Methods of treating metastatic castration resistant prostate cancer with bispecific anti-PSMA x anti-CD3 antibodies alone or in combination with anti-PD-1 antibodies

Abstract

The present disclosure provides methods for treating, reducing the severity, or inhibiting the growth of cancer (e.g., prostate cancer or metastatic castration-resistant prostate cancer). The methods of the present disclosure comprise administering to a subject in need thereof a therapeutically effective amount of a bispecific antibody, or antigen-binding fragment thereof, that specifically binds prostate specific membrane antigen (PSMA) and CD3, either alone or in combination with an antibody, or antigen-binding fragment thereof, that specifically binds to programmed death 1 (PD-1) receptor.

Description

Reference to sequence listing This application incorporates by reference a computer-readable sequence listing in ST.26 XML format, named 11050WO01_Sequence, created on May 15, 2023, and containing 38,992 bytes. Technical Field The present invention relates to a method for treating cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a bispecific antibody that specifically binds to prostate-specific membrane antigen (PSMA) and CD3, alone or in combination with an antibody that specifically binds to the programmed death 1 (PD-1) receptor. Background Art Prostate-specific membrane antigen (PSMA), also known as FOLH1, glutamate carboxypeptidase II (GCPII), N-acetyl-L-aspartyl-L-glutamate peptidase I (NAALADase I) or N-acetyl-aspartylglutamate (NAAG) peptidase, is a homodimeric, enzymatic type II transmembrane protein encoded by the folate hydrolase 1 (FOLH1) gene. PSMA is an intact, non-shedding membrane glycoprotein that is highly expressed in malignant prostate tissue and is a cell surface marker for prostate cancer, but shows limited expression in normal tissue. Its expression remains unchanged in castration-resistant prostate cancer, a condition with a poor outcome and limited treatment options. Methods for treating prostate cancer by targeting PSMA have been studied. For example, yttrium-90 carlosomab is a radiotherapeutic agent that contains a monoclonal antibody to an intracellular epitope of PSMA. In another example, J591 is a monoclonal antibody directed against an extracellular epitope of PSMA, is part of the radiotherapeutic agent Lutetium-177 J591, and in MLN2704 in which maytansinoid 1 (DM1, an anti-microtubule agent) is conjugated to J591. These therapies are associated with toxicity. PSMA is also expressed in the neovasculature of other tumors such as bladder cancer, kidney cancer, gastric cancer, and colorectal cancer. CD3 is a homodimer or heterodimer antigen expressed on T cells associated with the T cell receptor complex (TCR) and is required for T cell activation. Functional CD3 is formed by the association of dimers of two of four different chains: ε, ζ, δ and γ. CD3 dimer arrangements include γ / ε, δ / ε and ζ / ζ. It has been shown that antibodies against CD3 aggregate CD3 on T cells, thereby causing T cell activation in a manner similar to that of MHC molecules loaded with peptides engaging TCR. Therefore, anti-CD3 antibodies have been proposed for therapeutic purposes involving T cell activation. In addition, bispecific antibodies capable of binding CD3 and target antigens have been proposed for therapeutic uses involving targeting T cell immune responses to tissues and cells expressing target antigens. Programmed death-1 (PD-1) receptor signaling in the tumor microenvironment plays a key role in allowing tumor cells to escape immune surveillance by the host immune system. Blocking of the PD-1 signaling pathway has shown clinical activity in patients with a variety of tumor types, and antibody therapies that block PD-1 (e.g., nivolumab and pembrolizumab) have been approved for the treatment of metastatic melanoma and metastatic squamous non-small cell lung cancer. Recent data have demonstrated the clinical activity of PD-1 blockade in patients with aggressive NHL and Hodgkin's lymphoma (Hodgkin's lymphoma) (Lesokhin, et al. 2014, Abstract 291, 56th ASH Annual Meeting and Exhibition, San Francisco, Calif.; Ansell et al. 2015, N. Engl. J. Med. 372 (4): 311-9). Prostate cancer is the leading cause of new cancer diagnoses and the second most common cause of cancer-related death in men in the United States. In 2018, there were an estimated 1.3 million new cases of prostate cancer and 358,989 deaths worldwide. For decades, therapies that block androgen-related pathways have been the standard of care for prostate cancer. However, patients progress to androgen depletion and / or surgical castration and develop castration-resistant prostate cancer. For men with metastatic castration-resistant prostate cancer (mCRPC), the prognosis is particularly poor. Currently, metastatic prostate cancer remains incurable, and improving long-term survival remains a high unmet need. Summary of the invention According to certain embodiments, the present disclosure provides methods for treating, ameliorating at least one symptom or indication of a PSMA-expressing cancer in a subject, or inhibiting its growth. The method according to this aspect of the present disclosure comprises administering to a subject in need thereof a therapeutically effective amount of a bispecific antibody that specifically binds to prostate-specific membrane antigen (PSMA) and CD3, alone or in combination with an antibody or antigen-binding fragment thereof that specifically binds to programmed death 1 (PD-1). In certain embodiments of the present disclosure, methods for treating, ameliorating at least one symptom or indication of a PSMA-expressing cancer in a subject, or inhibiting its growth are provided. In certain embodiments of the present disclosure, methods for delaying tumor growth or preventing tumor recurrence are provided. According to this aspect and other aspects of the present disclosure, the method comprises sequentially administering to a subject in need thereof one or more doses of a therapeutically effective amount of a bispecific anti-PSMA x anti-CD3 antibody alone or in combination with one or more doses of a therapeutically effective amount of an anti-PD-1 antibody or an antigen-binding fragment thereof. In one aspect, the present disclosure provides a method of treating a PSMA-expressing cancer in a subject in need thereof, the method comprising administering to the subject a bispecific antibody comprising a first antigen binding domain that specifically binds to prostate-specific membrane antigen (PSMA) on tumor target cells and a second antigen binding domain that specifically binds to human CD3 on T cells, wherein the bispecific antibody is administered to the subject at a dose of at least 0.03 mg. In some embodiments, the PSMA-expressing cancer is prostate cancer. In some instances, the PSMA-expressing cancer is metastatic prostate cancer. In some instances, the PSMA-expressing cancer is castration-resistant prostate cancer. In some embodiments, the subject has received at least two prior therapies for metastatic and / or castration-resistant prostate cancer. In some cases, the subject has received at least one anti-androgen therapy. In some embodiments, the anti-androgen therapy is selected from abiraterone, enzalutamide, apalutamide, or darolutamide. In some embodiments, the subject has histologically or cytologically confirmed prostate adenocarcinoma without pure small cell carcinoma. In some embodiments, prior to treatment with the bispecific antibody, the subject already had metastatic castration-resistant prostate cancer with a prostate-specific antigen (PSA) value of ≥4 ng / ml. In some cases, the subject's cancer had progressed within a 6-month period prior to treatment with the bispecific antibody, wherein cancer progression was determined by: (a) an increase in PSA levels confirmed with an interval of ≥1 week between each assessment; (b) radiographic disease progression in soft tissues with or without an increase in PSA; and / or (c) radiographic disease progression in bones with the appearance of two or more bone lesions on a bone scan with or without an increase in PSA. In some embodiments, the subject has undergone orchiectomy.In some embodiments, the subject is receiving luteinizing hormone releasing hormone (LHRH) agonist or antagonist therapy and has a serum testosterone level of <50 ng / ml prior to treatment with the bispecific antibody. In any of the various embodiments discussed above or herein, the first antigen binding domain of the bispecific antibody comprises: (a) three heavy chain complementary determining regions (HCDR1, HCDR2, and HCDR3) contained within a heavy chain variable region (HCVR) having an amino acid sequence of SEQ ID NO: 1; and (b) three light chain complementary determining regions (LCDR1, LCDR2, and LCDR3) contained within a light chain variable region (LCVR) having an amino acid sequence of SEQ ID NO: 2. In some cases, the first antigen binding domain comprises a HCDR1 having an amino acid sequence of SEQ ID NO: 5, a HCDR2 having an amino acid sequence of SEQ ID NO: 6, and a HCDR3 having an amino acid sequence of SEQ ID NO: 7. In some cases, the first antigen binding domain comprises a LCDR1 having an amino acid sequence of SEQ ID NO: 8, a LCDR2 having an amino acid sequence of SEQ ID NO: 9, and a LCDR3 having an amino acid sequence of SEQ ID NO: 10. In some embodiments, the first antigen binding domain comprises a HCVR having the amino acid sequence of SEQ ID NO:1 and a LCVR having the amino acid sequence of SEQ ID NO:2. In any of the various embodiments discussed above or herein, the second antigen binding domain of the bispecific antibody comprises: (a) three heavy chain complementary determining regions (HCDR1, HCDR2, and HCDR3) contained within a heavy chain variable region (HCVR) having an amino acid sequence of SEQ ID NO: 4; and (b) three light chain complementary determining regions (LCDR1, LCDR2, and LCDR3) contained within a light chain variable region (LCVR) having an amino acid sequence of SEQ ID NO: 2. In some cases, the second antigen binding domain comprises a HCDR1 having an amino acid sequence of SEQ ID NO: 14, a HCDR2 having an amino acid sequence of SEQ ID NO: 15, and a HCDR3 having an amino acid sequence of SEQ ID NO: 16. In some cases, the second antigen binding domain comprises a LCDR1 having an amino acid sequence of SEQ ID NO: 8, a LCDR2 having an amino acid sequence of SEQ ID NO: 9, and a LCDR3 having an amino acid sequence of SEQ ID NO: 10. In some embodiments, the second antigen binding domain comprises a HCVR having the amino acid sequence of SEQ ID NO:4 and a LCVR having the amino acid sequence of SEQ ID NO:2. In any of the various embodiments discussed above or herein, the second antigen binding domain of the bispecific antibody comprises: (a) three heavy chain complementary determining regions (HCDR1, HCDR2, and HCDR3) contained within a heavy chain variable region (HCVR) having an amino acid sequence of SEQ ID NO: 3; and (b) three light chain complementary determining regions (LCDR1, LCDR2, and LCDR3) contained within a light chain variable region (LCVR) having an amino acid sequence of SEQ ID NO: 2. In some cases, the second antigen binding domain comprises a HCDR1 having an amino acid sequence of SEQ ID NO: 11, a HCDR2 having an amino acid sequence of SEQ ID NO: 12, and a HCDR3 having an amino acid sequence of SEQ ID NO: 13. In some cases, the second antigen binding domain comprises a LCDR1 having an amino acid sequence of SEQ ID NO: 8, a LCDR2 having an amino acid sequence of SEQ ID NO: 9, and a LCDR3 having an amino acid sequence of SEQ ID NO: 10. In some embodiments, the second antigen binding domain comprises a HCVR having the amino acid sequence of SEQ ID NO:3 and a LCVR having the amino acid sequence of SEQ ID NO:2. In any of the various embodiments discussed above or herein, the bispecific antibody can comprise a human IgG heavy chain constant region. In some cases, the human IgG heavy chain constant region is of isotype IgG1. In some cases, the human IgG heavy chain constant region is of isotype IgG4. In any of the various embodiments discussed above or herein, the bispecific antibody may comprise a chimeric hinge that reduces Fcγ receptor binding relative to a wild-type hinge of the same isotype. In any of the various embodiments discussed above or herein, the first heavy chain of the bispecific antibody or the second heavy chain of the bispecific antibody (but not both) may comprise a CH3 domain comprising a H435R (EU numbering) modification and a Y436F (EU numbering) modification. In any of the various embodiments discussed above or herein, the bispecific antibody comprises a first heavy chain having the amino acid sequence of SEQ ID NO:17. In any of the various embodiments discussed above or herein (except where the sequences are mutually exclusive), the bispecific antibody comprises a second heavy chain having the amino acid sequence of SEQ ID NO:20. In any of the various embodiments discussed above or herein (except where the sequences are mutually exclusive), the bispecific antibody comprises a second heavy chain having the amino acid sequence of SEQ ID NO:19. In any of the various embodiments discussed above or herein, the bispecific antibody comprises a light chain having the amino acid sequence of SEQ ID NO:18. In any of the various embodiments discussed above or herein (except where the sequences are mutually exclusive), the bispecific antibody comprises a first heavy chain having an amino acid sequence of SEQ ID NO: 17, a second heavy chain having an amino acid sequence of SEQ ID NO: 20, and a common light chain having an amino acid sequence of SEQ ID NO: 18. In any of the various embodiments discussed above or herein (except where the sequences are mutually exclusive), the bispecific antibody comprises a first heavy chain having an amino acid sequence of SEQ ID NO: 17, a second heavy chain having an amino acid sequence of SEQ ID NO: 19, and a common light chain having an amino acid sequence of SEQ ID NO: 18. In any of the various embodiments discussed above or herein, the method may further comprise administering a second therapeutic agent or treatment regimen. In some embodiments, the second therapeutic agent or treatment regimen comprises an anti-PD-1 antibody or antigen-binding fragment thereof. In some embodiments, the anti-PD-1 antibody or antigen-binding fragment comprises: (a) three heavy chain complementary determining regions (HCDR1, HCDR2, and HCDR3) contained within a heavy chain variable region (HCVR) having an amino acid sequence of SEQ ID NO: 21; and (b) three light chain complementary determining regions (LCDR1, LCDR2, and LCDR3) contained within a light chain variable region (LCVR) having an amino acid sequence of SEQ ID NO: 22. In some cases, the anti-PD-1 antibody or antigen-binding fragment comprises a HCDR1 having an amino acid sequence of SEQ ID NO: 23, a HCDR2 having an amino acid sequence of SEQ ID NO: 24, and a HCDR3 having an amino acid sequence of SEQ ID NO: 25. In some cases, the anti-PD-1 antibody or antigen-binding fragment comprises a LCDR1 having an amino acid sequence of SEQ ID NO: 26, a LCDR2 having an amino acid sequence of SEQ ID NO: 27, and a LCDR3 having an amino acid sequence of SEQ ID NO: 28. In some embodiments, the anti-PD-1 antibody or antigen-binding fragment comprises a HCVR having an amino acid sequence of SEQ ID NO: 21 and a LCVR having an amino acid sequence of SEQ ID NO: 22. In some embodiments, the anti-PD-1 antibody or antigen-binding fragment is an anti-PD-1 antibody comprising a heavy chain having an amino acid sequence of SEQ ID NO: 29 and a light chain having an amino acid sequence of SEQ ID NO: 30. In any of the various embodiments discussed above or herein, the bispecific antibody can be administered to a subject at a dosage of 0.01 mg to 1000 mg per week. In some cases, the bispecific antibody is administered to a subject at a dosage of 0.03 mg to 30 mg per week. In some cases, the bispecific antibody is administered to a subject at a dosage of 3 mg to 900 mg per week. In some cases, the bispecific antibody is administered to a subject at a dosage of 30 mg to 900 mg per week. In some cases, the bispecific antibody is administered to a subject at a dosage of 300 mg to 900 mg per week. In any of the various embodiments discussed above or herein, the bispecific antibody can be administered to a subject at a dosage of 0.01 mg to 1000 mg once every three weeks. In some cases, the bispecific antibody is administered to a subject at a dosage of 0.03 mg to 30 mg once every three weeks. In some cases, the bispecific antibody is administered to a subject at a dosage of 3 mg to 900 mg once every three weeks. In some cases, the bispecific antibody is administered to a subject at a dosage of 30 mg to 900 mg once every three weeks. In some cases, the bispecific antibody is administered to a subject at a dosage of 300 mg to 900 mg once every three weeks. In any of the various embodiments discussed above or herein, the anti-PD-1 antibody can be administered to the subject at a dose of 300 mg to 400 mg once every three weeks. In some cases, the anti-PD-1 antibody is administered to the subject at a dose of 350 mg once every three weeks. In any of the various embodiments discussed above or herein, the subject is in stable disease, partial remission, or complete remission after administration of the bispecific antibody at a dose of 0.03 mg to 900 mg for at least one week. In any of the various embodiments discussed above or herein, the subject can receive radiographic imaging before and / or after administration of one or more doses of the bispecific antibody. In some cases, the radiographic imaging includes a fluorine F18 DCFPyL PET / CT scan. The present disclosure also encompasses the use of bispecific antibodies and / or anti-PD-1 antibodies in the preparation of a medicament for treating a PSMA-expressing cancer, as described in any embodiment of the methods discussed above or herein. The present disclosure also encompasses bispecific antibodies and / or anti-PD-1 antibodies for use in any embodiment of the methods discussed above or herein. The present disclosure also encompasses pharmaceutical compositions comprising bispecific antibodies and / or anti-PD-1 antibodies for use in any embodiment of the methods discussed above or herein. In various embodiments, any features or components of the embodiments discussed above or herein can be combined, and such combinations are included in the scope of the present disclosure. Any specified value discussed above or herein can be combined with another related value discussed above or herein to list a range, and the value represents the upper and lower limits of the range, and such ranges are included in the scope of the present disclosure. Other embodiments of the present invention will become apparent upon reading the ensuing detailed description. BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 An embodiment of a patient-level study protocol for Module 1 (QW dosing), as discussed in Example 6, is shown. Figure 2 An embodiment of a patient-level study protocol for Module 1 (Q3W dosing), as discussed in Example 6, is shown. Figure 3 An embodiment of a patient-level study protocol for Module 2, as discussed in Example 6, is shown. DETAILED DESCRIPTION Before describing the present invention, it should be understood that the present invention is not limited to the specific methods and experimental conditions described, because such methods and conditions can change. It should also be understood that the terms used herein are only used for the purpose of describing specific embodiments, and are not intended to be limited, because the scope of the present invention will only be limited by the appended claims. The features of any embodiment or embodiment can be combined with each other, and such combinations are clearly included in the scope of the present invention. Any specified value discussed above or herein can be combined with another related value discussed above or herein to list a range, and the value represents the upper and lower limits of the range, and such ranges are included in the scope of the present disclosure. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the invention belongs. As used herein, the term "about" when used in reference to a specific recited numerical value means that the value may vary by no more than 1% from the recited value. For example, as used herein, the expression "about 100" includes 99 and 101 and all values ​​therebetween (e.g., 99.1, 99.2, 99.3, 99.4, etc.). Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods and materials are now described. All patents, applications and non-patent publications mentioned in this specification are incorporated herein by reference in their entirety. Methods for treating or inhibiting the growth of cancer The present disclosure includes methods for treating, improving or reducing the severity of at least one symptom or indication in a subject, or inhibiting the growth of cancer (e.g., metastatic castration-resistant prostate cancer). The method according to this aspect of the present disclosure includes administering to a subject in need thereof a therapeutically effective amount of a bispecific antibody against PSMA and CD3, alone or in combination with a therapeutically effective amount of an antibody or antigen-binding fragment thereof that specifically binds to PD-1. The term "treatment" and the like as used herein means alleviating symptoms, temporarily or permanently eliminating the cause of symptoms, delaying or inhibiting tumor growth, reducing tumor cell load or tumor burden, promoting tumor regression, causing tumor shrinkage, necrosis and / or disappearance, preventing tumor recurrence, and / or increasing the duration of survival of a subject. As used herein, the expression "a subject in need thereof" means a human or non-human mammal that exhibits one or more symptoms or signs of cancer, and / or has been diagnosed with cancer, including prostate cancer (e.g., metastatic castration-resistant prostate cancer), and is in need of treatment for the cancer. In many embodiments, the term "subject" can be used interchangeably with the term "patient." For example, a human subject may be diagnosed with a primary or metastatic tumor and / or one or more symptoms or signs, including, but not limited to, enlarged lymph nodes, abdominal swelling, unexplained pain, unexplained weight loss, fever, night sweats, persistent fatigue, loss of appetite, and / or splenomegaly. The expression includes subjects with primary or established prostate tumors. In specific embodiments, the expression includes human subjects with prostate cancer or another tumor that expresses PSMA and is in need of treatment. In other specific embodiments, the expression includes subjects with PSMA+ tumors (e.g., tumors with PSMA expression as determined by flow cytometry). In certain embodiments, the expression "subject in need" includes patients with prostate cancer, which is resistant to previous therapies (e.g., treatment with conventional anticancer agents, including anti-androgen therapy) or is difficult to treat with previous therapies, or cannot be fully controlled by previous therapies. For example, the expression includes subjects who have been treated with chemotherapy or anti-androgen therapy, such as abiraterone, enzalutamide, apalutamide or darolutamide. The expression also includes subjects with prostate tumors, for which conventional anticancer therapy is undesirable, for example, due to toxic side effects. For example, the expression includes patients who have received one or more cycles of chemotherapy or other anticancer therapies with toxic side effects. In certain embodiments, the expression "subject in need" includes patients with prostate tumors, who have been treated but subsequently relapsed or metastasized. For example, patients with prostate tumors who may have been treated with one or more anticancer agents leading to tumor regression; however, cancers resistant to one or more anticancer agents (e.g., castration-resistant prostate cancer) are subsequently treated with the methods of the present disclosure. In certain embodiments, the method of the present disclosure can be used to treat patients with prostate adenocarcinoma confirmed histologically or cytologically without pure small cell carcinoma. In certain embodiments, the method of the present disclosure can be used to treat patients with metastatic castration-resistant prostate cancer, and the prostate-specific antigen (PSA) value of the patient before treatment with the bispecific antibody is ≥4ng / ml (e.g., 4ng / ml, 4.5ng / ml, 5ng / ml, 5.5ng / ml, 6ng / ml, 6.5ng / ml, 7ng / ml, 7.5ng / ml, 8ng / ml, 8.5ng / ml, 9ng / ml, 9.5ng / ml or 10ng / ml or higher). In certain embodiments, the methods of the present disclosure can be used to treat patients with prostate cancer that have progressed within a period of time (e.g., 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months or longer) prior to treatment with a bispecific antibody, wherein cancer progression is determined by, for example, the following factors: (a) an increase in PSA levels confirmed with an interval of ≥1 week (e.g., 1 week, 2 weeks, 3 weeks, 4 weeks or longer) between each assessment; (b) radiographic disease progression in soft tissues, with or without elevated PSA; and / or (c) radiographic disease progression in bones, with two or more bone lesions appearing in a bone scan, with or without elevated PSA. In certain embodiments, the methods of the present disclosure can be used to treat patients who have undergone orchiectomy. In certain embodiments, the methods of the present disclosure can be used to treat patients who have been or are receiving luteinizing hormone releasing hormone (LHRH) agonist or antagonist therapy and whose serum testosterone levels are <50 ng / ml (e.g., 1 ng / ml to 49 ng / ml, about 45 ng / ml, about 40 ng / ml, about 35 ng / ml, about 30 ng / ml, about 25 ng / ml, about 20 ng / ml, about 15 ng / ml, about 10 ng / ml, or about 5 ng / ml) prior to treatment with the bispecific antibody. In certain embodiments, the methods of the present disclosure can be used for subjects suffering from prostate cancer. The terms "tumor", "cancer" and "malignant tumor" are used interchangeably herein. As used herein, the term "prostate cancer" refers to prostate tumors, including metastatic tumors derived from the prostate. According to certain embodiments, the present disclosure includes methods for treating or delaying or inhibiting tumor growth. In certain embodiments, the present disclosure includes methods for promoting tumor regression. In certain embodiments, the present disclosure includes methods for reducing tumor cell load or reducing tumor load. In certain embodiments, the present disclosure includes methods for preventing tumor recurrence. According to this aspect of the present disclosure, the method includes administering to a subject in need thereof a therapeutically effective amount of a bispecific anti-PSMA / anti-CD3 antibody alone or in combination with an anti-PD-1 antibody, wherein each antibody is administered to the subject in multiple doses, for example, as part of a specific therapeutic dosing regimen. For example, a therapeutic dosing regimen may include administering one or more doses of an anti-PSMA×CD3 antibody to a subject at a frequency of about once a day, once every two days, once every three days, once every four days, once every five days, once every six days, once a week, once every two weeks, once every three weeks, once every four weeks, once a month, once every two months, once every three months, once every four months, or less frequently. In certain embodiments, anti-PSMA x anti-CD3 antibodies are administered once a week. In certain embodiments, anti-PSMA x anti-CD3 antibodies are administered once every three weeks. In certain embodiments, one or more doses of an anti-PD-1 antibody are administered in combination with one or more doses of a therapeutically effective amount of a bispecific anti-PSMA / anti-CD3 antibody, wherein the one or more doses of the anti-PD-1 antibody are administered to the subject at a frequency of about once a day, once every two days, once every three days, once every four days, once every five days, once every six days, once a week, once every two weeks, once every three weeks, once every four weeks, once a month, once every two months, once every three months, once every four months, or less. In certain embodiments, the anti-PD-1 antibody is administered to the subject once every three weeks.

