Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
  • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
  • C07K16/28—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
  • C07K16/30—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants from tumour cells
  • C07K16/3069—Reproductive system, e.g. ovaria, uterus, testes, prostate
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
  • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
  • C07K16/28—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
  • C07K16/2803—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
  • C07K16/2809—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against the T-cell receptor (TcR)-CD3 complex
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
  • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
  • C07K16/28—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
  • C07K16/2803—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
  • C07K16/2818—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against CD28 or CD152
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K39/00—Medicinal preparations containing antigens or antibodies
  • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K39/00—Medicinal preparations containing antigens or antibodies
  • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
  • A61K2039/507—Comprising a combination of two or more separate antibodies
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K39/00—Medicinal preparations containing antigens or antibodies
  • A61K2039/54—Medicinal preparations containing antigens or antibodies characterised by the route of administration
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K39/00—Medicinal preparations containing antigens or antibodies
  • A61K2039/545—Medicinal preparations containing antigens or antibodies characterised by the dose, timing or administration schedule
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K2317/00—Immunoglobulins specific features
  • C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
  • C07K2317/31—Immunoglobulins specific features characterized by aspects of specificity or valency multispecific
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K2317/00—Immunoglobulins specific features
  • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
  • C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K2317/00—Immunoglobulins specific features
  • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
  • C07K2317/73—Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K2317/00—Immunoglobulins specific features
  • C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
  • C07K2317/92—Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value

Definitions

• the present invention relates to methods 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 programmed death 1 (PD-1) receptor.
• PSMA prostate-specific membrane antigen
• PD-1 programmed death 1
• Prostate-specific membrane antigen also known as FOLH1 , glutamate carboxypeptidase II (GCPII), N-acetyl-L-aspartyl-L-glutamate peptidase I (NAALADase I), or N- acetyl-aspartylglutamate (NAAG) peptidase
• FOLH1 glutamate carboxypeptidase II
• NAALADase I N-acetyl-L-aspartyl-L-glutamate peptidase I
• NAAG N- acetyl-aspartylglutamate
• PSMA is an integral, non-shed membrane glycoprotein highly expressed on malignant prostate tissue and is a cell-surface marker for prostate cancer, but shows limited expression on normal tissue.
• Yttrium-90 capromab is a radiotherapeutic comprising a monoclonal antibody to an intracellular epitope of PSMA.
• J591 a monoclonal antibody to an extracellular epitope of PSMA, is part of the radiotherapeutic Lutetium-177 J591 and in MLN2704, in which maytansinoid 1 (DM1 , an antimicrotubule agent) is conjugated to J591.
• DM1 maytansinoid 1
• PSMA is also expressed within the neovasculature of other tumors such as bladder, renal, gastric, and colorectal carcinomas.
• CD3 is a homodimeric or heterodimeric antigen expressed on T cells in association with the T cell receptor complex (TCR) and is required for T cell activation.
• Functional CD3 is formed from the dimeric association of two of four different chains: epsilon, zeta, delta and gamma.
• the CD3 dimeric arrangements include gamma/epsilon, delta/epsilon and zeta/zeta.
• Antibodies against CD3 have been shown to cluster CD3 on T cells, thereby causing T cell activation in a manner similar to the engagement of the TCR by peptide-loaded MHC molecules.
• anti-CD3 antibodies have been proposed for therapeutic purposes involving the activation of T cells.
• bispecific antibodies that are capable of binding CD3 and a target antigen have been proposed for therapeutic uses involving targeting T cell immune responses to tissues and cells expressing the target antigen.
• 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.
• Blockade of the PD-1 signaling pathway has demonstrated clinical activity in patients with multiple tumor types, and antibody therapeutics 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 has demonstrated the clinical activity of PD-1 blockade in patients with aggressive NHL and Hodgkin's lymphoma (Lesokhin, et al.
• 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. There were 1 .3 million new cases of prostate cancer and 358,989 deaths estimated worldwide in 2018. Therapies blocking androgen related pathways have been the standard for decades in treating prostate cancers. However, patients progress on androgen depletion and/or surgical castration and develop castration resistant prostate cancer. Prognosis is especially poor for men with metastatic castration resistant prostate cancer (mCRPC). Currently, metastatic prostate cancers remain incurable and improvement in long-term survival remains a high unmet need.
• mCRPC metastatic castration resistant prostate cancer
• the present disclosure provides methods for treating, ameliorating at least one symptom or indication, or inhibiting the growth of a PSMA-expressing cancer in a subject.
• the methods according to this aspect of the disclosure comprise administering 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) to a subject in need thereof.
• PSMA prostate specific membrane antigen
• PD-1 programmed death 1
• methods are provided for treating, ameliorating at least one symptom or indication, or inhibiting the growth of a PSMA-expressing cancer in a subject.
• methods for delaying the growth of a tumor or preventing tumor recurrence.
• the methods comprise sequentially administering 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 antigen-binding fragment thereof to a subject in need thereof.
• the present disclosure provides a method of treating a PSMA-expressing cancer in a subject in need thereof, comprising administering to the subject a bispecific antibody comprising a first antigen-binding domain that specifically binds prostate specific membrane antigen (PSMA) on a target tumor cell, and a second antigen-binding domain that specifically binds human CD3 on a T cell, wherein the bispecific antibody is administered to the subject at a dose of at least 0.03 mg.
• PSMA prostate specific membrane antigen
• the PSMA-expressing cancer is prostate cancer. In some cases, the PSMA-expressing cancer is metastatic prostate cancer. In some cases, the PSMA-expressing cancer is castration-resistant prostate cancer.
• the subject has received at least two prior therapies for metastatic and/or castration-resistant prostate cancer.
• the subject has received at least one anti-androgen therapy.
• the anti-androgen therapy is selected from abiraterone, enzalutamide, apalutamide, or darolutamide.
• the subject has histologically or cytologically confirmed adenocarcinoma of the prostate without pure small cell carcinoma.
• the subject has metastatic castration-resistant prostate cancer with a prostate specific antigen (PSA) value of >4 ng/ml prior to treatment with the bispecific antibody.
• PSA prostate specific antigen
• the subject’s cancer has progressed within a six month period prior to treatment with the bispecific antibody, wherein cancer progression is determined by: (a) a rising PSA level confirmed with an interval of > 1 week between each assessment; (b) radiographic disease progression in soft tissue with or without a rise in PSA; and/or (c) radiographic disease progression in bone with an appearance of two or more bone lesions on bone scan with or without a rise in PSA.
• the subject has had an orchiectomy.
• 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.
• LHRH luteinizing hormone-releasing hormone
• the first antigen-binding domain of the bispecific antibody comprises: (a) three heavy chain complementarity determining regions (HCDR1, HCDR2 and HCDR3) contained within a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 1 ; and (b) three light chain complementarity determining regions (LCDR1 , LCDR2 and LCDR3) contained within a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 2.
• the first antigenbinding domain comprises a HCDR1 comprising the amino acid sequence of SEQ ID NO: 5, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 6, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 7.
• the first antigen-binding domain comprises a LCDR1 comprising the amino acid sequence of SEQ ID NO: 8, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 9, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 10.
• the first antigen-binding domain comprises a HCVR comprising the amino acid sequence of SEQ ID NO: 1 , and a LCVR comprising the amino acid sequence of SEQ ID NO: 2.
• the second antigen-binding domain of the bispecific antibody comprises: (a) three heavy chain complementarity determining regions (HCDR1, HCDR2 and HCDR3) contained within a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 4; and (b) three light chain complementarity determining regions (LCDR1 , LCDR2 and LCDR3) contained within a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 2.
• the second antigenbinding domain comprises a HCDR1 comprising the amino acid sequence of SEQ ID NO: 14, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 15, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 16.
• the second antigen-binding domain comprises a LCDR1 comprising the amino acid sequence of SEQ ID NO: 8, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 9, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 10.
• the second antigen-binding domain comprises a HCVR comprising the amino acid sequence of SEQ ID NO: 4, and a LCVR comprising the amino acid sequence of SEQ ID NO: 2.
• the second antigen-binding domain of the bispecific antibody comprises: (a) three heavy chain complementarity determining regions (HCDR1, HCDR2 and HCDR3) contained within a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 3; and (b) three light chain complementarity determining regions (LCDR1 , LCDR2 and LCDR3) contained within a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 2.
• the second antigenbinding domain comprises a HCDR1 comprising the amino acid sequence of SEQ ID NO: 11 , a HCDR2 comprising the amino acid sequence of SEQ ID NO: 12, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 13.
• the second antigen-binding domain comprises a LCDR1 comprising the amino acid sequence of SEQ ID NO: 8, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 9, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 10.
• the second antigen-binding domain comprises a HCVR comprising the amino acid sequence of SEQ ID NO: 3, and a LCVR comprising the amino acid sequence of SEQ ID NO: 2.
• the bispecific antibody may comprise a human IgG heavy chain constant region.
• the human IgG heavy chain constant region is isotype lgG1.
• the human IgG heavy chain constant region is isotype lgG4.
• the bispecific antibody may comprise a chimeric hinge that reduces Fey receptor binding relative to a wild-type hinge of the same isotype.
• the first heavy chain of the bispecific antibody or the second heavy chain of the bispecific antibody may comprise a CH3 domain comprising a H435R (EU numbering) modification and a Y436F (EU numbering) modification.
• the bispecific antibody comprises a first heavy chain comprising the amino acid sequence of SEQ ID NO: 17.
• the bispecific antibody comprises a second heavy chain comprising the amino acid sequence of SEQ ID NO: 20.
• the bispecific antibody comprises a second heavy chain comprising the amino acid sequence of SEQ ID NO: 19.
• the bispecific antibody comprises a light chain comprising the amino acid sequence of SEQ ID NO: 18.
• the bispecific antibody comprises a first heavy chain comprising the amino acid sequence of SEQ ID NO: 17, a second heavy chain comprising the amino acid sequence of SEQ ID NO: 20, and a common light chain comprising the amino acid sequence of SEQ ID NO: 18.
• the bispecific antibody comprises a first heavy chain comprising the amino acid sequence of SEQ ID NO: 17, a second heavy chain comprising the amino acid sequence of SEQ ID NO: 19, and a common light chain comprising the amino acid sequence of SEQ ID NO: 18.
• the method may further comprise administering a second therapeutic agent or therapeutic regimen.
• the second therapeutic agent or therapeutic regimen comprises an anti-PD-1 antibody or antigenbinding fragment thereof.
• 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) comprising the amino acid sequence of SEQ ID NO: 21; and (b) three light chain complementarity determining regions (LCDR1 , LCDR2 and LCDR3) contained within a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 22.
• HCVR heavy chain variable region
• LCVR light chain complementarity determining regions
• the anti-PD-1 antibody or antigen-binding fragment comprises a HCDR1 comprising the amino acid sequence of SEQ ID NO: 23, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 24, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 25.
• the anti-PD-1 antibody or antigen-binding fragment comprises a LCDR1 comprising the amino acid sequence of SEQ ID NO: 26, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 27, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 28.
