WO2024102645A1 - Combination treatment with a bispecific antibody that binds ctla4 and pd1 for prostate cancer - Google Patents

Combination treatment with a bispecific antibody that binds ctla4 and pd1 for prostate cancer Download PDF

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Publication number
WO2024102645A1
WO2024102645A1 PCT/US2023/078791 US2023078791W WO2024102645A1 WO 2024102645 A1 WO2024102645 A1 WO 2024102645A1 US 2023078791 W US2023078791 W US 2023078791W WO 2024102645 A1 WO2024102645 A1 WO 2024102645A1
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male subject
amino acid
dose
day
treatment cycle
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PCT/US2023/078791
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French (fr)
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Raphael Clynes
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Xencor, Inc.
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Publication of WO2024102645A1 publication Critical patent/WO2024102645A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IGs], 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 [IGs], 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
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/502—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with carbocyclic ring systems, e.g. cinnoline, phthalazine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/555—Heterocyclic compounds containing heavy metals, e.g. hemin, hematin, melarsoprol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • A61K2039/545—Medicinal preparations containing antigens or antibodies characterised by the dose, timing or administration schedule
    • 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
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • 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

Definitions

  • a bispecific anti-CTLA4 x anti-PDl antibody in combination with at least one additional agent (e.g., carboplatin, carbazitaxel, docetaxel, and/or olaparib) to the subject.
  • additional agent e.g., carboplatin, carbazitaxel, docetaxel, and/or olaparib
  • a method of treating a prostate cancer in a male subject in need thereof comprising: (a) administering a bispecific antibody to the male subject at a dose of between about 5-15 mg/kg, wherein the dose of the bispecific antibody is intravenously administered to the male subject on Day 1 of a first treatment cycle and about every two weeks (Q2W) thereafter; (b) administering carboplatin to the male subject at a therapeutically effective dose that results in a target area under the serum concentration-time curve of 3 (AUC3) in the male subject, wherein the dose of the carboplatin is intravenously administered to the male subject twice in the first treatment cycle, wherein the twice is on Day 1 and about three weeks after Day 1 of the first treatment cycle; (c) administering a taxane to the male subject at a dose of between about 10 mg/m 2 and about 55 mg/m 2 , wherein the dose of the taxane is intravenously administered to the male subject twice in the first treatment cycle, wherein
  • a method of treating a prostate cancer in a male subject in need thereof comprising: (a) administering a bispecific antibody to the male subject at a dose of 10 mg/kg, wherein the dose of the bispecific antibody is intravenously administered to the male subject on day 1 of a first treatment cycle and about every two weeks (Q2W) thereafter; (b) administering carboplatin to the male subject at a therapeutically effective dose that results in a target area under the serum concentration-time curve of 3 (AUC3) in the male subject, wherein the dose of the carboplatin is intravenously administered to the male subject twice in the first treatment cycle, wherein the twice is on day 1 and about three weeks after day 1 of the first treatment cycle; (c) administering carbazitaxel to the male subject at a dose of 15 mg/m 2 , wherein the dose of the carbazitaxel is intravenously administered to the male subject twice in the first treatment cycle, wherein the twice is on day 1 and about
  • a method of treating a prostate cancer in a male subject in need thereof comprising: (a) administering a bispecific antibody to the male subject at a dose of 10 mg/kg, wherein the dose of the bispecific antibody is intravenously administered to the male subject on day 1 of a first treatment cycle and about every two weeks (Q2W) thereafter; (b) administering carboplatin to the male subject at a therapeutically effective dose that results in a target area under the serum concentration-time curve of 3 (AUC3) in the male subject, wherein the dose of the carboplatin is intravenously administered to the male subject twice in the first treatment cycle, wherein the twice is on day 1 and about three weeks after day 1 of the first treatment cycle; (c) administering docetaxel to the male subject at a dose of 50 mg/m 2 , wherein the dose of the docetaxel is intravenously administered to the male subject twice in the first treatment cycle, wherein the twice is on day 1 and about three weeks after day
  • a method of treating a prostate cancer in a male subject in need thereof comprising: (a) administering a bispecific antibody to the male subject at a dose of between about 5-15 mg/kg, wherein the dose of the bispecific antibody is intravenously administered to the male subject on Day 1 of a first treatment cycle and about every two weeks (Q2W) thereafter; and (b) administering a taxane to the male subject at a dose of between about 10 mg/m 2 and about 80 mg/m 2 , wherein the dose of the taxane is intravenously administered to the male subject on Day 1 of the first treatment cycle and about every three weeks (Q3W) thereafter; wherein each treatment cycle is about 28 days; wherein the prostate cancer progressed after the male subject received a polyadenosine diphosphate ribose polymerase (PARP) inhibitor prior to the administering of (a) and/or wherein the prostate cancer does not have a targetable mutation; and wherein the bispecific antibody
  • PARP polyadenosine diphosphate
  • a method of treating a prostate cancer in a male subject in need thereof comprising: (a) administering a bispecific antibody to the male subject at a dose of 10 mg/kg, wherein the dose of the bispecific antibody is intravenously administered to the male subject on day 1 of a first treatment cycle and about every two weeks (Q2W) thereafter; and (b) administering carbazitaxel to the male subject at a dose of 20 mg/m 2 , wherein the dose of the carbazitaxel is intravenously administered to the male subject on day 1 of the first treatment cycle and about every three weeks (Q3W) thereafter; wherein each treatment cycle is 28 days; wherein the prostate cancer progressed after the male subject received a polyadenosine diphosphate ribose polymerase (PARP) inhibitor prior to the administering of (a) and/or wherein the prostate cancer does not have a targetable mutation; and wherein the bispecific antibody comprises a first polypeptide comprising
  • PARP polyadenosine diphosphate
  • a method of treating a prostate cancer in a male subject in need thereof comprising: (a) administering a bispecific antibody to the male subject at a dose of 10 mg/kg, wherein the dose of the bispecific antibody is intravenously administered to the male subject on day 1 of a first treatment cycle and about every two weeks (Q2W) thereafter; and (b) administering docetaxel to the male subject at a dose of 75 mg/m 2 , wherein the dose of the docetaxel is intravenously administered to the male subject on day 1 of the first treatment cycle and about every three weeks (Q3W) thereafter; wherein each treatment cycle is 28 days; wherein the prostate cancer progressed after the male subject received a polyadenosine diphosphate ribose polymerase (PARP) inhibitor prior to the administering of (a) and/or wherein the prostate cancer does not have a targetable mutation; and wherein the bispecific antibody comprises a first polypeptide comprising an amino acid sequence
  • PARP polyadenosine diphosphate
  • a method of treating prostate cancer in a male subject in need thereof comprising: (a) administering a bispecific antibody to the male subject at a dose of between about 5-15 mg/kg, wherein the dose of the bispecific antibody is intravenously administered to the male subject on day 1 of a first treatment cycle and about every two weeks (Q2W) thereafter; and (b) administering olaparib to the male subject at a dose of between about 500 to about 700 mg per day on day 1 of a first treatment cycle and every day thereafter; wherein each treatment cycle is about 28 days; wherein the male subject has not been previously treated with a polyadenosine diphosphate ribose polymerase (PARP) inhibitor; and wherein the bispecific antibody comprises a first polypeptide comprising an amino acid sequence of SEQ ID NO: 1, a second polypeptide comprising an amino acid sequence of SEQ ID NO:2, and a third polypeptide comprising an amino acid sequence of SEQ ID NO:3.
  • PARP polyadenosine diphosphate rib
  • the AVPCa has a mutation or other aberrancy in at least two genes independently selected from the group consisting of Rbl, TP53 and PTEN.
  • the prostate cancer is not an aggressive variant (anaplastic) adenocarcinoma of the prostate (AVPCa).
  • the prostate cancer has a homologous recombination deficiency (HRD).
  • the prostate cancer has a biallelic loss of cyclin-dependent kinase 12 (CDK12).
  • the male subject has been previously treated with a polyadenosine diphosphate ribose polymerase (PARP) inhibitor.
  • PARP polyadenosine diphosphate ribose polymerase
  • the prostate cancer does not have a targetable mutation.
  • the dose of the olaparib is 600 mg per day. In one embodiment, the 600 mg per day is administered twice per day in an amount of 300 mg each. In one embodiment, the dose of the bispecific antibody is 10 mg/kg.
  • the taxane is carbazitaxel. In one embodiment, the taxane is carbazitaxel and the dose is 15 mg/m 2 for (c) and 20 mg/m 2 for (e). In one embodiment, the taxane is carbazitaxel and the dose is 20 mg/m 2 . In one embodiment, the taxane is docetaxel if the male subject has not been treated with docetaxel prior to the first treatment cycle.
  • the taxane is docetaxel if the male subject has not been treated with docetaxel prior to the first treatment cycle, and the dose is 50 mg/ m 2 for (c) and 60 mg/ m 2 for (e). In one embodiment, the taxane is docetaxel if the male subject has not been treated with docetaxel prior to the first treatment cycle, and the dose is 75 mg/m 2 .
  • the male subject has not been treated with docetaxel prior to the first treatment cycle.
  • the carboplatin is intravenously administered on administered on day 15 of the second treatment cycle.
  • the male subject has received at least two systemic therapies prior to the first treatment cycle.
  • the male subject has received at least three systemic therapies prior to the first treatment cycle.
  • the male subject has been treated with chemotherapy prior to the first treatment cycle.
  • the male subject has been treated with radiation therapy prior to the first treatment cycle.
  • the male subject is an adult male subject. In one embodiment, the adult male subject is 50 years of age or older.
  • the method results in a decrease in prostate specific antigen (PSA) in a biological sample obtained from the male subject compared to a reference.
  • PSA prostate specific antigen
  • the decrease in PSA is a decrease of about or at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or more than 95% as compared to the reference.
  • the decrease is about or at least about 50% as compared to the reference.
  • the reference is the level of PSA in a biological sample obtained from the male subject prior to the first treatment cycle.
  • the reference is the level of PSA at baseline.
  • the biological sample is blood, plasma, and/or serum.
  • the method further comprises orally administering a steroid to the male subject.
  • the carboplatin is administered for about 8 treatment cycles.
  • the male subject has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
  • the method results in stable disease classification of the prostate cancer as determined by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.
  • the method results in partial response classification of the prostate cancer as determined by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.
  • the method is for about or at least about 3 treatment cycles.
  • the method is for about or at least about 6 treatment cycles.
  • the method is for about or at least about 8 treatment cycles.
  • FIG. 1 depicts the structure of the antibody described herein.
  • the XmAb®20717 has a “bottle opener” format (also referred to as the “triple F” format).
  • Bottle opener format antibodies include a) a first monomer that includes a first Fc domain and an scFv region, wherein the scFv includes a first variable heavy chain and a first variable light chain (also referred herein as a “scFv-Fc heavy chain;” b) a second monomer that includes a VH-CH1- hinge-CH2-CH3, wherein VH is a second variable heavy chain and CH2 and CH3 is a second Fc domain (also referred herein as a “Fab-Fc heavy chain;” and c) a light chain that includes a second variable light chain.
  • the scFv is the PD1 binding domain and the second variable heavy chain and second variable light chain for the CTLA4 binding domain. It should be noted that the scFv and Fab domains can be switched (e.g., anti-PDl as a Fab and anti-CTLA4 as a scFv).
  • FIG. 2 depicts the amino acid sequences of the XmAb®20717 antibody.
  • the antibody is named using the Fab variable region first and the scFv variable region second, separated by a dash, followed by the chain designation (Fab-Fc heavy chain, scFv-Fc heavy chain or light chain).
  • CDRs are underlined and slashes indicate the border(s) of the variable regions.
  • FIG. 3 shows potent antitumor immune response in a mCRPC patient following XmAb®20717 treatment, as shown by multiplex immunofluorescence staining of paited pretreatment and post-treatment biopsies.
  • FIG. 4 depicts a study design showing the study population, cohorts, and their respective treatments with the XmAb®20717 antibody.
  • FIG. 5 depicts the study schema for subjects treated with the XmAb®20717 antibody.
  • FIG. 6 depicts a graph showing duration of treatment with the XmAb®20717 antibody, carboplatin, and taxane (cabazitaxel or docetaxel), or the XmAb®20717 antibody with olaparib (data cutoff date of September 7, 2022).
  • FIG. 6 shows treatment-related adverse events (TRAE; z.e., events attributed to any component of combination therapy) reported for > 2 of the 8 patients treated with XmAb®20717 and chemotherapy or any immunotherapy-related adverse event (irAE) by maximum Common Terminology Criteria for Adverse Events (CTCAE) grade. No irAEs or TRAEs were reported for the patient who received XmAb®20717 and olaparib.
  • TRAE treatment-related adverse events
  • CCAE Common Terminology Criteria for Adverse Events
  • AVPC aggressive variant prostate cancer
  • PARPiN HRD PARPi naive homologous recombination deficient
  • PARPiP HRD PARPi progressor homologous recombination deficient
  • NTM no targetable mutation.
  • FIG. 7 depicts a graph showing percent change from baseline in prostate specific antigen (PSA) (data cutoff date of September 7, 2022).
  • PSA prostate specific antigen
  • AVPC aggressive variant prostate cancer
  • PARPiN HRD PARPi naive homologous recombination deficient
  • PARPiP HRD PARPi progressor homologous recombination deficient
  • NTM no targetable mutation.
  • TRAE treatment-related adverse events
  • irAE immunotherapy-related adverse event
  • CCAE Common Terminology Criteria for Adverse Events
  • the conjunctive term “and/or” between multiple recited elements is understood as encompassing both individual and combined options. For instance, where two elements are conjoined by “and/or,” a first option refers to the applicability of the first element without the second. A second option refers to the applicability of the second element without the first. A third option refers to the applicability of the first and second elements together. Any one of these options is understood to fall within the meaning, and therefore satisfy the requirement of the term “and/or” as used herein. Concurrent applicability of more than one of the options is also understood to fall within the meaning, and therefore satisfy the requirement of the term “and/or.”
  • the term “about” in relation to a reference numerical value can include the numerical value itself and a range of values plus or minus 10% from that numerical value.
  • the amount “about 10” includes 10 and any amounts from 9 to 11.
  • the term “about” in relation to a reference numerical value can also include a range of values plus or minus 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% from that value.
  • the numerical disclosed throughout can be “about” that numerical value even without specifically mentioning the term “about.”
  • CTLA4 cytotoxic T-lymphocyte-associated protein 4
  • CD 152 CD 152
  • cluster of differentiation 152 e.g., GenBank Accession Number NP_001032720 (human isoform without transmembrane) and NP_005205 (human isoform with transmembrane)
  • NP_001032720 human isoform without transmembrane
  • NP_005205 human isoform with transmembrane
  • CTLA4 contains an extracellular V domain, a transmembrane domain, and a cytoplasmic tail. Alternate splice variants, encoding different isoforms, have been characterized. The membrane-bound isoform functions as a homodimer interconnected by a disulfide bond, while the soluble isoform functions as a monomer. CTLA4 is capable of providing a physiological counterbalance to immune cell activation and thereby to control the intensity of the immune response. It exerts this effect by outcompeting CD28, a costimulatory molecule necessary for T-cell activation, for binding to CD80 and CD86 on antigen-presenting cells and tumor cells.
  • CTLA4 up-modulation of T-cell activation (Postow et al., J Clin Oncol. 2015;33(17): 1974-1982).
  • CTLA4 can also inhibit T cell responses directly via SHP-2 and PP2A dephosphorylation of TCR-proximal signaling proteins such as CD3 and LAT.
  • CTLA4 is also known to bind PI3K.
  • PD1 By “PD1,” “PD1,” “Programmed cell death protein 1,” “CD279,” and “cluster of differentiation 279” (e.g., GenBank Accession Number NP_0015009 (human)) as used herein is meant a type I membrane protein that is a member of the extended CD28/CTLA4 family of T cell regulators.
  • the bispecific antibodies provided herein bind to the extracellular domain of human PD1.
  • PD1 includes an extracellular IgV domain followed by a transmembrane region and an intracellular tail PD1 is expressed on the surface of activated T cells, B cells and macrophage and is upregulated in the context of chronic and persistent antigen stimulation.
  • PD1 is upregulated on the surface of activated tumor-infiltrating CD8+ T cells, as well as activated B cells and myeloid cells.
  • PDL1 and PDL2 may be expressed on a wide range of cell types including antigen-presenting cells and tumor cells, and the overall effect of engagement of the ligands is to limit, terminate, or attenuate the cytotoxic and cytokine-producing capacity of cytotoxic T cells. This, in turn, results in an ineffective antitumor immune response and the persistence of tumors (Postow et al., J Clin Oncol. 2015;33(17): 1974-1982).
  • bispecific or “bispecific antibody” herein is meant any non-native or alternate antibody formats, including those described herein, that bind to two different antigens (e.g., PD1 x CTLA4 bispecific antibodies, such as XmAb®20717).
  • modification herein is meant an amino acid substitution, insertion, and/or deletion in a polypeptide sequence or an alteration to a moiety chemically linked to a protein.
  • a modification may be an altered carbohydrate or PEG structure attached to a protein.
  • amino acid modification herein is meant an amino acid substitution, insertion, and/or deletion in a polypeptide sequence.
  • the amino acid modification is always to an amino acid coded for by DNA, e.g., the 20 amino acids that have codons in DNA and RNA.
  • amino acid substitution or “substitution” herein is meant the replacement of an amino acid at a particular position in a parent polypeptide sequence with a different amino acid.
  • the substitution is to an amino acid that is not naturally occurring at the particular position, either not naturally occurring within the organism or in any organism.
  • the substitution E272Y refers to a variant polypeptide, in this case an Fc variant, in which the glutamic acid at position 272 is replaced with tyrosine.
  • any amino acid substitution is always to an amino acid coded for by DNA, e.g, the 20 amino acids that have codons in DNA and RNA.
  • a protein which has been engineered to change the nucleic acid coding sequence but not change the starting amino acid is not an “amino acid substitution”; that is, despite the creation of a new gene encoding the same protein, if the protein has the same amino acid at the particular position that it started with, it is not an amino acid substitution.
  • amino acid insertion or “insertion” as used herein is meant the addition of an amino acid sequence at a particular position in a parent polypeptide sequence.
  • - 233E or 233E designates an insertion of glutamic acid after position 233 and before position 234.
  • -233ADE or A233ADE designates an insertion of AlaAspGlu after position 233 and before position 234.
  • any amino acid insertion is to an amino acid coded for by DNA, e.g., the 20 amino acids that have codons in DNA and RNA.
  • amino acid deletion or “deletion” as used herein is meant the removal of an amino acid sequence at a particular position in a parent polypeptide sequence.
  • K447-, K447_, K447del or K447# designates a deletion of lysine at position 447.
  • N- or C-terminal clipping can occur during production, including the lysine at position 447, the glycine at position 446, or additional amino acids.
  • the nucleic acids encoding the heavy chains herein can terminate at position 447, 446, 445, 444, etc.
  • variant protein or “protein variant”, or “variant” as used herein is meant a protein that differs from that of a parent protein by virtue of at least one amino acid modification.
  • Protein variant may refer to the protein itself, a composition comprising the protein, or the amino sequence that encodes it.
  • the protein variant has at least one amino acid modification compared to the parent protein, e.g., from about one to about seventy amino acid modifications, and preferably from about one to about twenty amino acid modifications compared to the parent.
  • the variant Fc domains of XmAb®717 can have 14 amino acid variants as compared to a human IgGl.
  • the parent polypeptide for example an Fc parent polypeptide, is a human wild type sequence, such as the Fc region from IgGl, IgG2, IgG4, although human sequences with variants can also serve as “parent polypeptides”.
  • the protein variant sequence herein can preferably possess at least about 80% identity with a parent protein sequence, and most preferably at least about 90% identity, more preferably at least about 95-98-99% identity.
  • Variant protein can refer to the variant protein itself, compositions comprising the protein variant, or the DNA sequence that encodes it.
  • antibody variant or “variant antibody” as used herein is meant an antibody that differs from a parent antibody by virtue of at least one amino acid modification
  • IgG variant or “variant IgG” as used herein is meant an antibody that differs from a parent IgG (again, in many cases, from a human IgG sequence) by virtue of at least one amino acid modification
  • immunoglobulin variant or “variant immunoglobulin” as used herein is meant an immunoglobulin sequence that differs from that of a parent immunoglobulin sequence by virtue of at least one amino acid modification
  • Fc variant or “variant Fc” as used herein is meant a protein comprising an amino acid modification in an Fc domain.
  • N434S or 434S is an Fc variant with the substitution serine at position 434 relative to the parent Fc polypeptide, where the numbering is according to the EU index.
  • M428L/N434S defines an Fc variant with the substitutions M428L and N434S relative to the parent Fc polypeptide.
  • the identity of the WT amino acid may be unspecified, in which case the aforementioned variant is referred to as 428L/434S.
  • amino acid position numbering is according to the EU index.
  • the EU index or EU index as in Kabat or EU numbering scheme refers to the numbering of the EU antibody (Edelman et al., 1969, Proc Natl Acad Sci USA 63:78-85, hereby entirely incorporated by reference.)
  • the modification can be an addition, deletion, or substitution.
  • variant proteins within the scope of the present disclosure retain the biological activity of the parent protein, although it can differ in scale or scope.
  • amino acid substitutions can be made in the anti-CTLA4 antigen binding domains provided herein as long as they retain the ability to bind to human CTLA4 as measured by a BIOCORE or Octet assay.
  • protein is meant at least two covalently attached amino acids, which includes proteins, polypeptides, oligopeptides and peptides.
  • the peptidyl group may comprise naturally occurring amino acids and peptide bonds, or synthetic peptidomimetic structures, i.e. “analogs”, such as peptoids (see Simon et al., PNAS USA 89(20):9367 (1992), entirely incorporated by reference).
  • the amino acids may either be naturally occurring or synthetic (e.g., not an amino acid that is coded for by DNA); as will be appreciated by those in the art.
  • homo-phenylalanine, citrulline, ornithine and noreleucine are considered synthetic amino acids herein, and both D- and L-(R or S) configured amino acids may be utilized.
  • the variants herein may comprise modifications that include the use of synthetic amino acids incorporated using, for example, the technologies developed by Schultz and colleagues, including but not limited to methods described by Cropp & Shultz, 2004, Trends Genet. 20(12):625-30, Anderson et al., 2004, Proc Natl Acad Sci USA 101 (2):7566- 71, Zhang et al., 2003, 303(5656):371-3, and Chin et al., 2003, Science 301(5635):964-7, all entirely incorporated by reference.
  • polypeptides may include synthetic derivatization of one or more side chains or termini, glycosylation, PEGylation, circular permutation, cyclization, linkers to other molecules, fusion to proteins or protein domains, and addition of peptide tags or labels.