[0001] In certain embodiments, each dose of anti-PSMA / anti-CD3 antibody is administered in two or more portions, e.g., in 2-5 portions ("fractionated dosing"), within a given dosing cycle. Anti-PSMA / anti-CD3 bispecific antibodies can be administered in divided doses to reduce or eliminate cytokine "spikes" induced in response to antibody administration. Cytokine spikes refer to clinical symptoms of cytokine release syndrome ("cytokine storm") and infusion-related reactions. In certain embodiments, the methods of the present disclosure comprise administering one or more doses of an anti-PD-1 antibody in combination with one or more doses of a bispecific anti-PSMA / anti-CD3 antibody to a subject in need thereof, wherein within a given dosing period, a dose of the bispecific antibody is administered in divided doses, or in more than one portion, e.g., as 2 portions, as 3 portions, as 4 portions, or as 5 portions. In certain embodiments, a dose of a bispecific antibody is divided into 2 or more portions, wherein each portion contains an equal amount of antibody to the other portions. In certain embodiments, a dose of a bispecific antibody is administered in two or more portions, wherein the portions contain unequal amounts of antibody, eg, more or less than the first portion. In certain embodiments, the present disclosure includes methods of inhibiting, delaying or stopping tumor metastasis or tumor infiltration into peripheral organs. According to this aspect, the method comprises administering to a subject in need thereof a therapeutically effective amount of a bispecific anti-PSMA / anti-CD3 antibody, alone or in combination with an anti-PD-1 antibody. In specific embodiments, the present disclosure provides methods for increasing anti-tumor efficacy or increasing tumor inhibition. According to this aspect of the present disclosure, the method comprises administering a therapeutically effective amount of an anti-PD-1 antibody to a subject with prostate cancer prior to administering a therapeutically effective amount of a bispecific anti-PSMA / anti-CD3 antibody, wherein the anti-PD-1 antibody may be administered about 1 day, more than 1 day, more than 2 days, more than 3 days, more than 4 days, more than 5 days, more than 6 days, more than 7 days, or more than 8 days prior to the bispecific antibody. In certain embodiments, the method provides increased tumor inhibition, such as an increase of about 20%, more than 20%, more than 30%, more than 40%, more than 50%, more than 60%, more than 70%, or more than 80%, compared to a subject administered the bispecific antibody alone. In certain embodiments, the methods of the present disclosure are used to treat patients with MRD-positive diseases. Minimal residual disease (MRD) refers to a small amount of cancer cells remaining in a patient's body during or after treatment, wherein the patient may or may not show symptoms or signs of the disease. Such residual cancer cells, if not eliminated, often lead to recurrence of the disease. The present disclosure includes methods for inhibiting and / or eliminating residual cancer cells in a patient's body after an MRD test. MRD can be determined according to methods known in the art (e.g., MRD flow cytometry). According to this aspect of the present disclosure, the method comprises administering to a subject in need thereof a bispecific anti-PSMA / anti-CD3 antibody alone or in combination with an anti-PD-1 antibody. According to certain embodiments, the methods of the present disclosure comprise administering to a subject a therapeutically effective amount of a bispecific anti-PSMA / anti-CD3 antibody, alone or in combination with an anti-PD-1 antibody and, optionally, a third therapeutic agent. The third therapeutic agent can be an agent selected from the group consisting of: for example, radiation, chemotherapy, surgery, cancer vaccines, oncolytic viruses, PD-L1 inhibitors (e.g., anti-PD-L1 antibodies), LAG3 inhibitors (e.g., anti-LAG3 antibodies), CTLA-4 inhibitors (e.g., anti-CTLA-4 antibodies), TIM3 inhibitors, BTLA inhibitors, TIGIT inhibitors, CD47 inhibitors, indoleamine-2,3-dioxygenase (IDO) inhibitors, vascular endothelial growth factor (VEGF) antagonists, Ang2 inhibitors, transforming growth factor β (TGF.β.) inhibitors, epidermal growth factor receptor (EGFR) inhibitors, antibodies to tumor-specific antigens, cytotoxins, chemotherapeutic agents, IL-6R inhibitors, IL-4R inhibitors, IL-10 inhibitors, cytokines (such as IL-2, IL-7, IL-21 and IL-15), anti-inflammatory drugs (such as corticosteroids and non-steroidal anti-inflammatory drugs) and dietary supplements (such as antioxidants). In certain embodiments, the antibody can be administered in combination with a therapy including chemotherapeutic agents, radiation, and surgery. As used herein, the phrase "in combination with" means that the antibody is administered to the subject at the same time, just before, or just after administration of a third therapeutic agent. In certain embodiments, the antibody and the third therapeutic agent are administered in separate formulations. In any of the various embodiments discussed herein, the methods of the present disclosure may further include administering a steroid (e.g., dexamethasone or an equivalent steroid) or an anti-IL-6 receptor antibody. In some cases, the anti-IL-6 receptor antibody is tocilizumab or salilumab. In some cases, the steroid (e.g., dexamethasone) may be administered IV or PO at a dose of 1 mg to 20 mg (e.g., 5 mg to 10 mg). In some cases, these agents may be administered as prodrugs prior to administering the bispecific antibody (e.g., REGN4336). In certain embodiments, the methods of the present disclosure include administering to a subject in need thereof a therapeutically effective amount of a bispecific anti-PSMA / anti-CD3 antibody, alone or in combination with an anti-PD-1 antibody. In the case of administering a bispecific antibody or combination, administration of the antibody results in increased inhibition of tumor growth. In certain embodiments, tumor growth is inhibited by at least about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, or about 80%, respectively, compared to untreated subjects or subjects administered with either antibody as a monotherapy. In certain embodiments, administration of a bispecific antibody or combination results in increased tumor regression, tumor shrinkage, and / or disappearance. In certain embodiments, administration of a bispecific antibody or combination results in delayed tumor growth and development, for example, compared to untreated subjects or subjects treated with either antibody as a monotherapy, tumor growth can be delayed by about 3 days, more than 3 days, about 7 days, more than 7 days, more than 15 days, more than 1 month, more than 3 months, more than 6 months, more than 1 year, more than 2 years, or more than 3 years, respectively. In certain embodiments, the administration of bispecific antibodies or combinations prevents tumor recurrence and / or increases the survival duration of the subject, for example, relative to untreated subjects or subjects using either antibody as monotherapy, respectively increase the survival duration by more than 15 days, more than 1 month, more than 3 months, more than 6 months, more than 12 months, more than 18 months, more than 24 months, more than 36 months or more than 48 months. In certain embodiments, the administration of bispecific antibodies or combinations can increase progression-free survival or overall survival. In certain embodiments, the administration of bispecific antibodies or combinations can increase the reaction and reaction duration of the subject, for example, respectively increase by more than 2%, more than 3%, more than 4%, more than 5%, more than 6%, more than 7%, more than 8%, more than 9%, more than 10%, more than 20%, more than 30%, more than 40% or more than 50% compared to untreated subjects or subjects receiving either antibody as monotherapy. In certain embodiments, the administration of bispecific antibodies or combinations to subjects with prostate cancer causes all signs of tumor cells to disappear completely ("complete remission"). In certain embodiments, administration of a bispecific antibody or combination to a subject with prostate cancer results in a reduction in tumor cells or tumor size of at least 30% or more ("partial remission"). In certain embodiments, administration of a bispecific antibody or combination to a subject with prostate cancer results in complete or partial disappearance of tumor cells / lesions (including new measurable lesions). Tumor reduction can be measured by any method known in the art, such as X-ray, positron emission tomography (PET), computed tomography (CT), magnetic resonance imaging (MRI), cytology, histology, or molecular genetic analysis.In certain embodiments, administration of the bispecific antibody and the anti-PD-1 antibody results in a synergistic anti-tumor effect that exceeds the combined effect of the two agents when administered alone. In certain cases, a subject's response to therapy is classified as a complete response (CR), partial response (PR), progressive disease (PD), or stable disease (SD). CR is defined as the disappearance of all target lesions and a reduction in the short axis of any pathological lymph node (whether target or non-target) to <10mm (<1cm). PR is defined as a reduction of at least 30% in the sum of diameters of target lesions, with reference to the baseline sum diameter. PD is defined as an increase of at least 20% in the sum of diameters of target lesions, with reference to the minimum sum studied (including the baseline sum if it is the minimum for the study). In addition to a relative increase of 20%, the sum must also show an absolute increase of at least 5mm (0.5cm). (Note: The appearance of one or more new lesions is also considered progression). SD is defined as a reduction that is not sufficient to meet the requirements of PR, and an increase that is not sufficient to meet the requirements of PD, with reference to the minimum sum diameter during the study. In some cases, immune-based therapy response criteria can be used to assess response. The difference between immune-based therapy response criteria and RECIST (version 1.1) is that the confirmation of progressive disease is slightly more challenging because it must be scanned immediately after the unconfirmed progressive disease scan. This difference is based on the understanding that immunotherapy may lead to pseudo-progression based on inflammation, until and including the development of new lesions. Therefore, two scans with an interval of no less than 4 weeks must unanimously agree that the confirmed progressive disease is progressing. The criteria for evaluating target lesions and non-target lesions are discussed below. Evaluation of target lesions Immune complete response (iCR): All target lesions disappear. Any pathological lymph node (whether target or non-target) must be reduced to <10mm (<1cm) in the short axis Immune partial response (iPR): A decrease of at least 30% in the sum of diameters of target lesions, taking the baseline sum of diameters as reference. Immune Unconfirmed Progressive Disease (iUPD): The sum of diameters of new target lesions has increased by at least 20% since the last imaging was performed, taking the smallest sum on study as reference (this includes the baseline sum if that is the smallest sum on study). In addition to the 20% relative increase, the sum must also show an absolute increase of at least 5 mm (0.5 cm). Immune-confirmed progressive disease (iCPD): Progression in the target lesion category is confirmed if the next imaging assessment after iUPD (4 to 8 weeks later) confirms a further increase in the sum or measurement of target disease in the iUPD by at least 5 mm. Immune stable disease (iSD): measurement of the smallest sum of diameters during the study period as a reference and including new lesions, which has neither shrunk sufficiently to qualify as an iPR nor increased sufficiently to qualify as an iUPD or iCPD Evaluation of non-target lesions Immune complete response (iCR): disappearance of all non-target lesions and normalization of tumor marker levels. All lymph nodes must be non-pathological in size (<10 mm [<1 cm] short axis) 。 If tumor markers are initially above the upper limit of normal, they must be normalized for the patient to be considered in a complete clinical response Non-iCR / non-iUPD or non-iCPD: persistence of one or more non-target lesions and / or maintenance of tumor marker levels above normal limits Immune Unconfirmed Progressive Disease (iUPD): Unequivocal progression of an existing non-target lesion that did not have iUPD on the immediately preceding scan. Unequivocal progression should generally not exceed target lesion status. It must represent an overall disease status change, not an increase in a single lesion. Immune-confirmed progressive disease (iCPD): Definitive progression of an existing non-target lesion with iUPD on the immediately preceding scan. If follow-up imaging performed 4-8 weeks after iUPD shows a further increase in iUPD, progressive disease in the non-target lesion category is confirmed. Definite progression should generally not exceed target lesion status. It must represent an overall disease status change, not an increase in a single lesion. In some cases, imaging can be used to evaluate a subject's response to therapy (alone or in combination with an evaluation of PSA levels). PSMA PET / CT has been shown to provide a sensitive measurement of PSMA expression and tumor burden in patients with prostate cancer. Compared to conventional imaging modalities currently used for the detection of tumor lesions, PSMA PET / CT has greater sensitivity and specificity and has been shown to improve the effectiveness of tumor response assessments and treatment strategies. Fluorine F18 DCFPyL (18F-DCFPyL) is a radiolabeled small molecule that binds to the extracellular domain of PSMA with high affinity. Data from enzyme inhibition assays showed that DCFPyL competitively binds to PSMA-expressing LNCaP cells with a Ki of 1.1 nM. 18F-DCFPyL has been tested in multiple Phase 1 to 3 studies and found to be well tolerated in prostate cancer patients. 18 F-DCFPyL was approved by the FDA on May 26, 2021, for use on PET scans for PSMA-positive lesions in men with prostate cancer suspected of metastasis and suspected of recurrence based on rising serum prostate-specific antigen (PSA) levels who are candidates for initial definitive therapy. Biodistribution and optimal imaging time points were determined after administration of 18F-DCFPyL injection. The radiation dose used in the study was within the limits of radiotracers for PET diagnosis. The physiological accumulation of 18F-DCFPyL was found to correspond to the distribution in PSMA-expressing organs. Accumulation in primary tumors and metastatic lesions was very high, indicating that 18F-DCFPyL injection can be used to detect residual tumors and regional or distant metastases with high sensitivity and specificity. In summary, these findings strongly support the use of 18F-DCFPyL PSMA PET / CT in patients with mCRPC to assess systemic tumor burden and the antitumor activity of REGN4336 alone and in combination with cemiplimab. The expected dose of about 9 ± 1 mCi was injected intravenously 18 F-DCFPyL was generally feasible and safe. 18 The radiation dose from an F-DCFPyL PET / CT scan is about 7.4 mSv. In comparison, the typical CT scan dose of the chest, abdomen, and pelvis is estimated to be about 25 mSv, a bone scan is about 4.4 mSv, and the annual natural background radiation dose in the United States is about 3.1 mSv. 18 The planned maximum for F-DCFPyL PET / CT scans would result in an approximate dose of approximately 22.2 mSv, which is approximately 45% of the recommended maximum allowable dose of 50 mSv for an adult study patient in a year (21CRF361.1). For a patient who may receive 4 PSMA PET scans (3 planned plus 1 unplanned), the total radiation dose from these scans would be approximately 29.6 mSv, which is approximately 59% of the recommended maximum allowable annual dose for an adult study patient. 