• the anti-PD-1 antibody or antigen-binding fragment comprises a HCVR comprising the amino acid sequence of SEQ ID NO: 21 , and a LCVR comprising the amino acid sequence of SEQ ID NO: 22.
• the anti-PD-1 antibody or antigen-binding fragment is an anti-PD-1 antibody comprising a heavy chain comprising the amino acid sequence of SEQ ID NO: 29 and a light chain comprising the amino acid sequence of SEQ ID NO: 30.
• the bispecific antibody may be administered to the subject at a dose of from 0.01 mg to 1000 mg weekly. In some cases, the bispecific antibody is administered to the subject at a dose of from 0.03 mg to 30 mg weekly. In some cases, the bispecific antibody is administered to the subject at a dose of from 3 mg to 900 mg weekly. In some cases, the bispecific antibody is administered to the subject at a dose of from 30 mg to 900 mg weekly. In some cases, the bispecific antibody is administered to the subject at a dose of from 300 mg to 900 mg weekly.
• the bispecific antibody may be administered to the subject at a dose of from 0.01 mg to 1000 mg once every three weeks. In some cases, the bispecific antibody is administered to the subject at a dose of from 0.03 mg to 30 mg once every three weeks. In some cases, the bispecific antibody is administered to the subject at a dose of from 3 mg to 900 mg once every three weeks. In some cases, the bispecific antibody is administered to the subject at a dose of from 30 mg to 900 mg once every three weeks. In some cases, the bispecific antibody is administered to the subject at a dose of from 300 mg to 900 mg once every three weeks.
• the anti-PD-1 antibody may be administered to the subject at a dose of from 300 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. [0032] In any of the various embodiments discussed above or herein, the subject has stable disease, a partial response, or a complete response following administration of the bispecific antibody for at least one week at a dose of from 0.03 mg to 900 mg.
• the subject may be subjected to radiographic imaging prior to and/or following administration of one or more doses of the bispecific antibody.
• the radiographic imaging comprises a Fluorine F18 DCFPyL PET/CT scan.
• the present disclosure also encompasses the use of the bispecific antibodies and/or the anti-PD-1 antibodies in the manufacture of a medicament for treating a PSMA-expressing cancer as set forth in any of the embodiments of the methods discussed above or herein.
• the present disclosure also encompasses bispecific antibodies and/or anti-PD-1 antibodies for use in any of the embodiments of the methods discussed above or herein.
• the present disclosure also encompasses pharmaceutical compositions comprising the bispecific antibodies and/or anti-PD-1 antibodies for use in any of the embodiments of the methods discussed above or herein.
• any of the features or components of embodiments discussed above or herein may be combined, and such combinations are encompassed within the scope of the present disclosure. Any specific value discussed above or herein may be combined with another related value discussed above or herein to recite a range with the values representing the upper and lower ends of the range, and such ranges are encompassed within the scope of the present disclosure.
• Figure 1 illustrates an embodiment of the patient-level study schema for Module 1 (QW dosing), as discussed in Example 6.
• Figure 2 illustrates an embodiment of the patient-level study schema for Module 1 (Q3W dosing), as discussed in Example 6.
• Figure 3 illustrates an embodiment of the patient-level study schema for Module 2, as discussed in Example 6.
• the present disclosure includes methods for treating, ameliorating or reducing the severity of at least one symptom or indication, or inhibiting the growth of a cancer (e.g., metastatic castration-resistant prostate cancer) in a subject.
• the methods according to this aspect of the disclosure comprise administering 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 PD-1 to a subject in need thereof.
• the terms “treat”, “treating”, or the like mean to alleviate symptoms, eliminate the causation of symptoms either on a temporary or permanent basis, to delay or inhibit tumor growth, to reduce tumor cell load or tumor burden, to promote tumor regression, to cause tumor shrinkage, necrosis and/or disappearance, to prevent tumor recurrence, and/or to increase duration of survival of the subject.
• a subject in need thereof means a human or non-human mammal that exhibits one or more symptoms or indications of cancer, and/or who has been diagnosed with cancer, including a prostate cancer (e.g., metastatic castration-resistant prostate cancer) and who needs treatment for the same.
• a prostate cancer e.g., metastatic castration-resistant prostate cancer
• the term “subject” may be interchangeably used with the term “patient”.
• a human subject may be diagnosed with a primary or a metastatic tumor and/or with one or more symptoms or indications including, but not limited to, enlarged lymph node(s), swollen abdomen, unexplained pain, unexplained weight loss, fever, night sweats, persistent fatigue, loss of appetite, and/or enlargement of spleen.
• the expression includes subjects with primary or established prostate tumors.
• the expression includes human subjects that have and need treatment for prostate cancer or another tumor expressing PSMA.
• the expression includes subjects with PSMA+ tumors (e.g., a tumor with PSMA expression as determined by flow cytometry).
• the expression "a subject in need thereof includes patients with a prostate cancer that is resistant to or refractory to or is inadequately controlled by prior therapy (e.g., treatment with a conventional anti-cancer agent, including anti-androgen therapy).
• a conventional anti-cancer agent including anti-androgen therapy
• the expression includes subjects who have been treated with chemotherapy, or anti-androgen therapy such as, for example, abiraterone, enzalutamide, apalutamide, or darolutamide.
• the expression also includes subjects with a prostate tumor for which conventional anti-cancer therapy is inadvisable, for example, due to toxic side effects.
• the expression includes patients who have received one or more cycles of chemotherapy or other anti-cancer therpay with toxic side effects.
• the expression "a subject in need thereof” includes patients with a prostate tumor which has been treated but which has subsequently relapsed or metastasized.
• patients with a prostate tumor that may have received treatment with one or more anticancer agents leading to tumor regression; however, subsequently have relapsed with cancer resistant to the one or more anti-cancer agents (e.g., castration-resistant prostate cancer) are treated with the methods of the present disclosure.
• the methods of the present disclosure may be used to treat patients that have histologically or cytologically confirmed adenocarcinoma of the prostate without pure small cell carcinoma.
• the methods of the present disclosure may be used to treat patients that have metastatic castration-resistant prostate cancer with a prostate specific antigen (PSA) value of >4 ng/ml (e.g., 4 ng/ml, 4.5 ng/ml, 5 ng/ml, 5.5 ng/ml, 6 ng/ml, 6.5 ng/ml, 7 ng/ml, 7.5 ng/ml, 8 ng/ml, 8.5 ng/ml, 9 ng/ml, 9.5 ng/ml, or 10 ng/ml or more) prior to treatment with the bispecific antibody.
• PSA prostate specific antigen
• the methods of the present disclosure may be used to treat patients with prostate cancer that has progressed within a period (e.g., 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, or more) prior to treatment with the bispecific antibody, wherein cancer progression is determined by, for example,: (a) a rising PSA level confirmed with an interval of > 1 week (e.g., 1 week, 2 weeks, 3 weeks, 4 weeks, or more) between each assessment; (b) radiographic disease progression in soft tissue with or without a rise in PSA; and/or (c) radiographic disease progression in bone with an appearance of two or more bone lesions on bone scan with or without a rise in PSA.
• a rising PSA level confirmed with an interval of > 1 week (e.g., 1 week, 2 weeks, 3 weeks, 4 weeks, or more) between each assessment
• radiographic disease progression in soft tissue with or without a rise in PSA and/or
• the methods of the present disclosure may be used to treat patients that have had an orchiectomy.
• the methods of the present disclosure may be used to treat patient that have or are receiving luteinizing hormone-releasing hormone (LHRH) agonist or antagonist therapy, and have a serum testosterone level of ⁇ 50 ng/ml (e.g., froml 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.
• LHRH luteinizing hormone-releasing hormone
• the methods of the present disclosure are used in a subject with prostate cancer.
• tumor refers to tumors of the prostate, including metastatic tumors originating in the prostate.
• the present disclosure includes methods for treating, or delaying or inhibiting the growth of a tumor.
• the present disclosure includes methods to promote tumor regression.
• the present disclosure includes methods to reduce tumor cell load or to reduce tumor burden.
• the present disclosure includes methods to prevent tumor recurrence.
• the methods comprise administering a therapeutically effective amount of a bispecific anti- PSMA/anti-CD3 antibody alone, or in combination with an anti-PD-1 antibody to a subject in need thereof, wherein each antibody is administered to the subject in multiple doses, e.g., as part of a specific therapeutic dosing regimen.
• the therapeutic dosing regimen may comprise administering one or more doses of an anti-PSMA x CD3 antibody 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 frequently.
• the anti-PSMA x anti-CD3 antibody is administered once a week.
• the anti-PSMA x anti-CD3 antibody is administered once every three weeks.
• the one or more doses of anti-PD-1 antibody are administered in combination with the 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 frequently.
• the anti-PD-1 antibody is administered to the subject once every three weeks.
• each dose of the anti-PSMA/anti-CD3 antibody is administered in two or more fractions, e.g., in 2-5 fractions ("split dosing") within the given dosing period.
• the anti- PSMA/anti-CD3 bispecific antibody may be administered in split doses to reduce or eliminate the cytokine "spikes" induced in response to administration of the antibody. Cytokine spikes refer to the clinical symptoms of the cytokine release syndrome ("cytokine storm”) and infusion related reactions.
• the methods of the present disclosure comprise administering one or more doses of anti-PD-1 antibody in combination with the one or more doses of a bispecific anti-PSMA/anti-CD3 antibody to a subject in need thereof, wherein a dose of the bispecific antibody is administered as split doses, or in more than 1 fractions, e.g., as 2 fractions, as 3 fractions, as 4 fractions or as 5 fractions within the given dosing period.
• a dose of the bispecific antibody is split into 2 or more fractions, wherein each fraction comprises an amount of the antibody equal to the other fractions.
• a dose of the bispecific antibody is administered split into 2 or more fractions, wherein the fractions comprise unequal amounts of the antibody, e.g., more than or less than the first fraction.
• the present disclosure includes methods to inhibit, retard or stop tumor metastasis or tumor infiltration into peripheral organs.
• the methods comprise administering a therapeutically effective amount of a bispecific anti-PSMA/anti-CD3 antibody alone, or in combination with an anti-PD-1 antibody to a subject in need thereof.
• the present disclosure provides methods for increased antitumor efficacy or increased tumor inhibition.
• the methods comprise administering to a subject with prostate cancer a therapeutically effective amount of an anti-PD-1 antibody 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.
• the methods provide for increased tumor inhibition, e.g., by about 20%, more than 20%, more than 30%, more than 40% more than 50%, more than 60%, more than 70% or more than 80% as compared to a subject administered the bispecific antibody alone.
• the methods of the present disclosure are used to treat a patient with a MRD-positive disease.
• Minimum residual disease refers to small numbers of cancer cells that remain in the patient 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, frequently lead to relapse of the disease.
• the present disclosure includes methods to inhibit and/or eliminate residual cancer cells in a patient upon MRD testing. MRD may be assayed according to methods known in the art (e.g., MRD flow cytometry).
• the methods, according to this aspect of the disclosure comprise administering a bispecific anti-PSMA/anti-CD3 antibody alone, or in combination with an anti-PD-1 antibody to a subject in need thereof.