  • residue as used herein is meant a position in a protein and its associated amino acid identity.
  • Asparagine 297 also referred to as Asn297 or N297
  • Asn297 is a residue at position 297 in the human antibody IgGl .
  • the term “antibody” is used in a broad sense and includes immunoglobulin or antibody molecules.
  • antibodies are proteins or peptide chains that exhibit binding specificity to a specific antigen.
  • the antibodies provided herein are based on IgGl, IgG2, or IgG4.
  • the antibodies provided herein are based on IgGl, IgG2, or IgG4 and contain amino acid variants.
  • the antibodies provided herein are based on human IgGl, and contain amino acid variants as outlined herein.
  • Antibody light chains of vertebrate species can be assigned to one of two clearly distinct types, namely kappa and lambda, based on the amino acid sequences of their constant domains.
  • an antibody provided herein comprises a kappa light chain.
  • an antibody provided herein comprises a lambda light chain.
  • an antibody provided herein comprises a kappa light chain and a lambda light chain.
  • the antibodies provided herein can, in certain embodiments, contain a kappa light chain constant domain.
  • antibodies provided herein can, in certain embodiments, contain lambda light chain constant domains.
  • the antibodies provided herein can contain kappa light chain and lambda light chain constant domains.
  • antibodies contain an antigenbinding region that is made up of a light chain variable (VL) domain (or region) and a heavy chain variable (VH) domain (or region).
  • VL light chain variable
  • VH heavy chain variable
  • hypervariable region such as a VH or VL, when used herein refers to the regions of an antibody variable region that are hypervariable in sequence and/or form structurally defined loops.
  • antibodies comprise six hypervariable regions; three in the VH (HCDR1, HCDR2, HCDR3), and three in the VL (LCDR1, LCDR2, LCDR3).
  • a “CDR” refers to one of three hypervariable regions (VH CDR1, VH CDR2 or VH CDR3) within the non-framework region of the immunoglobulin (Ig or antibody) VH P-sheet framework, or one of three hypervariable regions (VL CDR1, VL CDR2 or VL CDR3) within the non-framework region of the antibody VL P-sheet framework. Accordingly, CDRs are variable region sequences interspersed within the framework region sequences.
  • the light chain variable region CDR1 domain is interchangeably referred to herein as LCDR1 or VL CDR1.
  • the light chain variable region CDR2 domain is interchangeably referred to herein as LCDR2 or VL CDR2.
  • the light chain variable region CDR3 domain is interchangeably referred to herein as LCDR3 or VL CDR3.
  • the heavy chain variable region CDR1 domain is interchangeably referred to herein as HCDR1 or VH CDR1.
  • the heavy chain variable region CDR2 domain is interchangeably referred to herein as HCDR2 or VH CDR2.
  • the heavy chain variable region CDR1 domain is interchangeably referred to herein as HCDR3 or VH CDR3.
  • a number of hypervariable region delineations are in use and are encompassed herein, for example, in the tables and/or Examples provided below.
  • the “Kabaf ’ CDRs are based on sequence variability and are the most commonly used (see, e.g., Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD. (1991)). “Chothia” refers instead to the location of the structural loops (see, e.g., Chothia and Lesk, J. Mol. Biol. 196:901-917 (1987)).
  • the end of the Chothia CDR-HCDR1 loop when numbered using the Kabat numbering convention varies between H32 and H34 depending on the length of the loop (this is because the Kabat numbering scheme places the insertions at H35A and H35B; if neither 35 A nor 35B is present, the loop ends at 32; if only 35A is present, the loop ends at 33; if both 35A and 35B are present, the loop ends at 34).
  • the “AbM” hypervariable regions represent a compromise between the Kabat CDRs and Chothia structural loops, and are used by Oxford Molecular’s AbM antibody modeling software (see, e.g., Martin, in Antibody Engineering, Vol. 2, Chapter 3, Springer Verlag).
  • IMGT ImMunoGeneTics
  • IG immunoglobulins
  • TR T cell receptors
  • MHC major histocompatibility complex
  • the numbering system including, for example, the Kabat numbering and the IMGT unique numbering system, is well known to one skilled in the art (see, e.g., Kabat, supra, Chothia and Lesk, supra, Martin, supra, Lafranc el al., supra).
  • An Exemplary system may also be used that combines Kabat and Chothia.
  • Hypervariable regions may comprise “extended hypervariable regions” as follows: 24-36 or 24-34 (LCDR1), 46-56 or 50-56 (LCDR2) and 89-97 or 89-96 (LCDR3) in the VL and 26-35 or 26-35A (HCDR1), 50-65 or 49-65 (HCDR2) and 93-102, 94-102, or 95-102 (HCDR3) in the VH.
  • CDR sequences reflecting each of the above numbering schemes, are provided herein.
  • constant region refers to a carboxy terminal portion of the light and heavy chain which is not directly involved in binding of the antibody to antigen but exhibits various effector function, such as interaction with the Fc receptor.
  • the terms refer to the portion of an immunoglobulin molecule having a more conserved amino acid sequence relative to the other portion of the immunoglobulin, the variable region, which contains the antigen binding site.
  • the constant region may contain the CHI, hinge, CH2 and CH3 regions of the heavy chain and the CL region of the light chain.
  • FR residues are those variable region residues flanking the CDRs. FR residues are those variable domain residues other than the hypervariable region residues or CDR residues.
  • antigen binding domain or “ABD” herein is meant a set of six Complementary Determining Regions (CDRs) that, when present as part of a polypeptide sequence, specifically binds a target antigen as discussed herein.
  • CDRs Complementary Determining Regions
  • a “CTLA4 antigen binding domain” binds human CTLA4.
  • a “checkpoint antigen binding domain” binds a target checkpoint antigen as outlined herein.
  • these CDRs are generally present as a first set of variable heavy CDRs (vhCDRs or VHCDRs) and a second set of variable light CDRs (vlCDRs or VLCDRs), each comprising three CDRs: vhCDRl, vhCDR2, vhCDR3 for the heavy chain and vlCDRl, vlCDR2 and vlCDR3 for the light.
  • the CDRs are present in the variable heavy and variable light domains, respectively, and together form an Fv region.
  • the six CDRs of the antigen binding domain are contributed by a variable heavy and a variable light domain.
  • the set of 6 CDRs are contributed by two different polypeptide sequences, the variable heavy domain (vh or VH; containing the vhCDRl, vhCDR2 and vhCDR3) and the variable light domain (vl or VL; containing the vlCDRl, vlCDR2 and vlCDR3), with the C-terminus of the vh domain being attached to the N-terminus of the CHI domain of the heavy chain and the C-terminus of the vl domain being attached to the N-terminus of the constant light domain (and thus forming the light chain).
  • VH variable heavy domain
  • VL variable light domain
  • vh and vl domains are covalently attached, generally through the use of a linker (a “scFv linker”) as outlined herein, into a single polypeptide sequence, which can be either (starting from the N-terminus) vh-linker-vl or vl- linker-vh (including optional domain linkers on each side, depending on the format used (e.g., from FIG. 1).
  • a linker a “scFv linker”
  • the C-terminus of the scFv domain is attached to the N- terminus of the hinge in the second monomer.
  • Fab or “Fab region” as used herein is meant the polypeptide that comprises the VH, CHI, VL, and CL immunoglobulin domains, generally on two different polypeptide chains (e.g., VH-CH1 on one chain and VL-CL on the other).
  • Fab may refer to this region in isolation, or this region in the context of a bispecific antibody provided herein.
  • the Fab comprises an Fv region in addition to the CHI and CL domains.
  • Fv or “Fv fragment” or “Fv region” as used herein is meant a polypeptide that comprises the VL and VH domains of an ABD. Fv regions can be formatted as both Fabs (as discussed above, generally two different polypeptides that also include the constant regions as outlined above) and scFvs, where the VL and VH domains are combined (generally with a linker as discussed herein) to form an scFv.
  • single chain Fv or “scFv” herein is meant a variable heavy domain covalently attached to a variable light domain, generally using a scFv linker as discussed herein, to form a scFv or scFv domain.
  • a scFv domain can be in either orientation from N- to C-terminus (vh-linker-vl or vl-linker-vh).
  • H.X L.Y means N- to C-terminal is vh-linker-vl
  • L.Y H.X is vl-linker-vh.
  • amino acid and “amino acid identity” as used herein is meant one of the 20 naturally occurring amino acids that are coded for by DNA and RNA.
  • IgG Fc ligand as used herein is meant a molecule, preferably a polypeptide, from any organism that binds to the Fc region of an IgG antibody to form an Fc/Fc ligand complex.
  • Fc ligands include but are not limited to FcyRIs, FcyRIIs, FcyRIIIs, FcRn, Clq, C3, mannan binding lectin, mannose receptor, staphylococcal protein A, streptococcal protein G, and viral FcyR.
  • Fc ligands also include Fc receptor homologs (FcRH), which are a family of Fc receptors that are homologous to the FcyRs (Davis et al., 2002, Immunological Reviews 190: 123-136, entirely incorporated by reference).
  • Fc ligands may include undiscovered molecules that bind Fc. Particular IgG Fc ligands are FcRn and Fc gamma receptors.
  • Fc ligand as used herein is meant a molecule, preferably a polypeptide, from any organism that binds to the Fc region of an antibody to form an Fc/Fc ligand complex.
  • Fc gamma receptor any member of the family of proteins that bind the IgG antibody Fc region and is encoded by an FcyR gene.
  • this family includes but is not limited to FcyRI (CD64), including isoforms FcyRIa, FcyRIb, and FcyRIc; FcyRII (CD32), including isoforms FcyRIIa (including allotypes H131 and R131), FcyRIIb (including FcyRIIb-1 and FcyRIIb-2), and FcyRIIc; and FcyRIII (CD16), including isoforms FcyRIIIa (including allotypes V158 and Fl 58) and FcyRIIIb (including allotypes FcyRIIb-NAl and FcyRIIb-NA2) (Jefferis et al., 2002, Immunol Lett 82:57-65, entirely incorporated by reference), as well as any undiscovered human FcyRs or FcyR isoforms or allotypes.
  • An FcyR may be from any organism, including but not limited to humans, mice, rats, rabbits, and monkeys.
  • Mouse FcyRs include but are not limited to FcyRI (CD64), FcyRII (CD32), FcyRIII (CD16), and FcyRIII-2 (CD16-2), as well as any undiscovered mouse FcyRs or FcyR isoforms or allotypes.
  • FcRn or “neonatal Fc Receptor” as used herein is meant a protein that binds the IgG antibody Fc region and is encoded at least in part by an FcRn gene.
  • the functional FcRn protein comprises two polypeptides, often referred to as the heavy chain and light chain.
  • the light chain is beta-2-microglobulin and the heavy chain is encoded by the FcRn gene.
  • FcRn or an FcRn protein refers to the complex of FcRn heavy chain with beta-2-microglobulin.
  • a variety of FcRn variants can be used to increase binding to the FcRn receptor, and in some cases, to increase serum halflife.
  • parent polypeptide as used herein is meant a starting polypeptide that is subsequently modified to generate a variant.
  • the parent polypeptide may be a naturally occurring polypeptide, or a variant or engineered version of a naturally occurring polypeptide.
  • Parent polypeptide may refer to the polypeptide itself, compositions that comprise the parent polypeptide, or the amino acid sequence that encodes it.
  • parent immunoglobulin as used herein is meant an unmodified immunoglobulin, polypeptide that is modified to generate a variant
  • parent antibody as used herein is meant an unmodified antibody that is modified to generate a variant antibody.
  • Fc or “Fc region” or “Fc domain” as used herein is meant the polypeptide comprising the CH2-CH3 domains of an IgG molecule, and in some cases, inclusive of the hinge.
  • the CH2-CH3 domain comprises amino acids 231 to 447, and the hinge is 216 to 230.
  • the definition of “Fc domain” includes both amino acids 231-447 (CH2-CH3) or 216-447 (hinge-CH2-CH3), or fragments thereof.
  • an “Fc fragment” in this context may contain fewer amino acids from either or both of the N- and C- termini but still retains the ability to form a dimer with another Fc domain or Fc fragment as can be detected using standard methods, generally based on size (e.g., non-denaturing chromatography, size exclusion chromatography, etc.)
  • Human IgG Fc domains are of particular use in the methods provided herein, and can be the Fc domain from human IgGl, IgG2 or IgG4.
  • heavy chain constant region herein is meant the CHl-hinge-CH2-CH3 portion of an antibody (or fragments thereof), excluding the variable heavy domain; in EU numbering of human IgGl this is amino acids 118-447.
  • heavy chain constant region fragment herein is meant a heavy chain constant region that contains fewer amino acids from either or both of the N- and C-termini but still retains the ability to form a dimer with another heavy chain constant region.
  • position as used herein is meant a location in the sequence of a protein. Positions may be numbered sequentially, or according to an established format, for example the EU index for antibody numbering.
  • target antigen as used herein is meant the molecule that is bound specifically by the antigen binding domain comprising the variable regions of a given antibody. As discussed below, in the present case the target antigens are CTLA4 and PD1.
  • strandedness in the context of the monomers of the heterodimeric antibodies provided herein is meant that, similar to the two strands of DNA that “match”, heterodimerization variants are incorporated into each monomer so as to preserve the ability to “match” to form heterodimers.
  • steric variants that are “charge pairs” that can be utilized as well do not interfere with the pl variants, e.g., the charge variants that make a pl higher are put on the same “strand” or “monomer” to preserve both functionalities.
  • charge variants that make a pl higher are put on the same “strand” or “monomer” to preserve both functionalities.
  • skew variants that come in pairs of a set as more fully outlined below, the skilled artisan will consider pl in deciding into which strand or monomer that incorporates one set of the pair will go, such that pl separation is maximized using the pl of the skews as well.
  • target cell as used herein is meant a cell that expresses a target antigen.
  • host cell in the context of producing a bispecific antibody provided herein is meant a cell that contains the exogeneous nucleic acids encoding the components of the bispecific antibody and is capable of expressing the bispecific antibody under suitable conditions. Suitable host cells are discussed herein.
  • variable region or “variable domain” as used herein is meant the region of an immunoglobulin that comprises one or more Ig domains substantially encoded by any of the VK, V , and/or VH genes that make up the kappa, lambda, and heavy chain immunoglobulin genetic loci respectively, and contains the CDRs that confer antigen specificity.
  • VK, V , and/or VH genes that make up the kappa, lambda, and heavy chain immunoglobulin genetic loci respectively, and contains the CDRs that confer antigen specificity.
  • a “variable heavy domain” pairs with a “variable light domain” to form an antigen binding domain (“ABD”).
  • each variable domain comprises three hypervariable regions (“complementary determining regions,” “CDRs”) (vhCDRl, vhCDR2 and vhCDR3 for the variable heavy domain and vlCDRl, vlCDR2 and vlCDR3 for the variable light domain) and four framework (FR) regions, arranged from amino-terminus to carboxy -terminus in the following order: FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4.
  • CDRs complex determining regions
  • antibody domains that have sequence identity to human antibody domains, or to the anti-CTLA4 domains, PD1 domains, or Fc domains of XmAb®717.
  • Sequence identity between two similar sequences can be measured by algorithms such as that of Smith, T.F. & Waterman, M.S. (1981) “Comparison of Biosequences,” Adv. Appl. Math. 2:482 [local homology algorithm]; Needleman, S.B. & Wunsch, CD. (1970) “A General Method Applicable To The Search For Similarities In The Amino Acid Sequence Of Two Proteins,” J. Mol. Biol.
  • wild type or WT herein is meant an amino acid sequence or a nucleotide sequence that is found in nature, including allelic variations.
  • a WT protein has an amino acid sequence or a nucleotide sequence that has not been intentionally modified.
  • the antibodies provided herein are generally isolated or recombinant. “Isolated,” when used to describe the various polypeptides disclosed herein, means a polypeptide that has been identified and separated and/or recovered from a cell or cell culture from which it was expressed. Ordinarily, an isolated polypeptide can be prepared by at least one purification step. An “isolated antibody,” refers to an antibody which is substantially free of other antibodies having different antigenic specificities. “Recombinant” means the antibodies are generated using recombinant nucleic acid techniques in exogeneous host cells, and they can be isolated as well.
  • Specific binding or “specifically binds to” or is “specific for” a particular antigen or an epitope means binding that is measurably different from a non-specific interaction. Specific binding can be measured, for example, by determining binding of a molecule compared to binding of a control molecule, which generally is a molecule of similar structure that does not have binding activity. For example, specific binding can be determined by competition with a control molecule that is similar to the target.
  • Specific binding for a particular antigen or an epitope can be exhibited, for example, by an antibody having a KD for an antigen or epitope of at least about 10' 4 M, at least about 10' 5 M, at least about 10' 6 M, at least about 10' 7 M, at least about 10' 8 M, at least about 10' 9 M, alternatively at least about 10' 10 M, at least about 10' 11 M, at least about 10' 12 M, or greater, where KD refers to a dissociation rate of a particular antibody-antigen interaction.
  • an antibody that specifically binds an antigen can have a KD that is 20-, 50-, 100-, 500-, 1000-, 5,000-, 10,000- or more times greater for a control molecule relative to the antigen or epitope.
  • binding for a particular antigen or an epitope can be exhibited, for example, by an antibody having a KA or Ka for an antigen or epitope of at least 20-, 50-, 100-, 500-, 1000-, 5,000-, 10,000- or more times greater for the epitope relative to a control, where KA or Ka refers to an association rate of a particular antibody-antigen interaction. Binding affinity is generally measured using a Biacore, SPR or BLI assay.
  • refractory in the context of a cancer is intended the particular cancer is resistant to, or non-responsive to, therapy with a particular therapeutic agent.
  • a cancer can be refractory to therapy with a particular therapeutic agent either from the onset of treatment with the particular therapeutic agent (z.e., non-responsive to initial exposure to the therapeutic agent), or as a result of developing resistance to the therapeutic agent, either over the course of a first treatment period with the therapeutic agent or during a subsequent treatment period with the therapeutic agent.
  • the terms “positive therapeutic response,” “treat,” “treatment,” and/or “treating” refer to the reduction or amelioration or elimination of the progression, severity and/or effect associated with a prostate cancer described herein, or the improvement in the prostate cancer condition, or the improvement in the disease associated with the prostate cancer, or the increase in the immune system response of the human subject (e.g., male subject for prostate cancer), or the amelioration of one or more symptoms (preferably, one or more discernible symptoms) of a prostate cancer described herein resulting from the administration of one or more therapies.
  • the terms “positive therapeutic response,” “treat,” “treatment,” and/or “treating” refer to the amelioration of at least one measurable physical parameter of a prostate cancer described herein, such as tumor size, rate of tumor growth, number of tumor cells, tumor invasiveness, presence of metastasis, or extent of metastasis.
  • the terms “positive therapeutic response,” “treat,” “treatment,” and/or “treating” refer to the inhibition of the progression of a prostate cancer described herein, either physically by, e.g., stabilization of a discernible symptom, physiologically by, e.g., stabilization of a physical parameter, or both.
  • achieving a positive therapeutic response against a prostate cancer provides an improvement, or a lack of progression, in the disease associated with the tumor or the tumor condition, and/or an improvement, or a lack of progression, in the symptoms associated with the disease or condition.
  • achieving a positive therapeutic response against a prostate cancer refers to one or more of the following: (1) a reduction in the number of cancer cells (e.g., prostate cancer cells); (2) an increase in cell death (e.g., prostate cancer cell death); (3) inhibition of cell survival (e.g., prostate cancer cell survival); (5) inhibition (z.e., slowing to some extent, preferably lack of progression) of cancer growth (e.g., prostate cancer growth), such as stable disease; (6) inhibition of cancer cell metastasis (e.g., prostate cancer cell metastasis); (7) an increase in progression-free survival; (8) an increase in overall survival rate; and (9) some relief from one or more symptoms associated with the disease or condition.
  • cancer cells e.g., prostate cancer cells
  • an increase in cell death e.g., prostate cancer cell death
  • inhibition of cell survival e.g., prostate cancer cell survival
  • inhibition z.e., slowing to some extent, preferably lack of progression
  • cancer growth e.g., prostate cancer growth
  • achieving a positive therapeutic response against a prostate cancer involves administering the compositions described herein for a pre-specified period of time, discontinuing administration for another specific period of time, and resuming administration of the compositions described herein for yet another specific period of time.
  • achieving a positive therapeutic response against a prostate cancer involves administering the compositions described herein until one of the responses described herein is achieved, pausing administration of the compositions described herein while this positive therapeutic response continues to be observed, and resuming administration of the compositions described herein if this positive therapeutic response ceases to be observed.
  • Positive therapeutic responses against a prostate cancer can be determined by standardized response criteria specific to the disease associated with the prostate cancer.
  • Prostate cancer response can be assessed for changes in tumor morphology (ie., with neoadjuvant use of a therapy, such as assessment of pathological response) or tumor metrics (z.e., overall tumor burden, tumor size, and the like) using screening techniques such as magnetic resonance imaging (MRI) scan, positron emission tomography (PET) scan, x-radiographic imaging, radionuclide scan, computed tomographic (CT) scan, bone scan imaging, endoscopy, tumor sampling including bone marrow aspiration (BMA), and counting of tumor marker levels and/or tumor cells in the circulation.
  • MRI magnetic resonance imaging
  • PET positron emission tomography
  • CT computed tomographic
  • BMA bone marrow aspiration
  • a positive therapeutic response or treating according to the present disclosure can include an improvement in one or more symptoms associated with a prostate cancer of the disclosure.
  • a symptom includes feeling less tired, feeling less weak, feeling less dizzy or lightheaded, reduction in shortness of breath, reduction in fever, fewer infections, quicker recovery from infections, reduction in ease of bruising, reduction in bleeding episodes, weight gain, reduction in night sweats, gain of appetite, reduction in abdominal swelling, reduction in lymph node swelling, reduction in bone or joint pain, and reduction in thymus swelling.
  • the positive therapeutic response is as compared to the response in the subject prior to treatment with the bispecific anti-CTLA4 x anti-PDl antibody.
  • a positive therapeutic response or treating according to the present disclosure includes a “therapeutically effective amount” of the medicaments used.
  • a “therapeutically effective amount” refers to an amount effective, at dosages and for periods of time necessary, to achieve a desired therapeutic result.
  • the desired therapeutic result is a complete response, partial response or stable disease.
  • the desired therapeutic result is an improvement in response according to the RECIST guidelines (v. 1.1) as outlined in Eisenhauer et al. Eur. J. Cancer, 2009, 45:228-247, which is incorporated herein by reference in its entirety regarding, e.g., tumor response evaluation criteria.