18 The risk of F-DCFPyL radiation exposure will be disclosed to the patient during the PET imaging informed consent form. Optional fluorodeoxyglucose (FDG) PET / CT can be used to assess the patient's metabolically active tumor burden. Tumors that express and do not express PSMA have been detected in prostate cancer patients by FDG PET / CT. Complementary FDG and PSMA PET / CT data are expected to provide insights into tumor response to therapy (e.g., REGN4336). Anti-PD-1 antibodies and antigen-binding fragments thereof According to certain exemplary embodiments of the present disclosure, the method comprises administering a therapeutically effective amount of an anti-PD-1 antibody or an antigen-binding fragment thereof. As used herein, the term "antibody" includes immunoglobulin molecules and multimers thereof (e.g., IgM) comprising four polypeptide chains (two heavy (H) chains and two light (L) chains) interconnected by disulfide bonds. In a typical antibody, each heavy chain comprises a heavy chain variable region (abbreviated herein as HCVR or V H) and the heavy chain constant region. The heavy chain constant region contains three domains: C H 1. C H 2 and C H 3. Each light chain comprises a light chain variable region (abbreviated herein as LCVR or V L ) and the light chain constant region. The light chain constant region consists of a domain (C L 1). V H Area and V L The V region can be further subdivided into regions of hypervariability, termed complementarity determining regions (CDRs), interspersed with regions that are more conserved, termed framework regions (FRs). H and V L It is composed of three CDRs and four FRs arranged in the following order from the amino terminus to the carboxyl terminus: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. In various embodiments of the present disclosure, the FRs of the anti-PD-1 antibody (or its antigen-binding portion) may be identical to the human germline sequence, or may be naturally or artificially modified. An amino acid consensus sequence may be defined based on a side-by-side analysis of two or more CDRs. The term "antibody" as used herein also includes the antigen binding fragment of a complete antibody molecule. The terms "antigen binding portion of an antibody", "antigen binding fragment of an antibody", etc. as used herein include any naturally occurring, enzymatically available, synthetic or genetically engineered polypeptide or glycoprotein that specifically binds to an antigen to form a complex. Antigen binding fragments of antibodies can be derived from full antibody molecules, for example, using any suitable standard technique (such as proteolytic digestion or the recombinant genetic engineering techniques involving the operation and expression of DNA encoding antibody variable domains and optionally antibody constant domains). Such DNA is known, and / or can be easily obtained from, for example, commercial sources, DNA libraries (including, for example, phage-antibody libraries), or can be synthesized. DNA sequencing can be performed, and chemically or by using molecular biology techniques, for example, to arrange one or more variable domains and / or constant domains into a suitable configuration, or to import codons, produce cysteine ​​residues, modify, add or delete amino acids, etc. Non-limiting examples of antigen-binding fragments include: (i) Fab fragments; (ii) F(ab')2 fragments; (iii) Fd fragments; (iv) Fv fragments; (v) single-chain Fv (scFv) molecules; (vi) dAb fragments; and (vii) minimal recognition units consisting of amino acid residues that mimic the hypervariable region of an antibody (e.g., isolated complementary determining regions (CDRs), such as CDR3 peptides), or binding FR3-CDR3-FR4 peptides. Other engineered molecules such as domain-specific antibodies, single domain antibodies, domain-deleted antibodies, chimeric antibodies, CDR-grafted antibodies, diabodies, tribodies, tetrabodies, microbodies, nanobodies (e.g., monovalent nanobodies, bivalent nanobodies, etc.), small modular immunopharmaceuticals (SMIPs), and shark variable IgNAR domains are also encompassed within the expression "antigen-binding fragment" as used herein. The antigen-binding fragment of an antibody generally includes at least one variable domain. The variable domain can have any size or amino acid composition and will generally include at least one CDR adjacent to or in frame with one or more framework sequences. H Domain and V L In the antigen-binding fragment associated with the structural domain, V H and V L The domains may be positioned relative to each other in any suitable arrangement. For example, the variable region may be a dimer and contain V H -V H 、V H -V L or V L -V L Alternatively, the antigen-binding fragment of the antibody may contain a monomer V H or V L Structural domain. In certain embodiments, an antigen-binding fragment of an antibody may contain at least one variable domain covalently linked to at least one constant domain. Non-limiting exemplary configurations of variable and constant domains that may be found within an antigen-binding fragment of an antibody of the present disclosure include: (i) V H -C H 1; (ii) V H -C H 2; (iii) V H -C H 3; (iv) V H -C H 1-C H 2; (v) V H -C H 1-C H 2-C H 3; (vi) V H -C H2-C H 3; (vii) V H -C L ; (viii) V L -C H 1; (ix) V L -C H 2; (x) V L -C H 3; (xi) V L -C H 1-C H 2; (xii) V L -C H 1-C H 2-C H 3; (xiii) V L -C H 2-C H 3; and (xiv) V L -C L . In any configuration of variable domains and constant domains (including any of the exemplary configurations listed above), the variable domains and constant domains may be directly connected to each other or may be connected by a full-length or partial hinge or linker region. The hinge region may be composed of at least 2 (e.g., 5, 10, 15, 20, 40, 60 or more) amino acids, which results in a flexible or semi-flexible connection between adjacent variable domains and / or constant domains in a single polypeptide molecule. In addition, the antigen-binding fragments of the antibodies of the present disclosure may comprise any of the variable domain and constant domain configurations listed above, which are connected to each other and / or to one or more monomeric V H or V L The domains are in non-covalent association (eg, through disulfide bonds) as homodimers or heterodimers (or other multimers). The term "antibody" as used herein also includes multispecific (e.g., bispecific) antibodies. Multispecific antibodies or antigen-binding fragments of antibodies generally include at least two different variable domains, each of which is capable of specifically binding to a separate antigen or a different epitope on the same antigen. Using conventional techniques available in the art, any multispecific antibody format can be applied to the context of the antibodies or antigen-binding fragments of antibodies disclosed herein. For example, the present disclosure includes methods comprising the use of bispecific antibodies, wherein one arm of the immunoglobulin is specific for PD-1 or a fragment thereof, and the other arm of the immunoglobulin is specific for a second therapeutic target or is conjugated to a therapeutic moiety. Exemplary bispecific formats that can be used in the context of the present disclosure include, but are not limited to, for example, scFv-based or bispecific bispecific formats, IgG-scFv fusions, dual variable domains (DVD)-Ig, quadromas, knobs-into-holes, common light chains (e.g., common light chains with knobs-into-holes, etc.), CrossMab, CrossFab, (SEED) bodies, leucine zippers, Duobody, IgG1 / IgG2, dual-acting Fab (DAF)-IgG, and Mab.sup.2 bispecific formats (for a review of the foregoing formats, see, e.g., Klein et al., 2012, mAbs 4:6, 1-11, and references cited therein). Bispecific antibodies can also be constructed using peptide / nucleic acid conjugation, for example, where non-natural amino acids with orthogonal chemical reactivity are used to generate site-specific antibody-oligonucleotide conjugates that are then self-assembled into multimeric complexes with defined composition, valency, and geometry. (See, e.g., Kazane et al., J. Am. Chem. Soc. [Electronic version: Dec. 4, 2012]). The antibody used in the disclosed method can be a human antibody. As used herein, the term "human antibody" is intended to include antibodies with variable regions and constant regions derived from human germline immunoglobulin sequences. However, the human antibody of the present disclosure may include amino acid residues not encoded by human germline immunoglobulin sequences (e.g., mutations introduced by random or site-directed mutagenesis in vitro or by somatic mutations in vivo), such as in CDR, particularly in CDR3. However, as used herein, the term "human antibody" is not intended to include antibodies that have been implanted into human framework sequences using CDR sequences derived from the germline of another mammalian species (such as a mouse). The antibody used in the disclosed method can be a recombinant human antibody. As used herein, the term "recombinant human antibody" is intended to include all human antibodies prepared, expressed, produced or separated by recombinant means, such as antibodies expressed by recombinant expression vectors transfected into host cells (described further below), antibodies separated from recombinant human antibody combinatorial libraries (described further below), antibodies separated from transgenic animals (e.g., mice) relative to human immunoglobulin genes (see, e.g., Taylor et al., (1992) Nucl. Acids Res. 20: 6287-6295) or antibodies prepared, expressed, produced or separated by any other means involving splicing of human immunoglobulin gene sequences to other DNA sequences. Such recombinant human antibodies have variable regions and constant regions derived from human germline immunoglobulin sequences. However, in certain embodiments, such recombinant human antibodies undergo in vitro mutagenesis (or, when using transgenic animals with respect to human Ig sequences, undergo in vivo somatic cell mutagenesis) and thus the V H and V L The amino acid sequence of the region is derived from human germline V H and V L Sequences that are related to but that may not naturally occur within the human antibody germline repertoire in vivo. According to certain embodiments, the antibody used in the disclosed method specifically binds to PD-1. The term "specific binding" and the like means that the antibody or its antigen-binding fragment forms a relatively stable complex with the antigen under physiological conditions. Methods for determining whether an antibody specifically binds to an antigen are well known in the art and include, for example, equilibrium dialysis, surface plasmon resonance, and the like. For example, as used in the context of the present disclosure, antibodies that "specifically bind" to PD-1 include antibodies with a K of less than about 500 nM, less than about 300 nM, less than about 200 nM, less than about 100 nM, less than about 90 nM, less than about 80 nM, less than about 70 nM, less than about 60 nM, less than about 50 nM, less than about 40 nM, less than about 30 nM, less than about 20 nM, less than about 10 nM, less than about 5 nM, less than about 4 nM, less than about 3 nM, less than about 2 nM, less than about 1 nM, or less than about 0.5 nM. D An antibody that binds to PD-1 or a portion thereof as measured in a surface plasmon resonance assay. However, an isolated antibody that specifically binds to human PD-1 may have cross-reactivity with other antigens, such as PD-1 molecules from other (non-human) species. According to certain exemplary embodiments of the present disclosure, an anti-PD-1 antibody or antigen-binding fragment thereof comprises a heavy chain variable region (HCVR), a light chain variable region (LCVR), and / or a complementarity determining region (CDR) comprising any amino acid sequence of the anti-PD-1 antibodies listed in U.S. Patent No. 9,987,500. In certain exemplary embodiments, an anti-PD-1 antibody or antigen-binding fragment thereof useful in the context of the present disclosure comprises a heavy chain complementarity determining region (HCDR) of a heavy chain variable region (HCVR) having an amino acid sequence of SEQ ID NO: 21 and a light chain complementarity determining region (LCDR) of a light chain variable region (LCVR) having an amino acid sequence of SEQ ID NO: 22. According to certain embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof comprises three HCDRs (HCDR1, HCDR2, and HCDR3) and three LCDRs (LCDR1, LCDR2, and LCDR3), wherein HCDR1 comprises the amino acid sequence of SEQ ID NO: 23; HCDR2 comprises the amino acid sequence of SEQ ID NO: 24; HCDR3 comprises the amino acid sequence of SEQ ID NO: 25; LCDR1 comprises the amino acid sequence of SEQ ID NO: 26; LCDR2 comprises the amino acid sequence of SEQ ID NO: 27; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 28. In other embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof comprises a HCVR having SEQ ID NO: 21 and a LCVR having SEQ ID NO: 22. In certain embodiments, the methods of the present disclosure comprise the use of an anti-PD-1 antibody, wherein the antibody comprises a heavy chain having the amino acid sequence of SEQ ID NO: 29. In some embodiments, the anti-PD-1 antibody comprises a light chain having the amino acid sequence of SEQ ID NO: 30. An exemplary antibody comprising a heavy chain variable region having the amino acid sequence of SEQ ID NO: 21 and a light chain variable region having the amino acid sequence of SEQ ID NO: 22 is designated REGN2810 (also known as cemiprilimab; ) of a fully human anti-PD-1 antibody. According to certain exemplary embodiments, the methods of the present disclosure include the use of REGN2810 or a bioequivalent thereof. The term "bioequivalent" as used herein refers to an anti-PD-1 antibody or PD-1-binding protein or a fragment thereof that is a pharmaceutical equivalent or pharmaceutical substitute, and whose absorption rate and / or extent do not show significant differences from the absorption rate and / or extent of REGN2810 when administered at the same molar dose (whether single or multiple doses) under similar experimental conditions. In the context of the present disclosure, the term refers to an antigen binding protein that binds to PD-1 that does not have clinically meaningful differences from REGN2810 in terms of its safety, purity and / or efficacy. Other anti-PD-1 antibodies that can be used in the context of the disclosed methods include, for example, antibodies mentioned and known in the art, such as nivolumab (U.S. Pat. No. 8,008,449), pembrolizumab (U.S. Pat. No. 8,354,509), MEDI0608 (U.S. Pat. No. 8,609,089), pidilizumab (U.S. Pat. No. 8,686,119), or any of the anti-PD-1 antibodies described in U.S. Pat. Nos. 6,808,710, 7,488,802, 8,168,757, 8,354,509, 8,779,105, or 8,900,587. The anti-PD-1 antibodies used in the context of the methods of the present disclosure may have pH-dependent binding characteristics. For example, the anti-PD-1 antibodies used in the methods of the present disclosure may exhibit reduced binding to PD-1 at acidic pH compared to neutral pH. Alternatively, the anti-PD-1 antibodies of the present disclosure may exhibit enhanced binding to their antigens at acidic pH compared to neutral pH. The expression "acidic pH" includes pH values ​​less than about 6.2, for example, about 6.0, 5.95, 5.9, 5.85, 5.8, 5.75, 5.7, 5.65, 5.6, 5.55, 5.5, 5.45, 5.4, 5.35, 5.3, 5.25, 5.2, 5.15, 5.1, 5.05, 5.0 or less. The expression "neutral pH" used herein refers to a pH of about 7.0 to about 7.4. The expression "neutral pH" includes pH values ​​of about 7.0, 7.05, 7.1, 7.15, 7.2, 7.25, 7.3, 7.35 and 7.4. In certain cases, "reduced binding to PD-1 at acidic pH compared to neutral pH" refers to the K of the antibody binding to PD-1 at acidic pH. D The K value of the antibody binding to PD-1 at neutral pH D For example, for the purposes of this disclosure, if an antibody or antigen-binding fragment thereof exhibits an acidic / neutral K of about 3.0 or greater, D In certain exemplary embodiments, the acidic / neutral K of an antibody or antigen-binding fragment of the present disclosure is preferably 0.0547 W / m , 0.0617 W / m . D The ratio can be about 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10.0, 10.5, 11.0, 11.5, 12.0, 12.5, 13.0, 13.5, 14.0, 14.5, 15.0, 20.0, 25.0, 30.0, 40.0, 50.0, 60.0, 70.0, 100.0 or more. Antibodies with pH-dependent binding characteristics can be obtained, for example, by screening antibody populations for reduced (or enhanced) binding to specific antigens at acidic pH compared to neutral pH. In addition, antibodies with pH-dependent characteristics can be produced by modifying the antigen-binding domain at the amino acid level. For example, by replacing one or more amino acids of the antigen-binding domain (e.g., inside the CDR) with histidine residues, antibodies with reduced antigen binding at acidic pH relative to neutral pH can be obtained. The expression "acidic pH" used herein refers to a pH of 6.0 or less. Bispecific anti-PSMA × anti-CD3 antibody According to certain exemplary embodiments of the present disclosure, the method comprises administering a therapeutically effective amount of a bispecific antibody that specifically binds to CD3 and PSMA. Such antibodies may be referred to herein as, for example, "anti-PSMA / anti-CD3" or "anti-PSMA xCD3" or "PSMA x CD3" bispecific antibodies or other similar terms. As used herein, the expression "bispecific antibody" refers to an immunoglobulin comprising at least a first antigen binding domain and a second antigen binding domain. In the context of the present disclosure, the first antigen binding domain specifically binds to a first antigen (e.g., PSMA), and the second antigen binding domain specifically binds to a second different antigen (e.g., CD3). Each antigen binding domain of a bispecific antibody comprises a heavy chain variable domain (HCVR) and a light chain variable domain (LCVR), each domain comprising three CDRs. In the context of a bispecific antibody, the CDR of the first antigen binding domain may be represented by the prefix "A", and the CDR of the second antigen binding domain may be represented by the prefix "B". Therefore, the CDRs of the first antigen binding domain may be referred to herein as A-HCDR1, A-HCDR2, and A-HCDR3; and the CDRs of the second antigen binding domain may be referred to herein as B-HCDR1, B-HCDR2, and B-HCDR3. The first antigen binding domain and the second antigen binding domain are each connected to a separate multimerization domain. As used herein, a "multimerization domain" is any macromolecule, protein, polypeptide, peptide or amino acid that has the ability to bind to a second multimerization domain of the same or similar structure or configuration. In the context of the present disclosure, the multimerization component is the Fc portion of an immunoglobulin (comprising a C H2 -C H3The bispecific antibodies of the present invention generally comprise two multimerization domains, such as two Fc domains, which are respectively parts of the heavy chains of individual antibodies. The first multimerization domain and the second multimerization domain may have the same IgG isotype, such as IgG1 / IgG1, IgG2 / IgG2, IgG4 / IgG4. Alternatively, the first multimerization domain and the second multimerization domain may have different IgG isotypes, such as IgG1 / IgG2, IgG1 / IgG4, IgG2 / IgG4, etc. Any bispecific antibody format or technology can be used to prepare the bispecific antibodies of the present disclosure. For example, an antibody or fragment thereof having a first antigen binding specificity can be functionally linked (e.g., by chemical coupling, genetic fusion, non-covalent binding or other means) to one or more other molecular entities, such as another antibody or antibody fragment having a second antigen binding specificity, to produce a bispecific antibody. Specific exemplary bispecific formats that can be used in the context of the present disclosure include, but are not limited to, for example, scFv-based or dual bispecific formats, IgG-scFv fusions, dual variable domains (DVD)-Ig, quadromas, knobs-in-holes, common light chains (e.g., common light chains with knobs-in-holes, etc.), CrossMab, CrossFab, (SEED) body, leucine zipper, Duobody, IgG1 / IgG2, dual-acting Fab (DAF)-IgG and Mab2 bispecific formats (for a review of the aforementioned