• 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 may be an agent selected from the group consisting of, e.g., radiation, chemotherapy, surgery, a cancer vaccine, an oncolytic virus, a PD-L1 inhibitor (e.g., an anti-PD-L1 antibody), a LAG3 inhibitor (e.g., an anti-LAG3 antibody), a CTLA-4 inhibitor (e.g., an anti-CTLA-4 antibody), a TIM3 inhibitor, a BTLA inhibitor, a TIGIT inhibitor, a CD47 inhibitor, an indoleamine-2,3-dioxygenase (IDO) inhibitor, a vascular endothelial growth factor (VEGF) antagonist, an Ang2 inhibitor, a transforming growth factor beta (TGF.beta.) inhibitor, an epidermal growth factor receptor (EGFR) inhibitor, an antibody to a tumor-specific antigen, a cytotoxin, a chemotherapeutic agent, an IL-6R inhibitor, an IL-4R inhibitor, an IL-10 inhibitor,
• the antibodies may be administered in combination with therapy including a chemotherapeutic agent, radiation and surgery.
• therapy including a chemotherapeutic agent, radiation and surgery.
• the phrase “in combination with” means that the antibodies are administered to the subject at the same time as, just before, or just after administration of the third therapeutic agent.
• the antibodies and the third therapeutic agent are administered in separate formulations.
• the methods of the present disclosure may further comprise administration of a steroid (e.g., dexamethasone or an equivalent steroid), or an anti-IL-6 receptor antibody.
• a steroid e.g., dexamethasone or an equivalent steroid
• the anti-IL-6 receptor antibody is tocilizumab or sarilumab.
• the steroid e.g., dexamethasone
• the steroid may be administered at a dose of from 1 mg to 20 mg (e.g., from 5 mg to 10 mg) IV or PO.
• these agents may be administered as premedications prior to administration of the bispecific antibody (e.g., REGN4336).
• the methods of the present disclosure comprise 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.
• the administration of the antibodies leads to increased inhibition of tumor growth.
• tumor growth is inhibited by at least about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70% or about 80% as compared to an untreated subject or a subject administered with either antibody as monotherapy, respectively.
• the administration of the bispecific antibody or the combination leads to increased tumor regression, tumor shrinkage and/or disappearance.
• the administration of the bispecific antibody or the combination leads to delay in tumor growth and development, e.g., tumor growth may 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 as compared to an untreated subject or a subject treated with either antibody as monotherapy, respectively.
• administration of the bispecific antibody or the combination prevents tumor recurrence and/or increases duration of survival of the subject, e.g., increases duration of survival 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 relative to an untreated subject or a subject which is administered either antibody as monotherapy, respectively.
• administration of the bispecific antibody or the combination increases progression-free survival or overall survival.
• administration of the bispecific antibody or the combination increases response and duration of response in a subject, e.g., 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% over an untreated subject or a subject which has received either antibody as monotherapy, respectively.
• administration of the bispecific antibody or the combination to a subject with prostate cancer leads to complete disappearance of all evidence of tumor cells ("complete response").
• administration of the bispecific antibody or the combination to a subject with prostate cancer leads to at least 30% or more decrease in tumor cells or tumor size ("partial response").
• administration of the bispecific antibody or the combination to a subject with prostate cancer leads to complete or partial disappearance of tumor cells/lesions including new measurable lesions.
• Tumor reduction can be measured by any of the methods known in the art, e.g., X-rays, positron emission tomography (PET), computed tomography (CT), magnetic resonance imaging (MRI), cytology, histology, or molecular genetic analyses.
• administration of the bispecific antibody and the anti-PD-1 antibody produces a synergistic anti-tumor effect that exceeds the combined effects of the two agents when administered alone.
• the response of a subject to therapy is categorized as a complete response (CR), a partial response (PR), progressive disease (PD), or as stable disease (SD).
• a CR is defined as disappearance of all target lesions, and a reduction in short axis of any pathological lymph nodes (whether target or non-target) to ⁇ 10 mm ( ⁇ 1 cm).
• a PR is defined as an at least 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.
• PD is defined as an at least 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study).
• immune-based therapy response criteria may be used to evaluate responses. Immune-based therapy response criteria differ from RECIST (Version 1.1) in that progressive disease is slightly more challenging to confirm, as it must occur in the scan immediately following an unconfirmed progressive disease scan. This difference is based upon understanding that immune therapies may cause pseudoprogression based on inflammation up to and including development of new lesions. Hence, two scans no less than 4 weeks apart must agree that disease is progressing for confirmed progressive disease. The criteria used to evaluate target lesions and non-target lesions are discussed below.
• Immune Complete Response Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to ⁇ 10 mm ( ⁇ 1 cm)
• Immune Partial Response At least a 30% decrease in the sum of the diameters of target lesions taking as reference the baseline sum diameters
• Immune Unconfirmed Progressive Disease At least a 20% increase in the sum of the diameters of target lesions taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study) that are new since the last imaging done. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm (0.5 cm)
• Immune Confirmed Progressive Disease Progression is confirmed in the target lesion category if the next imaging assessment after iUPD (4 to 8 weeks later) confirms a further increase in sum or measures of target disease from iUPD, with an increase of at least 5mm.
• Immune Stable Disease Neither sufficient shrinkage to qualify for iPR nor sufficient increase to qualify for iUPD or iCPD, taking as reference the smallest sum diameters while on study and including the measurements of new lesions
• Immune Complete Response Disappearance of all non-target lesions and normalization of tumor marker level. All lymph nodes must be non-pathological in size ( ⁇ 10 mm [ ⁇ 1 cm] short axis). Jf tumor markers are initially above the upper normal limit, they must normalize for a patient to be considered in complete clinical response
• Non-iCR/Non-iUPD or -iCPD Persistence of one or more non-target lesion(s) and/or maintenance of tumor marker level above the normal limits
• Immune Unconfirmed Progressive Disease iUPD: Unequivocal progression of existing non-target lesions without an iUPD on immediate prior scan. Unequivocal progression should not normally trump target lesion status. It must be representative of overall disease status change, not a single lesion increase.
• Immune Confirmed Progressive Disease iCPD: Unequivocal progression of existing non-target lesions with an iUPD on immediate prior scan. Progressive disease in the non-target lesion category is confirmed if subsequent imaging, done 4 to 8 weeks after iUPD, shows a further increase from iUPD. Unequivocal progression should not normally trump target lesion status. It must be representative of overall disease status change, not a single lesion increase.
• imaging may be used to evaluate a subject’s response to therapy (alone or in combination with evaluation of PSA levels).
• PSMA PET/CT has been shown to provide a sensitive measure of both PSMA expression and tumor burden in prostate cancer patients. With improved sensitivity and specificity over current conventional imaging modalities for tumor lesion detection, PSMA PET/CT has been shown to improve the effectiveness of tumor response assessment and treatment strategy.
• Fluorine F18 DCFPyL ( ⁇ F-DCFPyL) is a radiolabeled small molecule that binds to the extracellular domain of PSMA with high affinity. Data from an enzyme inhibition assay showed that DCFPyL binds competitively to PSMA expressing LNCaP cells with a Ki of 1.1 nM. 18 F-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 on 26 May 2021 by the FDA for PET scan of PSMA-positive lesions in men with prostate cancer with suspected metastasis who are candidates for initial definitive therapy and with suspected recurrence based on elevated serum prostate-specific antigen (PSA) level.
• PSA serum prostate-specific antigen
• 18 F-DCFPyl_ at the intended dose of ⁇ 9 ⁇ 1 mCi per IV injection is overall feasible and safe.
• Radiation dose from the 18 F-DCFPyL PET/CT scan is about 7.4 mSv.
• a typical CT scan dose of the chest, abdomen and pelvis is estimated to be - 25 mSv, one bone scan is - 4.4 mSv and annual natural background radiation dose in the US is ⁇ 3.1 mSv.
• the protocol maximum of three 18 F-DCFPyL PET/CT scans within a year would result in an approximate dose of ⁇ 22.2 mSv which is - 45% of the recommended maximum allowed dose of 50 mSv for an adult research patient in a single year (21CRF361.1).
• Optional fluorodeoxyglucose (FDG) PET/CT may be used to assess metabolically active tumor burden in patients.
• PSMA expressing and non-expressing tumors have been detected by FDG PET/CT in prostate cancer patients.
• Complementary FDG and PSMA PET/CT data is expected to provide insight on tumor responses to therapy (e.g., REGN4336).
• the methods comprise administering a therapeutically effective amount of an anti-PD-1 antibody or antigenbinding fragment thereof.
• antibody includes immunoglobulin molecules comprising four polypeptide chains, two heavy (H) chains and two light (L) chains inter-connected by disulfide bonds, as well as multimers thereof (e.g., IgM).
• each heavy chain comprises a heavy chain variable region (abbreviated herein as HCVR or VH) and a heavy chain constant region.
• the heavy chain constant region comprises three domains, CH1 , CH2 and CH3.
• Each light chain comprises a light chain variable region (abbreviated herein as LCVR or V L ) and a light chain constant region.
• the light chain constant region comprises one domain (CL1).
• the V and V regions can be further subdivided into regions of hypervariability, termed complementarity determining regions (CDRs), interspersed with regions that are more conserved, termed framework regions (FR).
• CDRs complementarity determining regions
• FR framework regions
• Each VH and VL is composed of three CDRs and four FRs, arranged from aminoterminus to carboxy-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4.
• the FRs of the anti-PD-1 antibody may be identical to the human germline sequences, 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 antigen-binding fragments of full antibody molecules.
• the terms "antigen-binding portion" of an antibody, “antigen-binding fragment” of an antibody, and the like, as used herein, include any naturally occurring, enzymatically obtainable, synthetic, or genetically engineered polypeptide or glycoprotein that specifically binds an antigen to form a complex.
• Antigen-binding fragments of an antibody may be derived, e.g., from full antibody molecules using any suitable standard techniques such as proteolytic digestion or recombinant genetic engineering techniques involving the manipulation and expression of DNA encoding antibody variable and optionally constant domains.
• DNA is known and/or is readily available from, e.g., commercial sources, DNA libraries (including, e.g., phage-antibody libraries), or can be synthesized.
• the DNA may be sequenced and manipulated chemically or by using molecular biology techniques, for example, to arrange one or more variable and/or constant domains into a suitable configuration, or to introduce codons, create 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 the amino acid residues that mimic the hypervariable region of an antibody (e.g., an isolated complementarity determining region (CDR) such as a CDR3 peptide), or a constrained FR3-CDR3-FR4 peptide.
• CDR complementarity determining region
• engineered molecules such as domain-specific antibodies, single domain antibodies, domain-deleted antibodies, chimeric antibodies, CDR-grafted antibodies, diabodies, triabodies, tetrabodies, minibodies, nanobodies (e.g. monovalent nanobodies, bivalent nanobodies, etc.), small modular immunopharmaceuticals (SMIPs), and shark variable IgNAR domains, are also encompassed within the expression "antigenbinding fragment," as used herein.