  • a “Complete Response” refers to the disappearance of all target lesions, where any pathological lymph nodes (whether target or non-target) must have reduction in short axis to ⁇ 10 mm.
  • a “Partial Response” refers to at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.
  • PR Partial Response
  • PD Progressive Disease
  • the sum must also demonstrate an absolute increase of at least 5 mm.
  • CR Complete Response
  • Non-CR/Non-PD persistence of one or more non-target lesion(s) and/or maintenance of tumor marker level above the normal limits.
  • PD Progressive Disease
  • a therapeutically effective amount may vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of the medicaments to elicit a desired response in the individual.
  • a therapeutically effective amount is also one in which any toxic or detrimental effects of the antibody or antibody portion are outweighed by the therapeutically beneficial effects.
  • a “therapeutically effective amount” for tumor therapy may also be measured by its ability to stabilize the progression of disease.
  • the ability of the compositions described herein to achieve a positive therapeutic response against a prostate cancer may be evaluated in an animal model system predictive of efficacy in human tumors.
  • this property of a composition may be evaluated by examining the ability of its components to inhibit cell growth or to induce apoptosis by in vitro assays known to the skilled practitioner.
  • a therapeutically effective amount of a composition described herein may decrease tumor size, or otherwise ameliorate symptoms in a subject.
  • One of ordinary skill in the art would be able to determine such amounts based on such factors as the human subject’s size, the severity of the human subject’s symptoms, and the particular composition or route of administration selected.
  • CTLA4-expressing cancer can refer to a cancer that expresses CTLA4 or a cancer that overexpresses CTLA4 as compared to normal tissue.
  • additional agent e.g., carboplatin, carbazitaxel, docetaxel, and/or olaparib.
  • CTLA4-expressing cancer can refer to a cancer that expresses CTLA4 or a cancer that overexpresses CTLA4 as compared to normal tissue.
  • PD1 -expressing cancer can refer to a cancer that expresses PD1 or a cancer that overexpresses PD1.
  • the methods provided herein include treating a prostate cancer that expresses both CTLA4 and PD1, through the administration of certain bispecific anti-PDl x CTLA4 antibodies at particular dosages in combination with an additional agent (e.g., carboplatin, carbazitaxel, docetaxel, and/or olaparib).
  • an additional agent e.g., carboplatin, carbazitaxel, docetaxel, and/or olaparib.
  • the methods provided herein are directed to the administration of the bispecific anti-PDl x CTLA4 antibodies (e.g., XmAb®20717) in combination with an additional agent (e.g., carboplatin, carbazitaxel, docetaxel, and/or olaparib) for the treatment of prostate cancer as outlined herein.
  • an additional agent e.g., carboplatin, carbazitaxel, docetaxel, and/or olaparib
  • additional agent e.g., carboplatin, carbazitaxel, docetaxel, and/or olaparib
  • the present disclosure also provides methods of treating prostate cancer through the administration of XmAb®20717 according to a dosage regimen described herein in combination with an additional agent (e.g., carboplatin, carbazitaxel, docetaxel, and/or olaparib). Also provided herein are methods of achieving a positive therapeutic response against prostate cancer through the administration of XmAb®20717, carboplatin, and cabazitaxel, according to a dosage regimen described herein. Also provided herein are methods of achieving a positive therapeutic response against prostate cancer through the administration of XmAb®20717, carboplatin, and docetaxel, according to a dosage regimen described herein. The disclosure also provides methods of achieving a positive therapeutic response against prostate cancer through the administration of XmAb®20717 and olaparib according to a dosage regimen described herein.
  • an additional agent e.g., carboplatin, carbazitaxel, docetaxel, and/or olaparib.
  • XmAb®20717 can be used as the bispecific anti-CTLA4 x anti-PDl antibody in all methods of the invention provided herein.
  • XmAb®20717 can be used as the bispecific anti-CTLA4 x anti-PDl antibody in all methods of the invention provided herein.
  • XmAb®20717 can be used as the bispecific anti-CTLA4 x anti-PDl antibody in all methods of the invention provided herein.
  • XmAb®20717 to achieve a positive therapeutic response against a prostate cancer in combination with at least one additional agent (e.g., carboplatin, carbazitaxel, docetaxel, and/or olaparib).
  • additional agent e.g., carboplatin, carbazitaxel, docetaxel, and/or olaparib.
  • the present disclosure is directed to the administration of XmAb®20717 for the treatment of a prostate cancer, as described herein and in U.S. Pat. App. No. 15/623,314, US Publication No. 2018/0118836, U.S. Prov. Pat. App. Nos. 62/350,145, 62/355,511, and 62/420,500, all of which are expressly incorporated herein by reference, particularly for the bispecific formats of the figures, as well as all sequences, Figures and accompanying Legends therein.
  • Antibodies (underlining refers to CDRs)
  • the bispecific anti-CTLA4 x anti-PDl antibodies have a “bottle opener” format (also referred to as the “triple F” format) as is generally depicted in FIG. 1.
  • the PD1 antigen binding domain is the scFv in the bottle opener format
  • the CTLA4 antigen binding domain is the Fab in the bottle opener format (terms as used in US Publication No. 20180118836 Al, all of which are expressly incorporated by reference in their entirety and specifically for all the definitions, sequences of CTLA4 antigen binding domains and sequences of PD1 antigen binding domains).
  • the anti-PDl scFv antigen binding domain can have the sequence depicted in FIG. 2, Table 1.
  • the anti-CTLA4 Fab binding domain can have the sequence depicted in FIG. 2, Table 1
  • XmAb®20717 includes a first monomer (or a first polypeptide) comprising SEQ ID NO: 1, a second monomer (or a second polypeptide) comprising SEQ ID NO: 2, and a light chain (or a third polypeptide) comprising SEQ ID NO: 3.
  • XmAb®20717 includes a first polypeptide comprising an amino acid sequence of SEQ ID NO: 1, a second polypeptide comprising an amino acid sequence of SEQ ID NO: 2, and a third polypeptide comprising an amino acid sequence of SEQ ID NO: 3.
  • XmAb®20717 can be made as known in the art.
  • XmAb®20717 is made by expressing a nucleic acid composition that includes a) a first nucleic that encodes a first amino acid monomer comprising “Fab-Fc Heavy Chain;” b) a second nucleic that encodes a second amino acid monomer comprising “scFv-Fc Heavy Chain;” and c) a third nucleic that encodes a “light chain,” as depicted in FIG 2
  • N- and/or C-terminal clipping can occur during protein synthesis, whereby the heavy chains depicted herein may have the C-terminal lysine (K447) removed, as well as the penultimate glycine (G446), and optionally additional amino acids residues (e.g., from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more C-terminal amino acids can be removed).
  • the nucleic acids encoding the heavy chains of the bispecific antibodies can be engineered such that these terminal residues are eliminated entirely to facilitate additional homogeneity.
  • XmAb717 included within the definition of XmAb717 are C- terminally truncated versions. As is known in the art, this C-terminal clipping can also occur in vivo in the patient.
  • XmAb®20717 consists of a first monomer (or a first polypeptide) comprising SEQ ID NO: 1, a second monomer (or a second polypeptide) comprising SEQ ID NO: 2, and a light chain (or a third polypeptide) comprising SEQ ID NO: 3.
  • XmAb®20717 includes a first monomer (or a first polypeptide) consisting of SEQ ID NO: 1, a second monomer (or a second polypeptide) comprising SEQ ID NO: 2, and a light chain (or a third polypeptide) comprising SEQ ID NO: 3.
  • XmAb®20717 includes a first monomer (or a first polypeptide) comprising SEQ ID NO: 1, a second monomer (or a second polypeptide) consisting of SEQ ID NO: 2, and a light chain (or a third polypeptide) comprising SEQ ID NO: 3.
  • XmAb®20717 includes a first monomer (or a first polypeptide) comprising SEQ ID NO: 1, a second monomer (or a second polypeptide) comprising SEQ ID NO: 2, and a light chain (or a third polypeptide) consisting of SEQ ID NO: 3.
  • XmAb®20717 includes a first monomer (or a first polypeptide) consisting of SEQ ID NO: 1, a second monomer (or a second polypeptide) consisting of SEQ ID NO: 2, and a light chain (or a third polypeptide) comprising SEQ ID NO: 3.
  • XmAb®20717 includes a first monomer (or a first polypeptide) consisting of SEQ ID NO: 1, a second monomer (or a second polypeptide) comprising SEQ ID NO: 2, and a light chain (or a third polypeptide) consisting of SEQ ID NO: 3.
  • XmAb®20717 includes a first monomer (or a first polypeptide) comprising SEQ ID NO: 1, a second monomer (or a second polypeptide) consisting of SEQ ID NO: 2, and a light chain (or a third polypeptide) consisting of SEQ ID NO: 3.
  • XmAb®20717 includes a first monomer (or a first polypeptide) consisting of SEQ ID NO: 1, a second monomer (or a second polypeptide) consisting of SEQ ID NO: 2, and a light chain (or a third polypeptide) consisting of SEQ ID NO: 3.
  • the VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3 sequences are according to the Kabat numbering system. In some embodiments, the VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3 sequences are according to the Chothia numbering system. In some embodiments, the VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3 sequences are according to the Exemplary numbering system.
  • the VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3 sequences are according to the Contact numbering system. In some embodiments, the VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3 sequences are according to the IMGT numbering system. In some embodiments, the VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3 sequences are according to the AbM numbering system. Exemplary sets of 6 CDRs (VH CDR1-3 and VL CDR1-3) of certain antibody embodiments are provided herein. Other sets of CDRs are contemplated and within the scope of the antibody embodiments provided herein.
  • the bispecific anti-CTLA4 x anti-PDl antibody comprises a first antigen binding domain that binds to PD1, wherein the first antigen binding domain comprises a VH comprising a VH CDR1, VH CDR2 and VH CDR3 having an amino acid sequence of a VH CDR1, VH CDR2 and VH CDR3, respectively, of a VH having an amino acid sequence provided in Table 1.
  • the bispecific anti-CTLA4 x anti-PDl antibody comprises a first antigen binding domain that binds to PD1, wherein the first antigen binding domain comprises a VL comprising a VL CDR1, VL CDR2 and VL CDR3 having an amino acid sequence of a VL CDR1, VL CDR2 and VL CDR3, respectively, of a VL having an amino acid sequence provided in Table 1.
  • the bispecific anti-CTLA4 x anti-PDl antibody comprises a first antigen binding domain that binds to PD1, wherein the first antigen binding domain comprises a VH comprising a VH CDR1, VH CDR2 and VH CDR3 having an amino acid sequence of a VH CDR1, VH CDR2 and VH CDR3, respectively, of a VH having an amino acid sequence provided in Table 1, and a VL comprising a VL comprising a VL comprising a VL CDR1, VL CDR2 and VL CDR3 having an amino acid sequence of a VL CDR1, VL CDR2 and VL CDR3, respectively, of a VL having an amino acid sequence provided in Table 1.
  • the bispecific anti-CTLA4 x anti-PDl antibody comprises a second antigen binding domain that binds to CTLA4, wherein the second antigen binding domain comprises a VH comprising a VH CDR1, VH CDR2 and VH CDR3 having an amino acid sequence of a VH CDR1, VH CDR2 and VH CDR3, respectively, of a VH having an amino acid sequence provided in Table 1.
  • the bispecific anti-CTLA4 x anti-PDl antibody comprises a second antigen binding domain that binds to CTLA4, wherein the second antigen binding domain comprises a VL comprising a VL CDR1, VL CDR2 and VL CDR3 having an amino acid sequence of a VL CDR1, VL CDR2 and VL CDR3, respectively, of a VL having an amino acid sequence provided in Table 1.
  • the bispecific anti-CTLA4 x anti-PDl antibody comprises a second antigen binding domain that binds to CTLA4, wherein the second antigen binding domain comprises a VH comprising a VH CDR1, VH CDR2 and VH CDR3 having an amino acid sequence of a VH CDR1, VH CDR2 and VH CDR3, respectively, of a VH having an amino acid sequence provided in Table 1, and a VL comprising a VL CDR1, VL CDR2 and VL CDR3 having an amino acid sequence of a VL CDR1, VL CDR2 and VL CDR3, respectively, of a VL having an amino acid sequence provided in Table 1.
  • the bispecific anti-CTLA4 x anti-PDl antibody comprises a first antigen binding domain that binds to PD1, wherein the first antigen binding domain comprises a VH comprising a VH CDR1, VH CDR2 and VH CDR3 having an amino acid sequence of a VH CDR1, VH CDR2 and VH CDR3, respectively, of a VH having an amino acid sequence provided in Table 1, and a VL comprising a VL CDR1, VL CDR2 and VL CDR3 having an amino acid sequence of a VL CDR1, VL CDR2 and VL CDR3, respectively, of a VL having an amino acid sequence provided in Table 1, and a second antigen binding domain that binds to CTLA4, wherein the second antigen binding domain comprises a VH comprising a VH CDR1, VH CDR2 and VH CDR3 having an amino acid sequence of a VH CDR1, VH CDR2 and VH CDR3, respectively, of a
  • the bispecific anti-CTLA4 x anti-PDl antibody comprises a first antigen binding domain that binds to PD1, wherein the first antigen binding domain comprises a VH comprising a VH CDR1, VH CDR2 and VH CDR3 having an amino acid sequence of a VH CDR1, VH CDR2 and VH CDR3, respectively, of a VH having an amino acid sequence of SEQ ID NO: 16.
  • the bispecific anti-CTLA4 x anti-PDl antibody comprises a first antigen binding domain that binds to PD1, wherein the first antigen binding domain comprises a VL comprising a VL CDR1, VL CDR2 and VL CDR3 having an amino acid sequence of a VL CDR1, VL CDR2 and VL CDR3, respectively, of a VL having an amino acid sequence of SEQ ID NO: 17.
  • the bispecific anti-CTLA4 x anti-PDl antibody comprises a first antigen binding domain that binds to PD1, wherein the first antigen binding domain comprises a VH comprising a VH CDR1, VH CDR2 and VH CDR3 having an amino acid sequence of a VH CDR1, VH CDR2 and VH CDR3, respectively, of a VH having an amino acid sequence of SEQ ID NO: 16, and a VL comprising a VL CDR1, VL CDR2 and VL CDR3 having an amino acid sequence of a VL CDR1, VL CDR2 and VL CDR3, respectively, of a VL having an amino acid sequence of SEQ ID NO: 17.
  • the bispecific anti-CTLA4 x anti-PDl antibody comprises a second antigen binding domain that binds to CTLA4, wherein the second antigen binding domain comprises a VH comprising a VH CDR1, VH CDR2 and VH CDR3 having an amino acid sequence of a VH CDR1, VH CDR2 and VH CDR3, respectively, of a VH having an amino acid sequence of SEQ ID NO: 18.
  • the bispecific anti-CTLA4 x anti-PDl antibody comprises a second antigen binding domain that binds to CTLA4, wherein the first antigen binding domain comprises a VL comprising a VL CDR1, VL CDR2 and VL CDR3 having an amino acid sequence of a VL CDR1, VL CDR2 and VL CDR3, respectively, of a VL having an amino acid sequence of SEQ ID NO: 19.
  • the bispecific anti-CTLA4 x anti-PDl antibody comprises a second antigen binding domain that binds to CTLA4, wherein the second antigen binding domain comprises a VH comprising a VH CDR1, VH CDR2 and VH CDR3 having an amino acid sequence of a VH CDR1, VH CDR2 and VH CDR3, respectively, of a VH having an amino acid sequence of SEQ ID NO: 18, and a VL comprising a VL CDR1, VL CDR2 and VL CDR3 having an amino acid sequence of a VL CDR1, VL CDR2 and VL CDR3, respectively, of a VL having an amino acid sequence of SEQ ID NO: 19.
  • the bispecific anti-CTLA4 x anti-PDl antibody comprises a first antigen binding domain that binds to PD1, wherein the first antigen binding domain comprises a VH comprising a VH CDR1, VH CDR2 and VH CDR3 having an amino acid sequence of a VH CDR1, VH CDR2 and VH CDR3, respectively, of a VH having an amino acid sequence of SEQ ID NO: 16, and a VL comprising a VL CDR1, VL CDR2 and VL CDR3 having an amino acid sequence of a VL CDR1, VL CDR2 and VL CDR3, respectively, of a VL having an amino acid sequence of SEQ ID NO: 17, and a second antigen binding domain that binds to CTLA4, wherein the second antigen binding domain comprises a VH comprising a VH CDR1, VH CDR2 and VH CDR3 having an amino acid sequence of a VH CDR1, VH CDR2 and VH CDR
  • the bispecific anti-CTLA4 x anti-PDl antibody comprises a first antigen binding domain that binds to PD1, wherein the first antigen binding domain comprises a VH domain comprising a VH CDR1, a VH CDR2, and a VH CDR3 having an amino acid sequence of SEQ ID NO:4, SEQ ID NO:5, and SEQ ID NO:6, respectively.
  • the bispecific anti-CTLA4 x anti-PDl antibody comprises a first antigen binding domain that binds to PD1, wherein the first antigen binding domain comprises a VL domain comprising a VL CDR1, a VL CDR2, and a VL CDR3 having an amino acid sequence of SEQ ID NO:7, SEQ ID NO:8, and SEQ ID NOV, respectively.
  • the bispecific anti-CTLA4 x anti-PDl antibody comprises a first antigen binding domain that binds to PD1, wherein the first antigen binding domain comprises a VH domain comprising a VH CDR1, a VH CDR2, and a VH CDR3 having the amino acid sequence of SEQ ID NO:4, SEQ ID NO:5, and SEQ ID NO:6, respectively, and a VL domain comprising a VL CDR1, a VL CDR2, and a VL CDR3 having an amino acid sequence of SEQ ID NO:7, SEQ ID NO:8, and SEQ ID NO:9, respectively.
  • the bispecific anti-CTLA4 x anti-PDl antibody comprises a second antigen binding domain that binds to CTLA4, wherein the second antigen binding domain comprises a VH domain comprising a VH CDR1, a VH CDR2, and a VH CDR3 having an amino acid sequence of SEQ ID NO: 10, SEQ ID NO: 11, and SEQ ID NO: 12, respectively.
  • the bispecific anti-CTLA4 x anti-PDl antibody comprises a second antigen binding domain that binds to CTLA4, wherein the second antigen binding domain comprises a VL domain comprising a VL CDR1, a VL CDR2, and a VL CDR3 having an amino acid sequence of SEQ ID NO: 13, SEQ ID NO: 14, and SEQ ID NO: 15, respectively.
  • the bispecific anti-CTLA4 x anti-PDl antibody comprises a second antigen binding domain that binds to CTLA4, wherein the second antigen binding domain comprises a VH domain comprising a VH CDR1, a VH CDR2, and a VH CDR3 having an amino acid sequence of SEQ ID NO: 10, SEQ ID NO: 11, and SEQ ID NO: 12, respectively, and a VL domain comprising a VL CDR1, a VL CDR2, and a VL CDR3 having an amino acid sequence of SEQ ID NO: 13, SEQ ID NO: 14, and SEQ ID NO: 15, respectively.
  • the second antigen binding domain comprises a VH domain comprising a VH CDR1, a VH CDR2, and a VH CDR3 having an amino acid sequence of SEQ ID NO: 10, SEQ ID NO: 11, and SEQ ID NO: 12, respectively, and a VL domain comprising a VL CDR1, a VL CDR2, and a VL CDR3 having an amino acid sequence of
  • the bispecific anti-CTLA4 x anti-PDl antibody comprises a first antigen binding domain that binds to PD1 and a second antigen binding domain that binds to CTLA4, wherein the first antigen binding domain comprises a VH domain comprising a VH CDR1, a VH CDR2, and a VH CDR3 having an amino acid sequence of SEQ ID NO:4, SEQ ID NO:5, and SEQ ID NO:6, respectively, and a VL domain comprising a VL CDR1, a VL CDR2, and a VL CDR3 having an amino acid sequence of SEQ ID NO:7, SEQ ID NO: 8, and SEQ ID NOV, respectively, and the second antigen binding domain comprises a VH domain comprising a VH CDR1, a VH CDR2, and a VH CDR3 having an amino acid sequence of SEQ ID NO: 10, SEQ ID NO: 11, and SEQ ID NO: 12, respectively, and a VL domain comprising a VL C
  • the bispecific anti-CTLA4 x anti-PDl antibody comprises a first antigen binding domain that binds to PD1, wherein the first antigen binding domain comprises a VH domain having an amino acid sequence that is about 90%, 95%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 16.
  • the first antigen binding domain comprises a VH domain having an amino acid sequence that is about 90% identical to the amino acid sequence of SEQ ID NO: 16.
  • the first antigen binding domain comprises a VH domain having an amino acid sequence that is about 95% identical to the amino acid sequence of SEQ ID NO: 16.
  • the first antigen binding domain comprises a VH domain having an amino acid sequence that is about 98% identical to the amino acid sequence of SEQ ID NO: 16. In another embodiment, the first antigen binding domain comprises a VH domain having an amino acid sequence that is about 99% identical to the amino acid sequence of SEQ ID NO: 16. In one embodiment, the first antigen binding domain comprises a VH domain having an amino acid sequence that is about 100% identical to the amino acid sequence of SEQ ID NO: 16.
  • the bispecific anti-CTLA4 x anti-PDl antibody comprises a first antigen binding domain that binds to PD1, wherein the first antigen binding domain comprises a VL domain having an amino acid sequence that is about 90%, 95%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 17.
  • the first antigen binding domain comprises a VL domain having an amino acid sequence that is about 90% identical to the amino acid sequence of SEQ ID NO: 17.
  • the first antigen binding domain comprises a VL domain having an amino acid sequence that is about 95% identical to the amino acid sequence of SEQ ID NO: 17.
  • the first antigen binding domain comprises a VL domain having an amino acid sequence that is about 98% identical to the amino acid sequence of SEQ ID NO: 17. In another embodiment, the first antigen binding domain comprises a VL domain having an amino acid sequence that is about 99% identical to the amino acid sequence of SEQ ID NO: 17. In another embodiment, the first antigen binding domain comprises a VL domain having an amino acid sequence that is about 100% identical to the amino acid sequence of SEQ ID NO: 17.
  • the bispecific anti-CTLA4 x anti-PDl antibody comprises a first antigen binding domain that binds to PD1, wherein the first antigen binding domain comprises a VH domain having an amino acid sequence that is about 90%, 95%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 16 and a VL domain having an amino acid sequence that is about 90%, 95%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 17.
  • the first antigen binding domain comprises a VH domain having an amino acid sequence that is about 90%, identical to the amino acid sequence of SEQ ID NO: 16 and a VL domain having an amino acid sequence that is about 90% identical to the amino acid sequence of SEQ ID NO: 17.
