method of any of the foregoing claims, wherein the other anti-cancer drug is the anticancer chemotherapeutic agent, preferably a taxane, preferably docetaxel or cabazitaxel.

124. The method of claim 123, wherein the anti-cancer chemotherapeutic agent is intravenously administered, such as via intravenous injection or infusion.

125. The method of claim 123, wherein docetaxel or cabazitaxel is intravenously administered to the subject every 1-6 weeks, preferably every 3 weeks.

126. The method of claim 125, wherein the other anti-cancer drug is docetaxel, preferably the other anti-cancer drug is docetaxel and is administered intravenously at a dose of 75 mg/m²

127. The method of claim 125, wherein the other anti-cancer drug is cabazitaxel, preferably the other anti-cancer drug is cabazitaxel and is administered intravenously at a dose of 20 mg/m².

128. The method of any one of claims 123-127, wherein the other anti-cancer drug is a taxane, and wherein no prednisone, preferably no corticosteroid, is administered as a (pre)medication prior to the administration of taxane, or together with the administration of taxane.

129. The method of any one of claims 1-128, wherein the other anti-cancer drug is the ARPI, such as apatulamide, enzatulamide, darolutamide, or abiraterone acetate.

130. The method of claim 129, wherein the ARPI is administered orally.

131. The method of claim 130, wherein the other anti-cancer drug is apatulamide, preferably the other anti-cancer drug is apalutamide and is administered orally at a dose of 240 mg per day, preferably 240 mg once daily, preferably four tablets of 60 mg once daily.

132. The method of claim 130, wherein the other anti-cancer drug is enzatulamide, preferably the other anti-cancer drug is enzalutamide and is administered orally at a dose of 160 mg per day, preferably 160 mg once daily, preferably four capsules of 40 mg once a day.

133. The method of claim 130, wherein the other anti-cancer drug is darolutamide, preferably the other anti-cancer drug is darolutamide and is administered orally at a dose of 1200 mg per day, preferably 600 mg twice daily, preferably two tablets of 300 mg twice daily.

134. The method of claim 130, wherein the other anti-cancer drug is abiraterone acetate, preferably the other anti-cancer drug is abiraterone acetate and is administered orally at a dose of 1000 mg per day, preferably 1000 mg once daily, preferably four tablets of 250 mg once daily.

135. The method of claim 134, further comprising orally administering to the subject prednisone, preferably at a dose of 5 mg or 10 mg per day, preferably of 5 mg once or twice a day, preferably one tablet of 5 mg once a day or one tablet of 5 mg twice a day.

136. The method any of the foregoing claims, wherein the prostate cancer is locally advanced prostate cancer, metastatic castration-sensitive prostate cancer (CSPC), metastatic castrationresistant prostate cancer (CRPC), non-metastatic CSPC, non-metastatic CRPC, or metastatic prostate cancer, preferably the prostate cancer is metastatic CRPC.

137. The method any of the foregoing claims, which does not comprise the administration of an anti-PDl antibody at least 6 weeks prior to the first dose of anti-KLK2xCD3 antibody or other anti-cancer agent.

138. The method any of the foregoing claims, which does not comprise the administration of an anti-PDl antibody.

139. The method of any of the foregoing claims, wherein the subject does not have one or more of the following:

3) solid organ or bone marrow transplantation;

4) known allergies or intolerance to any of the anti-KLK2xCD3 antibody, the anti-cancer chemotherapeutic agent and the androgen receptor pathway inhibitor (ARP I); 5) any of the following within 6 months prior to the initial administration of the anti-

KLK2xCD3 antibody: g. Myocardial infarction h. Severe or unstable angina i. Clinically significant ventricular arrhythmias j . Congestive heart failure (New York Heart Association [NYHA] class II to IV) k. Transient ischemic attack l. Cerebrovascular accident

7) active infection or condition that requires treatment with systemic antibiotics within 7 days prior to the initial administration of the anti-KLK2xCD3 antibody;

8) venous thromboembolic events (e g., pulmonary embolism) within 1 month prior to the first dose of study treatment; uncomplicated (Grade <2) deep vein thrombosis is not considered exclusionary;

9) clinically significant pulmonary compromise, particularly a requirement for supplemental oxygen use (>2 L/min by nasal cannula) to maintain adequate oxygenation;

10) active CNS involvement, except treated, stable and asymptomatic brain metastases requiring <10 mg prednisone or equivalent within 2 weeks prior to the first dose of study treatment are permitted;