• SMIPs small modular immunopharmaceuticals
• An antigen-binding fragment of an antibody will typically comprise at least one variable domain.
• the variable domain may be of any size or amino acid composition and will generally comprise at least one CDR which is adjacent to or in frame with one or more framework sequences.
• the V H and V L domains may be situated relative to one another in any suitable arrangement.
• the variable region may be dimeric and contain VH-V H , V H - L or V L -V dimers.
• the antigenbinding fragment of an antibody may contain a monomeric V H or V domain.
• an antigen-binding fragment of an antibody may contain at least one variable domain covalently linked to at least one constant domain.
• variable and constant domains that may be found within an antigen-binding fragment of an antibody of the present disclosure include: (i) V H -CH1 ; (ii) V H -CH2; (iii) V H -CH3; (iv) V H -CH1-CH2; (V) V H -CH1 -CH2-C H 3; (vi) VH-C H 2-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 -CH1 -CH2; (xii) -CH1-CH2-CH3; (xiii) V L -CH2-CH3; and (xiv) V -CL.
• variable and constant domains may be either directly linked to one another or may be linked by a full or partial hinge or linker region.
• a hinge region may consist of at least 2 (e.g., 5, 10, 15, 20, 40, 60 or more) amino acids which result in a flexible or semi-flexible linkage between adjacent variable and/or constant domains in a single polypeptide molecule.
• an antigen-binding fragment of an antibody of the present disclosure may comprise a homo-dimer or hetero-dimer (or other multimer) of any of the variable and constant domain configurations listed above in non-covalent association with one another and/or with one or more monomeric V H or V L domain (e.g., by disulfide bond(s)).
• antibody also includes multispecific (e.g., bispecific) antibodies.
• a multispecific antibody or antigen-binding fragment of an antibody will typically comprise at least two different variable domains, wherein each variable domain is capable of specifically binding to a separate antigen or to a different epitope on the same antigen.
• Any multispecific antibody format may be adapted for use in the context of an antibody or antigenbinding fragment of an antibody of the present disclosure using routine techniques available in the art.
• the present disclosure includes methods comprising the use of bispecific antibodies wherein one arm of an 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, without limitation, e.g., scFv-based or diabody bispecific formats, IgG-scFv fusions, dual variable domain (DVD)-lg, Quadroma, knobs-into-holes, common light chain (e.g., common light chain with knobs-into-holes, etc.), CrossMab, CrossFab, (SEED) body, leucine zipper, Duobody, lgG1/lgG2, dual acting Fab (DAF)-lgG, and Mab.sup.2 bispecific formats (see, e.g., Klein et al.
• Bispecific antibodies can also be constructed using peptide/nucleic acid conjugation, e.g., wherein unnatural amino acids with orthogonal chemical reactivity are used to generate site-specific antibody-oligonucleotide conjugates which then self-assemble into multimeric complexes with defined composition, valency and geometry. (See, e.g., Kazane et al., J. Am. Chem. Soc. [Epub: Dec. 4, 2012]).
• the antibodies used in the methods of the present disclosure may be human antibodies.
• the term "human antibody,” as used herein, is intended to include antibodies having variable and constant regions derived from human germline immunoglobulin sequences.
• the human antibodies of the disclosure may nonetheless include amino acid residues not encoded by human germline immunoglobulin sequences (e.g., mutations introduced by random or site-specific mutagenesis in vitro or by somatic mutation in vivo), for example in the CDRs and in particular CDR3.
• the term "human antibody,” as used herein is not intended to include antibodies in which CDR sequences derived from the germline of another mammalian species, such as a mouse, have been grafted onto human framework sequences.
• the antibodies used in the methods of the present disclosure may be recombinant human antibodies.
• the term "recombinant human antibody,” as used herein, is intended to include all human antibodies that are prepared, expressed, created or isolated by recombinant means, such as antibodies expressed using a recombinant expression vector transfected into a host cell (described further below), antibodies isolated from a recombinant, combinatorial human antibody library (described further below), antibodies isolated from an animal (e.g., a mouse) that is transgenic for human immunoglobulin genes (see e.g., Taylor et al. (1992) Nucl. Acids Res.
• Such recombinant human antibodies have variable and constant regions derived from human germline immunoglobulin sequences. In certain embodiments, however, such recombinant human antibodies are subjected to in vitro mutagenesis (or, when an animal transgenic for human Ig sequences is used, in vivo somatic mutagenesis) and thus the amino acid sequences of the V H and V regions of the recombinant antibodies are sequences that, while derived from and related to human germline VH and L sequences, may not naturally exist within the human antibody germline repertoire in vivo.
• the antibodies used in the methods of the present disclosure specifically bind PD-1.
• the term "specifically binds,” or the like, means that an antibody or antigen-binding fragment thereof forms a complex with an antigen that is relatively stable under physiologic 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.
• an antibody that "specifically binds" PD-1 includes antibodies that bind PD-1 or portion thereof with a K D 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, as measured in a surface plasmon resonance assay.
• An isolated antibody that specifically binds human PD-1 may, however, have cross-reactivity to other antigens, such as PD-1 molecules from other (non-human) species.
• the anti-PD-1 antibody, or antigen-binding fragment thereof comprises a heavy chain variable region (HCVR), light chain variable region (LCVR), and/or complementarity determining regions (CDRs) comprising any of the amino acid sequences of the anti-PD-1 antibodies as set forth in US Patent No.
• HCVR heavy chain variable region
• LCVR light chain variable region
• CDRs complementarity determining regions
• 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 the HCDR1 comprises the amino acid sequence of SEQ ID NO: 23; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 24; the HCDR3 comprises the amino acid sequence of SEQ ID NO: 25; the LCDR1 comprises the amino acid sequence of SEQ ID NO: 26; the LCDR2 comprises the amino acid sequence of SEQ ID NO: 27; and the LCDR3 comprises the amino acid sequence of SEQ ID NO: 28.
• the HCDR1 comprises the amino acid sequence of SEQ ID NO: 23
• the HCDR2 comprises the amino acid sequence of SEQ ID NO: 24
• the HCDR3 comprises the amino acid sequence of SEQ ID NO: 25
• the LCDR1 comprises the amino acid sequence of SEQ ID NO: 26
• the LCDR2 comprises the amino acid sequence of SEQ ID NO:
• the anti-PD-1 antibody or antigen-binding fragment thereof comprises an HCVR comprising SEQ ID NO: 21 and an LCVR comprising SEQ ID NO: 22.
• the methods of the present disclosure comprise the use of an anti-PD-1 antibody, wherein the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 29.
• the anti-PD-1 antibody comprises a light chain comprising the amino acid sequence of SEQ ID NO: 30.
• An exemplary antibody comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 21 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 22 is the fully human anti-PD-1 antibody known as REGN2810 (also known as cemiplimab; LIBTAYO®).
• REGN2810 also known as cemiplimab; LIBTAYO®
• the methods of the present disclosure comprise the use of REGN2810, or a bioequivalent thereof.
• bioequivalent refers to anti-PD-1 antibodies or PD-1 -binding proteins or fragments thereof that are pharmaceutical equivalents or pharmaceutical alternatives whose rate and/or extent of absorption do not show a significant difference with that of REGN2810 when administered at the same molar dose under similar experimental conditions, either single dose or multiple dose.
• the term refers to antigenbinding proteins that bind to PD-1 which do not have clinically meaningful differences with REGN2810 in their safety, purity and/or potency.
• the anti-PD-1 antibodies used in the context of the methods of the present disclosure may have pH-dependent binding characteristics.
• an anti-PD-1 antibody for use in the methods of the present disclosure may exhibit reduced binding to PD-1 at acidic pH as compared to neutral pH.
• an anti-PD-1 antibody of the disclosure may exhibit enhanced binding to its antigen at acidic pH as compared to neutral pH.
• the expression "acidic pH” includes pH values less than about 6.2, e.g., 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.
• neutral pH means a pH of about 7.0 to about 7.4.
• 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.
• "reduced binding to PD-1 at acidic pH as compared to neutral pH” is expressed in terms of a ratio of the KD value of the antibody binding to PD-1 at acidic pH to the KD value of the antibody binding to PD-1 at neutral pH (or vice versa).
• an antibody or antigen-binding fragment thereof may be regarded as exhibiting "reduced binding to PD-1 at acidic pH as compared to neutral pH” for purposes of the present disclosure if the antibody or antigenbinding fragment thereof exhibits an acidic/neutral K D ratio of about 3.0 or greater.
• the acidic/neutral K D ratio for an antibody or antigen-binding fragment of the present disclosure 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 greater.
• Antibodies with pH-dependent binding characteristics may be obtained, e.g., by screening a population of antibodies for reduced (or enhanced) binding to a particular antigen at acidic pH as compared to neutral pH. Additionally, modifications of the antigen-binding domain at the amino acid level may yield antibodies with pH-dependent characteristics. For example, by substituting one or more amino acids of an antigen-binding domain (e.g., within a CDR) with a histidine residue, an antibody with reduced antigen-binding at acidic pH relative to neutral pH may be obtained.
• the expression "acidic pH” means a pH of 6.0 or less.
• the methods comprise administering a therapeutically effective amount of a bispecific antibody that specifically binds CD3 and PSMA.
• a bispecific antibody that specifically binds CD3 and PSMA.
• Such antibodies may be referred to herein as, e.g., "anti-PSMA/anti-CD3," or “anti-PSMA x CD3” or “PSMA x CD3" bispecific antibodies, or other similar terminology.
• the expression "bispecific antibody” refers to an immunoglobulin protein comprising at least a first antigen-binding domain and a second antigen-binding domain.
• the first antigen-binding domain specifically binds a first antigen (e.g., PSMA)
• the second antigen-binding domain specifically binds a second, distinct 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 comprising three CDRs.
• the CDRs of the first antigen-binding domain may be designated with the prefix "A” and the CDRs of the second antigen-binding domain may be designated with the prefix "B".
• 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 multimerizing domain.
• a "multimerizing domain” is any macromolecule, protein, polypeptide, peptide, or amino acid that has the ability to associate with a second multimerizing domain of the same or similar structure or constitution.
• the multimerizing component is an Fc portion of an immunoglobulin (comprising a CH2-CH3 domain), e.g., an Fc domain of an IgG selected from the isotypes lgG1 , lgG2, lgG3, and lgG4, as well as any allotype within each isotype group.
• Bispecific antibodies of the present disclosure typically comprise two multimerizing domains, e.g., two Fc domains that are each individually part of a separate antibody heavy chain.
• the first and second multimerizing domains may be of the same IgG isotype such as, e.g., lgG1/lgG1 , lgG2/lgG2, lgG4/lgG4.
• the first and second multimerizing domains may be of different IgG isotypes such as, e.g., lgG1/lgG2, lgG1/lgG4, lgG2/lgG4, etc.
• any bispecific antibody format or technology may be used to make the bispecific antibodies of the present disclosure.
• an antibody or fragment thereof having a first antigen binding specificity can be functionally linked (e.g., by chemical coupling, genetic fusion, noncovalent association or otherwise) 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.