  • the first antigen binding domain comprises a VH domain having an amino acid sequence that is about 95%, identical to the amino acid sequence of SEQ ID NO: 16 and a VL domain having an amino acid sequence that is about 95% identical to the amino acid sequence of SEQ ID NO: 17.
  • the first antigen binding domain comprises a VH domain having an amino acid sequence that is about 98%, identical to the amino acid sequence of SEQ ID NO: 16 and a VL domain having an amino acid sequence that is about 98% identical to the amino acid sequence of SEQ ID NO: 17.
  • the first antigen binding domain comprises a VH domain having an amino acid sequence that is about 99%, identical to the amino acid sequence of SEQ ID NO: 16 and a VL domain having an amino acid sequence that is about 99% identical to the amino acid sequence of SEQ ID NO: 17.
  • the first antigen binding domain comprises a VH domain having an amino acid sequence that is about 100%, identical to the amino acid sequence of SEQ ID NO: 16 and a VL domain having an amino acid sequence that is about 100% identical to the amino acid sequence of SEQ ID NO: 17.
  • the bispecific anti-CTLA4 x anti-PDl antibody comprises a second antigen binding domain that binds to CTLA4, wherein the second antigen binding domain comprises a VH domain having an amino acid sequence that is about 90%, 95%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 18.
  • the second antigen binding domain comprises a VH domain having an amino acid sequence that is about 90% identical to the amino acid sequence of SEQ ID NO: 18.
  • the second antigen binding domain comprises a VH domain having an amino acid sequence that is about 95% identical to the amino acid sequence of SEQ ID NO: 18.
  • the second antigen binding domain comprises a VH domain having an amino acid sequence that is about 98% identical to the amino acid sequence of SEQ ID NO: 18. In another embodiment, the second antigen binding domain comprises a VH domain having an amino acid sequence that is about 99% identical to the amino acid sequence of SEQ ID NO: 18. In another embodiment, the second antigen binding domain comprises a VH domain having an amino acid sequence that is about 100% identical to the amino acid sequence of SEQ ID NO: 18.
  • the bispecific anti-CTLA4 x anti-PDl antibody comprises a second antigen binding domain that binds to CTLA4, wherein the second antigen binding domain comprises a VL domain having an amino acid sequence that is about 90%, 95%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 19.
  • the second antigen binding domain comprises a VL domain having an amino acid sequence that is about 90% identical to the amino acid sequence of SEQ ID NO: 19.
  • the second antigen binding domain comprises a VL domain having an amino acid sequence that is about 95% identical to the amino acid sequence of SEQ ID NO: 19.
  • the second antigen binding domain comprises a VL domain having an amino acid sequence that is about 98% identical to the amino acid sequence of SEQ ID NO: 19. In another embodiment, the second antigen binding domain comprises a VL domain having an amino acid sequence that is about 99% identical to the amino acid sequence of SEQ ID NO: 19. In another embodiment, the second antigen binding domain comprises a VL domain having an amino acid sequence that is about 100% identical to the amino acid sequence of SEQ ID NO: 19.
  • the bispecific anti-CTLA4 x anti-PDl antibody comprises a second antigen binding domain that binds to CTLA4, wherein the second antigen binding domain comprises a VH domain having an amino acid sequence that is about 90%, 95%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 18 and a VL domain having an amino acid sequence that is about 90%, 95%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 19.
  • the second antigen binding domain comprises a VH domain having an amino acid sequence that is about 90%, identical to the amino acid sequence of SEQ ID NO: 18 and a VL domain having an amino acid sequence that is about 90% identical to the amino acid sequence of SEQ ID NO: 19.
  • the second antigen binding domain comprises a VH domain having an amino acid sequence that is about 95%, identical to the amino acid sequence of SEQ ID NO: 18 and a VL domain having an amino acid sequence that is about 95% identical to the amino acid sequence of SEQ ID NO: 19.
  • the second antigen binding domain comprises a VH domain having an amino acid sequence that is about 98%, identical to the amino acid sequence of SEQ ID NO: 18 and a VL domain having an amino acid sequence that is about 98% identical to the amino acid sequence of SEQ ID NO: 19.
  • the second antigen binding domain comprises a VH domain having an amino acid sequence that is about 99%, identical to the amino acid sequence of SEQ ID NO: 18 and a VL domain having an amino acid sequence that is about 99% identical to the amino acid sequence of SEQ ID NO: 19.
  • the second antigen binding domain comprises a VH domain having an amino acid sequence that is about 100%, identical to the amino acid sequence of SEQ ID NO: 18 and a VL domain having an amino acid sequence that is about 100% identical to the amino acid sequence of SEQ ID NO: 19.
  • the bispecific anti-CTLA4 x anti-PDl antibody comprises a first antigen binding domain that binds to PD1 and a second antigen binding domain that binds to CTLA4, wherein the first antigen binding domain comprises a VH domain having an amino acid sequence that is about 90%, 95%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 16 and a VL domain having an amino acid sequence that is about 90%, 95%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 17, and the second antigen binding domain comprises a VH domain having an amino acid sequence that is about 90%, 95%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 18 and a VL domain having an amino acid sequence that is about 90%, 95%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 19.
  • the first antigen binding domain comprises a VH domain having an amino acid sequence that is about 90%, identical to the amino acid sequence of SEQ ID NO: 16 and a VL domain having an amino acid sequence that is about 90% identical to the amino acid sequence of SEQ ID NO: 17, and the second antigen binding domain comprises a VH domain having an amino acid sequence that is about 90%, identical to the amino acid sequence of SEQ ID NO: 18 and a VL domain having an amino acid sequence that is about 90% identical to the amino acid sequence of SEQ ID NO: 19.
  • the first antigen binding domain comprises a VH domain having an amino acid sequence that is about 95%, identical to the amino acid sequence of SEQ ID NO: 16 and a VL domain having an amino acid sequence that is about 95% identical to the amino acid sequence of SEQ ID NO: 17, and the second antigen binding domain comprises a VH domain having an amino acid sequence that is about 95%, identical to the amino acid sequence of SEQ ID NO: 18 and a VL domain having an amino acid sequence that is about 95% identical to the amino acid sequence of SEQ ID NO: 19.
  • the first antigen binding domain comprises a VH domain having an amino acid sequence that is about 98%, identical to the amino acid sequence of SEQ ID NO: 16 and a VL domain having an amino acid sequence that is about 98% identical to the amino acid sequence of SEQ ID NO: 17, and the second antigen binding domain comprises a VH domain having an amino acid sequence that is about 98%, identical to the amino acid sequence of SEQ ID NO: 18 and a VL domain having an amino acid sequence that is about 98% identical to the amino acid sequence of SEQ ID NO: 19.
  • the first antigen binding domain comprises a VH domain having an amino acid sequence that is about 99%, identical to the amino acid sequence of SEQ ID NO: 16 and a VL domain having an amino acid sequence that is about 99% identical to the amino acid sequence of SEQ ID NO: 17, and the second antigen binding domain comprises a VH domain having an amino acid sequence that is about 99%, identical to the amino acid sequence of SEQ ID NO: 18 and a VL domain having an amino acid sequence that is about 99% identical to the amino acid sequence of SEQ ID NO: 19.
  • the first antigen binding domain comprises a VH domain having an amino acid sequence that is about 100% identical to the amino acid sequence of SEQ ID NO: 16 and a VL domain having an amino acid sequence that is about 100% identical to the amino acid sequence of SEQ ID NO: 17, and the second antigen binding domain comprises a VH domain having an amino acid sequence that is about 100% identical to the amino acid sequence of SEQ ID NO: 18 and a VL domain having an amino acid sequence that is about 100% identical to the amino acid sequence of SEQ ID NO: 19.
  • the first monomer (or a first polypeptide) is about 90% identical to the amino acid sequence of SEQ ID NO: 1. In some embodiments, the first monomer (or a first polypeptide) is about 95% identical to the amino acid sequence of SEQ ID NO: 1. In some embodiments, the first monomer (or a first polypeptide) is about 97% identical to the amino acid sequence of SEQ ID NO: 1. In some embodiments, the first monomer (or a first polypeptide) is about 98% identical to the amino acid sequence of SEQ ID NO: 1. In some embodiments, the first monomer (or a first polypeptide) is about 99% identical to the amino acid sequence of SEQ ID NO: 1. In some embodiments, the first monomer (or a first polypeptide) is about 100% identical to the amino acid sequence of SEQ ID NO: 1.
  • the second monomer (or a second polypeptide) is about 90% identical to the amino acid sequence of SEQ ID NO:2. In some embodiments, the second monomer (or a second polypeptide) is about 95% identical to the amino acid sequence of SEQ ID NO:2. In some embodiments, the second monomer (or a second polypeptide) is about 97% identical to the amino acid sequence of SEQ ID NO:2. In some embodiments, the second monomer (or a second polypeptide) is about 98% identical to the amino acid sequence of SEQ ID NO:2. In some embodiments, the second monomer (or a second polypeptide) is about 99% identical to the amino acid sequence of SEQ ID NO:2. In some embodiments, the second monomer (or a second polypeptide) is about 100% identical to the amino acid sequence of SEQ ID NO:2.
  • the third monomer (or a third polypeptide) is about 90% identical to the amino acid sequence of SEQ ID NO:3. In some embodiments, the third monomer (or a third polypeptide) is about 95% identical to the amino acid sequence of SEQ ID NO:3. In some embodiments, the third monomer (or a third polypeptide) is about 97% identical to the amino acid sequence of SEQ ID NO:3. In some embodiments, the third monomer (or a third polypeptide) is about 98% identical to the amino acid sequence of SEQ ID NO:3. In some embodiments, the third monomer (or a third polypeptide) is about 99% identical to the amino acid sequence of SEQ ID NO:3. In some embodiments, the third monomer (or a third polypeptide) is about 100% identical to the amino acid sequence of SEQ ID NO:3.
  • the first monomer (or first polypeptide) is about 90% identical to the amino acid sequence of SEQ ID NO: 1, and the second monomer (or second polypeptide) is about 90% identical to the amino acid sequence of SEQ ID NO:2. In some embodiments, the first monomer (or first polypeptide) is about 95% identical to the amino acid sequence of SEQ ID NO: 1, and the second monomer (or second polypeptide) is about 95% identical to the amino acid sequence of SEQ ID NO:2. In some embodiments, the first monomer (or first polypeptide) is about 97% identical to the amino acid sequence of SEQ ID NO: 1, and the second monomer (or second polypeptide) is about 97% identical to the amino acid sequence of SEQ ID NO:2.
  • the first monomer (or first polypeptide) is about 98% identical to the amino acid sequence of SEQ ID NO: 1, and the second monomer (or second polypeptide) is about 98% identical to the amino acid sequence of SEQ ID NO:2. In some embodiments, the first monomer (or first polypeptide) is about 99% identical to the amino acid sequence of SEQ ID NO: 1, and the second monomer (or second polypeptide) is about 99% identical to the amino acid sequence of SEQ ID NO:2. In some embodiments, the first monomer (or first polypeptide) is about 100% identical to the amino acid sequence of SEQ ID NO: 1, and the second monomer (or second polypeptide) is about 100% identical to the amino acid sequence of SEQ ID NO:2.
  • the first monomer (or first polypeptide) is about 90% identical to the amino acid sequence of SEQ ID NO: 1 and the third monomer (or third polypeptide) is about 90% identical to the amino acid sequence of SEQ ID NO:3. In some embodiments, the first monomer (or first polypeptide) is about 95% identical to the amino acid sequence of SEQ ID NO: 1, and the third monomer (or third polypeptide) is about 95% identical to the amino acid sequence of SEQ ID NO:3. In some embodiments, the first monomer (or first polypeptide) is about 97% identical to the amino acid sequence of SEQ ID NO: 1, and the third monomer (or third polypeptide) is about 97% identical to the amino acid sequence of SEQ ID NO:3.
  • the first monomer (or first polypeptide) is about 98% identical to the amino acid sequence of SEQ ID NO: 1 and the third monomer (or third polypeptide) is about 98% identical to the amino acid sequence of SEQ ID NO:3. In some embodiments, the first monomer (or first polypeptide) is about 99% identical to the amino acid sequence of SEQ ID NO: 1, and the third monomer (or third polypeptide) is about 99% identical to the amino acid sequence of SEQ ID NO:3. In some embodiments, the first monomer (or first polypeptide) is about 100% identical to the amino acid sequence of SEQ ID NO: 1, and the third monomer (or third polypeptide) is about 100% identical to the amino acid sequence of SEQ ID NO:3.
  • the second monomer (or second polypeptide) is about 90% identical to the amino acid sequence of SEQ ID NO:2, and the third monomer (or third polypeptide) is about 90% identical to the amino acid sequence of SEQ ID NO:3. In some embodiments, the second monomer (or second polypeptide) is about 95% identical to the amino acid sequence of SEQ ID NO:2, and the third monomer (or third polypeptide) is about 95% identical to the amino acid sequence of SEQ ID NO:3. In some embodiments, the second monomer (or second polypeptide) is about 97% identical to the amino acid sequence of SEQ ID NO:2, and the third monomer (or third polypeptide) is about 97% identical to the amino acid sequence of SEQ ID NO:3.
  • the second monomer (or second polypeptide) is about 98% identical to the amino acid sequence of SEQ ID NO:2, and the third monomer (or third polypeptide) is about 98% identical to the amino acid sequence of SEQ ID NO:3.
  • the second monomer (or second polypeptide) is about 99% identical to the amino acid sequence of SEQ ID NO: 2
  • the third monomer (or third polypeptide) is about 99% identical to the amino acid sequence of SEQ ID NO:3.
  • the second monomer (or second polypeptide) is about 100% identical to the amino acid sequence of SEQ ID NO:2
  • the third monomer (or third polypeptide) is about 100% identical to the amino acid sequence of SEQ ID NO:3.
  • the first monomer (or first polypeptide) is about 90% identical to the amino acid sequence of SEQ ID NO: 1
  • the second monomer (or second polypeptide) is about 90% identical to the amino acid sequence of SEQ ID NO:2
  • the third monomer (or third polypeptide) is about 90% identical to the amino acid sequence of SEQ ID NO:3.
  • the first monomer (or first polypeptide) is about 95% identical to the amino acid sequence of SEQ ID NO: 1
  • the second monomer (or second polypeptide) is about 95% identical to the amino acid sequence of SEQ ID NO:2
  • the third monomer (or third polypeptide) is about 95% identical to the amino acid sequence of SEQ ID NO:3.
  • the first monomer (or first polypeptide) is about 97% identical to the amino acid sequence of SEQ ID NO: 1
  • the second monomer (or second polypeptide) is about 97% identical to the amino acid sequence of SEQ ID NO:2
  • the third monomer (or third polypeptide) is about 97% identical to the amino acid sequence of SEQ ID NO:3.
  • the first monomer (or first polypeptide) is about 98% identical to the amino acid sequence of SEQ ID NO: 1
  • the second monomer (or second polypeptide) is about 98% identical to the amino acid sequence of SEQ ID NO:2
  • the third monomer (or third polypeptide) is about 98% identical to the amino acid sequence of SEQ ID NO:3.
  • the first monomer (or first polypeptide) is about 99% identical to the amino acid sequence of SEQ ID NO: 1
  • the second monomer (or second polypeptide) is about 99% identical to the amino acid sequence of SEQ ID NO:2
  • the third monomer (or third polypeptide) is about 99% identical to the amino acid sequence of SEQ ID NO:3.
  • the first monomer (or first polypeptide) is about 100% identical to the amino acid sequence of SEQ ID NO: 1
  • the second monomer (or second polypeptide) is about 100% identical to the amino acid sequence of SEQ ID NO:2
  • the third monomer (or third polypeptide) is about 100% identical to the amino acid sequence of SEQ ID NO:3.
  • nucleic acids encoding the components provided herein can be incorporated into expression vectors as is known in the art, and depending on the host cells used to produce an antibody of the disclosure (e.g., XmAb®20717). Generally, the nucleic acids are operably linked to any number of regulatory elements (promoters, origin of replication, selectable markers, ribosomal binding sites, inducers, etc.).
  • the expression vectors can be extra-chromosomal or integrating vectors.
  • nucleic acids and/or expression vectors provided herein are then transformed into any number of different types of host cells as is well known in the art, including mammalian, bacterial, yeast, insect and/or fungal cells, with mammalian cells (e.g., CHO cells), finding use in many embodiments.
  • mammalian cells e.g., CHO cells
  • nucleic acids encoding each monomer (polypeptide) and the nucleic acid encoding a light chain are each contained within a single expression vector, generally under different or the same promoter controls.
  • each of these two or three nucleic acids are contained on a different expression vector. That is, in certain embodiments, a first expression vector comprises the nucleic acid encoding the first monomer (or first polypeptide), a second expression vector comprises the nucleic acid encoding the second monomer (or second polypeptide), and a third expression vector comprises the nucleic acid encoding the light chain (or a third polypeptide).
  • XmAb®20717 can be made by culturing host cells comprising the expression vector(s) as is well known in the art. Once produced, traditional antibody purification steps are done, including an ion exchange chromatography step. As discussed in U.S. Pat. App. No. 15/623,314 and US Publication No. 2018/0118836, hereby incorporated by reference in their entirety and particularly for the discussions concerning purification, having the pls of the two monomers differ by at least 0.5 can allow separation by ion exchange chromatography or isoelectric focusing, or other methods sensitive to isoelectric point.
  • pl substitutions that alter the isoelectric point (pl) of each monomer so that such that each monomer has a different pl and the heterodimer also has a distinct pl, thus facilitating isoelectric purification of the “triple F” heterodimer (e.g., anionic exchange columns, cationic exchange columns).
  • substitutions also aid in the determination and monitoring of any contaminating dual scFv-Fc and mAb homodimers post-purification (e.g., IEF gels, cIEF, and analytical IEX columns).
  • XmAb®20717 can be administered to human subjects according to a dosage regimen described herein.
  • Bispecific anti-CTLA4 x anti-PDl antibody e.g., XmAb®20717
  • XmAb®20717 is incorporated into pharmaceutical compositions suitable for administration to a human subject according to a dosage regimen described herein.
  • dosage regimen refers to a systematic plan of drug administration regarding formulation, route of administration, drug dose, dosing interval and/or treatment duration.
  • the pharmaceutical composition comprises a anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) and a pharmaceutically acceptable carrier.
  • pharmaceutically acceptable carrier includes any and all solvents, dispersion media, coatings, isotonic and absorption delaying agents, and the like that are physiologically compatible and are suitable for administration to a subject for the methods described herein.
  • pharmaceutically acceptable carriers include one or more of water, saline, phosphate buffered saline, dextrose, glycerol, ethanol and the like, as well as combinations thereof.
  • isotonic agents for example, sugars, polyalcohols such as mannitol, sorbitol, or sodium chloride in the composition.
  • Pharmaceutically acceptable carriers may further comprise minor amounts of auxiliary substances such as surfactants (such as nonionic surfactants) wetting or emulsifying agents (such as a polysorbate), preservatives or buffers (such as an organic acid, which as a citrate or an acetate), which enhance the shelf life or effectiveness of the bispecific anti-CTLA4 x anti-PDl antibodies (e.g., XmAb®20717).
  • auxiliary substances such as surfactants (such as nonionic surfactants) wetting or emulsifying agents (such as a polysorbate), preservatives or buffers (such as an organic acid, which as a citrate or an acetate), which enhance the shelf life or effectiveness of the bispecific anti-CTLA4 x anti-PDl antibodies (e.g., XmAb®20717).
  • auxiliary substances such as surfactants (such as nonionic surfactants) wetting or emulsifying agents (such as a polysorbate), preservatives or buffer
  • the pharmaceutical composition comprises a bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717), and a preservative or buffer.
  • the pharmaceutical composition comprises a bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717), and histidine.
  • the pharmaceutical composition comprises a bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717), and an acetate.
  • the pharmaceutical composition comprises a bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717), and sodium acetate.
  • the pharmaceutical composition comprises a bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) and a citrate.
  • the pharmaceutical composition comprises a bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) and sodium citrate.
  • the pharmaceutical composition comprises a bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) and a succinate.
  • the pharmaceutical composition comprises a bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) and sodium succinate.
  • the pharmaceutical composition comprises a bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) and an isotonic agent.
  • the pharmaceutical composition comprises a bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) and a polyalcohol.
  • the pharmaceutical composition comprises a bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) and mannitol.
  • the pharmaceutical composition comprises a bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) and sorbitol.
  • the pharmaceutical composition comprises a bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) and sodium chloride.
  • the pharmaceutical composition comprises a bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) and potassium chloride.
  • the pharmaceutical composition comprises a bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) and a wetting or emulsifying agent.
  • the pharmaceutical composition comprises a bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) and a polysorbate.
  • the pharmaceutical composition comprises a bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) and polysorbate-80.
  • the pharmaceutical composition comprises a bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) and an intravenous solution stabilizer.
  • the intravenous solution stabilizer comprises a polysorbate and a citrate.
  • the pharmaceutical composition comprises a bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) and sodium citrate and polysorbate-80.
  • the intravenous solution stabilizer comprises a polysorbate and a succinate.
  • the pharmaceutical composition comprises a bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) and sodium succinate and polysorbate-80.
  • the pharmaceutical composition comprises a bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) and a buffer and an isotonic agent.
  • the pharmaceutical composition comprises a bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) and a buffer and sorbitol.
  • the pharmaceutical composition comprises a bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) and an acetate and an isotonic agent.
  • the pharmaceutical composition comprises a bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) and histidine and an isotonic agent.
  • the pharmaceutical composition comprises a bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) and an acetate and sorbitol.
  • the pharmaceutical composition comprises a bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) and sodium acetate and sorbitol.
  • the pharmaceutical composition comprises a bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) and histidine and sorbitol.
  • the pharmaceutical composition comprises a bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) and a buffer and sodium chloride.
  • the pharmaceutical composition comprises a bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) and a succinate and an isotonic agent.
  • the pharmaceutical composition comprises a bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) and a succinate and sodium chloride.
  • the pharmaceutical composition comprises a bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) and sodium succinate and sodium chloride.
  • the pharmaceutical composition comprises a bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) and a buffer and an isotonic agent and an intravenous solution stabilizer.
  • the pharmaceutical composition comprises a bispecific anti-CTLA4 x anti-PDl antibody e.g., XmAb®20717) and a buffer and sorbitol and an intravenous solution stabilizer.
  • the pharmaceutical composition comprises a bispecific anti-CTLA4 x anti-PDl antibody e.g., XmAb®20717) and an acetate and an isotonic agent and an intravenous solution stabilizer.