11) prior treatment with KLK2 -targeted therapy;

12) treatment with any anti-cancer or investigational agents within 28 days or 5-half-lives, whichever is shorter, prior to the initial administration of the anti-KLK2xCD3 antibody, such as,

• No restrictions on GnRH agonist/antagonists,

• External beam radiation therapy within 14 days prior to start of study treatment. However, if palliative focal radiation was used, the participant is eligible irrespective of the end date of radiotherapy, • Radionuclide therapy within 6 weeks prior to start of study treatment,

140. The method of any of the foregoing claims, wherein the subject has not received immunosuppressive doses of systemic medications, such as glucocorticoids (doses >10 mg/day prednisone or equivalent) within 7 days prior to the first dose of study treatment, provided that a single course of glucocorticoids is permitted as prophylaxis for imaging contrast (i.e., for participants with allergies to contrast).

141. The method of any of the foregoing claims, wherein the subject is i) a subject having metastatic CRPC (mCRPC); ii) a subject having prior orchiectomy, or the subject having not undergone orchiectomy and receives ongoing androgen deprivation therapy with a gonadotropin releasing hormone (GnRH) analog (agonist or antagonist) prior to the initial administration of the anti-KLK2xCD3 antibody and continue androgen deprivation therapy throughout the treatment phase; iii) a subject having microsatellite instability (MSI-H)/mismatch repair deficient (dMMR) disease not previously received and progressed on PD-(L)1 therapy; iv) a subject having received at least 1 prior treatment with an ARPI (e.g., apalutamide, enzalutamide, darolutamide, or abiraterone acetate) and/or taxane (e.g., docetaxel or cabazitaxel) prior to the initial administration of the anti-KLK2xCD3 antibody; and/or v) a subject living with HIV; and wherein the subject preferably is 18 years of age or older.

142. The method of any one of the foregoing claims, wherein the prostate cancer is metastatic prostate cancer.

143. The method of any one of the foregoing claims, wherein the prostate cancer is metastatic castration-resistant prostate cancer (mCRPC).

144. The method of any one of the foregoing claims, wherein the subject has metastatic castration-resistant prostate cancer and is taxane naive.

145. The method of any one of claims 1-142, wherein the prostate cancer is metastatic hormonesensitive prostate cancer.

146. The method of claim 145, wherein the prostate cancer is oligometastatic hormone-sensitive prostate cancer.

147. The method of any one of the preceding claims, wherein the anti-KLK2xCD3 antibody is pasritamig.

148. The anti-KLK2xCD3 antibody for use in the method of any one of the foregoing claims.

149. The taxane for use in the method of any one of claims 1-128 and 136-147.

150. Docetaxel for use in the method of any one of claims 1-126, 128 and 136-147.

151. Cabazitaxel for use in the method of any one of claims 1-125, 127 and 136-147.

152. The ARPI for use in the method of any one of claims 1-124, and 129-147.

153. Apalutamide for use in the method of any one of claims 1-124, 129-131 and 136-147.

154. Enzalutamide for use in the method of any one of claims 1-124, 129-130, 132 and 136-147.

155. Darolutamide for use in the method of any one of claims 1-124, 129-130, 133 and 136-147.

156. Abiraterone acetate for use in the method of any one of claims 1-124, 129-130 and 134-147.

157. A combination of the anti-KLK2xCD3 and the anti -cancer chemotherapeutic agent or the ARPI for use in the method of any one of claims 1-147.

158. A combination of the anti-KLK2xCD3 and the taxane for use in the method of any one of claims 1-128 and 136-146.

159. A combination of the anti-KLK2xCD3 and docetaxel for use in the method of any one of claims 1-126, 128 and 136-147.

160. A combination of the anti-KLK2xCD3 and cabazitaxel for use in the method of any one of claims 1-125, 127 and 136-147.

161. A combination of the anti-KLK2xCD3 and the ARPI for use in the method of any one of claims 1-124, and 129-147.

162. A combination of the anti-KLK2xCD3 and apalutamide for use in the method of any one of claims 1-124, 129-131 and 136-147.

163. A combination of the anti-KLK2xCD3 and enzalutamide for use in the method of any one of claims 1-124, 129-130, 132 and 136-147.

164. A combination of the anti-KLK2xCD3 and darolutamide for use in the method of any one of claims 1-124, 129-130, 133 and 136-147.

165. A combination of the anti-KLK2xCD3 and abiraterone acetate for use in the method of any one of claims 1-124, 129-130 and 134-147.

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