formats, see, e.g., Klein et al., 2012, mAbs 4:6, 1-11, and references cited therein). In the context of the bispecific antibodies of the present disclosure, the Fc domain may comprise one or more amino acid changes (e.g., insertions, deletions, or substitutions) compared to a wild-type, naturally occurring Fc domain. For example, the present disclosure includes bispecific antibodies comprising one or more modifications in the Fc domain that result in the modified Fc domain having a modified binding interaction (e.g., enhanced or weakened) between Fc and FcRn. In one embodiment, the bispecific antibody has a modified Fc domain in the Fc domain. H2 or C H3 The Fc domain comprises a modification in the region, wherein the modification increases the affinity of the Fc domain to FcRn in an acidic environment (e.g., in an endosome at a pH range of from about 5.5 to about 6.0). Non-limiting examples of such Fc modifications are disclosed in U.S. Patent Publication No. 20150266966, which is incorporated herein in its entirety. The present disclosure also includes a first C H 3 domain and the second Ig C H3-domain bispecific antibody, wherein the first and second Ig C H The at least one amino acid in the first Ig C domain and the second Ig C domain differs from each other, and wherein the at least one amino acid difference reduces binding of the bispecific antibody to protein A compared to a bispecific antibody lacking the amino acid difference. H 3 domains bind protein A and the second Ig C H The 3 domain contains a mutation that reduces or eliminates protein A binding, such as the H95R modification (according to IMGT exon numbering; H435R according to EU numbering). H 3 may also contain a Y96F modification (according to IMGT; Y436F according to EU). See, e.g., U.S. Pat. No. 8,586,713. H Other modifications within 3 include: D16E, L18M, N44S, K52N, V57M and V82I (by IMGT; D356E, L358M, N384S, K392N, V397M and V422I by EU) in the case of IgG1 antibodies; N44S, K52N and V82I (IMGT; N384S, K392N and V422I by EU) in the case of IgG2 antibodies; and Q15R, N44S, K52N, V57M, R69K, E79Q and V82I (by IMGT; Q355R, N384S, K392N, V397M, R409K, E419Q and V422I by EU) in the case of IgG4 antibodies. In certain embodiments, the Fc domain can be chimeric, combining Fc sequences from more than one immunoglobulin isotype. For example, a chimeric Fc domain can comprise Fc sequences from human IgG1, human IgG2, or human IgG4. H C in Zone 2 H 2 sequence, and C derived from human IgG1, human IgG2 or human IgG4 H 3 sequence. The chimeric Fc domain may also contain a chimeric hinge region. For example, the chimeric hinge may comprise an "upper hinge" sequence derived from a human IgG1, human IgG2, or human IgG4 hinge region, combined with a "lower hinge" sequence derived from a human IgG1, human IgG2, or human IgG4 hinge region. Specific examples of chimeric Fc domains that may be included in any of the antibodies described herein include, from N-terminus to C-terminus: [IgG4C H 1]-[IgG4 upper hinge]-[IgG2 lower hinge]-[IgG4 CH2]-[IgG4 CH3]. Another example of a chimeric Fc domain that can be included in any of the antibodies described herein comprises, from N-terminus to C-terminus: [IgG1 CH 1]-[IgG1 upper hinge]-[IgG2 lower hinge]-[IgG4 CH2]-[IgG1 CH3]. These and other examples of chimeric Fc domains or chimeric heavy chain constant regions that can be included in any antibody of the present disclosure are described in U.S. Patent Publication No. 20140243504, which is incorporated herein in its entirety. Chimeric Fc domains and chimeric heavy chain constant regions and variants thereof having these general structural arrangements can have altered Fc receptor binding, which in turn affects Fc effector function. According to certain exemplary embodiments of the present disclosure, the bispecific anti-PSMA / anti-CD3 antibody or antigen-binding fragment thereof comprises a heavy chain variable region (A-HCVR and B-HCVR), a light chain variable region (A-LCVR and B-LCVR), and / or a complementarity determining region (CDR) comprising any amino acid sequence of the bispecific anti-PSMA / anti-CD3 antibody listed in U.S. Patent Publication No. 20170051074. In certain exemplary embodiments, a bispecific anti-PSMA / anti-CD3 antibody or antigen-binding fragment thereof useful in the context of the disclosed methods comprises: (a) a first antigen-binding arm comprising heavy chain complementarity determining regions (A-HCDR1, A-HCDR2, and A-HCDR3) of a heavy chain variable region (A-HCVR) comprising the amino acid sequence of SEQ ID NO:1, and light chain complementarity determining regions (A-LCDR1, A-LCDR2, and A-LCDR3) comprising the amino acid sequence of SEQ ID NO:2; and (b) a second antigen-binding arm comprising heavy chain CDRs (B-HCDR1, B-HCDR2, and B-HCDR3) of a HCVR (B-HCVR) comprising the amino acid sequence of SEQ ID NO:3 or SEQ ID NO:4, and light chain CDRs (B-LCDR1, B-LCDR2, and B-LCDR3) of a LCVR (B-LCVR) comprising the amino acid sequence of SEQ ID NO:2. According to certain embodiments, A-HCDR1 comprises the amino acid sequence of SEQ ID NO:5; A-HCDR2 comprises the amino acid sequence of SEQ ID NO:6; A-HCDR3 comprises the amino acid sequence of SEQ ID NO:7; A-LCDR1 comprises the amino acid sequence of SEQ ID NO:8; A-LCDR2 comprises the amino acid sequence of SEQ ID NO:9; A-LCDR3 comprises the amino acid sequence of SEQ ID NO:10; B-HCDR1 comprises the amino acid sequence of SEQ ID NO:11 or SEQ ID NO:14; B-HCDR2 comprises the amino acid sequence of SEQ ID NO:12 or SEQ ID NO:15; and B-HCDR3 comprises the amino acid sequence of SEQ ID NO:13 or SEQ ID NO:16; and B-LCDR1 comprises the amino acid sequence of SEQ ID NO:8; B-LCDR2 comprises the amino acid sequence of SEQ ID NO:9; and B-LCDR3 comprises the amino acid sequence of SEQ ID NO:10.In other embodiments, the bispecific anti-PSMA / anti-CD3 antibody or antigen-binding fragment thereof comprises: (a) a first antigen-binding arm comprising a HCVR having SEQ ID NO: 1 (A-HCVR) and a LCVR having SEQ ID NO: 2 (A-LCVR); and (b) a second antigen-binding arm comprising a HCVR having SEQ ID NO: 3 or SEQ ID NO: 4 (B-HCVR) and a LCVR having SEQ ID NO: 2 (B-LCVR). In certain exemplary embodiments, the bispecific anti-PSMA x CD3 antibody comprises: a PSMA-binding arm comprising a heavy chain having an amino acid sequence of SEQ ID NO: 17 and a light chain having an amino acid sequence of SEQ ID NO: 18; and a CD3-binding arm comprising a heavy chain having an amino acid sequence of SEQ ID NO: 19 and a light chain having an amino acid sequence of SEQ ID NO: 18. In certain exemplary embodiments, the bispecific anti-PSMA×CD3 antibody comprises: a PSMA-binding arm comprising a heavy chain having an amino acid sequence of SEQ ID NO: 17 and a light chain having an amino acid sequence of SEQ ID NO: 18; and a CD3-binding arm comprising a heavy chain having an amino acid sequence of SEQ ID NO: 20 and a light chain having an amino acid sequence of SEQ ID NO: 18. An exemplary bispecific anti-PSMA / anti-CD3 antibody for use in the methods of the present disclosure comprising: (a) a first antigen-binding arm comprising a HCVR having SEQ ID NO: 1 (A-HCVR) and a LCVR having SEQ ID NO: 2 (A-LCVR); and (b) a second antigen-binding arm comprising a HCVR having SEQ ID NO: 4 (B-HCVR) and a LCVR having SEQ ID NO: 2 (B-LCVR) is REGN4336 (referred to herein as “PSMA / CD3-002”). Combination therapy According to certain embodiments, the methods of the present disclosure include administering an anti-PSMA / anti-CD3 bispecific antibody in combination with an anti-PD-1 antibody to a subject. In certain embodiments, the methods of the present disclosure include administering an antibody with additive or synergistic activity to treat a PSMA-expressing cancer, preferably prostate cancer. As used herein, the expression "in combination with" refers to administering an anti-PSMA / anti-CD3 bispecific antibody before, after, or simultaneously with the administration of an anti-PD-1 antibody. The term "in combination with" also includes sequential or concomitant administration of an anti-PD-1 antibody and a bispecific anti-PSMA / anti-CD3 antibody. For example, when administered "before" the bispecific anti-PSMA / anti-CD3 antibody, the anti-PD-1 antibody can be administered more than 150 hours, about 150 hours, about 100 hours, about 72 hours, about 60 hours, about 48 hours, about 36 hours, about 24 hours, about 12 hours, about 10 hours, about 8 hours, about 6 hours, about 4 hours, about 2 hours, about 1 hour, about 30 minutes, about 15 minutes, or about 10 minutes before the administration of the bispecific anti-PSMA / anti-CD3 antibody. When administered "after" the bispecific anti-PSMA / anti-CD3 antibody, the anti-PD-1 antibody can be administered about 10 minutes, about 15 minutes, about 30 minutes, about 1 hour, about 2 hours, about 4 hours, about 6 hours, about 8 hours, about 10 hours, about 12 hours, about 24 hours, about 36 hours, about 48 hours, about 60 hours, about 72 hours, or more than 72 hours after the administration of the bispecific anti-PSMA / anti-CD3 antibody. Administration "concurrently" with the bispecific anti-PSMA / anti-CD3 antibody means that the anti-PD-1 antibody is administered to the subject in a separate dosage form within less than 5 minutes after (before, after, or simultaneously with) administration of the bispecific anti-PSMA / anti-CD3 antibody, or is administered to the subject in a single combined dosage form comprising both the anti-PD-1 antibody and the bispecific anti-PSMA / anti-CD3 antibody. In certain embodiments, the methods of the present disclosure include administering a third therapeutic agent, wherein the third therapeutic agent is an anti-cancer drug. In certain embodiments, the methods of the present disclosure include administering an anti-PD-1 antibody and an anti-PSMA / anti-CD3 bispecific antibody in combination with radiation therapy, surgery, or other anti-cancer therapy to produce a long-term durable anti-tumor response and / or increase the survival of patients with PSMA-expressing cancers. In some embodiments, the methods of the present disclosure include administering radiation therapy before, simultaneously with, or after administering an anti-PD-1 antibody and a bispecific anti-PSMA / anti-CD3 antibody to a patient with cancer. For example, radiation therapy may be administered to a tumor lesion in one or more doses after administering one or more doses of the antibody. In some embodiments, radiation therapy may be administered locally to a tumor lesion after systemic administration of an anti-PD-1 antibody and / or a bispecific anti-PSMA / anti-CD3 antibody to enhance the local immunogenicity of the patient's tumor (adjuvant radiation) and / or to kill tumor cells (ablative radiation). Pharmaceutical compositions and administration The present disclosure includes methods comprising administering to a subject a bispecific anti-PSMA / anti-CD3 antibody, alone or in combination with an anti-PD-1 antibody, wherein one or more of the antibodies is contained in a separate or combined (single) pharmaceutical composition. The pharmaceutical compositions of the present disclosure may be formulated with suitable carriers, excipients, and other agents that provide suitable transfer, delivery, tolerance, and the like. Numerous suitable formulations may be found in the formulary known to all medicinal chemists: Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pa. These formulations include, for example, powders, pastes, ointments, gels, waxes, oils, lipids, lipid (cationic or anionic)-containing vesicles (such as LIPOFECTIN TM ), DNA conjugates, anhydrous absorption pastes, oil-in-water and water-in-oil emulsions, emulsion carbowax (polyethylene glycol of various molecular weights), semisolid gels and semisolid mixtures containing carbowax. See also Powell et al. "Compendium of excipients for parenteral formulations" PDA (1998) JPharmSci Technol 52: 238-311. Various delivery systems are known and can be used to administer the pharmaceutical compositions of the present disclosure, such as encapsulation in liposomes, microparticles, microcapsules, recombinant cells capable of expressing mutant viruses, receptor-mediated endosomes (see, e.g., Wu et al., 1987, J. Biol. Chem. 262: 4429-4432). Methods of administration include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, and oral routes. The compositions can be administered by any convenient route, such as by infusion or bolus or by injection, and can be administered with other biologically active agents. The pharmaceutical compositions of the present disclosure can be delivered subcutaneously or intravenously with a standard needle and syringe. In addition, for subcutaneous delivery, pen delivery devices are readily applicable to the delivery of the pharmaceutical compositions of the present disclosure. Such pen delivery devices can be reusable or disposable. Reusable pen delivery devices generally utilize a replaceable cartridge containing the pharmaceutical composition. Once all of the pharmaceutical composition in the cartridge has been administered and the cartridge becomes empty, the empty cartridge can be easily discarded and replaced with a new cartridge containing the pharmaceutical composition. The pen delivery device can then be reused. In a disposable pen delivery device, there is no replaceable cartridge. In fact, the disposable pen delivery device is pre-filled with the pharmaceutical composition in a reservoir within the device. Once the pharmaceutical composition in the reservoir is emptied, the entire device is discarded. A variety of reusable pen delivery devices and auto-injector delivery devices are used to subcutaneously deliver the pharmaceutical compositions of the present disclosure. Examples include, but are not limited to, AUTOPEN TM (Owen Mumford, Inc., Woodstock, UK), DISSETRONIC TM Pen (Disetronic Medical Systems, Bergdorf, Switzerland), HUMALOG MIX75 / 25 TM Pen, HUMALOG TM Pen, HUMALIN 70 / 30 TM Pen (Eli Lilly and Co., Indianapolis, IN), NOVOPEN TM I, II and III (Novo Nordisk, Copenhagen, Denmark), NOVOPEN JUNIOR TM (NovoNordisk,Copenhagen,Denmark)、BD TM Pen (Becton Dickinson, Franklin Lakes, NJ), OPTIPEN TM 、OPTIPEN PRO TM 、OPTIPEN STARLET TM and OPTICLIK TM (sanofi-aventis, Frankfurt, Germany), etc. Examples of disposable pen delivery devices that can be used for subcutaneous delivery of the pharmaceutical compositions of the present disclosure include, but are not limited to, SOLOSTAR TM Pen (sanofi-aventis), FLEXPEN TM (Novo Nordisk), and KWIKPEN TM(Eli Lilly), SURECLICK TM Autoinjector (Amgen, Thousand Oaks, CA), PENLET TM (Haselmeier, Stuttgart, Germany), EPIPEN (Dey, LP), and HUMIRA TM pen (Abbott Labs, Abbott Park IL), etc. In some cases, the pharmaceutical composition can be delivered in a controlled release system. In one embodiment, a pump can be used. In another embodiment, a polymeric material can be used; see, Medical Applications of Controlled Release, Langer and Wise (eds.), 1974, CRC Pres., Boca Raton, Fla. In yet another embodiment, a controlled release system can be placed near the target of the composition, thus requiring only a small portion of the systemic dose (see, e.g., Goodson, 1984, in Medical Applications of Controlled Release, supra, Vol. 2, pp. 115-138). Other controlled release systems are discussed in the review of Langer, 1990, Science 249: 1527-1533. The injectable preparations can include dosage forms for intravenous, subcutaneous, intradermal and intramuscular injections, drip infusions, etc. These injectable preparations can be prepared by known methods. For example, the injectable preparations can be prepared by, for example, dissolving, suspending or emulsifying the antibody described above or its salt in a sterile aqueous medium or an oily medium conventionally used for injection. As aqueous media for injection, there are, for example, physiological saline, isotonic solutions containing glucose and other adjuvants, etc., which can be used in combination with appropriate solubilizers. The injection thus prepared is preferably filled in an appropriate ampoule. Advantageously, the pharmaceutical composition for use as described above is prepared in a unit dosage form suitable for matching the dosage of the active ingredient. Such unit dosage forms include, for example, vials or prefilled syringes. Administration regimen The present disclosure includes methods comprising administering to a subject a bispecific anti-PSMA x CD3 antibody, alone or in combination with an anti-PD-1 antibody, at a dosing frequency of about four times a week, twice a week, once a week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, once every six weeks, once every eight weeks, once every twelve weeks, or less frequently, as long as a therapeutic response is achieved. According to certain embodiments of the present disclosure, multiple doses of bispecific anti-PSMA / anti-CD3 antibodies alone or in combination with anti-PD-1 antibodies may be administered to a subject over a specified time course. The method according to this aspect of the present disclosure includes sequentially administering to a subject one or more doses of bispecific anti-PSMA / anti-CD3 antibodies alone or in combination with one or more doses of anti-PD-1 antibodies. As used herein, "sequential administration" refers to administering each dose of the antibody to a subject at different time points, such as different days separated by a predetermined interval (e.g., hours, days, weeks, or months). The present disclosure includes such a method: the method includes sequentially administering a single initial dose of the antibody, followed by one or more second doses of the antibody, and optionally followed by one or more third doses of the antibody to the patient. The terms "initial dose", "second dose", and "third dose" indicate the temporal order of administration. Therefore, the "initial dose" is a dose administered at the beginning of the treatment regimen (also referred to as a "baseline amount"); the "second dose" is a dose administered after the initial dose; and the "tertiary dose" is a dose administered after the second dose. The initial dose, the second dose, and the third dose may all contain the same amount of antibody (anti-PD-1 antibody or bispecific antibody). However, in certain