  • the pharmaceutical composition comprises a bispecific anti-CTLA4 x anti-PDl antibody e.g., XmAb®20717) and histidine and an isotonic agent and an intravenous solution stabilizer.
  • the pharmaceutical composition comprises a bispecific anti-CTLA4 x anti-PDl antibody e.g., XmAb®20717) and an acetate and sorbitol and an intravenous solution stabilizer.
  • the pharmaceutical composition comprises a bispecific anti-CTLA4 x anti-PDl antibody e.g., XmAb®20717) and sodium acetate and sorbitol and an intravenous solution stabilizer.
  • the pharmaceutical composition comprises a bispecific anti-CTLA4 x anti-PDl antibody e.g., XmAb®20717) and histidine and sorbitol and an intravenous solution stabilizer.
  • the pharmaceutical composition comprises a bispecific anti-CTLA4 x anti-PDl antibody e.g., XmAb®20717) and sodium chloride.
  • the pharmaceutical composition comprises a bispecific anti-CTLA4 x anti-PDl antibody e.g., XmAb®20717) and sodium chloride and polysorbate-80.
  • the pharmaceutical composition comprises a bispecific anti-CTLA4 x anti-PDl antibody e.g., XmAb®20717) and sodium citrate and sodium chloride.
  • the pharmaceutical composition comprises a bispecific anti-CTLA4 x anti-PDl antibody e.g., XmAb®20717) and sodium citrate, sodium chloride, and polysorbate-80.
  • the pharmaceutical composition comprises a bispecific anti-CTLA4 x anti-PDl antibody e.g., XmAb®20717) and sodium citrate, sodium chloride, sodium acetate, sorbitol and polysorbate-80.
  • the pharmaceutical composition comprises a bispecific anti-CTLA4 x anti-PDl antibody e.g., XmAb®20717) and sodium citrate, sodium chloride, histidine, sorbitol and polysorbate-80.
  • the pharmaceutical composition comprises a bispecific anti- CTLA4 x anti-PDl antibody (e.g., XmAb®20717) and sodium succinate and sucrose.
  • the pharmaceutical composition comprises a bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) and sodium succinate and polysorbate-80.
  • the pharmaceutical composition comprises a bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) and sodium succinate and sodium chloride.
  • the pharmaceutical composition comprises a bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) and sucrose and polysorbate-80.
  • the pharmaceutical composition comprises a bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) and sucrose and sodium chloride.
  • the pharmaceutical composition comprises a bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) and sucrose and polysorbate-80.
  • the pharmaceutical composition comprises a bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) and polysorbate-80 and sodium chloride.
  • the pharmaceutical composition comprises a bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) and sodium succinate and sucrose and polysorbate-80.
  • the pharmaceutical composition comprises a bispecific anti-CTLA4 x anti-PDl antibody (e.g, XmAb®20717) and sodium succinate and sucrose and sodium chloride.
  • the pharmaceutical composition comprises a bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) and sucrose and polysorbate-80 and sodium chloride.
  • the pharmaceutical composition comprises a bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) and sucrose and polysorbate-80 and sodium chloride and sodium succinate.
  • compositions provided herein may be in a variety of forms. These include, for example, liquid, semi-solid and solid dosage forms, such as liquid solutions (e.g., injectable and infusible solutions), dispersions or suspensions.
  • liquid solutions e.g., injectable and infusible solutions
  • dispersions or suspensions e.g., dispersions or suspensions.
  • the form depends on the intended mode of administration and therapeutic application.
  • Exemplary compositions are in the form of injectable or infusible solutions, such as compositions similar to those used for passive immunization of humans with other antibodies.
  • the mode of administration is intravenous.
  • the antibody is administered by intravenous infusion or injection.
  • compositions typically must be sterile and stable under the conditions of manufacture and storage.
  • Sterile injectable solutions can be prepared by incorporating the antibody in the required amount in an appropriate solvent with one or a combination of ingredients enumerated herein, as required, followed by filtered sterilization.
  • dispersions are prepared by incorporating the antibody into a sterile vehicle that contains a basic dispersion medium and the required other ingredients from those enumerated herein.
  • prophylactic premedication can be administered to a subject to reduce infusion related reactions.
  • acetaminophen e.g., 650 mg orally
  • diphenhydramine hydrochloride e.g., 25 - 50 mg IV
  • dexamethasone e.g., 10 mg IV
  • diphenhydramine hydrochloride e.g., 50 mg IV
  • dexamethasone e.g., 10 - 20 mg IV
  • epinephrine and/or bronchodilators is administered to a subject to reduce infusion related reactions.
  • epinephrine, antihistamines, corticosteroids, IV fluids, vasopressors, oxygen, bronchodilators, and/or acetaminophen is administered to a subject to reduce infusion related reactions.
  • one or more medications to reduce infusion related reactions is administered to a subject prior to the administration of a bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) to the subject.
  • a bispecific anti-CTLA4 x anti-PDl antibody e.g., XmAb®20717
  • one or more medications to reduce infusion related reactions is administered to a subject prior to but on the same day as the administration of a bispecific anti-CTLA4 x anti- PDl antibody (e.g., XmAb®20717) to the subject.
  • one or more medications to reduce infusion related reactions is administered to a subject after the administration of a bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) to the subject.
  • the anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) can be administered by a variety of methods known in the art.
  • the route/mode of administration is intravenous injection.
  • the route and/or mode of administration will vary depending upon the desired results.
  • the bispecific anti-CTLA4 x anti-PDl antibody is a front line therapy, second line therapy, third line therapy, fourth line therapy, fifth line therapy, or sixth line therapy.
  • a medical professional can readily determine and prescribe the effective amount of the antibody composition required. For example, a physician could start doses of the medicament employed in the antibody composition at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.
  • the compositions of the disclosure can be used to treat certain prostate cancers, for example, as described herein.
  • a composition of the disclosure is administered according to a method of the disclosure to treat a prostate cancer.
  • the prostate cancer is receptive to treatment by an antibody which binds to PD1.
  • the prostate cancer is receptive to treatment by an antibody which binds to CTLA4.
  • the prostate cancer is receptive to treatment by an antibody which binds to PD1 and CTLA4. In some embodiments, the prostate cancer is refractory. In some embodiments, the prostate cancer is relapsed. In some embodiments, the prostate cancer is refractory and relapsed. In some embodiments, a bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717; 5-15 mg/kg; or 10 mg/kg) is used in a method of the disclosure. In some embodiments, the bispecific anti-CTLA4 x anti- PDl antibody (e.g, XmAb®20717) that is used in a method of the disclosure is described throughout the disclosure and in Section 4.3. In some embodiments, any dosage described in this disclosure can be used in a method of the disclosure. In some embodiments, any dosage described in Section 4.8 can be used in a method of the disclosure
  • AVPCa adenocarcinoma of the prostate
  • a bispecific anti-CTLA4 x anti-PDl antibody e.g, XmAb®20717; 5-15 mg/kg; or 10 mg/kg
  • carboplatin in a therapeutically effective dose that results in a target area under the serum concentration-time curve of 3 (AUC3)
  • taxane e.g., carbazitaxel or docetaxel
  • the dose of the carbazitaxel or docetaxel in (e) is higher than the dose of the carbazitaxel or docetaxel in (c).
  • carbazitaxel or docetaxel is intravenously administered on Day 15 of the second treatment cycle.
  • carboplatin is intravenously administered on Day 15 of the second treatment cycle.
  • the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) of the disclosure is intravenously administered to the male subject on day 1 of a first treatment cycle and about every two weeks (Q2W) thereafter.
  • the dose of the carboplatin of (b) is intravenously administered to the male subject twice in the first treatment cycle, wherein the twice is on Day 1 and about three weeks after Day 1 of the first treatment cycle.
  • the dose of carbazitaxel or docetaxel of (c) is intravenously administered to the male subject twice in a first treatment cycle, wherein the twice is on Day 1 and about three weeks after Day 1 of the first treatment cycle.
  • the dose of the carboplatin of (d) is intravenously administered to the male subject between Day 13 and Day 17 of a second treatment cycle and about every three weeks (Q3W) thereafter.
  • the dose of carbazitaxel or docetaxel of (e) is intravenously administered to the male subject between Day 13 and Day 17 of the second treatment cycle and about every three weeks (Q3W) thereafter.
  • each treatment cycle is about 28 days.
  • each treatment cycle is 28 days.
  • each treatment cycle is between about 26-30 days.
  • the dose of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) of the disclosure in (a) is 10 mg/kg.
  • carbazitaxel in (c) is administered at a dose of 15 mg/m 2 .
  • docetaxel in (c) is administered at a dose of 50 mg/m 2 (e.g., if the subject has not been administered with docetaxel previously, or prior to the first administration of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) of the disclosure, or prior to the start of the method of the disclosure).
  • carbazitaxel in (e) is administered at a dose of 20 mg/m 2 .
  • docetaxel in (e) is administered at a dose of 60 mg/m 2 (e.g., if the subject has not been administered with docetaxel previously, or prior to the first administration of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) of the disclosure, or prior to the start of the method of the disclosure).
  • carbazitaxel in (c) is administered at a dose of between about 5-20 mg/m 2 .
  • docetaxel in (c) is administered at a dose of between about 40-60 mg/m 2 or 45- 55 mg/m 2 (e.g., if the subject has not been administered with docetaxel previously, or prior to the first administration of the bispecific anti-CTLA4 x anti-PDl antibody (e.g, XmAb®20717) of the disclosure, or prior to the start of the method of the disclosure).
  • carbazitaxel in (e) is administered at a dose of between about 15-25 mg/m 2 .
  • docetaxel in (e) is administered at a dose of between about 50- 70 mg/m 2 or about 55-65 mg/m 2 (e.g., if the subject has not been administered with docetaxel previously, or prior to the first administration of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) of the disclosure, or prior to the start of the method of the disclosure).
  • (b) and (c) are administered during the first treatment cycle.
  • (b) and (c) are for the starting dose.
  • (b) and (c) are administered for the first administration of the first treatment cycle.
  • (b) and (c) are administered for the first two administrations of the first treatment cycle. In some embodiments, (b) and (c) are administered on Day 1 of the first treatment cycle. In some embodiments, (b) and (c) are administered on Day 1 of the first treatment cycle and about 3 weeks thereafter. In some embodiments, (b) and (c) are administered on Day 1 of the first treatment cycle and in one day about 3 weeks after (e.g., about Day 21 of the first treatment cycle). In some embodiments, (b) and (c) are administered on Day 1 of the first treatment cycle and in one day between about Day 20 to Day 28 of the first treatment cycle.
  • (b) and (c) are administered on Day 1 of the first treatment cycle and in one day between about Day 20 to Day 23 of the first treatment cycle. In some embodiments, (b) and (c) are administered on Day 1 of the first treatment cycle and about Day 21 of the first treatment cycle. In some embodiments, (b) and (c) are administered on Day 1 of the first treatment cycle and on Day 21 of the first treatment cycle. In some embodiments, (d) and (e) start on the second treatment cycle. In some embodiments, (d) and (e) start on the second treatment cycle and continues to a subsequence cycle and/or for the duration of treatment (e.g., third treatment cycle, fourth treatment cycle, fifth treatment cycle, and/or any subsequent cycle).
  • a subsequence cycle and/or for the duration of treatment e.g., third treatment cycle, fourth treatment cycle, fifth treatment cycle, and/or any subsequent cycle.
  • (d) and (e) start on the first administration of the second treatment cycle and every 3 weeks (Q3W) thereafter. In some embodiments, (d) and (e) are administered on Day 15 of the second treatment cycle and about every 3 weeks thereafter. In some embodiments, (d) and (e) are administered between about Day 14 to Day 16 of the second treatment cycle and about every 3 weeks thereafter. In some embodiments, (d) and (e) are administered on the second week of the second treatment cycle and about every 3 weeks thereafter. In some embodiments, (d) and (e) are administered on Day 15 of the second treatment cycle, fifth treatment cycle, eight treatment cycle, and/or any other suitable treatment cycle.
  • (d) and (e) are administered between about Day 14 to Day 16 of the second treatment cycle, fifth treatment cycle, eight treatment cycle, and/or any other suitable treatment cycle. In some embodiments, (d) and (e) are administered on Day 8 of the third treatment cycle, sixth treatment cycle, ninth treatment cycle, and/or any other suitable treatment cycle. In some embodiments, (d) and (e) are administered between about Day 7 to Day 9 of the third treatment cycle, sixth treatment cycle, ninth treatment cycle, and/or any other suitable treatment cycle. In some embodiments, (b) and (c) are administered on Day 1 of the first treatment cycle and Day 21 of the first treatment cycle, and (d) and (e) are administered every three weeks after Day 21 of the first treatment cycle.
  • (a) is administered on Day 1 of the first treatment cycle and about every two weeks thereafter (e.g., Day 1 and Day 15 of each treatment cycle; between about Days 1-3 of each treatment cycle and/or Days 14-17 of each treatment cycle); (b) and (c) are administered on Day 1 of the first treatment cycle and about three weeks after Day 1 (e.g., Day 21 of the first treatment cycle; between about Days 19-23 of the first treatment cycle); and (d) and (e) are administered every three weeks thereafter (e.g., every three weeks after Day 21 or after Days 19-23 of the first treatment cycle).
  • (a) is administered on Day 1 and Day 15 of each treatment cycle; (b) and (c) are administered on Day 1 of the first treatment cycle and Day 21 of the first treatment cycle; and (d) and (e) are administered every three weeks after Day 21 of the first treatment cycle. In some embodiments, (b) and (c) are administered on Day 1 of the first treatment cycle and Day 21 of the first treatment cycle, and (d) and (e) are administered on Day 15 of the second treatment cycle, Day 8 of the third treatment cycle, and every three weeks thereafter for the duration of treatment and/or for any other suitable time.
  • (a) is administered on Day 1 and Day 15 of each treatment cycle; (b) and (c) are administered on Day 1 of the first treatment cycle and Day 21 of the first treatment cycle; and (d) and (e) are administered on Day 15 of the second treatment cycle, Day 8 of the third treatment cycle, and every three weeks thereafter for the duration of treatment and/or for any other suitable time.
  • the carboplatin is administered for about or at most about 7-9 cycles. In some embodiments, the carboplatin is administered for about or at most about 8 cycles. In some embodiments, carboplatin is administered for about or at most about 8 cycles. In some embodiments, (d) is administered for about or at most about 7 cycles.
  • (d) is administered for about or at most about 8 cycles.
  • the method of the disclosure includes stopping administration of (d) after the carboplatin is administered to a subject for a total of 8 treatment cycles.
  • the method of the disclosure includes (b) and (c) for the first treatment cycle, (d) and (e) for the following seven treatment cycles, and (e) for any subsequent treatment cycle.
  • the method of the disclosure includes (a), (b) and (c) for the first treatment cycle; (a), (d) and (e) for the following eigth treatment cycles; and (a) and (e) for any subsequent treatment cycle.
  • the method of the disclosure includes (a), (b) and (c) for the first treatment cycle; (a), (d) and (e) for following seven treatment cycles; and (a) and (e) for any subsequent treatment cycle.
  • the prostate cancer is an aggressive variant (anaplastic) adenocarcinoma of the prostate (AVPCa).
  • the AVPCa has a mutation or other aberrancy in at least two genes independently selected from the group consisting of Rbl, TP53, and PTEN.
  • the prostate cancer is metastatic castration-resistant prostate cancer.
  • a bispecific anti-CTLA4 x anti-PDl antibody e.g., XmAb®20717; 5-15 mg/kg; or 10 mg/kg
  • administering taxane e.g., carbazitaxel or docetaxel
  • taxane e.g., carbazitaxel or docetaxel
  • carbazitaxel e.g., between about 10 mg/m 2 and about 80 mg/m 2 , between about 15 mg/m 2 and about 25 mg/m 2 , or between about 70 mg/m 2 and about 80 mg/m 2 ; carbazitaxel at 20 mg/m 2 ; or docetaxel at 75 mg/m 2 or 60 mg/m 2 ).
  • the dose of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) of the disclosure is 10 mg/kg.
  • carbazitaxel is administered at a dose of 20 mg/m 2 .
  • carbazitaxel is administered at a dose of about 20 mg/m 2 .
  • docetaxel is administered at a dose of 75 mg/m 2 (e.g., if the subject has not been administered with docetaxel previously, or prior to the first administration of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) of the disclosure, or prior to the start of the method of the disclosure).
  • docetaxel is administered at a dose of about 75 mg/m 2 (e.g., if the subject has not been administered with docetaxel previously, or prior to the first administration of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) of the disclosure, or prior to the start of the method of the disclosure). In some embodiments, docetaxel is administered at a dose of 60 mg/m 2 (e.g., if the subject has not been administered with docetaxel previously, or prior to the first administration of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) of the disclosure, or prior to the start of the method of the disclosure).
  • carbazitaxel is administered at a dose of between about 5-25 mg/m 2 or between about 15-25 mg/m 2 .
  • docetaxel is administered at a dose of between about 50-80 mg/m 2 or between about 70-90 mg/m 2 or between about 70-80 mg/m 2 or between about 65-85 mg/m 2 (e.g., if the subject has not been administered with docetaxel previously, or prior to the first administration of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) of the disclosure, or prior to the start of the method of the disclosure).
  • the bispecific anti-CTLA4 x anti-PDl antibody e.g., XmAb®20717
  • the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717; 5-15 mg/kg; or 10 mg/kg) of the disclosure is administered on Day 1 of the first treatment cycle and about every two weeks thereafter for the duration of treatment and/or for any suitable period of time.
  • the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717; 5-15 mg/kg; or 10 mg/kg) of the disclosure is administered on Day 1 of the first treatment cycle and about Day 15 of the first treatment cycle and about every two weeks thereafter for the duration of treatment and/or for any suitable period of time.
  • the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717; 5-15 mg/kg; or 10 mg/kg) of the disclosure is administered on Day 1 of the first treatment cycle and between about Day 13-17 of the first treatment cycle and about every two weeks thereafter for the duration of treatment and/or for any suitable period of time.
  • the bispecific anti- CTLA4 x anti-PDl antibody (e.g., XmAb®20717; 5-15 mg/kg; or 10 mg/kg) of the disclosure is administered on Day 1 of each treatment cycle and between about Day 13-17 of each treatment cycle.
  • the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717; 5-15 mg/kg; or 10 mg/kg) of the disclosure is administered on Day 1 of each treatment cycle and Day 15 of each treatment cycle.
  • the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717; 5-15 mg/kg; or 10 mg/kg) of the disclosure is administered on Day 1 of the first treatment cycle and every two weeks thereafter and carbazitaxel or docetaxel is administered on Day 1 of the first treatment cycle and every three weeks thereafter.
  • the bispecific anti-CTLA4 x anti- PDl antibody (e.g., XmAb®20717; 5-15 mg/kg; or 10 mg/kg) of the disclosure is administered on Day 1 of each treatment cycle and Day 15 of each treatment cycle and carbazitaxel or docetaxel is administered on Day 1 of the first treatment cycle, on Day 21 of the first treatment cycle, and about every two weeks thereafter.
  • the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717; 5-15 mg/kg; or 10 mg/kg) of the disclosure is administered on Day 1 of each treatment cycle and between Day 13-17 of each treatment cycle and carbazitaxel or docetaxel is administered on Day 1 of the first treatment cycle, between about Day 19-22 of the first treatment cycle, and about every two weeks thereafter (e.g., between about every 19-23 days).
  • the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717; 5-15 mg/kg; or 10 mg/kg) of the disclosure is administered on Day 1 and Day 15 of each treatment cycle; and carbazitaxel or docetaxel is administered on Day 1 of the first treatment cycle and Day 21 of the first treatment cycle, on Day 15 of the second treatment cycle, on Day 8 of the third treatment cycle, and every three weeks thereafter for the duration of treatment and/or for any other suitable time.
  • carbazitaxel or docetaxel is administered on Day 1 of the first treatment cycle and about every 3 weeks thereafter.
  • carbazitaxel or docetaxel is administered on Day 1 and Day 21 of the first treatment cycle and about every 3 weeks thereafter. In some embodiments, carbazitaxel or docetaxel is administered on Day 15 of the second treatment cycle and about every 3 weeks thereafter. In some embodiments, carbazitaxel or docetaxel is administered between about Day 1 to Day 3 of the first treatment cycle and about every 3 weeks thereafter. In some embodiments, carbazitaxel or docetaxel is administered between about Day 19 to Day 23 of the first treatment cycle and about every 3 weeks thereafter. In some embodiments, carbazitaxel or docetaxel is administered between about Day 14 to Day 16 of the second treatment cycle and about every 3 weeks thereafter.
  • carbazitaxel or docetaxel is administered on the first week of the first treatment cycle and about every 3 weeks thereafter. In some embodiments, carbazitaxel or docetaxel is administered on the third week of the first treatment cycle and about every 3 weeks thereafter. In some embodiments, carbazitaxel or docetaxel is administered on the second week of the second treatment cycle and about every 3 weeks thereafter. In some embodiments, carbazitaxel or docetaxel is administered on Day 15 of the second treatment cycle, fifth treatment cycle, eight treatment cycle, and/or any other suitable treatment cycle.
  • carbazitaxel or docetaxel is administered between about Day 14 to Day 16 of the second treatment cycle, fifth treatment cycle, eight treatment cycle, and/or any other suitable treatment cycle. In some embodiments, carbazitaxel or docetaxel is administered on Day 8 of the third treatment cycle, sixth treatment cycle, ninth treatment cycle, and/or any other suitable treatment cycle. In some embodiments, carbazitaxel or docetaxel is administered between about Day 7 to Day 9 of the third treatment cycle, sixth treatment cycle, ninth treatment cycle, and/or any other suitable treatment cycle. In some embodiments, the prostate cancer is not an aggressive variant (anaplastic) adenocarcinoma of the prostate (AVPCa).
  • the prostate cancer has a homologous recombination deficiency (HRD). In some embodiments, the prostate cancer has a biallelic loss of cyclin-dependent kinase 12 (CDK12). In some embodiments, the male subject has been previously treated with a polyadenosine diphosphate ribose polymerase (PARP) inhibitor. In some embodiments, the prostate cancer does not have a targetable mutation. In some embodiments, the prostate cancer is metastatic castration-resistant prostate cancer.
  • HRD homologous recombination deficiency
  • CDK12 biallelic loss of cyclin-dependent kinase 12
  • PARP polyadenosine diphosphate ribose polymerase
  • the prostate cancer does not have a targetable mutation. In some embodiments, the prostate cancer is metastatic castration-resistant prostate cancer.