• bispecific formats that can be used in the context of the present disclosure include, without limitation, e.g., scFv-based or diabody bispecific formats, IgG-scFv fusions, dual variable domain (DVD)-lg, Quadroma, knobs-into-holes, common light chain (e.g., common light chain with knobs-into-holes, etc.), CrossMab, CrossFab, (SEED)body, leucine zipper, Duobody, IgG 1/lgG2, dual acting Fab (DAF)-lgG, and Mab2 bispecific formats (see, e.g., Klein et al. 2012, mAbs 4:6, 1-11 , and references cited therein, for a review of the foregoing formats).
• Fc domains may comprise one or more amino acid changes (e.g., insertions, deletions or substitutions) as compared to the wild-type, naturally occurring version of the Fc domain.
• the disclosure includes bispecific antibodies comprising one or more modifications in the Fc domain that results in a modified Fc domain having a modified binding interaction (e.g., enhanced or diminished) between Fc and FcRn.
• the bispecific antibody comprises a modification in a CH2 or a CH3 region, wherein the modification increases the affinity of the Fc domain to FcRn in an acidic environment (e.g., in an endosome where pH ranges from about 5.5 to about 6.0).
• Non-limiting examples of such Fc modifications are disclosed in US Patent Publication No. 20150266966, incorporated herein in its entirety.
• the present disclosure also includes bispecific antibodies comprising a first CH3 domain and a second Ig CH3 domain, wherein the first and second Ig CH3 domains differ from one another by at least one amino acid, and wherein at least one amino acid difference reduces binding of the bispecific antibody to Protein A as compared to a bi-specific antibody lacking the amino acid difference.
• the first Ig CH3 domain binds Protein A and the second Ig CH3 domain contains a mutation that reduces or abolishes Protein A binding such as an H95R modification (by IMGT exon numbering; H435R by EU numbering).
• the second CH3 may further comprise a Y96F modification (by IMGT; Y436F by EU). See, for example, US Patent No.
• the Fc domain may be chimeric, combining Fc sequences derived from more than one immunoglobulin isotype.
• a chimeric Fc domain can comprise part or all of a CH2 sequence derived from a human lgG1 , human lgG2 or human lgG4 CH2 region, and part or all of a CH3 sequence derived from a human IgG 1 , human lgG2 or human lgG4.
• a chimeric Fc domain can also contain a chimeric hinge region.
• a chimeric hinge may comprise an "upper hinge" sequence, derived from a human lgG1 , a human lgG2 or a human lgG4 hinge region, combined with a "lower hinge” sequence, derived from a human IgG 1 , a human lgG2 or a human lgG4 hinge region.
• a particular example of a chimeric Fc domain that can be included in any of the antibodies set forth herein comprises, from N- to C-terminus: [lgG4 CHl]-[lgG4 upper hinge]- [lgG2 lower hinge]-[lgG4 CH2]-[lgG4 CH3],
• Another example of a chimeric Fc domain that can be included in any of the antibodies set forth herein comprises, from N- to C-terminus: [IgG 1 CH1]- [IgG 1 upper hinge]-[lgG2 lower hinge]-[lgG4 CH2]-[lgG1 CH3]
• These and other examples of chimeric Fc domains or chimeric heavy chain constant regions that can be included in any of the antibodies of the present disclosure are described in US Patent Publication No. 20140243504, which is herein incorporated in its entirety. Chimeric Fc domains and chimeric heavy chain constant regions having these general structural arrangements, and variants thereof, can have altered Fc receptor binding, which
• the bispecific anti- PSMA/anti-CD3 antibody, or antigen-binding fragment thereof comprises heavy chain variable regions (A-HCVR and B-HCVR), light chain variable regions (A-LCVR and B-LCVR), and/or complementarity determining regions (CDRs) comprising any of the amino acid sequences of the bispecific anti-PSMA/anti-CD3 antibodies as set forth in US Patent Publication No. 20170051074.
• A-HCVR and B-HCVR heavy chain variable regions
• A-LCVR and B-LCVR light chain variable regions
• CDRs complementarity determining regions
• the bispecific anti-PSMA/anti-CD3 antibody or antigen-binding fragment thereof that can be used in the context of the methods of the present disclosure comprises: (a) a first antigen-binding arm comprising the 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 the light chain complementarity determining regions (A-LCDR1, A-LCDR2 and A-LCDR3) of a light chain variable region (A-LCVR) comprising the amino acid sequence of SEQ ID NO: 2; and (b) a second antigen-binding arm comprising the heavy chain CDRs (B-HCDR1 , B-HCDR2 and B-HCDR3) of a HCVR (B-HCVR) comprising an amino acid sequence of SEQ ID NO: 3 or SEQ ID NO: 4, and the light chain CDRs (B-LCDR1 , B-
• the bispecific anti-PSMA/anti-CD3 antibody or antigen-binding fragment thereof comprises: (a) a first antigen-binding arm comprising a HCVR (A-HCVR) comprising SEQ ID NO: 1 and a LCVR (A-LCVR) comprising SEQ ID NO: 2; and (b) a second antigen-binding arm comprising a HCVR (B-HCVR) comprising SEQ ID NO: 3 or SEQ ID NO: 4, and a LCVR (B-LCVR) comprising SEQ ID NO: 2.
• the bispecific anti-PSMA x CD3 antibody comprises a PSMA-binding arm comprising a heavy chain comprising the amino acid sequence of SEQ ID NO: 17 and a light chain comprising the amino acid sequence of SEQ ID NO: 18, and a CD3-binding arm comprising a heavy chain comprising the amino acid sequence of SEQ ID NO: 19 and a light chain comprising the amino acid sequence of SEQ ID NO: 18.
• the bispecific ant-PSMA x CD3 antibody comprises a PSMA-binding arm comprising a heavy chain comprising the amino acid sequence of SEQ ID NO: 17 and a light chain comprising the amino acid sequence of SEQ ID NO: 18, and a CD3-binding arm comprising a heavy chain comprising the amino acid sequence of SEQ ID NO: 20 and a light chain comprising the amino acid sequence of SEQ ID NO: 18.
• An exemplary bispecific anti-PSMA/anti-CD3 antibody comprising: (a) a first antigen-binding arm comprising a HCVR (A-HCVR) comprising SEQ ID NO: 1 and a LCVR (A-LCVR) comprising SEQ ID NO: 2; and (b) a second antigen-binding arm comprising a HCVR (B-HCVR) comprising SEQ ID NO: 4, and a LCVR (B-LCVR) comprising SEQ ID NO: 2 that is used in the methods of the present disclosure is REGN4336 (herein referred to as “PSMA/CD3-002”).
• the methods of the present disclosure comprise administering to the subject an anti-PSMA/anti-CD3 bispecific antibody in combination with an anti- PD-1 antibody.
• the methods of the present disclosure comprise administering the antibodies for additive or synergistic activity to treat a PSMA-expressing cancer, preferably prostate cancer.
• the expression "in combination with” means that the anti-PSMA/anti-CD3 bispecific antibody is administered before, after, or concurrent with the anti- PD-1 antibody.
• the term "in combination with” also includes sequential or concomitant administration of anti-PD-1 antibody and a bispecific anti-PSMA/anti-CD3 antibody.
• the anti-PD-1 antibody when administered "before" the bispecific anti-PSMA/anti-CD3 antibody, may 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 prior to the administration of the bispecific anti-PSMA/anti-CD3 antibody.
• the anti-PD-1 antibody When administered “after” the bispecific anti-PSMA/anti-CD3 antibody, the anti-PD-1 antibody may 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 "concurrent" 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 (before, after, or at the same time) of administration of the bispecific anti-PSMA/anti-CD3 antibody, or administered to the subject as a single combined dosage formulation comprising both the anti-PD-1 antibody and the bispecific anti-PSMA/anti-CD3 antibody.
• the methods of the present disclosure comprise administration of a third therapeutic agent wherein the third therapeutic agent is an anti-cancer drug.
• the methods of the disclosure comprise administering an anti-PD-1 antibody and an anti-PSMA/anti-CD3 bispecific antibody in combination with radiation therapy, surgery or other anticancer therapy to generate long-term durable anti-tumor responses and/or enhance survival of patients with a PSMA-expressing cancer.
• the methods of the disclosure comprise administering radiation therapy prior to, concomitantly or after administering an anti-PD-1 antibody and a bispecific anti- PSMA/anti-CD3 antibody to a cancer patient.
• radiation therapy may be administered in one or more doses to tumor lesions after administration of one or more doses of the antibodies.
• radiation therapy may be administered locally to a tumor lesion to enhance the local immunogenicity of a patient's tumor (adjuvinating radiation) and/or to kill tumor cells (ablative radiation) after systemic administration of an anti-PD-1 antibody and/or a bispecific anti- PSMA/anti-CD3 antibody.
• the present disclosure includes methods which comprise administering a bispecific anti- PSMA/anti-CD3 antibody alone, or in combination with an anti-PD-1 antibody to a subject wherein the antibody or antibodies are contained within separate or a combined (single) pharmaceutical composition.
• the pharmaceutical compositions of the disclosure may be formulated with suitable carriers, excipients, and other agents that provide suitable transfer, delivery, tolerance, and the like.
• suitable carriers, excipients, and other agents that provide suitable transfer, delivery, tolerance, and the like.
• a multitude of appropriate formulations can be found in the formulary known to all pharmaceutical chemists: Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pa.
• formulations include, for example, powders, pastes, ointments, jellies, waxes, oils, lipids, lipid (cationic or anionic) containing vesicles (such as LIPOFECTINTM), DNA conjugates, anhydrous absorption pastes, oil-in-water and water-in-oil emulsions, emulsions carbowax (polyethylene glycols of various molecular weights), semi-solid gels, and semi-solid mixtures containing carbowax. See also Powell et al. "Compendium of excipients for parenteral formulations" PDA (1998) J Pharm Sci Technol 52:238-311.
• compositions of the disclosure e.g., encapsulation in liposomes, microparticles, microcapsules, recombinant cells capable of expressing the mutant viruses, receptor mediated endocytosis (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 composition may be administered by any convenient route, for example by infusion or bolus injection, or by injection, and may be administered together with other biologically active agents.
• a pharmaceutical composition of the present disclosure can be delivered subcutaneously or intravenously with a standard needle and syringe.
• a pen delivery device readily has applications in delivering a pharmaceutical composition of the present disclosure.
• Such a pen delivery device can be reusable or disposable.
• a reusable pen delivery device generally utilizes a replaceable cartridge that contains a pharmaceutical composition. Once all of the pharmaceutical composition within the cartridge has been administered and the cartridge is empty, the empty cartridge can readily be discarded and replaced with a new cartridge that contains the pharmaceutical composition. The pen delivery device can then be reused.
• a disposable pen delivery device there is no replaceable cartridge. Rather, the disposable pen delivery device comes prefilled with the pharmaceutical composition held in a reservoir within the device. Once the reservoir is emptied of the pharmaceutical composition, the entire device is discarded.
• Numerous reusable pen and autoinjector delivery devices have applications in the subcutaneous delivery of a pharmaceutical composition of the present disclosure.