embodiments, the amounts contained in the initial dose, the second dose, and / or the third dose differ from one another during the course of treatment (e.g., adjusted upward or downward when appropriate). In certain embodiments, one or more (e.g., 1, 2, 3, 4, or 5) doses are administered at the beginning of the treatment regimen as a "loading dose," followed by subsequent doses (e.g., "maintenance doses") administered at a lower frequency. In an exemplary embodiment of the present disclosure, each second dose and / or third dose is administered 1 / 2 to 14 weeks (e.g., 1 / 2, 1, 11 / 2, 2, 21 / 2, 3, 31 / 2, 4, 41 / 2, 5, 51 / 2, 6, 61 / 2, 7, 71 / 2, 8, 81 / 2, 9, 91 / 2, 10, 101 / 2, 11, 111 / 2, 12, 121 / 2, 13, 131 / 2, 14, 141 / 2 weeks or longer) immediately after the previous dose. As used herein, the phrase "immediately preceding dose" means that in a sequence of multiple administrations, a dose of the bispecific anti-PSMA / anti-CD3 (and / or anti-PD-1 antibody) is administered to the patient before the next dose in the sequence is administered without an intermediate dose. The method according to this aspect of the present disclosure may include administering any number of second and / or third doses of a bispecific anti-PSMA / anti-CD3 antibody (and / or anti-PD-1 antibody) to a patient. For example, in certain embodiments, only a single second dose is administered to a patient. In other embodiments, two or more (e.g., 2, 3, 4, 5, 6, 7, 8, or more) second doses are administered to a patient. Similarly, in certain embodiments, only a single third dose is administered to a patient. In other embodiments, two or more (e.g., 2, 3, 4, 5, 6, 7, 8, or more) third doses are administered to a patient. In embodiments involving multiple second doses, each second dose can be administered at the same frequency as other second doses. For example, each second dose can be administered to a patient 1 week, 2 weeks, or 3 weeks (e.g., 1 week or 3 weeks) after the previous dose. Similarly, in embodiments involving multiple third doses, each third dose can be administered at the same frequency as other third doses. For example, each third dose can be administered to a patient 1 to 4 weeks (e.g., 1 week or 3 weeks) after the previous dose. Alternatively, during the course of the treatment regimen, the frequency of the second and / or third dose administered to the patient can vary. The physician can also adjust the frequency of administration during the course of treatment, depending on the needs of each patient after the clinical examination. In certain embodiments, one or more doses of a bispecific anti-PSMA / anti-CD3 antibody (e.g., anti-PD-1 antibody) are administered more frequently (twice a week, once a week, once every 2 weeks, or once every 3 weeks) at the beginning of the treatment regimen as an "induction dose," followed by subsequent doses ("consolidation doses" or "maintenance doses") at the same frequency or less frequently (e.g., once every 4-12 weeks). The present disclosure includes methods comprising sequentially administering to a patient a bispecific anti-PSMA / anti-CD3 antibody alone or in combination with an anti-PD-1 antibody to treat prostate cancer (e.g., metastatic castration-resistant prostate cancer). In some embodiments, the methods of the present invention include administering one or more doses of a bispecific anti-PSMA / anti-CD3 antibody, optionally preceded or followed by one or more doses of an anti-PD-1 antibody. In certain embodiments, the method comprises administering a single dose of an anti-PD-1 antibody followed by one or more doses of a bispecific anti-PSMA / anti-CD3 antibody. In some embodiments, one or more doses of an anti-PD-1 antibody of about 0.1 mg / kg to about 20 mg / kg (e.g., 100 mg to 600 mg) may be administered, followed by one or more doses of a bispecific antibody of about 0.1 mg / kg to about 20 mg / kg (e.g., 0.01 mg to 1000 mg) to inhibit tumor growth and / or prevent tumor recurrence in patients with prostate cancer. In some embodiments, the bispecific antibody or combination results in increased anti-tumor efficacy (e.g., greater inhibition of tumor growth and increased prevention of tumor recurrence compared to untreated subjects or subjects administered either antibody as a monotherapy, respectively). Alternative embodiments of the present disclosure relate to concomitant administration of anti-PD-1 antibodies and bispecific antibodies, which are administered in separate doses at a frequency similar to or different from that of the anti-PD-1 antibodies. In some embodiments, the bispecific antibody is administered before, after, or simultaneously with the anti-PD-1 antibody. In certain embodiments, the bispecific antibody is administered as a single-dose formulation with the anti-PD-1 antibody. dose The amount of bispecific anti-PSMA / anti-CD3 antibody, and optionally anti-PD-1 antibody, administered to a subject according to the methods of the present disclosure is generally a therapeutically effective amount. As used herein, the phrase "therapeutically effective amount" refers to an amount of an antibody (anti-PD-1 antibody or bispecific anti-PSMA / anti-CD3 antibody) that results in one or more of the following: (a) reducing the severity or duration of symptoms of cancer (e.g., prostate cancer); (b) inhibiting tumor growth, or increasing tumor necrosis, tumor shrinkage, and / or tumor disappearance; (c) delaying tumor growth and development; (d) inhibiting or delaying or stopping tumor metastasis; (e) preventing tumor recurrence; (f) increasing the survival of subjects with cancer (e.g., prostate cancer); and / or (g) reducing the use or need for conventional anti-cancer therapy (e.g., reducing or eliminating the use of chemotherapeutic agents or cytotoxic agents) compared to untreated subjects or subjects administered either antibody as a monotherapy. In the case of a bispecific anti-PSMA / anti-CD3 antibody, a therapeutically effective amount can be from about 0.01 milligrams (mg) to about 2000 mg, such as about 0.01 mg, about 0.03 mg, about 0.09 mg, about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about or about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, or about 1000 mg of a bispecific anti-PSMA / anti-CD3 antibody. In certain embodiments, 0.03 mg, 0.09 mg, 0.1 mg, 0.3 mg, 0.9 mg, 1 mg, 3 mg, 9 mg, 10 mg, 30 mg, 90 mg, 100 mg, 300 mg, or 900 mg of the bispecific anti-PSMA x anti-CD3 antibody is administered to a subject (e.g., once a week or once every three weeks) to treat a PSMA-expressing cancer or prostate cancer (e.g., metastatic and / or castration-resistant prostate cancer). In the case of an anti-PD-1 antibody, a therapeutically effective amount can be from about 0.05 mg to about 600 mg, for example, about 0.05 mg, about 0.1 mg, about 1.0 mg, about 1.5 mg, about 2.0 mg, about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg g, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, about 350 mg, about 360 mg, about 370 mg, about 380 mg, about 390 mg, about 400 mg, about 410 mg, about 420 mg, about 430 mg, about 440 mg, about 450 mg, about 460 mg, about 470 mg, about 480 mg, about 490 mg, about 500 mg, about 510 mg, about 520 mg, about 530 mg, about 540 mg, about 550 mg, about 560 mg, about 570 mg, about 580 mg, about 590 mg or about 600 mg of anti-PD-1 antibody. In certain embodiments, 300 mg to 400 mg of an anti-PD-1 antibody is administered to a subject in combination with a bispecific antibody (e.g., once every three weeks) to treat a PSMA-expressing cancer or prostate cancer (e.g., metastatic and / or castration-resistant prostate cancer). In certain embodiments, 350 mg of an anti-PD-1 antibody is administered to a subject in combination with a bispecific antibody (e.g., once every three weeks) to treat a PSMA-expressing cancer or prostate cancer (e.g., metastatic and / or castration-resistant prostate cancer). The amount of bispecific anti-PSMA / anti-CD3 antibody and optionally anti-PD-1 antibody contained in a single dose can be expressed in milligrams of antibody per kilogram of subject body weight (i.e., mg / kg). In certain embodiments, the bispecific anti-PSMA / anti-CD3 antibody used in the methods of the present disclosure, and optionally anti-PD-1 antibody, can be administered to a subject at a dose of about 0.0001 to about 100 mg / kg of subject body weight. For example, the bispecific anti-PSMA / anti-CD3 antibody can be administered at a dose of about 0.1 mg / kg to about 20 mg / kg of patient body weight, and optionally the anti-PD-1 antibody can be administered at a dose of about 0.1 mg / kg to about 20 mg / kg of patient body weight. A summary of the sequences cited herein and the corresponding SEQ ID NOs is shown in Table 1 below. Table 1: Sequence summary Example The following examples are provided to provide a person of ordinary skill in the art with a complete disclosure and description of how to prepare and use the methods and compositions of the present invention, and are not intended to limit the scope of what the inventors consider to be their invention. Efforts have been made to ensure the accuracy of the numbers used (e.g., amounts, temperatures, etc.), but certain experimental errors and deviations should be considered. Unless otherwise indicated, parts are parts by weight, molecular weights are average molecular weights, temperatures are in degrees Celsius, and pressures are at or near atmospheric pressure. Example 1: Generation of bispecific antibodies that bind prostate-specific membrane antigen (PSMA) and CD3 The present disclosure provides bispecific antibodies that bind to CD3 and prostate-specific membrane antigen (PSMA); such bispecific antibodies are also referred to herein as anti-PSMA x anti-CD3 bispecific antibodies or anti-PSMA xCD3 bispecific antibodies. The anti-PSMA portion of the anti-PSMA x anti-CD3 bispecific antibody can be used to target tumor cells expressing PSMA, and the anti-CD3 portion of the bispecific antibody can be used to activate T cells. The binding of PSMA to tumor cells and CD3 to T cells promotes the directed killing (cell lysis) of targeted tumor cells by activated T cells. Bispecific antibodies comprising an anti-PSMA specific binding domain and an anti-CD3 specific binding domain were constructed using standard methods, wherein the anti-PSMA antigen binding domain and the anti-CD3 antigen binding domain each comprised a different, unique pair of HCVRs and a common LCVR. The bispecific antibodies were constructed using a heavy chain from an anti-CD3 antibody, a heavy chain from an anti-PSMA antibody, and a common light chain. A summary of the components of the antigen binding domains of the various anti-PSMA x CD3 bispecific antibodies constructed is shown in Table 2. Table 2: Summary of components of PSMAxCD3 bispecific antibodies Example 2: Binding affinity of exemplary bispecific antibodies as measured by FACS analysis In this example, the ability of the anti-PSMA x anti-CD3 bispecific antibody described in Example 1 to bind to human PSMA-expressing cell lines and to human and cynomolgus CD3-expressing cell lines was determined by FACS. In short, 2x10 5Jurkat cells expressing human CD3, cynomolgus monkey T cells, or cells expressing human PSMA specificity were incubated with serial dilutions of bispecific antibodies at 4°C for 30 minutes. After incubation, the cells were washed and goat F(ab')2 anti-human FcγPE-labeled secondary antibody (Jackson Immunolabs) was added to the cells and incubated for another 30 minutes. Next, the cells were washed, resuspended in cold PBS + 1% BSA, and analyzed by flow cytometry on a BD FACS Canto II. For FACS analysis, cells were gated by forward scatter height selected by single events followed by side and forward scatter. The EC of cell-bound titrations was determined using Prism software. 50 Values ​​were calculated using 4-parameter nonlinear regression analysis. Table 3: FACS binding on CD3 and PSMA specific cell lines NB = no binding; NT = not tested As shown in Table 2, the tested anti-PSMA x anti-CD3 bispecific antibodies demonstrated specific binding to B16F10.9 / hPSMA and 22RV1 cell lines expressing human PSMA by FACS. The detection limit of FACS binding was 1 μM EC50. As shown in Table 2, the CD3 binding arm of each PSMA x CD3 bispecific antibody exhibited a range of cell binding affinities for Jurkat cells expressing human CD3 (15 nM to 300 nM EC50 range). Importantly, the CD3 arm that showed weak to undetectable binding to human CD3 heterodimeric protein by surface plasmon resonance (see Table 4 below) was also associated with weak to unobservable binding on Jurkat cells (i.e., CD3-VH-G5). Both tested bispecific antibodies showed similar cell binding on their respective PSMA-expressing cell lines, confirming that bispecific pairing with the CD3 arm alone did not affect or reduce PSMA-specific binding. Example 3: Binding affinity of exemplary antibodies as measured by surface plasmon resonance binding assay The binding affinity and kinetic constants of the anti-PSMA x anti-CD3 bispecific antibodies to the soluble heterodimeric hCD3 mFc protein were determined by surface plasmon resonance at 37°C using an antigen capture format (Table 4). Measurements were performed on a SierraSensors MASS-1 instrument. In the antigen capture format, the MASS-1 high-density amine sensor surface was derivatized with goat anti-mouse IgG2a polyclonal antibody (Southern Biotech). Soluble heterodimeric CD3 protein was captured and the corresponding antibody was injected over the captured antigen. Kinetic binding rate constant (k a ) and the dissociation rate constant (k d ) was determined by processing the data and fitting them to a 1:1 binding model using MASS-1 analyzer R2 curve fitting software. The binding dissociation equilibrium constant (K) was calculated from the kinetic rate constants. D )Reconciliation life(t 1 / 2 ) is calculated as follows: D (M) = k d / k a ; and t 1 / 2 (min)=(ln2 / (60*k d ). Table 4: Affinity of anti-CD3 bispecific antibodies for soluble human CD3 As shown in Table 4, the anti-PSMA x anti-CD3 bispecific antibodies either retained very weak binding to soluble CD3 in the surface plasmon resonance binding assay, e.g., with a K of 334 nM. D values, or did not show any detectable binding. Example 4: T cell activation and tumor-specific cytotoxicity exhibited by bispecific antibodies as measured in vitro In this example, specific killing of target cells expressing PSMA in the presence of anti-PSMA x anti-CD3 bispecific antibodies was monitored by flow cytometry. As previously reported, the bispecific antibodies showed a range of affinities for CD3 proteins and CD3 expressing cell lines. This pair of bispecific antibodies was tested for their ability to induce naive human T cells to redirect killing of cells expressing the target. Briefly, PSMA-expressing (C4-2, 22Rv1, and TRAMPC2_PSMA) cell lines were labeled with 1 μM of the fluorescent tracking dye Violet Cell Tracker. After labeling, cells were plated overnight at 37°C. In addition, human PBMCs were plated at 1×10 6Cells / mL were plated in supplemented RPMI medium and incubated overnight at 37°C to enrich lymphocytes by depleting adherent macrophages, dendritic cells, and some monocytes. The next day, target cells were co-incubated with primary PBMCs depleted of adherent cells (effector cell / target cell ratio of 4:1) and serial dilutions of the relevant bispecific antibody or isotype control for 48 hours at 37°C. Cells were removed from the cell culture plates using enzyme-free cell dissociation buffer and analyzed by FACS. For FACS analysis, cells were stained with a dead / live far-erythrocyte tracer (Invitrogen). Immediately prior to FACS analysis, 5x10 5 For each sample, collect 1x10 4 To assess the specificity of killing, cells were gated on the live purple-labeled population. The percentage of the live population was recorded and used to calculate normalized viability. T cell activation was assessed by incubating cells with directly conjugated antibodies against CD2 and CD69 and reporting the percentage of activated (CD69+) T cells over total T cells (CD2+). As shown in the results in Table 5, depletion of PSMA-expressing cells was observed with the anti-PSMA x anti-CD3 bispecific antibodies. The tested bispecific antibodies activated and directed human T cells to ECs in the picomolar range. 50 In addition, the observed target cell lysis was associated with upregulation of CD69 cells on CD2+ T cells, with pM EC 50 . Importantly, the results of this example demonstrate that a bispecific antibody utilizing a CD3-binding arm that exhibits weak to unobservable binding to CD3 protein or CD3-expressing cells (i.e., CD3-VH-G5) still retains the ability to activate T cells and exhibits potent cytotoxicity against tumor antigen-expressing cells. Table 5: Selected PSMAxCD3 Cytotoxicity and T cell activation properties of bispecific antibodies NT = Not Tested Example 5: Anti-PSMA / anti-CD3 bispecific antibodies show potent anti-tumor efficacy in vivo To determine the in vivo efficacy of exemplary anti-PSMA / anti-CD3 bispecific antibodies, studies were performed in immunocompromised mice bearing human prostate cancer xenografts. Additional studies were also performed in immunocompetent mice bearing mouse prostate cancer xenografts engineered to express human PSMA. Efficacy of anti-PSMA / anti-CD3 bispecific antibodies in human tumor xenograft models To evaluate the in vivo efficacy of the anti-PSMA / anti-CD3 bispecific antibody in human tumor xenograft studies, NOD scidγ (NSG) mice (Jackson Laboratories, Bar Harbor, Maine) were co-implanted with human peripheral blood mononuclear cells (PBMCs) and C4-2 human prostate tumor cells that endogenously express PSMA. In short, 5x10 6 C4-2 cells (MD Anderson, TX) and 1x10 6 Human PBMCs (ReachBio, LLC., Seattle, WA) were co-implanted subcutaneously into the right flank of male NSG mice in a 50:50 mixture of Matrigel matrix (BD Biosciences). Mice were treated intraperitoneally with 0.1 mg / kg of PSMA / CD3-002 on days 0, 4, and 7 after tumor implantation. In another xenogeneic model, the anti-PSMA x anti-CD3 bispecific antibody was tested in mice transplanted with human hematopoietic CD34+ stem cells. Briefly, newborn SIRPαBALB / c-Rag2-IL2rγ-(BRG) pups were implanted with hCD34+ fetal hepatocytes. After 3-6 months, hCD34-transplanted SIRPa BRG mice were then implanted with C4-2 cells (5x10 6 8 days later, mice were treated with 10 ug PSMA / CD3-001 or isotype control antibody and subsequently dosed twice weekly throughout the study. In all studies, tumor size was measured twice weekly using calipers, and tumor volume was calculated as volume = (length x width 2 ) 2 . As shown by the results in Table 6, the bispecific antibodies tested in the xenogeneic models described above were all effective in inhibiting tumor growth compared to treatment with isotype controls. Efficacy of anti-PSMA / anti-CD3 bispecific antibodies in immunocompetent tumor models In addition, the anti-tumor activity of the anti-PSMA x anti-CD3 bispecific antibody was evaluated in an immunocompetent model. Mice humanized for three chains of CD3 (δγε) and for PSMA were implanted with a variant murine prostate cancer cell line TRAMP-C2 transfected with human PSMA. Prior to the start of the study, a tumorigenic cell line variant, TRAMP-C2_hPSMAv#1, was generated. Briefly, 7.5x10 6TRAMP-C2_hPSMA cells were implanted subcutaneously into the right flank of male mice humanized for CD3 and PSMA. The tumor was excised and cut into 3 mm fragments and then implanted into the right flank of new male humanized mice. The tumors generated by the implanted tumor fragments were then harvested and dissociated into single cell suspensions. These cells (TRAMP-C2_hPSMAv#1) were then cultured in vitro under G418 selection. 