  • the prostate cancer progressed after the male subject received a polyadenosine diphosphate ribose polymerase (PARP) inhibitor prior to the start of the method or prior to the first administration of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) of the disclosure; and/or the prostate cancer does not have a targetable mutation.
  • PARP polyadenosine diphosphate ribose polymerase
  • each treatment cycle is about 28 days. In some embodiments, each treatment cycle is 28 days. In some embodiments, each treatment cycle is between about 26-30 days.
  • a bispecific anti-CTLA4 x anti-PDl antibody e.g., XmAb®20717; 5-15 mg/kg; or 10 mg/kg
  • administering olaparib e.g., 300 mg per day; 300 mg twice daily; 600 mg per day; between about 400-800 mg per day; or between about 250 to 650 mg per day.
  • the dose of the olaparib is about, at least about, or at most about 600 mg per day.
  • the dose of the olaparib is 600 mg per day.
  • the dose of the olaparib is 300 mg twice daily.
  • the dose of the olaparib is about, at least about, or at most about 300 mg twice daily.
  • olaparib is administered to a male subject with prostate cancer at a dose of between about 500-700 mg on Day 1 of a first treatment cycle.
  • olaparib is administered to a male subject with prostate cancer at a dose of between about 500-700 mg on Day 1 of a first treatment cycle and every day thereafter.
  • olaparib is administered to a male subject with prostate cancer at a dose of between about 500-700 mg daily.
  • olaparib is administered to a male subject with prostate cancer at a dose of between about 500-700 mg as needed.
  • olaparib is administered to a male subject with prostate cancer two times a day. In some embodiments, olaparib is administered to a male subject with prostate cancer three times a day. In some embodiments, olaparib is administered to a male subject with prostate cancer four times a day. In some embodiments, olaparib is administered to a male subject with prostate cancer at a dose of 300 mg two times a day. In some embodiments, olaparib is administered to a male subject with prostate cancer at a dose of 150 mg four times a day. In some embodiments, olaparib is administered to a male subject with prostate cancer at a dose of 200 mg three times a day.
  • the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717; 5-15 mg/kg; or 10 mg/kg) of the disclosure is administered on Day 1 of the first treatment cycle and about every two weeks thereafter for the duration of treatment and/or for any suitable period of time.
  • the bispecific anti- CTLA4 x anti-PDl antibody (e.g., XmAb®20717; 5-15 mg/kg; or 10 mg/kg) of the disclosure is administered on Day 1 of the first treatment cycle and about Day 15 of the first treatment cycle and about every two weeks thereafter for the duration of treatment and/or for any suitable period of time.
  • the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717; 5-15 mg/kg; or 10 mg/kg) of the disclosure is administered on Day 1 of the first treatment cycle and between about Day 13-17 of the first treatment cycle and about every two weeks thereafter for the duration of treatment and/or for any suitable period of time.
  • the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717; 5-15 mg/kg; or 10 mg/kg) of the disclosure is administered on Day 1 of each treatment cycle and between about Day 13-17 of each treatment cycle.
  • the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717; 5-15 mg/kg; or 10 mg/kg) of the disclosure is administered on Day 1 of each treatment cycle and Day 15 of each treatment cycle.
  • the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717; 5-15 mg/kg; or 10 mg/kg) of the disclosure is administered on Day 1 of the first treatment cycle and every two weeks thereafter and olaparib is administered to the subject on Day 1 of the first treatment cycle and every day thereafter.
  • the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717; 5-15 mg/kg; or 10 mg/kg) of the disclosure is administered on Day 1 of the first treatment cycle and every two weeks thereafter and olaparib is administered to the subject on Day 1 of the first treatment cycle.
  • the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717; 5-15 mg/kg; or 10 mg/kg) of the disclosure is administered on Day 1 of the first treatment cycle and every two weeks thereafter and olaparib is administered to the subject on about Day 1 of the first treatment cycle and about every day thereafter.
  • the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717; 5-15 mg/kg; or 10 mg/kg) of the disclosure is administered on Day 1 of the first treatment cycle and every two weeks thereafter and olaparib is administered to the subject during every treatment cycle. In some embodiments, olaparib is not administered during every treatment cycle. In some embodiments, olaparib is administered to a subject daily.
  • olaparib is administered to a subject at least once (or one day), 2 times (or days), 3 times (or days), 4 times (or days), 5 times (or days), 6 times (or days), 7 times (or days), 8 times (or days), 9 times (or days), 10 times (or days), 11 times (or days), 12 times (or days), 13 times (or days), 14 times (or days), 15 times (or days), 16 times (or days), 17 times (or days), 18 times (or days), 19 times (or days), 20 times (or days), 21 times (or days), 22 times (or days), 23 times (or days), 24 times (or days), 25 times (or days), 26 times (or days), 27 times (or days), and/or 28 times (or days) in a treatment cycle.
  • the prostate cancer is not an aggressive variant (anaplastic) adenocarcinoma of the prostate (AVPCa).
  • the prostate cancer has a homologous recombination deficiency (HRD).
  • the prostate cancer has a biallelic loss of cyclin- dependent kinase 12 (CDK12).
  • the male subject has not been previously treated with a polyadenosine diphosphate ribose polymerase (PARP) inhibitor.
  • PARP polyadenosine diphosphate ribose polymerase
  • the prostate cancer does not have a targetable mutation.
  • the prostate cancer is metastatic castration-resistant prostate cancer.
  • each treatment cycle is about 28 days. In some embodiments, each treatment cycle is 28 days.
  • each treatment cycle is between about 26-30 days.
  • a method of treating a prostate cancer in a male human subject in need thereof comprising: administering to the subject according to a 28 day treatment cycle, a bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717; 5-15 mg/kg; or 10 mg/kg) of the disclosure at a dose of about 5-15 mg/kg or about 10 mg/kg, wherein the dose of the bispecific antibody is intravenously administered to the subject on day 1 of a first 28 day treatment cycle and about every two weeks (Q2W) thereafter.
  • a bispecific anti-CTLA4 x anti-PDl antibody e.g., XmAb®20717; 5-15 mg/kg; or 10 mg/kg
  • the prostate cancer is microsatellite instability-high (MSI-H) prostate cancer. In one embodiment, the prostate cancer is mismatch repair deficient (MMRD) prostate cancer. In one embodiment, the subject receives treatment about every 2 weeks (Q2W) for about two years.
  • the prostate cancer is mCRPC.
  • the prostate cancer is microsatellite instability-high [MSI-H]
  • the prostate cancer is mismatch repair deficient [MMRD]
  • the mCRPC is microsatellite instability -high [MSI-H]
  • the mCRPC is mismatch repair deficient [MMRD]
  • the prostate cancer is MSI-H positive. In an exemplary embodiment, the prostate cancer is MMRD positive. In an exemplary embodiment, the mCRPC is MSI-H positive. In an exemplary embodiment, the mCRPC is MMRD positive.
  • the prostate cancer is aggressive variant (anaplastic) adenocarcinoma of the prostate (AVPCa).
  • the mCRPC is aggressive variant (anaplastic) adenocarcinoma of the prostate (AVPCa).
  • the prostate cancer is neuroendocrine prostate cancer.
  • the mCRPC is neuroendocrine prostate cancer.
  • the prostate cancer is positive for Rbl. In an exemplary embodiment, the prostate cancer is positive for TP53. In an exemplary embodiment, the prostate cancer is positive for PTENb. In an exemplary embodiment, the mCRPC is positive for aberrancy for at least two of Rbl, TP53, and PTENb. In an exemplary embodiment, the mCRPC is positive for Rbl. In an exemplary embodiment, the mCRPC is positive for TP53. In an exemplary embodiment, the mCRPC is positive for PTENb. In an exemplary embodiment, the mCRPC is positive for aberrancy for at least two of Rbl, TP53, and PTENb.
  • the prostate cancer has a homologous recombination deficiency (HRD).
  • the prostate cancer is mCRPC with a homologous recombination deficiency.
  • the prostate cancer has a cyclin-dependent kinase 12 (CDK12) mutation.
  • the prostate cancer is mCRPC with a CDK12 mutation.
  • the prostate cancer is HRD positive in at least one gene selected from the group consisting of BRCA1, BRCA2, ATM, PALB2, CHEK2, and FANCA.
  • the prostate cancer is mCRPC and is HRD positive in at least one gene selected from the group consisting of BRCA1, BRCA2, ATM, PALB2, CHEK2, and FANCA.
  • the prostate cancer is positive for biallelic loss of CDK12.
  • the prostate cancer is mCRPC and is positive for biallelic loss of CDK12.
  • the prostate cancer is positive for HRD in one or more of the following genes: BRCA1, BRCA2, ATM, PALB2, CHEK2, FANCA; and/or positive for biallelic loss of CDK12.
  • the prostate cancer is mCRPC which is a HRD/CDK12 mutation positive cancer which is one of the following: Positive for HRD in one or more of the following genes: BRCA1, BRCA2, ATM, PALB2, CHEK2, FANCA; and/or Positive for biallelic loss of CDK12.
  • the prostate cancer is not positive for aberrancy for at least two of Rbl, TP53, and PTENb; not positive for HRD in one or more of the following genes: BRCA1, BRCA2, ATM, PALB2, CHEK2, FANCA; not positive for biallelic loss of CDK12; and not positive for microsatellite instability-high [MSI-H] or mismatch repair deficient [MMRD],
  • the mCRPC is not positive for aberrancy for at least two of Rbl, TP53, and PTENb; not positive for HRD in one or more of the following genes: BRCA1, BRCA2, ATM, PALB2, CHEK2, FANCA; not positive for biallelic loss of CDK12; and not positive for microsatellite instability-high [MSI-H] or mismatch repair deficient [MMRD]
  • the human male subject with prostate cancer, prior to the dosing regimen, or the first occurrence of the dosing regimen had not been administered a PARP inhibitor.
  • the human male subject with mCRPC, prior to the dosing regimen, or the first occurrence of the dosing regimen had not been administered a PARP inhibitor.
  • the prostate cancer is a HRD/CDK12 mutation positive cancer, and the human male subject with prostate cancer, prior to the dosing regimen, or the first occurrence of the dosing regimen, had not been administered a PARP inhibitor.
  • the prostate cancer is mCRPC and is a HRD/CDK12 mutation positive cancer, and the human male subject with prostate cancer, prior to the dosing regimen, or the first occurrence of the dosing regimen, had not been administered a PARP inhibitor.
  • the prostate cancer is a HRD/CDK12 mutation positive cancer which is one of the following: positive for HRD in one or more of the following genes: BRCA1, BRCA2, ATM, PALB2, CHEK2, FANCA; and/or positive for biallelic loss of CDK12, and the human male subject with prostate cancer, prior to the dosing regimen, or the first occurrence of the dosing regimen, had not been administered a PARP inhibitor.
  • the prostate cancer is mCRPC which is a HRD/CDK12 mutation positive cancer which is one of the following: Positive for HRD in one or more of the following genes: BRCA1, BRCA2, ATM, PALB2, CHEK2, FANCA; and/or Positive for biallelic loss of CDK12, and the human male subject with prostate cancer, prior to the dosing regimen, or the first occurrence of the dosing regimen, had not been administered a PARP inhibitor.
  • the prostate cancer described herein is a primary tumor. In an exemplary embodiment, the prostate cancer described herein is a locally advanced primary tumor. In an exemplary embodiment, the prostate cancer described herein is a locally advanced primary tumor. In an exemplary embodiment, the prostate cancer described herein is a metastatic tumor.
  • the prostate cancer is treated according to a method described herein.
  • the cancer is treated (such as by achieving a positive therapeutic response) by administering a bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) to the human subject in one or more cycles.
  • a bispecific anti-CTLA4 x anti-PDl antibody e.g., XmAb®20717
  • Each cycle comprises dose amount(s) of a bispecific anti-CTLA4 x anti-PDl antibody e.g., XmAb®20717
  • Each cycle can last for one or more weeks or months, or until a positive therapeutic response is achieved, or so long as there is a positive therapeutic response.
  • administration of the bispecific anti-CTLA4 x anti-PDl antibody stops after the positive therapeutic response is achieved, and the administration of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) begins again once the positive therapeutic response diminishes or disappears.
  • the bispecific anti-CTLA4 x anti-PDl antibody e.g., XmAb®20717
  • the bispecific anti-CTLA4 x anti-PDl antibody is administered until partial remission.
  • the bispecific anti-CTLA4 x anti- PDl antibody is administered until complete remission.
  • the method of treatment comprises a bispecific anti- CTLA4 x anti-PDl antibody (e.g., XmAb®20717) being administered in one to twenty cycles in combination with at least one additional agent of the disclosure.
  • the method of treatment comprises a bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) being administered in one, or two, or three, or four, or five, or six, or seven, or eight, or nine, or ten, or more than ten cycles.
  • the dosage regimen has a dose amount (quantity of an antibody) and an administration time (the length of time in which the dose amount is administered).
  • the method comprises a first cycle. In one embodiment, the method comprises a first cycle and a second cycle. In one embodiment, the method comprises a first cycle and a second cycle, where each cycle is different or wherein each cycle is the same. In one embodiment, the method comprises a first cycle and a second cycle and a third cycle. In one embodiment, the method comprises a first cycle and a second cycle and a third cycle, where each cycle is different or wherein each cycle is the same. In one embodiment, the method comprises a first cycle and a second cycle and a third cycle and a fourth cycle. In one embodiment, the method comprises a first cycle and a second cycle and a third cycle and a fourth cycle, where each cycle is different or wherein each cycle is the same.
  • the method comprises a first cycle and a second cycle and a third cycle and a fourth cycle and a fifth cycle. In one embodiment, the method comprises a first cycle and a second cycle and a third cycle and a fourth cycle and a fifth cycle, where each cycle is different or wherein each cycle is the same. In one embodiment, the method comprises a first cycle and a second cycle and a third cycle and a fourth cycle and a fifth cycle and a sixth cycle. In one embodiment, the method comprises a first cycle and a second cycle and a third cycle and a fourth cycle and a fifth cycle and a sixth cycle, where each cycle is different or wherein each cycle is the same.
  • the method comprises a first cycle and a second cycle and a third cycle and a fourth cycle and a fifth cycle and a sixth cycle and a seventh cycle.
  • the method comprises a first cycle and a second cycle and a third cycle and a fourth cycle and a fifth cycle and a sixth cycle and a seventh cycle, where each cycle is different or wherein each cycle is the same.
  • the method comprises a first cycle and a second cycle and a third cycle and a fourth cycle and a fifth cycle and a sixth cycle and a seventh cycle and an eighth cycle.
  • the method comprises a first cycle and a second cycle and a third cycle and a fourth cycle and a fifth cycle and a sixth cycle and a seventh cycle and an eighth cycle, where each cycle is different or wherein each cycle is the same.
  • the method comprises a first cycle and a second cycle and a third cycle and a fourth cycle and a fifth cycle and a sixth cycle and a seventh cycle and an eighth cycle and a ninth cycle.
  • the method comprises a first cycle and a second cycle and a third cycle and a fourth cycle and a fifth cycle and a sixth cycle and a seventh cycle and an eighth cycle and a ninth cycle, where each cycle is different or wherein each cycle is the same.
  • different dosages are used in each cycle or in each administration.
  • the same dosage e.g., of the bispecific anti-CTLA4 x anti-PDl antibody
  • the same dosage e.g., of the bispecific anti-CTLA4 x anti-PDl antibody
  • the same dosage e.g., of the bispecific anti-CTLA4 x anti-PDl antibody
  • the same dosage is used between any two cycles, any three cycles, any four cycles, or more than any four cycles.
  • different dosage e.g., of the bispecific anti-CTLA4 x anti-PDl antibody
  • different dosage e.g., of the bispecific anti-CTLA4 x anti-PDl antibody
  • different dosage e.g., of the bispecific anti-CTLA4 x anti-PDl antibody
  • XmAb®20717 can be used as the bispecific anti-CTLA4 x anti-PDl antibody in all methods of the invention provided herein. It will be understood that a biosimilar or XmAb®20717 can be used as the bispecific anti-CTLA4 x anti-PDl antibody in all methods of the invention provided herein. It will be understood that a bioequivalent or XmAb®20717 can be used as the bispecific anti-CTLA4 x anti-PDl antibody in all methods of the invention provided herein. It will be understood that a biobetter or XmAb®20717 can be used as the bispecific anti-CTLA4 x anti-PDl antibody in all methods of the invention provided herein.
  • a steroid is administered to a male subject of the disclosure.
  • the steroid is prednisone administered at a dose of about 5 mg twice per day (b.i.d.) on day 1 of the first treatment cycle, and about twice per day (b.i.d.) thereafter.
  • a method of the disclosure includes about, at least about, or at most about 1 treatment cycle, 2 treatment cycles, 3 treatment cycles, 4 treatment cycles, 5 treatment cycles, 6 treatment cycles, 7 treatment cycles, 8 treatment cycles, 9 treatment cycles, 10 treatment cycles, 11 treatment cycles, 12 treatment cycles, 13 treatment cycles, 14 treatment cycles, 15 treatment cycles, 16 treatment cycles, 17 treatment cycles, 18 treatment cycles, 19 treatment cycles, 20 treatment cycles, 21 treatment cycles, 22 treatment cycles, 23 treatment cycles, 24 treatment cycles, 25 treatment cycles, 26 treatment cycles, 27 treatment cycles, 28 treatment cycles, 29 treatment cycles, 30 treatment cycles, or more than 30 treatment cycles.
  • each treatment cycle is about 28 days. In some embodiments, each treatment cycle is 28 days.
  • each treatment cycle is between about 26-30 days.
  • a method of the disclosure results in stable disease classification of the prostate cancer as determined by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.
  • a method of the disclosure results in partial response classification of the prostate cancer as determined by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.
  • a method of the disclosure results in less or a reduced number of adverse events as compared to the average adverse events observed for an approved therapy (e.g., FDA approved) for treating the same prostate cancer that the male subject has.
  • the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) is administered with Carboplatin (e.g., prior to, after, or at the same time or same day).
  • the methods of the present disclosure comprises administration of Carboplatin to a subject.
  • a pharmaceutical composition of the disclosure comprises Carboplatin.
  • Carboplatin can be obtained through purchase from companies such as Sagent Pharma, Meitheal Pharmaceuticals, AdooQ Bioscience or Accord BioPharma (as Paraplatin®). Carboplatin is available in 10 mg/mL solutions. Calvert's formula can be utilized to calculate the dose of carboplatin.
  • the bispecific anti-CTLA4 x anti-PDl antibody e.g., XmAb®20717
  • the methods of the present disclosure comprises administration of Cabazitaxel to a subject.
  • a pharmaceutical composition of the disclosure comprises Cabazitaxel.
  • Cabazitaxel (Jevtana®, Sanofi -Aventis) can be obtained through purchase in 60 mg/1.5 mL solutions.
  • the bispecific anti-CTLA4 x anti-PDl antibody e.g., XmAb®20717
  • the methods of the present disclosure comprises administration of Docetaxel to a subject.
  • a pharmaceutical composition of the disclosure comprises Docetaxel.
  • Docetaxel (Taxotere®, Sanofi -Aventis) can be obtained through purchase in 20 mg/mL and 80 mg/4 mL solutions.
  • the bispecific anti-CTLA4 x anti-PDl antibody e.g., XmAb®20717
  • the methods of the present disclosure comprises administration of Olaparib to a subject.
  • a pharmaceutical composition of the disclosure comprises Olaparib.
  • Olaparib (Lynparza®, AstraZeneca) can be obtained through purchase in 100 mg or 150 mg tablets.
  • a 300 mg oral dosage of olaparib is provided by the administration of two 150 mg tablets to the male human subject.
  • a 300 mg oral dosage of olaparib is provided by the administration of three 100 mg tablets to the male human subject.
  • a twice daily 300 mg oral dosage of olaparib is provided by the administration of two administrations per day of two 150 mg tablets to the male human subject, or two administrations per day of three 100 mg tablets to the male human subject or a combination thereof.
  • 300 mg twice a day is administered to a male subject for a total daily dosage of 600 mg.
  • between about 400-700 mg of Olaparib is administered to a subject.
  • between about 300-900 mg of Olaparib is administered to a subject.
  • between about 550-650 mg of Olaparib is administered to a subject.
  • the bispecific anti-CTLA4 x anti-PDl antibody e.g., XmAb®20717
  • the methods of the present disclosure comprises administration of Prednisone to a subject.
  • a pharmaceutical composition of the disclosure comprises Prednisone.
  • Prednisone can be obtained through purchase from companies such as Roxane Laboratories in 5 mg/mL solutions.
  • the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) is the only therapeutic antibody administered to the subject during the treatment methods provided herein.
  • the male subject has received one or at least one systemic therapy prior to the start of a method of the disclosure.
  • the male subject has received one or at least one systemic therapy prior to the first administration of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) of the disclosure.
  • the male subject has received two or at least two systemic therapies prior to the start of a method of the disclosure.
  • the male subject has received two or at least two systemic therapies prior to the first administration of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) of the disclosure. In some embodiments, the male subject has received three or at least three systemic therapies prior to the start of a method of the disclosure. In some embodiments, the male subject has received three or at least three systemic therapies prior to the first administration of the bispecific anti-CTLA4 x anti-PDl antibody (e.g, XmAb®20717) of the disclosure. In some embodiments, the male subject has received four or at least four systemic therapies prior to the start of a method of the disclosure.
  • the bispecific anti-CTLA4 x anti-PDl antibody e.g., XmAb®20717
  • the male subject has received four or at least four systemic therapies prior to the first administration of the bispecific anti-CTLA4 x anti-PDl antibody (e.g, XmAb®20717) of the disclosure.
  • the male subject has been treated with chemotherapy prior to the start of a method of the disclosure.
  • the male subject has been treated with chemotherapy prior to the first administration of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) of the disclosure.
  • the male subject has been treated with radiation therapy prior to the start of a method of the disclosure.
  • the male subject has been treated with radiation therapy prior to the first administration of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) of the disclosure.
  • a bispecific anti-CTLA4 x anti-PDl antibody e.g., XmAb®20717
  • another therapeutic agent e.g., Carboplatin, Cabazitaxel, Docetaxel, Prednisone, Olaparib, or any other appropriate therapeutic agent.
  • Administered “in combination”, as used herein, means that two (or more) different treatments are delivered to the subject during the course of the subject’s affliction with the disorder, e.g.., the two or more treatments are delivered after the subject has been diagnosed with the disorder and before the disorder has been cured or eliminated or treatment has ceased for other reasons.
  • the two or more treatments are delivered during the maintenance period following administration of the bispecific anti- CTLA4 x anti-PDl antibody and after the disorder has been cured or eliminated.