• Examples include, but are not limited to AUTOPENTM (Owen Mumford, Inc., Woodstock, UK), DISETRONICTM pen (Disetronic Medical Systems, Bergdorf, Switzerland), HUMALOG MIX 75/25TM pen, HUMALOGTM pen, HUMALIN 70/30TM pen (Eli Lilly and Co., Indianapolis, IN), NOVOPENTM I, II and III (Novo Nordisk, Copenhagen, Denmark), NOVOPEN JUNIORTM (Novo Nordisk, Copenhagen, Denmark), BDTM pen (Becton Dickinson, Franklin Lakes, NJ), OPTIPENTM, OPTIPEN PROTM, OPTIPEN STARLETTM, and OPTICLIKTM (sanofi-aventis, Frankfurt, Germany), to name only a few.
• Examples of disposable pen delivery devices having applications in subcutaneous delivery of a pharmaceutical composition of the present disclosure include, but are not limited to the SOLOSTARTM pen (sanofi-aventis), the FLEXPENTM (Novo Nordisk), and the KWIKPENTM (Eli Lilly), the SURECLICKTM Autoinjector (Amgen, Thousand Oaks, CA), the PENLETTM (Haselmeier, Stuttgart, Germany), the EPIPEN (Dey, L.P.), and the HUMIRATM Pen (Abbott Labs, Abbott Park IL), to name only a few.
• the pharmaceutical composition can be delivered in a controlled release system.
• a pump may be used.
• polymeric materials can be used; see, Medical Applications of Controlled Release, Langer and Wise (eds.), 1974, CRC Pres., Boca Raton, Fla.
• a controlled release system can be placed in proximity of the composition's target, thus requiring only a fraction 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 by Langer, 1990, Science 249:1527-1533.
• the injectable preparations may include dosage forms for intravenous, subcutaneous, intracutaneous and intramuscular injections, drip infusions, etc. These injectable preparations may be prepared by known methods.
• the injectable preparations may be prepared, e.g., by dissolving, suspending or emulsifying the antibody or its salt described above in a sterile aqueous medium or an oily medium conventionally used for injections.
• aqueous medium for injections there are, for example, physiological saline, an isotonic solution containing glucose and other auxiliary agents, etc., which may be used in combination with an appropriate solubilizing agent.
• the injection thus prepared is preferably filled in an appropriate ampoule.
• the pharmaceutical compositions for use described above are prepared into dosage forms in a unit dose suited to fit a dose of the active ingredients.
• dosage forms in a unit dose include, for example, a vial or a prefilled syringe.
• 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 so long as a therapeutic response is achieved.
• multiple doses of a bispecific anti-PSMA/anti-CD3 antibody alone, or in combination with an anti-PD-1 antibody may be administered to a subject over a defined time course.
• the methods according to this aspect of the disclosure comprise sequentially administering to a subject one or more doses of a bispecific anti- PSMA/anti-CD3 antibody alone, or in combination with one or more doses of an anti-PD-1 antibody.
• sequentially administering means that each dose of the antibody is administered to the subject at a different point in time, e.g., on different days separated by a predetermined interval (e.g., hours, days, weeks or months).
• the present disclosure includes methods which comprise sequentially administering to the patient a single initial dose of an antibody, followed by one or more secondary doses of the antibody, and optionally followed by one or more tertiary doses of the antibody.
• the terms “initial dose,” “secondary doses,” and “tertiary doses,” refer to the temporal sequence of administration.
• the “initial dose” is the dose which is administered at the beginning of the treatment regimen (also referred to as the “baseline dose”);
• the “secondary doses” are the doses which are administered after the initial dose;
• the “tertiary doses” are the doses which are administered after the secondary doses.
• the initial, secondary, and tertiary doses may all contain the same amount of the antibody (anti-PD-1 antibody or bispecific antibody).
• the amount contained in the initial, secondary and/or tertiary doses varies from one another (e.g., adjusted up or down as appropriate) during the course of treatment.
• one or more (e.g., 1, 2, 3, 4, or 5) doses are administered at the beginning of the treatment regimen as "loading doses" followed by subsequent doses that are administered on a less frequent basis (e.g., "maintenance doses").
• each secondary and/or tertiary dose is administered 1/2 to 14 (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, or more) weeks after the immediately preceding dose.
• the phrase "the immediately preceding dose,” as used herein, means, in a sequence of multiple administrations, the dose of a bispecific anti-PSMA/anti-CD3 (and/or anti- PD-1 antibody) which is administered to a patient prior to the administration of the very next dose in the sequence with no intervening doses.
• the methods according to this aspect of the disclosure may comprise administering to a patient any number of secondary and/or tertiary doses of bispecific anti-PSMA/anti-CD3 antibody (and/or an anti-PD-1 antibody).
• a single secondary dose is administered to the patient.
• two or more (e.g., 2, 3, 4, 5, 6, 7, 8, or more) secondary doses are administered to the patient.
• only a single tertiary dose is administered to the patient.
• two or more (e.g., 2, 3, 4, 5, 6, 7, 8, or more) tertiary doses are administered to the patient.
• each secondary dose may be administered at the same frequency as the other secondary doses.
• each secondary dose may be administered to the patient 1 , 2 or 3 weeks (e.g., 1 week or 3 weeks) after the immediately preceding dose.
• each tertiary dose may be administered at the same frequency as the other tertiary doses.
• each tertiary dose may be administered to the patient 1 to 4 weeks (e.g., 1 week or 3 weeks) after the immediately preceding dose.
• the frequency at which the secondary and/or tertiary doses are administered to a patient can vary over the course of the treatment regimen. The frequency of administration may also be adjusted during the course of treatment by a physician depending on the needs of the individual patient following clinical examination.
• one or more doses of a bispecific anti-PSMA/anti-CD3 antibody are administered at the beginning of a treatment regimen as "induction doses" on a more frequent basis (twice a week, once a week, once in 2 weeks, or once in 3 weeks) followed by subsequent doses (“consolidation doses” or "maintenance doses”) that are administered on the same or a less frequent basis (e.g., once in 4-12 weeks).
• the present disclosure includes methods comprising sequential administration of a bispecific anti-PSMA/anti-CD3 antibody alone, or in combination with an anti-PD-1 antibody to a patient to treat prostate cancer (e.g., metastatic castration-resistant prostate cancer).
• the present methods comprise administering one or more doses of a bispecific anti- PSMA/anti-CD3 antibody, optionally preceded by or followed by one or more doses of an anti-PD-1 antibody.
• the present methods comprise administering a single dose of an anti-PD-1 antibody followed by one or more doses of a bispecific anti-PSMA/anti-CD3 antibody.
• one or more doses of about 0.1 mg/kg to about 20 mg/kg (e.g., 100 to 600 mg) of an anti-PD-1 antibody may be administered followed by one or more doses of about 0.1 mg/kg to about 20 mg/kg (e.g., 0.01 to 1000 mg) of the bispecific antibody to inhibit tumor growth and/or to prevent tumor recurrence in a subject with prostate cancer.
• the bispecific antibody or the combination results in increased anti-tumor efficacy (e.g., greater inhibition of tumor growth, increased prevention of tumor recurrence as compared to an untreated subject or a subject administered with either antibody as monotherapy, respectively).
• Alternative embodiments of the disclosure pertain to concomitant administration of the anti-PD-1 antibody and the bispecific antibody, which is administered at a separate dosage at a similar or different frequency relative to the anti-PD-1 antibody.
• the bispecific antibody is administered before, after or concurrently with the anti-PD-1 antibody.
• the bispecific antibody is administered as a single dosage formulation with the anti-PD-1 antibody.
• 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.
• the phrase "therapeutically effective amount” means an amount of antibody (anti-PD-1 antibody or bispecific anti-PSMA/anti-CD3 antibody) that results in one or more of: (a) a reduction in the severity or duration of a symptom of a cancer (e.g., prostate cancer); (b) inhibition of tumor growth, or an increase in tumor necrosis, tumor shrinkage and/or tumor disappearance; (c) delay in tumor growth and development; (d) inhibit or retard or stop tumor metastasis; (e) prevention of recurrence of tumor growth; (f) increase in survival of a subject with cancer (e.g., prostate cancer); and/or (g) a reduction in the use or need for conventional anti- cancer therapy (e.g., reduced or eliminated use of chemotherapeutic or cytotoxic agents
• a therapeutically effective amount can be from about 0.01 milligrams (mg) to about 2000 mg, e.g., 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 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
• 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 (e.g., once weekly or once every three weeks) to the subject to treat a PSMA-expressing cancer or prostate cancer (e.g., metastatic and/or castration-resistant prostate cancer).
• a therapeutically effective amount can be from about 0.05 mg to about 600 mg, e.g., 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, 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
• 300 mg to 400 mg of the anti-PD-1 antibody is administered (e.g., once every three weeks) to the subject in combination with the bispecific antibody to treat a PSMA-expressing cancer or prostate cancer (e.g., metastatic and/or castration-resistant prostate cancer).
• 350 mg of an anti-PD-1 antibody is administered (e.g., once every three weeks) to the subject in combination with the bispecific antibody 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 within the individual doses may be expressed in terms of milligrams of antibody per kilogram of subject body weight (/.e., mg/kg).
• the bispecific anti-PSMA/anti- CD3 antibody, and optionally the anti-PD-1 antibody, used in the methods of the present disclosure may be administered to a subject at a dose of about 0.0001 to about 100 mg/kg of subject body weight.
• the bispecific anti-PSMA/anti-CD3 antibody may be administered at a dose of about 0.1 mg/kg to about 20 mg/kg of a patient's body weight
• the optional anti-PD-1 antibody may be administered at dose of about 0.1 mg/kg to about 20 mg/kg of a patient's body weight.
• the present disclosure provides bispecific antibodies that bind 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 x CD3 bispecific antibodies.
• PSMA Prostate-Specific Membrane Antigen
• the anti-PSMA portion of the anti-PSMA x anti-CD3 bispecific antibodies is useful for targeting tumor cells that express PSMA, and the anti-CD3 portion of the bispecific antibodies is useful for activating T-cells.
• the simultaneous binding of PSMA on a tumor cell and CD3 on a T-cell facilitates directed killing (cell lysis) of the targeted tumor cell by the activated T-cell.
• Bispecific antibodies comprising an anti-PSMA-specific binding domain and an anti-CD3- specific binding domain were constructed using standard methodologies, wherein the anti-PSMA antigen binding domain and the anti-CD3 antigen binding domain each comprise different, distinct HCVRs paired with a common LCVR.
• the bispecific antibodies were constructed utilizing a heavy chain from an anti-CD3 antibody, a heavy chain from an anti-PSMA antibody and a common light chain.
• the anti-PSMA x anti-CD3 bispecific antibodies tested demonstrated specificity of binding to human PSMA-expressing B16F10.9/hPSMA and 22RV1 cell lines via FACS.
• the detection limit for FACS binding is 1 pM EC50.