4.10 6 Cells from this variant cell line were implanted into the flanks of male PSMA / CD3 humanized mice for bispecific antibody efficacy studies. Humanized PSMA / CD3 mice transplanted with TRAMPC2_hPSMAv#1 were treated twice a week with 100ug or 10ug anti-PSMA x anti-CD3 bispecific antibody PSMA / CD3-001 or isotype control starting from the day of tumor implantation. Serum cytokine levels and spleen T cell levels 4h after injection were also examined. The study was terminated on day 27. As shown in the results in Table 7, the anti-PSMA x anti-CD3 bispecific antibody showed significant efficacy in delaying tumor growth in each treatment group. Minimal cytokine release was observed after administration of PSMA / CD3-001, likely due to weak binding of anti-CD3. Notably, no T cell activation was observed in the absence of PSMA-expressing tumor cells. Additionally, in non-tumor bearing mice, blood samples were collected 4 hours after PSMAxCD3 bispecific antibody treatment and serum cytokine levels were determined. A transient increase in cytokine levels (i.e., interferon-γ (IFN-g), tumor necrosis factor (TNF), interleukin-2 (IL-2), and interleukin-6 (IL-6)) was determined and was dose-dependent (data not shown). Table 6: Efficacy of anti-PSMA / anti-CD3 bispecific antibodies in immunocompromised xenograft models Table 7: Efficacy of anti-PSMA / anti-CD3 bispecific antibodies in an immunocompetent syngeneic model (TRAMP-C2 / PSMA Hum / hum CD3 Hum / Hum ) * Mice were dosed with antibodies or isotype controls twice per week starting from the day of tumor implantation #Measured as the percentage of CD4+ or CD8+ cells in the spleen to live mCD45+ cells Example 6: Phase 1 / 2 Study of a Bispecific Anti-PSMA x Anti-CD3 Antibody Administered Alone or in Combination with an Anti-PD-1 Antibody in Patients with Metastatic Castration-Resistant Prostate Cancer This is an open-label, phase 1 / 2, first-in-human, multicenter, dose-escalation study that evaluated the safety, tolerability, pharmacokinetics (PK), and antitumor activity of PSMA / CD3-002 administered subcutaneously alone and in combination with intravenous cemiplimab in patients with metastatic castration-resistant prostate cancer (mCRPC) through cohort expansion. Patients must have received at least two prior lines of approved systemic therapy for metastatic and / or castration-resistant disease, including second-generation anti-androgen therapy. PSMA / CD3-002 is administered once a week as a monotherapy, but can be extended to once every 3 weeks after identification of the lowest pharmacologically active dose. After a 4-week PSMA / CD3-002 monotherapy lead-in cycle, a combination of PSMA / CD3-002 and cemiplimab (350 mg) is administered once every 3 weeks. Study therapy is administered until disease progression, intolerable adverse events, withdrawal of consent, or meeting study withdrawal criteria. The main purpose of dose escalation is to evaluate the safety, tolerability, PK and recommended Phase 2 dosing regimen (RP2DR) of PSMA / CD3-002 alone and in combination with Cimiprilimab. Once the RP2DR is determined, an expansion group will be recruited. During the expansion phase, the main purpose is to evaluate clinical activity, as measured by the objective response rate (ORR) of PSMA / CD3-002 alone or in combination with Cimiprilimab according to the modified Prostate Cancer Working Group 3 criteria. At the selected site, PSMA positron emission tomography / computed tomography will be performed at the scheduled time point of the study. Additional details are provided below. Purpose The primary objectives of this study are: to evaluate the safety, tolerability, and PK of PSMA / CD3-002 alone as monotherapy or in combination with cemiplimab and determine its RP2DR (in dose escalation); and to evaluate the preliminary anti-tumor activity of PSMA / CD3-002 as monotherapy or in combination with cemiplimab, as measured by objective response rate (ORR) according to the modified Prostate Cancer Working Group (PCWG3) criteria (in dose expansion). The secondary objectives of this study are: to evaluate the preliminary anti-tumor activity of PSMA / CD3-002 as a monotherapy or in combination with cemiplimab, as measured by ORR according to modified PCWG3 criteria (in dose escalation); to characterize the safety profile in each expansion cohort (in dose expansion); to characterize the PK of PSMA / CD3-002 as a monotherapy or in combination with cemiplimab (in dose expansion); to evaluate the preliminary anti-tumor activity of PSMA / CD3-002 as a monotherapy or in combination with cemiplimab, as measured by PSA decline (in dose escalation and dose expansion); and to evaluate the immunogenicity of PSMA / CD3-002 in module 1 and the immunogenicity of PSMA / CD3-002 and cemiplimab in module 2 (in dose escalation and dose expansion). The exploratory aims of this study are to: To evaluate the preliminary anti-tumor activity of PSMA / CD3-002 as monotherapy or in combination with cemiplimab as measured by percent change in PSA, disease control rate (DCR), duration of response (DOR), radiographic progression-free survival (rPFS), PSA progression-free survival, overall survival (OS), time to response, and time to progression To evaluate exploratory molecular biomarkers for assessing the impact of PSMA / CD3-002 alone or in combination with cemiplimab to understand the mechanism of action of PSMA / CD3-002, observed toxicities, disease / target, and potential genomic determinants of disease and responsiveness in this patient population To characterize the relationship between serum cytokine levels and clinical tolerability of PSMA / CD3-002 monotherapy or in combination with cemiplimab To identify features of the tumor and its diseased tissue microenvironment that may predict anti-tumor activity or pharmacodynamic response to PSMA / CD3-002 therapy To identify signatures of peripheral immune cell populations that may predict anti-tumor activity or toxicity or pharmacodynamic response to PSMA / CD3-002 therapy To evaluate the effect of PSMA / CD3-002 alone or in combination with cemiplimab on PSMA-positive and fluorodeoxyglucose (FDG)-positive tumors as assessed by PET / CT To assess changes from baseline in the worst pain, average pain, and pain interference in the daily activities scale of the Brief Pain Inventory-Short Form (BPI-SF) To assess the time to pain progression based on BPI-SF item 3 “worst pain in the past 24 hours” To evaluate the effects of PSMA / CD3-002 alone or in combination with cemiplimab on patient-reported disease-specific symptoms, function, and health-related quality of life measures (QLQ-C30, QLQ-PR25, PGIC, PGIS). To evaluate changes in opioid use among patient populations Study Design This is a Phase 1 / 2, first-in-human (FIH), open-label, multicenter study evaluating the safety, tolerability, efficacy, and PK of PSMA / CD3-002, an anti-PSMA x anti-CD3 bispecific antibody (bsAb), administered subcutaneously (SC) as monotherapy (Module 1) or in combination with intravenously (IV) administered cemiplimab (Module 2) in patients with treatment-experienced metastatic castration-resistant prostate cancer (mCRPC). Module 1 will be initiated first; Module 2 will be initiated after the lowest pharmacologically active dose level is identified in Module 1. The study has two parts, dose escalation and dose expansion. All patients in this study will be treated with 2 consecutive "escalating" doses (initial dose and transition dose) of PSMA / CD3-002 until the target dose is reached. The RP2DR determined in dose escalation (including the escalating dosing schedule and the target dose of PSMA / CD3-002) will be further evaluated in dose expansion. Dose escalation: Dose levels are defined by the target dose of PSMA / CD3-002. Five (or up to eight) potential dose levels are designed, where the target dose of PSMA / CD3-002 will be increased in 1 / 2 (half) log increments. Dose escalation of <100% may be implemented depending on the toxicity observed at any given dose level. Module 1 - Determination of the ascending dosing regimen and dose escalation of PSMA / CD3-002 monotherapy; The initial dose of the ascending dosing regimen starts with a 0.03 mg SC dose. All three doses will be increased by 1 / 2 log increments / dose level until the occurrence of specific adverse events (AEs) leads to a modification of the dosing regimen (for the initial dose and transition dose) or the definition of the maximum tolerated dose (MTD) / RP2DR (for the target dose). Administration of the target dose will start on a weekly (QW) schedule and, after the lowest pharmacologically active dose as assessed by PSA or tumor response has been reached, will be converted to once every 3 weeks (Q3W). Module 2 - Dose escalation of PSMA / CD3-002 in combination with cemiplimab: Patients enrolled in Module 2 will receive a 4-week PSMA / CD3-002 monotherapy lead-in cycle (Cycle 0; QW SC, including "escalation" doses). During Module 2, PSMA / CD3-002 will be administered Q3W SC together with cemiplimab 350 mg Q3W IV (Cycle 1+). Dose escalation of PSMA / CD3-002 in Module 2 will start at least 1 dose level below the lowest pharmacologically active dose level of PSMA / CD3-002 determined in Module 1. Evaluation of dose-limiting toxicities during dose escalation: Dose-limiting toxicity (DLT) is any adverse event (AE) that may prevent advancement to a higher dose level. DLT criteria incorporate AEs reported with other bsAbs and checkpoint inhibitors. Toxicity will be graded according to NCI-CTCAE v5.0, except for cytokine release syndrome (CRS), which will be graded according to current American Society for Transplantation and Cellular Therapy (ASTCT) criteria. In both modules, dose level escalation (i.e., target dose escalation) will follow the BOIN (Bayesian Optimal Interval) design rule, which applies the following conditions: 1) DLTs associated with previously untested PSMA / CD3-002 doses will be considered, 2) dose levels will be escalated until the MTD of the PSMA / CD3-002 target dose is observed (toxicity rate 30%); and 3) the maximum number of patients treated at one dose level is 12. In module 1, because the escalation regimen consists of doses that have been tested as target doses and deemed tolerable in the previous escalation cohort (after DL1 in module 1), separate rules will be applied to modify the escalation regimen based on the incidence and severity of cytokine release syndrome (CRS) and other DLTs. DLT Observation Period: Module 1: The DLT observation period in Module 1 (minimum duration of 28 days) begins at the time of administration of the first dose of study drug. Monitoring for DLTs will continue for at least 2 weeks after the first administration of the PSMA / CD3-002 target dose at a given dose level. Because a dose delay of up to 2 weeks is allowed during the escalation period prior to the first administration of the target dose, the maximum duration of the DLT period is 42 days. DLTs observed during the escalation period will be considered separately from DLTs observed at the target dose and considered for modifications to the escalation dosing regimen. DLTs observed at the target dose will determine the tolerability of the target dose and be considered for dose level escalation. Module 2: The DLT observation period was defined as 21 days after the first dose of combination therapy (PSMA / CD3-002 and cemiplimab) starting on Day 1 of Cycle 1. Dose Expansion: During the dose expansion period, patients will receive monotherapy PSMA / CD3-002 (module 1) or combination therapy with cemiplimab 350 mg IV Q3W (module 2) at a designated DL (e.g., RP2DR). If multiple DLs reveal pharmacodynamic activity and are well tolerated, up to 2 expansion cohorts may be opened. Safety evaluations will be performed at each study drug dosing visit during dose escalation and dose expansion. Radiographic response assessments will be performed every 9 weeks (Q9W) throughout the study. The investigator should continue to treat patients with study drug until clinical or confirmed radiographic disease progression according to the modified PCWG3, intolerable AEs, elective discontinuation due to clinical response, withdrawal of consent, or meeting other study withdrawal criteria. Patients who do not withdraw consent will then be expected to continue the non-treatment follow-up program. Study duration All patients will undergo three consecutive trial phases: screening, treatment, and follow-up. The screening period is up to 28 days. The treatment period is divided into multiple cycles based on the frequency of tumor assessments. During the treatment period, treatment cycles in two modules are typically 9 weeks, and tumor assessments are planned at the beginning of each cycle. Module 2 includes 2 shorter cycles (Cycle 0 and Cycle 1), which will be described in detail below. Treatment will continue until disease progression, intolerable AEs, selective discontinuation due to clinical response, withdrawal of consent, or meeting other study withdrawal criteria. Module 1 - PSMA / CD3-002 Monotherapy: The Module 1 treatment period consists of 9-week cycles. During Cycle 1, individual patients will receive at least 2 incremental "escalation" doses of PSMA / CD3-002 (i.e., an initial dose and a transition dose) before reaching the target dose. During the initial dose and / or transition dose period, administration of the first target dose of PSMA / CD3-002 may be delayed for up to 2 weeks to allow for resolution of CRS symptoms. The patient-level study plan for Module 1 is as follows Figure 1 (QW) and Figure 2 (Q3W) provided. Figure 1 and Figure 2 As depicted, during the first three administrations of PSMA / CD3-002, patients will be observed in a monitored setting for at least 72 hours, or if CRS occurs, until systemic symptoms of CRS resolve. If ≥ Grade 2 CRS is observed following an administration, patients should continue to be observed in a monitored setting at each subsequent administration until CRS is ≤ Grade 1 post-injection, at which point their subsequent treatment administrations can be performed in an outpatient setting. Following identification of the lowest pharmacologically active dose level, the next dose level will begin on a Q3W schedule at the PSMA / CD3-002 target dose for subsequently enrolled patients. Figure 2 , the initial, transition, and first two consecutive target dosing intervals will be maintained QW for all patients enrolled into the study. All doses will be administered subcutaneously. For patients enrolled after Q3W dosing was established and who require a prolonged escalation period for resolution of CRS symptoms before receiving the first target dose, Cycle 1 may be extended to maintain the Q3W dosing regimen. The dose escalation schedule and alternatives for Block 1 are shown in Tables 8A and 8B below. Table 8A: Dose escalation schedule for module 1 (monotherapy PSMA / CD3-002) 1 The dosing schedule for the target dose of PSMA / CD3-002 can be QW or Q3W. Table 8B: Alternative dose escalation schedule for Module 1 (PSMA / CD3-002 monotherapy) <![CDATA[DL 1 ]]> Initial dose Transition dose Target dose DL1 0.03mg 0.1mg 0.3mg DL2 0.1mg 0.3mg 1mg DL3 0.3 mg 1mg 3mg DL4 1mg 3mg 10mg DL5 3mg 10mg 30mg DL6 10mg 30mg 100mg DL7 30mg 100mg 300mg DL8 100mg 300mg 900mg 1 The dosing schedule for the target dose of PSMA / CD3-002 can be QW or Q3W. Module 2 - Combination therapy with PSMA / CD3-002 and cemiplimab: The treatment period for patients enrolled in Module 2 will begin with a PSMA / CD3-002 monotherapy lead-in cycle (Cycle 0) consisting of weekly escalating dosing. Due to the potential for enhanced CRS with combination therapy, patients must tolerate the target dose of PSMA / CD3-002 without CRS during the monotherapy lead-in period before starting the combination with cemiplimab. Dosing will be QW during Cycle 0 and will transition to Q3W in Cycle 1. Cycle 0 will consist of weekly monotherapy dosing of PSMA / CD3-002 as initial, transition, and 2 target doses. The planned length of Cycle 0 is 4 weeks but may be extended to 6 weeks to allow for resolution of CRS from the initial and transition doses, or to repeat the target dose to demonstrate tolerability without symptoms of CRS. When initiating PSMA / CD3-002 and cemiplizumab combination therapy, Cycle 1 will be 6 weeks (42 days) to accommodate the timing of the first on-treatment tumor assessment. Subsequent cycles (Cycle 2+) will be 9 weeks (63 days). The patient-level study protocol for Module 2 is as follows: Figure 3 Provided. In module 2, the target dose of PSMA / CD3-002 will not exceed the target dose of PSMA / CD3-002 considered tolerable in module 1. All PSMA / CD3-002 doses will be administered by SC, and cemiplimab will be administered by IV. If ≥ Grade 2 CRS is observed in module 1 for the same dose, the patient will be observed in a monitored environment for the first three injections in cycle 0 (Figure 5). For the first combination treatment in cycle 1, all patients will be observed in a monitored environment for at least 72 hours, or until all CRS symptoms subside. In addition, if ≥ Grade 2 CRS is observed at the start of the combination administration, the patient should continue to receive treatment in a monitored environment for each subsequent administration until the CRS is ≤ Grade 1 after injection, at which time their subsequent treatment can be performed as an outpatient. Table 9A: Dose escalation schedule for Block 2 (PSMA / CD3-002 in combination with Cemiplimab) <![CDATA[DL 1,2 ]]> <![CDATA[Initial dose QW > <![CDATA[Transition dose QW > <![CDATA[Target dose Q3W > <![CDATA[Cemiplimab Q3W > DL1 0.03 0.1 0.3mg 350mg DL2 From M1 From M1 0.9mg 350mg DL3 From M1 From M1 3mg 350mg DL4 From M1 From M1 9mg 350mg DL5 From M1 From M1 30mg 350mg 1 If module 2 starts with initial and transition doses at dose levels defined in module 1, these defined doses will be implemented in module 2. 