  • combination with another therapeutic agent refers to another therapeutic agent that is known to treat or is used to treat the same disease or disorder that the bispecific anti- CTLA4 x anti-PDl antibody (e.g., XmAb®20717) of the disclosure is being used to treat in the subject.
  • the delivery of one treatment is still occurring when the delivery of the second begins, so that there is overlap in terms of administration. This is sometimes referred to herein as “simultaneous” or “concurrent delivery”.
  • the delivery of one treatment ends before the delivery of the other treatment begins.
  • the treatment is more effective because of combined administration.
  • the second treatment is more effective, e.g., an equivalent effect is seen with less of the second treatment, or the second treatment reduces one or more symptoms to a greater extent, than would be seen if the second treatment were administered in the absence of the first treatment, or the analogous situation is seen with the first treatment.
  • delivery is such that the reduction in a symptom, or other parameter related to the disorder is greater than what would be observed with one treatment delivered in the absence of the other.
  • the effect of the two treatments can be partially additive, wholly additive, or greater than additive.
  • the delivery can be such that an effect of the first treatment delivered is still detectable when the second is delivered.
  • the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) and at least one additional therapeutic agent can be administered simultaneously, in the same or in separate compositions, or sequentially.
  • the bispecific anti- CTLA4 x anti-PDl antibody (e.g., XmAb®20717) described herein can be administered first, and the additional agent can be administered second, or vice versa.
  • the bispecific anti-CTLA4 x anti-PDl antibody e.g., XmAb®20717
  • additional therapeutic agents, procedures or modalities can be administered during periods of active disorder, or during a period of positive therapeutic response or less active disease.
  • the bispecific anti-CTLA4 x anti-PDl antibody e.g., XmAb®20717
  • the bispecific anti-CTLA4 x anti-PDl antibody e.g., XmAb®20717
  • the one or more additional agents e.g., second or third agent
  • the administered amount or dosage of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) and the one or more additional agents (e.g., second or third agent), is lower (e.g., at least about 10%, at least about 20%, at least about 30%, at least about 40%, or at least about 50%) than the amount or dosage of each agent used individually, e.g., as a monotherapy.
  • the amount or dosage of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) and the one or more additional agents (e.g., second or third agent, that results in a desired effect (e.g., treatment of cancer) is lower (e.g., at least about 10%, at least about 20%, at least about 30%, at least about 40%, or at least about 50%) than the amount or dosage of each agent used individually, e.g., as a monotherapy, required to achieve the same therapeutic effect.
  • a bispecific antibody is administered to a human subject in combination with one or more side-effect ameliorating agent(s).
  • the one or more side-effect ameliorating agent(s) is administered prior to the first administration of the bispecific antibody.
  • the one or more side-effect ameliorating agent(s) is administered prior to each administration of the bispecific antibody.
  • Possible side effects include, but are not limited to, increased amounts of alanine transaminase (ALT) in the blood, increased amounts of aspartate transaminase (AST) in the blood, fever, vomiting, nausea, diarrhea, hypotension, hypoxia, rash, dysphagia, gastroparesis, capillary leak syndrome, hypophosphatemia, anemia, fatigue, and increased lipase in the blood.
  • Symptoms of treatment with the bispecific anti-CTLA4 x anti-PDl antibody e.g., XmAb®20717) of the disclosure can include high fevers, nausea, transient hypotension, hypoxia, and the like.
  • Symptoms can also include clinical constitutional signs and symptoms such as fever, fatigue, anorexia, myalgias, arthralgias, nausea, vomiting, headache, clinical skin signs, and rash.
  • Symptoms can include clinical gastrointestinal signs and symptoms such as nausea, vomiting and diarrhea.
  • Symptoms can include clinical respiratory signs and symptoms such as tachypnea and hypoxemia.
  • Symptoms can include clinical cardiovascular signs and symptoms such as tachycardia, widened pulse pressure, hypotension, increased cardiac output (early) and potentially diminished cardiac output.
  • Symptoms can include clinical coagulation signs and symptoms such as elevated d-dimer, hypofibrinogenemia with or without bleeding.
  • Symptoms can include clinical renal signs and symptoms such as azotemia.
  • Symptoms can include clinical hepatic signs and symptoms such as transaminitis and hyperbilirubinemia. Symptoms can include clinical neurologic signs and symptoms such as headache, mental status changes, confusion, delirium, word finding difficulty or frank aphasia, hallucinations, tremor, dysmetria, altered gait, and seizures.
  • the administration of XmAb®20717 described herein to the human subject produces a low rate of one or more symptoms described herein. In an exemplary embodiment, the administration of XmAb®20717 described herein to the human subject produces a low level of one or more symptoms described herein. In an exemplary embodiment, the administration of XmAb®20717 described herein to the human subject produces a low Grade (such as Grade 1 or Grade 2) of one or more symptoms described herein. In an exemplary embodiment, the administration of XmAb®20717 described herein to the human subject produces a low Grade (such as Grade 1 or Grade 2) of at least one symptom.
  • the one or more side-effect ameliorating agent(s) include steroids, antihistamines, anti-allergic agents, antinausea agents (or anti-emetics), analgesic agents, antipyretic agents, cytoprotective agents, vasopressor agents, anticonvulsant agents, anti-inflammatories, or any combination thereof.
  • epinephrine, antihistamines, corticosteroids, IV fluids, vasopressors, oxygen, bronchodilators, and/or acetaminophen is administered to a subject.
  • At least one of epinephrine, antihistamines, corticosteroids, IV fluids, vasopressors, oxygen, bronchodilators, and/or acetaminophen is administered to a subject prior to administration of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) to the subject.
  • the bispecific anti-CTLA4 x anti-PDl antibody e.g., XmAb®20717
  • At least one of epinephrine, antihistamines, corticosteroids, IV fluids, vasopressors, oxygen, bronchodilators, and/or acetaminophen is administered to a subject after administration of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) to the subject.
  • the bispecific anti-CTLA4 x anti-PDl antibody e.g., XmAb®20717
  • At least one of epinephrine, antihistamines, corticosteroids, IV fluids, vasopressors, oxygen, bronchodilators, and/or acetaminophen is administered to a subject on the same day as the administration of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) to the subject.
  • the bispecific anti-CTLA4 x anti-PDl antibody e.g., XmAb®20717
  • the side-effect ameliorating agent is a steroid.
  • the steroid is a corticosteroid.
  • the corticosteroid is a glucocorticoid.
  • the corticosteroid is betamethasone, dexamethasone, prednisone, prednisolone, methylprednisolone (e.g., 0.5-1 mg/kg/day or 1-2 mg/kg/day), triamcinolone, or any combination thereof.
  • the corticosteroid is hydrocortisone, cortisone, betamethasone, or any combination thereof.
  • the steroid is fludrocortisone.
  • the steroid is dexamethasone.
  • the side-effect ameliorating agent is an antihistamine.
  • the antihistamine is an Hi antagonist.
  • the Hi antagonist is acrivastine, azelastine, bilastine, bromodiphenhydramine, brompheniramine, buclizine, carbinoxamine, cetirizine (Zyrtec®), chlorodiphenhydramine, chlorphenamine, clemastine, cyclizine, cyproheptadine, dexbrompheniramine, dexchlorpheniramine, dimenhydrinate, dimetindene, diphenhydramine, doxylamine, ebastine, embramine, fexofenadine (Allegra®), hydroxyzine (Vistaril®), loratadine (Claritin®), meclizine, mirtazapine, olopatadine, orphenadrine, phenindamine, pheniramine, phenylto
  • the antihistamine is acrivastine. In one embodiment, the antihistamine is cetirizine. In one embodiment, the antihistamine is diphenhydramine. In one embodiment, the antihistamine is Benadryl®.
  • the antihistamine is an Hi inverse agonist.
  • the Hi inverse agonist is acrivastine, cetirizine, levocetirizine, desloratadine, pyrilamine, or any combination thereof.
  • the antihistamine is an H2 antihistamine.
  • the H2 antihistamine is an H2 antagonist.
  • the H2 antihistamine is an H2 inverse agonist.
  • the H2 antihistamine is cimetidine, famotidine, lafutidine, nizatidine, ranitidine, roxatidine, tiotidine, or any combination thereof.
  • the side-effect ameliorating agent is an antiallergy agent.
  • the side-effect ameliorating agent is antihistamines, glucocorticoids, epinephrine (adrenaline), mast cell stabilizers, antileukotriene agents, anti-cholinergics, decongestants, or any combination thereof.
  • the side-effect ameliorating agent is a decongestant.
  • the side-effect ameliorating agent is an adrenaline releasing agent.
  • the side-effect ameliorating agent is levomethamphetamine, phenylpropanolamine, propylhexedrine (Benzedrex®), loratadine, or any combination thereof.
  • the side-effect ameliorating agent is an a- adrenergic receptor agonist. In one embodiment, the side-effect ameliorating agent is naphazoline, oxymetazoline, phenylephrine, synephrine, tetryzoline, tramazoline, xylometazoline, or any combination thereof. 4.5.5. Combination Therapy: Side-effect ameliorating agent, Antinausea agents (or anti-emetic)
  • the side-effect ameliorating agent is an antinausea agent. In one embodiment, the side-effect ameliorating agent is an antiemetic agent. In one embodiment, the side-effect ameliorating agent is a 5-HT3 receptor antagonist. In one embodiment, the side-effect ameliorating agent is a dolasetron (Anzemet®), granisetron (Kytril®, Sancuso®), ondansetron (Zofran®), tropisetron (Setrovel®, Navoban®), palonosetron (Aloxi®), mirtazapine (Remeron®), or any combination thereof. In one embodiment, the sideeffect ameliorating agent is a dopamine antagonist.
  • the side-effect ameliorating agent is a 5-HT3 receptor antagonist.
  • the side-effect ameliorating agent is domperidone (Motilium®), olanzapine (Zyprexa®), droperidol, haloperidol, chlorpromazine, prochlorperazine, alizapride, prochlorperazine (Compazine®, Stemzine®, Buccastem®, Stemetil®, Phenotil®), metoclopramide (Reglan®), or any combination thereof.
  • the side-effect ameliorating agent is a NK1 receptor antagonist.
  • the side-effect ameliorating agent is aprepitant or fosaprepitant (Emend®), casopitant, rolapitant (Varubi®), or any combination thereof.
  • the side-effect ameliorating agent is an anticholinergic.
  • the side-effect ameliorating agent is scopolamine.
  • the side-effect ameliorating agent is an analgesic agent. In one embodiment, the side-effect ameliorating agent is an antipyretic agent. In one embodiment, the side-effect ameliorating agent is a salicylate, any derivative thereof, or any combination thereof. In one embodiment, the salicylate is selected from the group consisting of aspirin, diflunisal, salsalate, salicylic acid, any derivative thereof, or any combination thereof. In one embodiment, the salicylate is choline salicylate, magnesium salicylate, sodium salicylate, or any combination thereof. In one embodiment, the side-effect ameliorating agent is aspirin. In one embodiment, the side-effect ameliorating agent is acetaminophen, any derivative thereof.
  • the side-effect ameliorating agent is an NSAID, any derivative thereof.
  • the NSAID is a propionic acid derivative.
  • the NSAID is ibuprofen, dexibuprofen, naproxen, fenoprofen, ketoprofen, dexketoprofen, flurbiprofen, oxaprozin, loxoprofen, any derivative thereof, or any combination thereof.
  • the NSAID is ibuprofen.
  • the NSAID is naproxen.
  • the NSAID is an acetic acid derivative.
  • the NSAID is indomethacin, tolmetin, sulindac, etodolac, ketorolac, diclofenac, aceclofenac, nabumetone, any derivative thereof, or any combination thereof.
  • the NSAID is an enolic acid derivative.
  • the NSAID is piroxicam, meloxicam, tenoxicam, droxicam, lornoxicam, phenylbutazone, any derivative thereof, or any combination thereof.
  • the NSAID is an anthranilic acid derivative.
  • the NSAID is mefenamic acid, meclofenamic acid, flufenamic acid, tolfenamic acid, any derivative thereof, or any combination thereof.
  • the side-effect ameliorating agent is phenazone, metamizole, nabumetone, any derivative thereof, or any combination thereof.
  • the side-effect ameliorating agent is an opiate.
  • the sideeffect ameliorating agent is codeine, morphine, thebaine, fentanyl, or any combination thereof.
  • the side-effect ameliorating agent is dihydrocodeine, oxymorphol, oxycodone, oxymorphone, metopon, or any combination thereof.
  • the side-effect ameliorating agent is a vasopressor agent.
  • the vasopressor agent is norepinephrine, phenylephrine, epinephrine, ephedrine, dopamine, vasopressin, or any combination thereof.
  • the vasopressor agent is dobutamine, midodrine, amezinium, or any combination thereof.
  • the side-effect ameliorating agent is an anticonvulsant agent.
  • the anticonvulsant is an aldehyde. In one embodiment, the aldehyde is paraldehyde.
  • the anticonvulsant is an aromatic allylic alcohol. In one embodiment, the aromatic allylic alcohol is stiripentol.
  • the anticonvulsant is a barbiturate. In one embodiment, the barbiturate is phenobarbital, primidone, methylphenobarbital, barbexaclone, or any combination thereof. In one embodiment, the anticonvulsant is a benzodiazepine.
  • the benzodiazepine is clobazam, clonazepam, clorazepate, diazepam, midazolam, lorazepam, nitrazepam, temazepam, nimetazepam, or any combination thereof.
  • the anticonvulsant is a carboxamide.
  • the carboxamide is carbamazepine, oxcarbazepine, eslicarbazepine acetate or any combination thereof.
  • the anticonvulsant is a fatty acid. In one embodiment, the fatty acid is a valproate.
  • the valproate is valproic acid, sodium valproate, divalproex sodium, or any combination thereof. In one embodiment, the valproate is vigabatrin, progabide, and tiagabine.
  • the anticonvulsant is a fructose derivative. In one embodiment, the fructose derivative is topiramate. In one embodiment, the anticonvulsant is a GABA analog. In one embodiment, the GABA analog is gabapentin, pregabalin, or any combination thereof. In one embodiment, the anticonvulsant is a hydantoin.
  • the hydantoin is ethotoin, phenytoin, mephenytoin, fosphenytoin, or any combination thereof.
  • the anticonvulsant is an oxazolidinedione. In one embodiment, the oxazolidinedione is paramethadione, trimethadione, ethadione, or any combination thereof. In one embodiment, the anticonvulsant is a propionate. In one embodiment, the anticonvulsant is a pyrimidinedione. In one embodiment, the anticonvulsant is a pyrrolidine.
  • the pyrrolidine is brivaracetam, etiracetam, levetiracetam, seletracetam, or any combination thereof.
  • the anticonvulsant is levetiracetam.
  • the anticonvulsant is a succinimide.
  • the succinimide is ethosuximide, phensuximide, mesuximide, or any combination thereof.
  • the anticonvulsant is a sulfonamide.
  • the succinimide is acetazolamide, sultiame, methazolamide, zonisamide, or any combination thereof.
  • the anticonvulsant is a triazine.
  • the triazine is lamotrigine.
  • the anticonvulsant is a urea.
  • the urea is pheneturide, phenacemide, or any combination thereof.
  • the anticonvulsant is a valproylamide.
  • the anticonvulsant is a valproylamide.
  • the valproylamide is valpromide, valnoctamide, or any combination thereof.
  • the anticonvulsant is perampanel, stiripentol, pyridoxine, or any combination thereof.
  • the side-effect ameliorating agent is an anti-inflammatory agent.
  • the side-effect ameliorating agent is a TNF-a inhibitor.
  • the TNF-a inhibitor is an antibody.
  • an anti-TNFa antibody molecule such as, infliximab (Remicade®) (e.g., 5 mg/kg), adalimumab (Humira®), certolizumab pegol (Cimzia®), golimumab (Simponi®), or any combination thereof.
  • a TNFa inhibitor is a fusion protein such as entanercept (Enbrel®).
  • the TNF-a inhibitor is a small molecule.
  • Small molecule inhibitor of TNFa include, but are not limited to, xanthine derivatives (e.g., pentoxifylline), bupropion, or any combination thereof.
  • xanthine derivatives e.g., pentoxifylline
  • bupropion e.g., a protriptyline
  • Combination Therapy Side-effect ameliorating agent, IL6 inhibitor
  • the side-effect ameliorating agent is an anti-inflammatory agent.
  • the side-effect ameliorating agent is a IL-6 inhibitor.
  • An example of an IL-6 inhibitor is an anti-IL-6 antibody molecule such as tocilizumab (toe), sarilumab, elsilimomab, CNTO 328, ALD518/BMS-945429, CNTO 136, CPSL2364, CDP6038, VX30, ARGX-109, FE301, FM101, or any combination thereof.
  • the anti -IL-6 antibody molecule is tocilizumab.
  • the methods described herein can comprise administering a bispecific antibody described herein to a human subject and further administering one or more agents to manage elevated levels of a soluble factor resulting from treatment with a bispecific antibody.
  • the soluble factor elevated in the human subject is one or more of IFN-y, TNFa, IL-2 and IL-6.
  • the factor elevated in the human subject is one or more of IL-1, GM-CSF, IL- 10, IL-8, IL-5 and fraktalkine. Therefore, an agent administered to treat this side effect can be an agent that neutralizes one or more of these soluble factors.
  • the agent that neutralizes one or more of these soluble forms is an antibody or antigen binding fragment thereof.
  • agents include, but are not limited to a steroid (e.g., corticosteroid), an inhibitor of TNFa, and inhibitor of IL-1R, and an inhibitor of IL-6.
  • a steroid e.g., corticosteroid
  • an inhibitor of TNFa e.g., TNFa
  • IL-1R IL-1 receptor
  • an inhibitor of IL-6 examples include anakinra or rilonacept or canakinumab.
  • the side-effect ameliorating agent is one that reduces an immune-mediated side effect.
  • immune-mediated side effects include, but are not limited to pneumonitis, colitis, hepatitis, nephritis and renal dysfunction, hypothyroidism, hyperthyroidism, and endocrinopathies (e.g., hypophysitis, Type 1 diabetes mellitus and thyroid disorders such as hypothyroidism and hyperthyroidism).
  • the side-effect ameliorating agent reduces embryofetal toxicity.
  • the human subject can be administered an antipyretic agent.
  • the human subject can be administered an analgesic agent.
  • a steroid is administered prior to the bispecific antibody. In one embodiment, the steroid is administered in an amount between about 5 mg and about 30 mg. In one embodiment, the steroid described herein is administered in an amount between about 5 mg and about 25 mg. In one embodiment, the steroid is administered in an amount between about 5 mg and about 15 mg. In one embodiment, the steroid is administered in an amount between about 8 mg and about 12 mg. In one embodiment, the steroid is administered in an amount between about 10 mg and about 20 mg. In one embodiment, the steroid is administered in an amount of about 10 mg. In one embodiment, the steroid is administered in an amount of 10 mg. In one embodiment, the steroid is administered in an amount of 10 mg. In one embodiment, the steroid is administered in an amount between about 18 mg and about 22 mg.
  • the steroid is administered in an amount of about 20 mg. In one embodiment, the steroid is administered in an amount of 20 mg. In one embodiment, the steroid is dexamethasone. In one embodiment, the steroid is dexamethasone and is administered in an amount between about 10 mg and about 20 mg. In one embodiment, the steroid is dexamethasone and is administered in an amount of about 10 mg. In one embodiment, the steroid is dexamethasone. In one embodiment, the steroid is dexamethasone and is administered in an amount of about 20 mg.
  • the steroid is dexamethasone and is administered between about 45 minutes and 75 minutes before each administration of a bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717). In one embodiment, the steroid is dexamethasone and is administered about 60 minutes before each administration of a bispecific anti-CTLA4 x anti- PDl antibody (e.g., XmAb®20717). In one embodiment, the steroid is dexamethasone and is administered about 60 minutes before an administration of bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717).
  • about 20 mg of dexamethasone is administered about 60 minutes before each administration of a bispecific anti-CTLA4 x anti- PDl antibody (e.g., XmAb®20717). In one embodiment, about 20 mg of dexamethasone is administered about 60 minutes before an administration of a bispecific anti-CTLA4 x anti- PDl antibody (e.g., XmAb®20717).
  • an antihistamine is administered prior to the bispecific antibody.
  • the antihistamine is an Hi antagonist.
  • the Hi antagonist is a first generation Hi antagonist.
  • the antihistamine is an ethanolamine.
  • the ethanolamine is diphenhydramine, carbinoxamine, doxylamine, orphenadrine, bromazine, clemastine, dimenhydrinate, or any combination thereof.
  • the antihistamine is diphenhydramine.
  • the antihistamine is administered in an amount between about 20 mg and 60 mg. In one embodiment, the antihistamine is administered in an amount between about 20 mg and 30 mg.
  • the antihistamine is administered in an amount of about 25 mg. In one embodiment, the antihistamine is administered in an amount of 25 mg. In one embodiment, the antihistamine is administered in an amount between about 40 mg and 60 mg. In one embodiment, the antihistamine is administered in an amount between about 45 mg and 55 mg. In one embodiment, the antihistamine is administered in an amount of about 50 mg. In one embodiment, the antihistamine is administered in an amount of 50 mg. In one embodiment, the antihistamine is diphenhydramine and the amount between about 20 mg and about 30 mg. In one embodiment, the antihistamine is diphenhydramine and the amount is about 25 mg.
  • the antihistamine is diphenhydramine and is administered between about 20 minutes and 70 minutes before each administration of a bispecific anti- CTLA4 x anti-PDl antibody (e.g., XmAb®20717). In one embodiment, the antihistamine is diphenhydramine and is administered between about 30 minutes and 60 minutes before each administration of a bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717). In one embodiment, the antihistamine is diphenhydramine and is administered between about 30 minutes and 60 minutes before an administration of a bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717).
  • a bispecific anti-CTLA4 x anti-PDl antibody e.g., XmAb®20717
  • acetaminophen is administered prior to the bispecific antibody. In one embodiment, acetaminophen is administered in an amount between about 100 mg and 1000 mg. In one embodiment, acetaminophen is administered in an amount between about 400 mg and 600 mg.
  • acetaminophen is administered in an amount of about 500 mg. In one embodiment, acetaminophen is administered in an amount of 500 mg. In one embodiment, acetaminophen is administered in an amount between about 500 mg and 800 mg. In one embodiment, acetaminophen is administered in an amount between about 550 mg and 750 mg. In one embodiment, acetaminophen is administered in an amount between about 600 mg and 700 mg. In one embodiment, acetaminophen is administered in an amount of about 650 mg. In one embodiment, acetaminophen is administered in an amount of 650 mg.