• the CD3 binding arms of each PSMA x CD3 bispecific antibody displayed a range of cell binding affinity to human CD3 expressing Jurkat cells (15 to 300 nM EC50 range).
• the CD3 arms that showed weak-to-non detectable binding to human CD3 heterodimeric protein via surface plasmon resonance also correlated with weak to no observable binding on Jurkat cells (/.e. CD3-VH-G5).
• Both tested bispecific antibodies displayed similar cell binding on respective PSMA-expressing cell lines, confirming that bispecific pairing with individual CD3 arms did not affect or diminish PSMA-specific binding.
• Example 3 Binding Affinities of Exemplified Antibodies as Measured by a Surface Plasmon Resonance Binding Assay
• Binding affinities and kinetic constants of anti-PSMA x anti-CD3 bispecific antibodies to soluble heterodimeric hCD3 mFc protein were determined by surface plasmon resonance at 37°C using an antigen-capture format (Table 4). Measurements were conducted on a Sierra Sensors MASS-1 instrument.
• the MASS-1 high-density amine sensor surface was derivatized with a goat anti-mouse lgG2a polyclonal antibody (Southern Biotech). Soluble heterodimeric CD3 protein was captured and the respective antibodies were injected over the captured antigen.
• K D dissociation equilibrium constants
• ti/ 2 dissociative half-lives
• the anti-PSMA x anti-CD3 bispecific antibodies either maintained very weak binding to soluble CD3 in the surface plasmon resonance binding assay, e.g. having a KD value of 334 nM, or did not exhibit any detectable binding.
• Example 4 T-Cell Activation and Tumor-specific Cytotoxicity Exhibited by Bispecific Antibodies as Measured In Vitro
• PSMA-expressing (C4-2, 22Rv1 and TRAMPC2_PSMA) cell lines were labeled with 1 M of the fluorescent tracking dye Violet Cell Tracker. After labeling, cells were plated overnight at 37°C. Separately, human PBMCs were plated in supplemented RPMI media at 1x10 6 cells/mL and incubated overnight at 37°C in order to enrich for lymphocytes by depleting adherent macrophages, dendritic cells, and some monocytes.
• target cells were co-incubated with adherent cell-depleted naive PBMC (Effector/Target cell 4:1 ratio) and a serial dilution of relevant bispecific antibodies or isotype control for 48 hours at 37°C.
• Cells were removed from cell culture plates using an enzyme-free cell dissociation buffer, and analyzed by FACS.
• T cell activation was assessed by incubating cells with directly conjugated antibodies to CD2 and CD69, and by reporting the percent of activated (CD69+) T cells out of total T cells (CD2+).
• the results of this example demonstrate that the bispecific antibody that utilized a CD3 binding arm that displayed weak-to-non-observable binding to CD3 protein or CD3- expressing cells (/.e., CD3-VH-G5) still retained the ability to activate T-cells and exhibited potent cytotoxicity of tumor antigen-expressing cells.
• NSG mice (Jackson Laboratories, Bar Harbor, Maine) were co-implanted with human peripheral blood mononuclear cells (PBMCs) along with C4-2 human prostate tumor cells which endogenously express PSMA.
• PBMCs peripheral blood mononuclear cells
• mice 5x10 6 C4-2 cells (MD Anderson, TX) cells were co-implanted s.c. with 1x10 6 human PBMCs (ReachBio, LLC., Seattle, WA) in a 50:50 mix of matrigel matrix (BD Biosciences) into the right flank of male NSG mice. The mice were treated i.p. on days 0, 4, and 7 post tumor implantation with 0.1 mg/kg of PSMA/CD3-002.
• mice In an additional xenogenic model, an anti-PSMA x anti-CD3 bispecific was tested in mice engrafted with human hematopoietic CD34+ stem cells. Briefly, newborn SIRPa BALB/c-Rag2- I L2ry- (BRG) pups were engrafted with hCD34+ fetal liver cells. 3-6 months later hCD34-eng rafted SIRPa BRG mice were then implanted with C4-2 cells (5x10 6 s.c. in matrigel). 8 days later, mice were treated with 10 ug of PSMA/CD3-001 or an isotype control antibody, followed by 2x/week doses throughout the study.
• an anti-PSMA x anti-CD3 bispecific was assessed for anti-tumor activity in an immune-competent model.
• Mice humanized for the three chains (8ye) of CD3 as well as for PSMA were implanted with a variant murine prostate cancer cell line TRAMP-C2 transfected with human PSMA.
• TRAMP-C2_hPSMAv#1 Prior to study initiation, the tumorigenic cell line variant TRAMP-C2_hPSMAv#1 was generated. Briefly, 7.5x10 6 TRAMP-C2_hPSMA cells were implanted s.c. into the right flank of male mice humanized for CD3 and PSMA. A tumor was excised and cut into 3 mm fragments and subsequently implanted into the right flank of new male humanized mice. A tumor arising from the implanted tumor fragments was then harvested and disaggregated into a single cell suspension. These cells (TRAMP-C2_hPSMAv#1) were then cultured in vitro under G418 selection. 4.10 s cells of this variant cell line were then implanted into the right flank of male PSMA/CD3 humanized mice for the bispecific antibody efficacy studies.
• the anti-PSMA x anti-CD3 bispecific antibody showed efficacy in significantly delaying tumor growth across treatment groups.
• Minimal cytokine release was observed after administration of PSMA/CD3-001 , possibly due to the weak binding of the anti- CD3.
• mice bearing no tumors blood samples were collected 4 hours following PSMAxCD3 bispecific antibody treatment, and serum cytokine levels were determined. Transient increases in levels of cytokines, namely interferon-gamma (IFN-g), tumor necrosis factor (TNF), interleukin-2 (IL-2), and interleukin-6 (IL-6) were determined and the transient increases were dosedependent (data not shown).
• IFN-g interferon-gamma
• TNF tumor necrosis factor
• IL-2 interleukin-2
• IL-6 interleukin-6
• Example 6 A 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
• PSMA/CD3-002 in combination with cemiplimab 350 mg will be administered once every 3 weeks after a 4-week PSMA/CD3-002 monotherapy lead-in cycle.
• Study therapies are administered until disease progression, intolerable adverse events, withdrawal of consent, or study withdrawal criterion is met.
• the primary objectives in dose escalation are to evaluate the safety, tolerability, PK, and recommended phase 2 dosing regimen (RP2DR) of PSMA/CD3-002 alone and in-combination with cemiplimab.
• Expansion cohort(s) will be enrolled once RP2DRs have been determined.
• the primary objective is to assess clinical activity, as measured by objective response rate (ORR) with PSMA/CD3-002 alone or in combination with cemiplimab per modified Prostate Cancer Working Group 3 criteria.
• ORR objective response rate
• PSMA positron emission tomography/computed tomography scans will be performed at predefined timepoints on study. Additional details are provided below.
• the primary objectives of the study are: to assess the safety, tolerability, and PK and to determine RP2DR of PSMA/CD3-002 separately as monotherapy or in combination with cemiplimab (in dose escalation); and to assess preliminary anti-tumor activity of PSMA/CD3-002 as monotherapy or in combination with cemiplimab as measured by objective response rate (ORR) per modified Prostate Cancer Working Group (PCWG3) criteria (in dose expansion).
• ORR objective response rate
• PCWG3 modified Prostate Cancer Working Group
• the secondary objectives of the study are: to assess preliminary anti-tumor activity of PSMA/CD3-002 as monotherapy or in combination with cemiplimab as measured by ORR per modified PCWG3 criteria (in dose escalation); to characterize the safety profile in each expansion cohort (in does expansion); to characterize the PK of PSMA/CD3-002 as monotherapy or in combination with cemiplimab (in dose expansion); to assess preliminary anti-tumor activity of PSMA/CD3-002 as monotherapy or in combination with cemiplimab as measured by PSA decline (in dose escalation and dose expansion); and to evaluate immunogenicity of PSMA/CD3-002 in Module 1 and immunogenicity of PSMA/CD3-002 and cemiplimab in Module 2 (in dose escalation and dose expansion).
• BPI-SF Brief Pain Inventory - Short Form
• Dose levels are defined by the target dose of PSMA/CD3-002. Five (or up to eight) potential dose levels are designed in which the target dose of PSMA/CD3-002 will be escalated in ! (half)-log increments. Dose increments of ⁇ 100% may be implemented based on observed toxicities at any given dose level.
• Module 1 - Determination of the step-up dosing regimen and dose escalation of monotherapy PSMA/CD3-002 The initial dose of the step-up dosing regimen starts at a dose of 0.03 mg SC. All three doses will be escalated in %-log increments per dose level until the occurrence of specified adverse events (AEs) result in a modification to the dosing regimen (for initial and transitional doses) or the maximum tolerated dose (MTD)/RP2DR is defined (for the target dose). Administration of target doses will start on a once weekly (QW) schedule, and switch to once every 3 weeks (Q3W) after a minimum pharmacologically active dose has been reached as assessed by PSA or tumor response.
• QW once weekly
• Q3W once every 3 weeks
• Module 2 Dose escalation of PSMA/CD3-002 in combination with cemiplimab: Patients enrolling in Module 2 will receive a 4-week PSMA/CD3-002 monotherapy lead-in cycle (Cycle 0; QW SC, including “step-up” doses). During Module 2, PSMA/CD3-002 will be administered Q3W SC with cemiplimab 350 mg Q3W IV (Cycle 1+). Dose escalation of PSMA/CD3-002 in Module 2 will begin at least 1 dose level below the minimum pharmacologically active dose level of PSMA/CD3-002 determined in Module 1.
• a dose limiting toxicity (DLT) is any adverse event (AE) that could preclude advancing to higher dose levels.
• the DLT criteria incorporate AEs reported with other bsAbs and checkpoint inhibitors.
• Toxicities will be graded according to the 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.
• CRS cytokine release syndrome
• ASTCT current American Society for Transplantation and Cellular Therapy
• dose level escalation (/.e., target dose escalation) will follow BOIN (Bayesian optimal interval) design rules applied with the following conditions: 1) DLTs associated with previously untested doses of PSMA/CD3-002 will be considered, 2) dose levels will be escalated until a MTD with a toxicity rate of 30% is observed for the target dose of PSMA/CD3-002, and 3) the maximum number of patients treated at a dose level is 12.
• Module 1 because the step-up dosing regimen consists of doses that has been tested and deemed tolerable as a target dose in prior escalation cohorts (after DL1 in Module 1), separate rules will be applied to modify the step-up dosing regimen based on the occurrence and severity of cytokine release syndrome (CRS) and other DLTs.
• CRS cytokine release syndrome
• Module 1 The DLT observation period (minimum duration of 28 days) in Module 1 begins when the first dose of study drug is administered. Monitoring for DLTs continues for at least 2 weeks following the first administration of the PSMA/CD3-002 target dose at the given dose level. Due to the allowance of up to 2 weeks of dose delays during step-up dosing prior to the first administration of the target dose, the maximum duration of the DLT period is 42 days. DLTs observed during step-up dosing will be considered separately from DLTs observed at the target dose and be considered for modification of the step-up dosing regimen. DLTs observed at the target dose will determine tolerability of the target dose and considered for dose level escalation. [0157] Module 2: The DLT observation period is defined as 21 days from the first dose of combination therapy (PSMA/CD3-002 and cemiplimab) beginning on cycle 1 day 1.