2 If Module 2 is started before the initial and transition doses are defined, the same dose of PSMA / CD3-002 as specified in Table 8A will be used for the initial and transition doses in Module 2. Table 9B: Alternative dose escalation schedule for Block 2 (PSMA / CD3-002 in combination with cemiplimab) <![CDATA[DL 1,2 ]]> <![CDATA[Initial dose QW > <![CDATA[Transition dose QW > <![CDATA[Target dose Q3W > <![CDATA[Cemiplimab Q3W > DL1 0.03 0.1 0.3mg 350mg DL2 From M1 From M1 1mg 350mg DL3 From M1 From M1 3mg 350mg DL4 From M1 From M1 10mg 350mg DL5 From M1 From M1 30mg 350mg DL6 From M1 From M1 100mg 350mg DL7 From M1 From M1 300mg 350mg DL8 From M1 From M1 900mg 350mg 1 If module 2 starts with initial and transition doses at dose levels defined in module 1, these defined doses will be implemented in module 2. 2 If Module 2 is started before the initial and transition doses are defined, the same dose of PSMA / CD3-002 as specified in Table 8B will be used for the initial and transition doses in Module 2. Study population The study will enroll approximately 199 patients as follows: in the dose escalation phase, approximately 91 patients are expected to be enrolled (43 patients in module 1 and 48 patients in module 2); and in the dose expansion phase, approximately 108 patients are expected to be enrolled. Sample size estimates are based on up to 2 expansion cohorts per module, with a maximum of 27 patients per cohort. The study population included treatment-experienced men with mCRPC. To be included in this study, patients had to have received at least 2 approved therapies for metastatic and / or castration-resistant disease, including a second-generation antiandrogen therapy (eg, abiraterone, enzalutamide, apalutamide, or darolutamide). Inclusion criteria : Patients must meet the following criteria to be eligible for inclusion in this study: 1. Males aged ≥ 18 years 2. Histologically or cytologically confirmed prostate adenocarcinoma without pure small cell carcinoma 3. Metastatic castration-resistant prostate cancer (mCRPC) with a PSA value ≥ 4 ng / mL at screening, which has progressed within 6 months prior to screening according to one of the following: a. PSA progression as defined by a confirmed rise in PSA level with an interval of ≥ 1 week between each assessment. b. Radiographic disease progression in soft tissues based on RECIST version 1.1 criteria (with or without PSA progression) c. Radiographic disease progression in bone, defined as the appearance of 2 or more new bone lesions on bone scan, with or without PSA progression. Note: Measurable lesions according to RECIST version 1.1 based on local readout at screening are not an eligibility criterion for inclusion 4. Progression after or intolerance to ≥2 lines of prior systemic therapy (other than androgen deprivation therapy [ADT]) approved for the metastatic and / or castration-resistant setting, including at least 1 line of second-generation antiandrogen therapy (e.g., abiraterone, enzalutamide, apalutamide, or darolutamide) NOTE: The use of non-taxane-based chemotherapy regimens for metastatic prostate cancer with mixed histology is permitted and will be included when evaluating lines of therapy 5. Able and willing to provide tumor tissue, either archived or newly obtained. Note: For dose escalation only, if archived or fresh tissue is not available, a pathology report confirming the diagnosis of prostate cancer may be submitted 6. Patients who have undergone orchiectomy or are currently receiving luteinizing hormone-releasing hormone (LHRH) agonist or antagonist therapy (serum testosterone <50 ng / dL) and agree to continue receiving LHRH agonist or antagonist therapy during the study 7. ECOG performance status is 0 or 1 8. Adequate organ and bone marrow function documented by the following data: a. Hemoglobin ≥8.5 g / dL b. Absolute neutrophil count ≥ 1.0 x 10 9 / L c. Platelet count ≥100×10 9 pcs / L 9. Serum creatinine ≤1.5x ULN or estimated glomerular filtration rate >50mL / min / 1.73m 2 A 24-hour urine creatinine collection can be used as an alternative to calculating creatinine clearance to meet eligibility criteria. 10. Adequate Liver Function: (1) Total bilirubin ≤1.5x ULN; for patients with known Gilbert's syndrome, ≤3x institutional ULN is permitted (2) AST ≤2.5x ULN (3) ALT ≤2.5x ULN (4) ALP ≤2.5x ULN 11. Willing and able to comply with clinical visit and research related procedures and requirements 12. Willing and able to provide informed consent as specified by health authorities and institutional guidelines 13. Able to understand and complete research-related questionnaires Exclusion criteria Patients who meet any of the following criteria will be excluded from the study: 1. Currently receiving treatment in another study 2. Participated in a study of an investigational agent or device within 4 weeks of the first dose of study therapy 3. Has received treatment with approved systemic therapy (including sipuleucel-T) within 3 weeks of dosing or has not recovered (i.e., ≤ Grade 1 or baseline) from any acute toxicity, except for laboratory changes as described in the inclusion criteria and as follows: a. Patients with neuropathy ≤ grade 2 4. Received radiation therapy or major surgery within 14 days of first administration of study drug, or has not recovered from an AE (i.e., ≤ Grade 1 or baseline), except for laboratory changes as described in the inclusion criteria and as follows: a. Patients with neuropathy ≤ grade 2 5. Received any prior systemic biologic therapy within 5 half-lives of the first dose of study therapy. Note: Patients previously treated with cetuximab, rituximab, or other non-immunomodulatory antibodies with a half-life greater than 7 days are allowed to be included after discussion with the sponsor if at least 30 days have passed since the last treatment. 6. Received previous PSMA targeted therapy 7. Dose escalation and module 1 dose expansion: Patients who have received anticancer immunotherapy (except sipuleucel-T) within 5 half-lives before the study therapy. Examples of immunomodulators include blockers of CTLA-4, 4-1BB (CD137), or OX-40, therapeutic vaccines, anti-PD-1 / PD-L1, phosphoinositide 3-kinase (PI3K) δ inhibitors, or cytokine anticancer therapy. Note: Patients who have received previous investigational cell-based therapy (e.g., CAR-T cells) are excluded 8. Module 2 Dose Expansion: Patients who have received previous anticancer immunotherapy. Examples of immunomodulators include CTLA-4, 4-1BB (CD137), or OX-40 blockers, therapeutic vaccines, anti-PD-1 / PD-L1, PI3Kδ inhibitors, CAR-T cells, or cytokine anticancer therapy. Note: Previous treatment with sipuleucel-T is allowed 9. Patients who have not recovered (i.e., ≤ Grade 1 or baseline) from an immune-mediated AE within 3 months prior to starting study drug therapy, except for endocrine disease adequately managed by hormone replacement therapy 10. Patients who permanently discontinued anticancer immunomodulatory therapy due to immune-related AEs 11. Any condition requiring ongoing / continuous corticosteroid therapy (>10 mg prednisone / day or anti-inflammatory equivalent) within 1 week prior to the first dose of study drug. Physiological replacement doses are permitted, even if they are >10 mg prednisone / day or equivalent, as long as they are not administered for immunosuppressive purposes. Inhaled or topical steroids are permitted provided they are not used to treat autoimmune disorders. NOTE: Patients requiring short-term use of steroids (up to 2 days in the week prior to recruitment) or physiological replacement therapy may be recruited into this study 12. Evidence of current or recent (within 5 years) significant autoimmune disease requiring systemic immunosuppressive therapy. The following conditions are not excluded: vitiligo, resolved childhood asthma, endocrine diseases requiring only hormone replacement therapy (such as hypothyroidism or type 1 diabetes), or psoriasis that does not require systemic treatment. 13. Liver metastasis 14. Suffering from another malignant tumor that is progressing or requires active treatment, except: a. Non-melanoma skin cancer that has undergone potentially curative therapy b. Any tumor that is considered to be effectively treated by definitive local control (with or without continued adjuvant hormonal therapy) 15. Dose escalation: History of CNS metastases (including previously treated metastases) Dose expansion: Untreated or active primary brain tumor, CNS metastasis, leptomeningeal disease, or spinal cord compression. Exceptions: Patients with previously treated CNS metastasis or spinal cord compression may participate if: a. No evidence of progression for at least 6 weeks prior to the first dose of study drug, and any neurological symptoms have recovered to baseline b. No evidence of new or expanding central nervous system metastases c. No need for systemic corticosteroids to manage CNS metastases or spinal cord compression within 2 weeks prior to the first dose of study drug 16. Encephalitis, meningitis, neurodegenerative disease (except mild dementia that does not interfere with activities of daily living [ADL]), or uncontrolled epilepsy within one year prior to the first dose of study therapy 17. Known history or any evidence of interstitial lung disease or active non-infectious pneumonitis within 5 years before the first dose of study drug. History of radiation pneumonitis in the radiation field is allowed 18. Uncontrolled human immunodeficiency virus infection, hepatitis B or hepatitis C infection; or diagnosed with immunodeficiency a. Patients will be tested for Hepatitis C virus (HCV) and Hepatitis B virus (HBV) at screening b. Patients with known HIV infection whose infection has been controlled (undetectable viral load (HIV RNA PCR) and CD4 count above 350, either spontaneously or while receiving a stable antiviral regimen) are allowed to be included. Patients with controlled HIV infection will be monitored according to local standards. c. Patients with hepatitis B (HBsAg+) whose infection has been controlled (serum HBV DNA PCR below the limit of detection and receiving HBV antiviral therapy) are allowed to be included. Patients with controlled infection must have HBV DNA monitored regularly. Patients must continue to receive antiviral therapy for at least 6 months after the last dose of study drug d. Patients who are HCV Ab+ and whose infection is controlled (undetectable HCV RNA by PCR, either spontaneously or as a response to previous successful anti-HCV therapy) can be enrolled in this study 19. Any infection requiring hospitalization or intravenous anti-infective medication within 2 weeks after the first dose of study drug 20. Received a live vaccine within 28 days of planned start of study drug 21. Received allogeneic stem cell transplantation or organ transplantation at any time, or received autologous stem cell transplantation within 12 weeks of starting study drug 22. Known allergic reaction or hypersensitivity to components of the study drug. 23. Known to have a mental illness or substance abuse disorder that may interfere with participation in this study 24. Any medical condition, comorbidity, physical examination findings, metabolic dysfunction, or clinical laboratory abnormalities that the investigator believes makes the patient unsuitable for participation in the clinical study due to high safety risks and / or the possibility of affecting the interpretation of study results, including but not limited to severe cardiovascular disease (e.g., New York Heart Association class III or IV heart disease, myocardial infarction within the previous 6 months, unstable arrhythmia, or unstable angina) and / or severe pulmonary disease (e.g., history of obstructive pulmonary disease and symptomatic bronchospasm) 25. Cardiac ejection fraction < 40% as measured by echocardiography or multi-gated acquisition scan (MUGA) Study treatment PSMA / CD3-002 will be administered by SC administration at a dose of 0.3 mg to 30 mg (but up to 900 mg) QW or Q3W as a target dose level. Cimiprizumab will be administered Q3W at a dose of 350 mg via intravenous infusion over 30 minutes. When both drugs are administered on the same day, PSMA / CD3-002 will be administered first, and cemiplimab should be administered no less than 30 minutes after the completion of PSMA / CD3-002 administration. Starting from C1D1, all enrolled patients will require regular steroid premedication as follows: · 10 mg dexamethasone IV / PO on the day of dosing and one day after dosing until the second full dose (e.g., C1D22) · After the second full dose, start tapering 10 mg IV / PO at 3rd full dose (e.g., C1D29) 6 mg IV / PO at 4th full dose (e.g., C1D36) Study Endpoints The primary endpoints of this study were: dose-limiting toxicities, other treatment-emergent adverse events (TEAEs; including irAEs), serious AEs (SAEs), adverse events of special interest (AESIs), and laboratory abnormalities (in dose escalation); serum concentrations of PSMA / CD3-002 alone or in combination with cemiplimab (in dose escalation); and objective response rate (ORR) according to modified Prostate Cancer Working Group 3 (PCWG3) criteria (in dose expansion), which was defined as the percentage of patients achieving a response based on: - PSA decrease of ≥50% from baseline, confirmed by a second PSA test ≥4 weeks later, and / or - Radiographically confirmed response of complete remission (CR) or partial remission (PR) Key secondary endpoints were: ORR according to modified PCWG3 criteria (in dose escalation), defined as the percentage of patients who achieved a response based on a ≥50% decrease in PSA from baseline (confirmed by a second PSA test ≥4 weeks later), and / or the percentage of patients with a radiographically confirmed response of a complete response (CR) or partial response (PR); dose-limiting toxicities, other TEAEs (including irAEs), SAEs, AESIs, and laboratory abnormalities (in dose expansion); serum levels of PSMA / CD3-002 as monotherapy or in combination with cemiplimab concentration (in dose expansion); percentage of patients with a ≥50% decline from baseline in PSA confirmed by a second PSA test ≥4 weeks later (in dose escalation and dose expansion); percentage of patients with a ≥90% decline from baseline in PSA confirmed by a second PSA test ≥4 weeks later (in dose escalation and dose expansion); and immunogenicity, as measured by anti-drug antibodies (ADA) to PSMA / CD3-002 in module 1 and ADA to PSMA / CD3-002 and cemiplimab in module 2 (in dose escalation and dose expansion). Exploratory endpoints were: Percent change in PSA Disease control rate (DCR) (by modified PCWG3 and iRECIST) Duration of response (DOR) based on radiographic response (rDOR) (by modified PCWG3 and iRECIST) DOR based on PSA response Radiographic progression-free survival (rPFS) (determined by modified PCWG3 and iRECIST) PSA progression-free survival Overall survival (OS) Time to response based on radiographic response (by modified PCWG3 and iRECIST) ·Based on the time to reaction of PSA reaction Time to progression based on radiographic progression Time to progression based on PSA progression Abundance and distribution of therapeutic targets (e.g., PD-1 / PD-L1, PSMA, and CD3+ T cells) in tumor tissue samples at baseline and over time during therapy Association of CTC abundance and molecular characteristics with clinical efficacy Tumor mutation profiles of ctDNA, CTCs, and / or tumor tissue at baseline and during treatment, including assessment of individual somatic variants, tumor mutational burden (TMB), alterations in DNA repair pathway genes, and evaluation of the relationship between these features and drug response The abundance and phenotype of circulating T cell subsets at baseline and during treatment, and their pharmacodynamic responsiveness and association with clinical efficacy or toxicity Concentrations of systemic inflammatory markers (eg, serum cytokines) as well as immune activity and clinical toxicity Changes from baseline in tumor PSMA and FDG PET signals after initiation of therapy Association of baseline PSMA PET tumor positivity with clinical activity Time to pain progression (TTPP) as assessed by the Brief Pain Inventory-SF (BPI-SF) item 3 (“worst pain in 24 hours”) and use of opioid analgesics Change from baseline in pain severity and pain interference as measured by the BPI-SF Change from baseline in GHS / QoL as measured by the EORTC QLQ-C30 GHS / QoL scale score Change from baseline in physical function as measured by the EORTC QLQ-C30 physical function scale score Change from baseline in urinary symptoms as measured by the EORTC QLQ-PR25 urinary symptom scale score Results: It is expected that administration of PSMA / CD3-002 and cemiplimab in patients with prostate cancer will result in complete or partial responses with durable disease control. The scope of the present invention is not limited by the specific embodiments described herein. In fact, various modifications of the present invention, except those described herein, will become apparent to those skilled in the art from the foregoing description. Such modifications are intended to fall within the scope of the appended claims. Table 10: Sequences excluded from ST.26 format sequence listing SEQ ID NO: sequence 9 AAS 27 AAS *******

Claims

1. A method of treating a PSMA-expressing cancer in a subject in need thereof, the method comprising administering to the subject a bispecific antibody comprising a first antigen binding domain that specifically binds to prostate specific membrane antigen (PSMA) on a target tumor cell and a second antigen binding domain that specifically binds to human CD3 on a T cell, wherein the bispecific antibody is administered to the subject at a dose of at least 0.03 mg.

2. The method of claim 1, wherein the PSMA-expressing cancer is prostate cancer.

3. The method of claim 1 or 2, wherein the PSMA-expressing cancer is metastatic prostate cancer.

4. The method of any one of claims 1 to 3, wherein the PSMA-expressing cancer is castration-resistant prostate cancer.

5. The method of any one of claims 1 to 4, wherein the subject has received at least two prior therapies for metastatic and / or castration-resistant prostate cancer.

6. The method of claim 5, wherein the subject has received at least one anti-androgen therapy.

7. The method of claim 6, wherein the anti-androgen therapy is selected from abiraterone, enzalutamide, apalutamide, or darolutamide.

8. The method of any one of claims 1 to 7, wherein the subject has histologically or cytologically confirmed prostate adenocarcinoma without pure small cell carcinoma.

9. The method of any one of claims 1 to 8, wherein the subject has metastatic castration-resistant prostate cancer with a prostate-specific antigen (PSA) value ≥ 4 ng / ml prior to treatment with the bispecific antibody.

10. The method of claim 9, wherein the subject's cancer has progressed within a 6 month period prior to treatment with the bispecific antibody, wherein cancer progression is determined by: (a) an increase in PSA levels confirmed with ≥ 1 week between each assessment; (b) radiographic disease progression in soft tissues, with or without an increase in PSA; and / or (c) radiographic disease progression in bones, with the appearance of two or more bone lesions on a bone scan, with or without an increase in PSA.

11. The method of any one of claims 1 to 10, wherein the subject has undergone an orchiectomy.

12. The method of any one of claims 1 to 10, wherein the subject is receiving luteinizing hormone releasing hormone (LHRH) agonist or antagonist therapy and has a serum testosterone level of <50 ng / ml prior to treatment with the bispecific antibody.

13. The method of any one of claims 1 to 12, wherein the first antigen binding domain comprises: (a) three heavy chain complementarity determining regions (HCDR1, HCDR2 and HCDR3) contained within a heavy chain variable region (HCVR) having the amino acid sequence of SEQ ID NO: 1; and (b) three light chain complementarity determining regions (LCDR1, LCDR2 and LCDR3), wherein the three light chain complementarity determining regions are contained in a light chain variable region (LCVR) having the amino acid sequence of SEQ ID NO:

2.

14. The method of claim 13, wherein the first antigen binding domain comprises a HCDR1 having an amino acid sequence of SEQ ID NO: 5, a HCDR2 having an amino acid sequence of SEQ ID NO: 6, and a HCDR3 having an amino acid sequence of SEQ ID NO:

7.

15. The method of claim 13 or claim 14, wherein the first antigen binding domain comprises LCDR1 having the amino acid sequence of SEQ ID NO: 8, LCDR2 having the amino acid sequence of SEQ ID NO: 9, and LCDR3 having the amino acid sequence of SEQ ID NO:

10.

16. The method of any one of claims 13 to 15, wherein the first antigen binding domain comprises a HCVR having the amino acid sequence of SEQ ID NO: 1 and a LCVR having the amino acid sequence of SEQ ID NO:

2.

17. The method of any one of claims 1 to 16, wherein the second antigen binding domain comprises: (a) three heavy chain complementarity determining regions (HCDR1, HCDR2 and HCDR3) contained within a heavy chain variable region (HCVR) having the amino acid sequence of SEQ ID NO: 4; and (b) three light chain complementarity determining regions (LCDR1, LCDR2 and LCDR3), wherein the three light chain complementarity determining regions are contained in a light chain variable region (LCVR) having the amino acid sequence of SEQ ID NO:

2.

18. The method of claim 17, wherein the second antigen binding domain comprises a HCDR1 having the amino acid sequence of SEQ ID NO: 14, a HCDR2 having the amino acid sequence of SEQ ID NO: 15, and a HCDR3 having the amino acid sequence of SEQ ID NO:

16.

19. The method of claim 17 or claim 18, wherein the second antigen binding domain comprises LCDR1 having the amino acid sequence of SEQ ID NO: 8, LCDR2 having the amino acid sequence of SEQ ID NO: 9, and LCDR3 having the amino acid sequence of SEQ ID NO:

10.

20. The method of any one of claims 17 to 19, wherein the second antigen binding domain comprises a HCVR having the amino acid sequence of SEQ ID NO: 4 and a LCVR having the amino acid sequence of SEQ ID NO:

2.

21. The method of any one of claims 1 to 16, wherein the second antigen binding domain comprises: (a) three heavy chain complementarity determining regions (HCDR1, HCDR2 and HCDR3) contained within a heavy chain variable region (HCVR) having the amino acid sequence of SEQ ID NO: 3; and (b) three light chain complementarity determining regions (LCDR1, LCDR2 and LCDR3), wherein the three light chain complementarity determining regions are contained in a light chain variable region (LCVR) having the amino acid sequence of SEQ ID NO:

2.

22. The method of claim 21, wherein the second antigen binding domain comprises a HCDR1 having the amino acid sequence of SEQ ID NO: 11, a HCDR2 having the amino acid sequence of SEQ ID NO: 12, and a HCDR3 having the amino acid sequence of SEQ ID NO:

13.

23. The method of claim 21 or claim 22, wherein the second antigen binding domain comprises LCDR1 having the amino acid sequence of SEQ ID NO:8, LCDR2 having the amino acid sequence of SEQ ID NO:9, and LCDR3 having the amino acid sequence of SEQ ID NO:

10.

24. The method of any one of claims 21 to 23, wherein the second antigen binding domain comprises a HCVR having the amino acid sequence of SEQ ID NO: 3 and a LCVR having the amino acid sequence of SEQ ID NO:

2.

25. The method of any one of claims 1 to 24, wherein the bispecific antibody comprises a human IgG heavy chain constant region.

26. The method of claim 25, wherein the human IgG heavy chain constant region is of isotype IgGl.

27. The method of claim 25, wherein the human IgG heavy chain constant region is of isotype IgG4.

28. The method of claim 26 or claim 27, wherein the bispecific antibody comprises a chimeric hinge that reduces Fcγ receptor binding compared to a wild-type hinge of the same isotype.

29. The method of any one of claims 25 to 28, wherein the first heavy chain or the second heavy chain, but not both, comprises a CH3 domain comprising a H435R (EU numbering) modification and a Y436F (EU numbering) modification.

30. The method of any one of claims 1 to 24, wherein the bispecific antibody comprises a first heavy chain having the amino acid sequence of SEQ ID NO:

17.

31. The method of any one of claims 1 to 24, wherein the bispecific antibody comprises a second heavy chain having the amino acid sequence of SEQ ID NO:

20.

32. The method of any one of claims 1 to 24, wherein the bispecific antibody comprises a second heavy chain having the amino acid sequence of SEQ ID NO:

19.

33. The method of any one of claims 1 to 24, wherein the bispecific antibody comprises a first heavy chain having an amino acid sequence of SEQ ID NO: 17, a second heavy chain having an amino acid sequence of SEQ ID NO: 20, and a common light chain having an amino acid sequence of SEQ ID NO:

18.

34. The method of any one of claims 1 to 24, wherein the bispecific antibody comprises a first heavy chain having the amino acid sequence of SEQ ID NO: 17, a second heavy chain having the amino acid sequence of SEQ ID NO: 19, and a common light chain having the amino acid sequence of SEQ ID NO:

18.

35. The method of any one of claims 1 to 34, further comprising administering a second therapeutic agent or treatment regimen.

36. The method of claim 35, wherein the second therapeutic agent or treatment regimen comprises an anti-PD-1 antibody or antigen-binding fragment thereof.

37. The method of claim 36, wherein the anti-PD-1 antibody or antigen-binding fragment comprises: (a) three heavy chain complementarity determining regions (HCDR1, HCDR2 and HCDR3) contained within a heavy chain variable region (HCVR) having the amino acid sequence of SEQ ID NO: 21; and (b) three light chain complementarity determining regions (LCDR1, LCDR2 and LCDR3), wherein the three light chain complementarity determining regions are contained in a light chain variable region (LCVR) having the amino acid sequence of SEQ ID NO:

22.

38. The method of claim 37, wherein the anti-PD-1 antibody or antigen-binding fragment comprises a HCDR1 having an amino acid sequence of SEQ ID NO: 23, a HCDR2 having an amino acid sequence of SEQ ID NO: 24, and a HCDR3 having an amino acid sequence of SEQ ID NO:

25.

39. The method of claim 37 or claim 38, wherein the anti-PD-1 antibody or antigen-binding fragment comprises LCDR1 having the amino acid sequence of SEQ ID NO: 26, LCDR2 having the amino acid sequence of SEQ ID NO: 27, and LCDR3 having the amino acid sequence of SEQ ID NO:

28.

40. The method of any one of claims 37 to 39, wherein the anti-PD-1 antibody or antigen-binding fragment comprises a HCVR having the amino acid sequence of SEQ ID NO: 21 and a LCVR having the amino acid sequence of SEQ ID NO:

22.

41. The method of claim 40, wherein the anti-PD-1 antibody or antigen-binding fragment is an anti-PD-1 antibody comprising a heavy chain having the amino acid sequence of SEQ ID NO: 29 and a light chain having the amino acid sequence of SEQ ID NO:

30.

42. The method of any one of claims 1 to 41, wherein the bispecific antibody is administered to the subject at a dose of 0.01 mg to 1000 mg per week.

43. The method of claim 42, wherein the bispecific antibody is administered to the subject at a dose of 0.03 mg to 30 mg per week.

44. The method of claim 42, wherein the bispecific antibody is administered to the subject at a dose of 3 mg to 900 mg per week.

45. The method of any one of claims 1 to 41, wherein the bispecific antibody is administered to the subject at a dose of 0.01 mg to 1000 mg once every three weeks.

46. ​​The method of claim 45, wherein the bispecific antibody is administered to the subject at a dose of 0.03 mg to 30 mg once every three weeks.

47. The method of claim 45, wherein the bispecific antibody is administered to the subject at a dose of 3 mg to 900 mg once every three weeks.

48. The method of any one of claims 36 to 47, wherein the anti-PD-1 antibody is administered to the subject at a dose of 300 to 400 mg once every three weeks.

49. The method of claim 48, wherein the anti-PD-1 antibody is administered to the subject at a dose of 350 mg once every three weeks.

50. The method of any one of claims 1 to 49, wherein the subject is in stable disease, partial remission, or complete remission after administration of the bispecific antibody at a dose of 0.03 mg to 900 mg for at least one week.

51. The method of any one of claims 1 to 50, wherein following administration of one or more doses of the bispecific antibody, radiographic imaging is performed on the subject.

52. The method of claim 51, wherein the radiographic imaging comprises a fluorine F18DCFPyL PET / CT scan.

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