• Dose Expansion During dose expansion, patients will receive either monotherapy PSMA/CD3-002 (Module 1) or combination therapy with cemiplimab 350 mg IV Q3W (Module 2) at the assigned DL (e.g., RP2DR). If multiple DLs reveal pharmacodynamic activity and are well tolerated, up to 2 expansion cohorts in total may be opened. In both dose escalation and dose expansion, safety evaluations will be conducted at each study drug dosing visit. Radiographic response assessment will be performed every 9 weeks (Q9W) throughout the study.
• DL e.g., RP2DR
• All patients will proceed through three successive periods of the trial: Screening, Treatment, and Follow-Up.
• the screening period is up to 28 days.
• the treatment period is divided into cycles to align with the frequency of tumor assessments.
• Treatment cycles are generally 9 weeks in both modules, with tumor assessments scheduled to occur at the beginning of each cycle.
• Module 2 includes 2 shorter cycles (cycles 0 and 1) that are described in detail below. Treatment will continue until either disease progression, intolerable AEs, elective discontinuation for clinical response, withdrawal of consent, or other study withdrawal criterion is met.
• Module 1 - Monotherapy PSMA/CD3-002 The Module 1 treatment period is comprised of 9-week cycles. During cycle 1 , individual patients will receive at least 2 escalating, “step-up” doses (/.e., initial dose and transitional dose) of PSMA/CD3-002 before reaching the target dose. Administration of the first target dose of PSMA/CD3-002 may be delayed by up to 2 weeks to resolve symptoms of CRS during initial and/or transitional doses.
• Patient-level study schema for Module 1 are provided in Figure 1 (QW) and Figure 2 (Q3W).
• QW Figure 1
• Figure 2 Figure 2
• 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 after administration, patients should continue to be observed in a monitored setting for each subsequent administration until post-injection CRS is grade ⁇ 1 , at which time their subsequent treatment administrations can occur in the outpatient setting.
• the next dose level will open with a Q3W schedule for the target dose of PSMA/CD3-002 for subsequently enrolled patients.
• the initial, transitional, and the first two consecutive target dosing intervals will remain QW for all patients enrolled in the study per Figure 2. All doses will be administered SC.
• cycle 1 For patients enrolled after the establishment of Q3W dosing and who require a lengthened step-up dosing period to resolve symptoms of CRS prior to receiving the first target dose, cycle 1 may be extended to maintain Q3W dosing schedule.
• the dosing schedule for the target dose of PSMA/CD3-002 may be QW or Q3W.
• the dosing schedule for the target dose of PSMA/CD3-002 may 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), comprising of weekly step-up dosing. Due to the possible potentiation of CRS with combination therapy, patients must tolerate the target dose of PSMA/CD3-002 without CRS during the monotherapy lead-in prior to initiating combination with cemiplimab.
• Cycle 0 consists of weekly monotherapy dosing of PSMA/CD3-002 as initial, transitional, and 2 target doses.
• the planned length of cycle 0 is 4 weeks but may be extended up to 6 weeks to allow for the resolution of CRS from initial and transitional doses or to repeat the target dose to demonstrate tolerability without symptoms of CRS.
• Cycle 1 when PSMA/CD3-002 and cemiplimab combination therapy is initiated, is 6 weeks (42 days) to accommodate the timing of the first on-treatment tumor assessment. Subsequent cycles (cycles 2+) will be 9 weeks (63 days).
• Patient-level study schema for Module 2 is provided in Figure 3.
• the target dose of PSMA/CD3-002 will not exceed the target dose of PSMA/CD3-002 that has been deemed tolerable in Module 1.
• All PSMA/CD3-002 doses will be administered SC, and cemiplimab will be administered by IV. Patients will be observed in a monitored setting for the first three injections in cycle 0 if grade > 2 CRS was observed in Module 1 for the same doses ( Figure 5) All patients will be observed in a monitored setting for the first combination treatment in cycle 1 for at least 72 hours or until all symptoms of CRS resolve. In addition, if grade >2 CRS is observed upon initial combination administration, then patients should continue to receive treatment in a monitored setting for each subsequent administration until postinjection CRS is grade ⁇ 1 , at which time their subsequent treatment can be administered as an outpatient.
• Module 2 begins at a dose level in which the initial and transitional doses are defined in Module 1 , those defined doses will be implemented in Module 2. 2 If Module 2 begins prior to the definition of initial and transitional doses, then the same doses of PSMA/CD3- 002 as specified in Table 8A will be used for initial and transitional doses in Module 2.
• Module 2 begins at a dose level in which the initial and transitional doses are defined in Module 1 , those defined doses will be implemented in Module 2.
• the study population includes men with treatment-experienced mCRPC.
• patients must have received at least 2 approved therapies for metastatic and/or castration-resistant disease, including a second-generation anti-androgen therapy (e.g., abiraterone, enzalutamide, apalutamide, or darolutamide).
• abiraterone e.g., abiraterone, enzalutamide, apalutamide, or darolutamide.
• Measurable lesion per RECIST Version 1.1 per local reading at screening is not an eligibility criterion for enrollment Has progressed upon or is intolerant to >2 lines prior systemic therapy approved in the metastatic and/or castration resistant setting (in addition to androgen deprivation therapy [ADT]) including at least 1 second-generation anti-androgen therapy (eg, abiraterone, enzalutamide, apalutamide, or darolutamide)
• ADT androgen deprivation therapy
• a non-taxane based chemotherapy regimen given for metastatic prostate cancer with mixed histology is permissible and will be included when evaluating line of therapy Able and willing to provide tumor tissue, either archival or newly obtained.
• a pathology report that confirms diagnosis of prostate cancer may be submitted Have had either orchiectomy OR be on luteinizing hormone-releasing hormone (LHRH) agonist or antagonist therapy with serum testosterone ⁇ 50 ng/dL AND agree to stay on LHRH agonist or antagonist therapy during the study Has an ECOG performance status of 0 or 1 Has adequate organ and bone marrow function documented by: a. Hemoglobin >8.5 g/dL b.
• Dose Escalation and Module 1 Dose Expansion: Has had prior anti-cancer immunotherapy (other than sipuleucel-T) within 5 half-lives prior to study therapy.
• immune modulating agents include blockers of CTLA-4, 4-1BB (CD137), or OX-40, therapeutic vaccines, anti-PD-1/PD-L1 , phosphoinositide 3-kinase (PI3K) delta inhibitors, or cytokine anticancer treatments.
• PI3K phosphoinositide 3-kinase
• Module 2 Dose Expansion: Has had prior anti-cancer immunotherapy.
• immune modulating agents include blockers of CTLA-4, 4-1BB (CD137), or OX-40, therapeutic vaccines, anti-PD-1/PD-L1 , PI3Kdelta inhibitors, CAR-T cells, or cytokine anticancer treatments.
• No requirement for systemic corticosteroids for management of central nervous system metastases or spinal cord compression within 2 weeks prior to the first dose of study drug Has encephalitis, meningitis, neurodegenerative disease (with the exception of mild dementia that does not interfere with activities of daily living [ADLs]) or uncontrolled seizures in the year prior to first dose of study therapy has a known history of, or any evidence of, interstitial lung disease or active, noninfectious pneumonitis within 5 years prior to the first dose of study drug.
• a history of radiation pneumonitis in the radiation field is permitted Has uncontrolled infection with human immunodeficiency virus, hepatitis B, or hepatitis C infection; or has a diagnosis of immunodeficiency a.
• HCV hepatitis C virus
• HBV hepatitis B virus
• HBV RNA PCR undetectable viral load
• CD4 count above 350 either spontaneously or on a stable antiviral regimen
• monitoring will be performed per local standards c.
• Patients with hepatitis B (HBsAg+) who have controlled infection serum hepatitis B virus DNA PCR that is below the limit of detection and receiving anti-viral therapy for hepatitis B) are permitted.
• Patients with controlled infections must undergo periodic monitoring of HBV DNA.
• Patients must remain on anti-viral therapy for at least 6 months beyond the last dose of investigational study drug d.
• Patients who are hepatitis C virus antibody positive (HCV Ab+) who have controlled infection (undetectable HCV RNA by PCR either spontaneously or in response to a successful prior course of anti-HCV therapy) may be enrolled into the study Has any infection requiring hospitalization or treatment with intravenous anti- infectives within 2 weeks of first dose of study drug Has received a live vaccine within 28 days of planned start of study drug Has had prior allogeneic stem cell transplantation or received organ transplants at any time, or autologous stem cell transplantation within 12 weeks of the start of study drug Has known allergy or hypersensitivity to components of study drugs Has known psychiatric or substance abuse disorders that would interfere with participation with the requirements of the study Has any medical condition, co-morbidity, physical examination finding, or metabolic dysfunction, or clinical laboratory abnormality that, in the opinion of the investigator, renders the patient unsuitable for participation in a clinical study due to high safety risks and/
• PSMA/CD3-002 will be administered at a dose of from 0.3 mg to 30 mg (but may be up to 900 mg) either QW or Q3W by SC administration as target dose levels.
• Cemiplimab will be administered at a dose of 350 mg concomitantly Q3W by IV infusion over 30 minutes.
• PSMA/CD3-002 When both drugs are administered on the same day, PSMA/CD3-002 will be administered first and cemiplimab administration should follow no sooner than 30 minutes following completion of PSMA/CD3-002 administration.
• the primary endpoints of the study are: Dose-limiting toxicities, other treatment-emergent adverse events (TEAEs; including irAEs), serious AEs (SAEs), adverse events of special interests (AESIs), and laboratory abnormalities (in dose escalation); PSMA/CD3-002 concentrations in serum as monotherapy or in combination with cemiplimab (in dose escalation); and Objective Response Rate (ORR) per modified Prostate Cancer Working Group 3 (PCWG3) criteria, (in dose expansion) defined as the percentage of patients who have achieved response based on:
• ORR per modified PCWG3 criteria in dose escalation
• dose escalation defined as the percentage of patients who have achieved response based on >50% decline of PSA from baseline, confirmed by a second PSA test >4 weeks later, and/or confirmed radiographic response of complete response (CR) or partial response (PR); dose-limiting toxicities, other TEAEs (including irAEs), SAEs, AESIs, and laboratory abnormalities (in does expansion); PSMA/CD3-002 concentrations in serum as monotherapy or in combination with cemiplimab (in dose expansion); percentage of patients with >50% reduction PSA from baseline, confirmed by a second PSA test >4 weeks later (in dose escalation and expansion); percentage of patients with >90% reduction PSA from baseline, confirmed by a second PSA test >4 weeks later (in dose escalation and expansion); and immunogenicity, as measured by anti-drug antibodies (ADA) to PSMA/CD3-002 in Module 1 and ADA to PSMA/CD3-002
• ADA anti-
• DCR Disease Control Rate
• TMB tumor mutational burden

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