  • the acetaminophen is administered between about 15 minutes and about 45 minutes before each administration of a bispecific anti-CTLA4 x anti-PDl antibody (e.g, XmAb®20717). In one embodiment, the acetaminophen is administered about 30 minutes before each administration of a bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717). In one embodiment, the acetaminophen is administered between about 60 minutes and about 30 minutes before an administration of a bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717).
  • the acetaminophen is administered between about 60 minutes and about 30 minutes before each administration of a bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717). In one embodiment, about 650 mg of acetaminophen is administered about 30 minutes before each administration of a bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717).
  • a steroid, an Hi antagonist, and acetaminophen are administered prior to the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717).
  • dexamethasone, an Hi antagonist, and acetaminophen are administered prior to the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717).
  • a steroid, diphenhydramine, and acetaminophen are administered prior to the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717).
  • dexamethasone, diphenhydramine, and acetaminophen are administered prior to the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717).
  • dexamethasone is administered in an amount of about 10 mg or about 20 mg
  • diphenhydramine is administered in an amount of about 25 mg
  • acetaminophen is administered in an amount of about 650 mg prior to the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717).
  • a side-effect ameliorating agent described herein does not occur.
  • an antinausea agent is administered prior to the bispecific antibody.
  • the antinausea agent is a 5-HT3 receptor antagonist.
  • the 5-HT3 receptor antagonist is administered in an amount between about 5 mg and 30 mg. In one embodiment, the 5-HT3 receptor antagonist is administered in an amount between about 5 mg and 15 mg. In one embodiment, the 5-HT3 receptor antagonist is administered in an amount between about 5 mg and 10 mg. In one embodiment, the 5-HT3 receptor antagonist is administered in an amount of about 8 mg. In one embodiment, the 5- HT3 receptor antagonist is administered in an amount of 8 mg. In one embodiment, the 5- HT3 receptor antagonist is ondansetron.
  • an NK1 receptor antagonist is administered prior to the bispecific antibody. In one embodiment, the NK1 receptor antagonist is administered in an amount between about 100 mg and 300 mg. In one embodiment, the NK1 receptor antagonist is administered in an amount between about 125 mg and 200 mg. In one embodiment, the NK1 receptor antagonist is administered in an amount between about 125 mg and 175 mg. In one embodiment, the NK1 receptor antagonist is administered in an amount of about 150 mg. In one embodiment, the NK1 receptor antagonist is administered in an amount of 150 mg. In one embodiment, the NK1 receptor antagonist is aprepitant, fosaprepitant, or combination thereof. In one embodiment, the NK1 receptor antagonist is fosaprepitant dimeglumine.
  • compositions of the disclosure can be used to achieve a positive therapeutic response against prostate cancer.
  • a bispecific anti-CTLA4 x anti-PDl antibody e.g., XmAb®20717
  • a bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) composition and a carboplatin composition and a cabazitaxel composition are administered according to a method described herein to achieve a positive therapeutic response against prostate cancer.
  • a bispecific anti-CTLA4 x anti-PDl antibody e.g., XmAb®20717
  • a carboplatin composition and a docetaxel composition are administered according to a method described herein to achieve a positive therapeutic response against prostate cancer.
  • a bispecific anti-CTLA4 x anti-PDl antibody e.g., XmAb®20717
  • a cabazitaxel composition are administered according to a method described herein to achieve a positive therapeutic response against prostate cancer.
  • a bispecific anti-CTLA4 x anti-PDl antibody e.g., XmAb®20717
  • a docetaxel composition are administered according to a method described herein to achieve a positive therapeutic response against prostate cancer.
  • a bispecific anti-CTLA4 x anti-PDl antibody e.g., XmAb®20717
  • an olaparib composition are administered according to a method described herein to achieve a positive therapeutic response against prostate cancer.
  • the prostate cancer is receptive to treatment by an antibody which binds to CTLA4.
  • the prostate cancer is receptive to treatment by an antibody which binds to PD1.
  • the prostate cancer is receptive to treatment by an antibody which binds to CTLA4 and PD1.
  • the prostate cancer is receptive to treatment by carboplatin.
  • the prostate cancer is receptive to treatment by cabazitaxel.
  • the prostate cancer is receptive to treatment by docetaxel.
  • the prostate cancer is receptive to treatment by olaparib.
  • the positive therapeutic response can be assessed by assays or tools described herein.
  • the positive therapeutic response is a reduction in cancer tumor size, a reduction in the rate of cancer tumor growth, a reduction in the number of cancer-associated cells, an increase in cancer-associated cell death, an inhibition of cancer-associated cell survival, and/or an inhibition (z.e., slowing to some extent, preferably halting) of cancer-associated proliferation.
  • the positive therapeutic response is a reduction in prostate cancer tumor size, a reduction in the rate of prostate cancer tumor growth, a reduction in the number of prostate cancer-associated cells, an increase in prostate cancer-associated cell death, an inhibition of prostate cancer-associated cell survival, an inhibition (z.e., slowing to some extent, preferably halting) of prostate cancer-associated proliferation, and/or a lowering of prostate-specific antigen (PSA) levels in the male human subject.
  • PSA prostate-specific antigen
  • the desired therapeutic result is a complete response, partial response or stable disease.
  • the desired therapeutic result is an improvement in response according to the RECIST guidelines (v. 1.1) as outlined in Eisenhauer et al. Eur. J. Cancer, 2009, 45:228-247, which is incorporated herein by reference in its entirety regarding, e.g., tumor response evaluation criteria.
  • the positive therapeutic response is assessed by the size of the target lesion(s). In some embodiments, the positive therapeutic response is a complete response as compared to baseline. In other embodiments, the positive therapeutic response is a partial response as compared to baseline. In some embodiments, the subject does not have progressive disease as compared to baseline. In other embodiments, the subject has stable disease as compared to baseline.
  • the positive therapeutic response is assessed by the size of the non-target lesion(s). In some embodiments, the positive therapeutic response is a complete response as compared to baseline. In other embodiments, the positive therapeutic response is a partial response as compared to baseline. In some embodiments, the subject does not have progressive disease as compared to baseline. In other embodiments, the subject has stable disease as compared to baseline.
  • measuring of visceral lesions are used to assess the positive therapeutic response. Visceral lesions can be measured by computed tomography, or by caliper measurement by clinical examination, or by chest X-ray. The measurement methods are standardized and known to one of skill in the art.
  • a visceral lesion baseline assessment is taken prior to the first administration of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717).
  • a visceral lesion baseline assessment is taken prior to the first administration of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717), and involves: i) assessing the visceral lesions which have a minimum diameter along the longest plane of measurement of at least 10 mm by CT, 10 mm by caliper measurement by clinical examination, and 20 mm by chest X-ray, thereby assessing the target visceral lesions; ii) adding the sum of the diameters together of up to 5 of the target visceral lesions, thereby obtaining the visceral lesion baseline assessment.
  • the bispecific anti-CTLA4 x anti-PDl antibody e.g., XmAb®20717
  • a visceral lesion baseline assessment is taken between 28 days and 2 days prior to the first administration of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717).
  • a visceral lesion response assessment is taken after the first administration of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717).
  • a visceral lesion response assessment is taken between about 52 days and about 56 days after the first administration of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717).
  • a visceral lesion response assessment is taken after the first administration of the bispecific anti-CTLA4 x anti-PDl antibody e.g., XmAb®20717) and involves: i) assessing the diameter of the up to 5 target visceral lesions; ii) adding the sum of the diameters together of up to 5 of the target visceral lesions, thereby obtaining the visceral lesion response assessment.
  • a visceral lesion baseline assessment is taken prior to the first administration of the bispecific anti- CTLA4 x anti-PDl antibody (e.g., XmAb®20717) or carboplatin or cabazitaxel or docetaxel.
  • a visceral lesion baseline assessment is taken prior to the first administration of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) or carboplatin or cabazitaxel or docetaxel, and involves: i) assessing the visceral lesions which have a minimum diameter along the longest plane of measurement of at least 10 mm by CT, 10 mm by caliper measurement by clinical examination, and 20 mm by chest X-ray, thereby assessing the target visceral lesions; ii) adding the sum of the diameters together of up to 5 of the target visceral lesions, thereby obtaining the visceral lesion baseline assessment.
  • the bispecific anti-CTLA4 x anti-PDl antibody e.g., XmAb®20717
  • carboplatin or cabazitaxel or docetaxel e.g., XmAb®20717
  • carboplatin or cabazitaxel or docetaxel
  • a visceral lesion baseline assessment is taken between 28 days and 2 days prior to the first administration of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) or carboplatin or cabazitaxel or docetaxel.
  • a visceral lesion response assessment is taken after the first administration of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) or carboplatin or cabazitaxel or docetaxel.
  • a visceral lesion response assessment is taken between about 52 days and about 56 days (about 8 weeks) after the first administration of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) or carboplatin or cabazitaxel or docetaxel.
  • the bispecific anti-CTLA4 x anti-PDl antibody e.g., XmAb®20717
  • carboplatin or cabazitaxel or docetaxel e.g., XmAb®20717
  • a visceral lesion response assessment is taken after the first administration of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) or carboplatin or cabazitaxel or docetaxel and involves: i) assessing the diameter of the up to 5 target visceral lesions; ii) adding the sum of the diameters together of up to 5 of the target visceral lesions, thereby obtaining the visceral lesion response assessment.
  • a visceral lesion baseline assessment is taken prior to the first administration of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) or olaparib.
  • a visceral lesion baseline assessment is taken prior to the first administration of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) or olaparib, and involves: i) assessing the visceral lesions which have a minimum diameter along the longest plane of measurement of at least 10 mm by CT, 10 mm by caliper measurement by clinical examination, and 20 mm by chest X-ray, thereby assessing the target visceral lesions; ii) adding the sum of the diameters together of up to 5 of the target visceral lesions, thereby obtaining the visceral lesion baseline assessment.
  • the bispecific anti-CTLA4 x anti-PDl antibody e.g., XmAb®20717
  • a visceral lesion baseline assessment is taken between 28 days and 2 days prior to the first administration of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) or olaparib.
  • a visceral lesion response assessment is taken after the first administration of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) or olaparib.
  • a visceral lesion response assessment is taken between about 52 days and about 56 days (about 8 weeks) after the first administration of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) or olaparib.
  • a visceral lesion response assessment is taken after the first administration of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) or olaparib and involves: i) assessing the diameter of the up to 5 target visceral lesions; ii) adding the sum of the diameters together of up to 5 of the target visceral lesions, thereby obtaining the visceral lesion response assessment.
  • the positive therapeutic response is achieved against the prostate cancer when there are fewer visceral lesions in the response assessment than in the baseline assessment. In an exemplary embodiment, the positive therapeutic response is achieved against the prostate cancer when the visceral lesions are smaller in the response assessment than in the baseline assessment. In an exemplary embodiment, the positive therapeutic response is achieved when the visceral lesion response assessment is at least 10%, or at least 20%, or at least 30%, or at least 40%, or at least 50%, or at least 60%, or last 70%, or at least 80%, or at least 90%, or 100% below the visceral lesion baseline assessment. In an exemplary embodiment, the positive therapeutic response is achieved when the visceral lesion response assessment is at least 30%, below the visceral lesion baseline assessment.
  • the prostate cancer can be assessed for positive therapeutic purposes by assessing one or more properties of the prostate cancer in the patient prior to the administration of the compositions described herein, thereby obtaining a baseline assessment or evaluation. After the first administration of at least one of the compositions described herein, the prostate cancer property is assessed or evaluated again, thereby obtaining a response assessment. By comparing the baseline assessment and the response assessment, a determination can be made if the positive therapeutic response has been achieved. If the response assessment is an improvement over the baseline assessment, then the positive therapeutic response against prostate cancer is achieved. In an exemplary embodiment, more than one response assessment is made at different times during the course of treatment (during one or more of the times in which the dosing regimen is implemented).
  • assessing the prostate cancer is done by assessing one or more oncologic markers of the human subject.
  • the oncologic marker is selected from the group consisting of prostate-specific antigen (PSA) levels (for prostate cancer), bone lesions, visceral lesions, and malignant lymph nodes.
  • PSA prostate-specific antigen
  • a positive therapeutic response can be in one oncologic marker category or more than one. That is, for example, a combination of lowered PSA level and/or reduced number of bone lesions and/or reduced diameter sum of target visceral lesions and/or reduced diameter sum of target malignant lymph nodes marks the achievement of the positive therapeutic response.
  • the methods of the disclosure results in a decrease in prostate specific antigen (PSA) compared to a reference.
  • PSA prostate specific antigen
  • the decrease in PSA is a decrease of about or at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or more than 95% as compared to the reference.
  • the decrease is about or at least about 50% as compared to the reference.
  • the reference is the level of PSA in a biological sample obtained from the male subject prior to the first administration of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717).
  • the reference is the level of PSA of the male subject at baseline.
  • the reference is the level of PSA in a biological sample obtained from the male subject at a previous timepoint.
  • the reference is the level of PSA of at least one male subject with the same stage and/or disease progression of the prostate cancer and/or age group classification of the subject being treated with a method of the disclosure.
  • the reference is the level of PSA is a predetermined number.
  • a reference is the PSA level obtained from a biological sample from a male subject. In some embodiments, a reference is the PSA level obtained from a biological sample from a male subject with prostate cancer. In some embodiments, a reference is the PSA level obtained from a biological sample from one or more male subjects with prostate cancer. In some embodiments, a reference is the PSA level obtained from a biological sample from a male subject with prostate cancer before the first administration of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) of the disclosure. In some embodiments, a reference is the PSA level obtained from a biological sample from a male subject with prostate cancer from a previous time point.
  • the bispecific anti-CTLA4 x anti-PDl antibody e.g., XmAb®20717
  • a reference is the PSA level obtained from a biological sample from a male subject with prostate cancer before an administration of the bispecific anti-CTLA4 x anti- PDl antibody (e.g., XmAb®20717) of the disclosure.
  • a reference is the PSA level obtained from a biological sample from a male subject with prostate cancer obtained from an earlier treatment cycle.
  • PSA levels are used to assess a positive therapeutic response. PSA levels are obtained by PSA tests, and PSA tests are standardized and known to one of skill in the art.
  • a PSA level baseline assessment is taken prior to the first administration of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717).
  • a PSA level baseline assessment is taken between 28 days and 2 days prior to the first administration of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717).
  • a PSA level baseline assessment is taken the day prior to the first administration of bispecific anti-CTLA4 x anti- PDl antibody (e.g., XmAb®20717).
  • a PSA level response assessment is taken after the first administration of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717).
  • a PSA level response assessment is taken between about 21 days and about 28 days after the intravenous dose of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717).
  • a PSA level baseline assessment is taken prior to the first administration of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) or carboplatin or cabazitaxel or docetaxel.
  • a PSA level baseline assessment is taken between 28 days and 2 days prior to the first administration of the bispecific anti- CTLA4 x anti-PDl antibody (e.g., XmAb®20717) or carboplatin or cabazitaxel or docetaxel.
  • a PSA level baseline assessment is taken the day prior to the first administration of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) or carboplatin or cabazitaxel or docetaxel.
  • a PSA level response assessment is taken after the first administration of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) or carboplatin or cabazitaxel or docetaxel.
  • a PSA level response assessment is taken between about 21 days and about 28 days after the intravenous dose of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717). In an exemplary embodiment, a PSA level response assessment is taken between about 26 days and about 30 days, or between about 54 days and about 58 days, or between about 82 days and about 86 days, or between about 110 days and about 114 days, after the first administration of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) or carboplatin or cabazitaxel or docetaxel.
  • the bispecific anti-CTLA4 x anti-PDl antibody e.g., XmAb®20717
  • carboplatin or cabazitaxel or docetaxel e.g., XmAb®20717
  • a PSA level response assessment is taken between about 82 days and about 86 days after the first administration of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) or carboplatin or cabazitaxel or docetaxel.
  • a PSA level baseline assessment is taken prior to the first administration of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) or olaparib.
  • a PSA level baseline assessment is taken between 28 days and 2 days prior to the first administration of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) or olaparib.
  • a PSA level baseline assessment is taken the day prior to the first administration of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) or olaparib.
  • a PSA level response assessment is taken after the first administration of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) or olaparib.
  • a PSA level response assessment is taken between about 21 days and about 28 days after the intravenous dose of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717). In an exemplary embodiment, a PSA level response assessment is taken between about 26 days and about 30 days (about 4 weeks), or between about 54 days and about 58 days (about 7 weeks), or between about 82 days and about 86 days (about 12 weeks), or between about 110 days and about 114 days, after the first administration of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) or olaparib.
  • the bispecific anti-CTLA4 x anti-PDl antibody e.g., XmAb®20717
  • a PSA level response assessment is taken between about 82 days and about 86 days (about 12 weeks) after the first administration of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) or olaparib.
  • the bispecific anti-CTLA4 x anti-PDl antibody e.g., XmAb®20717
  • olaparib e.g., XmAb®20717
  • the positive therapeutic response is achieved when the PSA level in the response assessment is below the PSA level in the baseline assessment. In an exemplary embodiment, the positive therapeutic response is achieved when the PSA level in the response assessment is at least 10%, or at least 20%, or at least 30%, or at least 40%, or at least 50%, or at least 60%, or last 70%, or at least 80%, or at least 90% below the PSA level in the baseline assessment. In an exemplary embodiment, the positive therapeutic response is achieved when the PSA level in the response assessment is at least 50% below the PSA level in the baseline assessment.
  • measuring of bone lesions are used to assess the positive therapeutic response.
  • Bone lesions can be measured by a bone scan, and these are standardized and known to one of skill in the art.
  • a bone lesion baseline assessment is taken prior to the first administration of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717).
  • a bone lesion baseline assessment is taken between 28 days and 2 days prior to the first administration of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717).
  • a bone lesion response assessment is taken after the first administration of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717). In an exemplary embodiment, a bone lesion response assessment is taken between about 52 days and about 56 days (about 8 weeks) after the first administration of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717). In an exemplary embodiment, a bone lesion response assessment involves counting the number of bone lesions in a bone scan taken between about 52 days and about 56 days (about 8 weeks) after the first administration of the bispecific anti- CTLA4 x anti-PDl antibody (e.g., XmAb®20717).
  • a bone lesion baseline assessment is taken prior to the first administration of the bispecific anti- CTLA4 x anti-PDl antibody (e.g., XmAb®20717) or carboplatin or cabazitaxel or docetaxel.
  • a bone lesion baseline assessment involves counting the number of bone lesions in a bone scan taken prior to the first administration of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) or carboplatin or cabazitaxel or docetaxel.
  • a bone lesion baseline assessment is taken between 28 days and 2 days prior to the first administration of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) or carboplatin or cabazitaxel or docetaxel.
  • a bone lesion response assessment is taken after the first administration of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) or carboplatin or cabazitaxel or docetaxel.
  • a bone lesion response assessment is taken between about 52 days and about 56 days (about 8 weeks) after the first administration of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) or carboplatin or cabazitaxel or docetaxel.
  • a bone lesion response assessment involves counting the number of bone lesions in a bone scan taken between about 52 days and about 56 days (about 8 weeks) after the first administration of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) or carboplatin or cabazitaxel or docetaxel.
  • a bone lesion baseline assessment is taken prior to the first administration of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) or olaparib.
  • a bone lesion baseline assessment involves counting the number of bone lesions in a bone scan taken prior to the first administration of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) or olaparib.
  • a bone lesion baseline assessment is taken between 28 days and 2 days prior to the first administration of the bispecific anti-CTLA4 x anti-PDl antibody (e.g, XmAb®20717) or olaparib.
  • a bone lesion response assessment is taken after the first administration of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) or olaparib. In an exemplary embodiment, a bone lesion response assessment is taken between about 52 days and about 56 days (about 8 weeks) after the first administration of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) or olaparib.
  • a bone lesion response assessment involves counting the number of bone lesions in a bone scan taken between about 52 days and about 56 days (about 8 weeks) after the first administration of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) or olaparib.
  • the bispecific anti-CTLA4 x anti-PDl antibody e.g., XmAb®20717
  • olaparib e.g., XmAb®20717
  • the positive therapeutic response is achieved against the prostate cancer when there are fewer bone lesions in the response assessment than in the baseline assessment. In an exemplary embodiment, the positive therapeutic response is achieved against the prostate cancer when the number of bone lesions in the response assessment is lower than the number of bone lesions in the baseline assessment. In an exemplary embodiment, the positive therapeutic response is achieved when the number of bone lesions in the bone scan in the response assessment is at least 1 fewer, or at least 2 fewer, or at least 3 fewer, or at least 4 fewer, or at least 5 fewer than the number of bone lesions in the bone scan in the baseline assessment. In an exemplary embodiment, the positive therapeutic response is achieved against the prostate cancer when the bone lesions are smaller in the response assessment than in the baseline assessment.
  • measuring of malignant lymph nodes are used to assess the positive therapeutic response.
  • Malignant lymph nodes can be measured by computed tomography. The measurement method is standardized and known to one of skill in the art.
  • a malignant lymph node baseline assessment is taken prior to the first administration of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717).
  • a malignant lymph node baseline assessment is taken prior to the first administration of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717), and involves: assessing the malignant lymph nodes which have a minimum diameter of at least 15 mm in the short axis by CT, thereby assessing the target malignant lymph nodes; ii) adding the sum of the diameters together of up to 5 of the target malignant lymph nodes, thereby obtaining the target malignant lymph node baseline assessment.
  • the bispecific anti-CTLA4 x anti-PDl antibody e.g., XmAb®20717
  • a malignant lymph node baseline assessment is taken between 28 days and 2 days prior to the first administration of the bispecific anti- CTLA4 x anti-PDl antibody (e.g., XmAb®20717).
  • a malignant lymph node response assessment is taken after the first administration of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717).
  • a malignant lymph node response assessment is taken between about 52 days and about 56 days after the first administration of the bispecific anti-CTLA4 x anti-PDl antibody (e.g, XmAb®20717).
  • a visceral lesion response assessment is taken after the first administration of the bispecific anti-CTLA4 x anti-PDl antibody (e.g, XmAb®20717) and involves: i) assessing the diameter of the up to 5 target malignant lymph nodes; ii) adding the sum of the diameters together of up to 5 of the target malignant lymph nodes, thereby obtaining the target malignant lymph node response assessment.
  • a malignant lymph node baseline assessment is taken prior to the first administration of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) or carboplatin or cabazitaxel or docetaxel.
  • a malignant lymph node baseline assessment is taken prior to the first administration of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) or carboplatin or cabazitaxel or docetaxel, and involves: assessing the malignant lymph nodes which have a minimum diameter of at least 15 mm in the short axis by CT, thereby assessing the target malignant lymph nodes; ii) adding the sum of the diameters together of up to 5 of the target malignant lymph nodes, thereby obtaining the target malignant lymph node baseline assessment.
  • the bispecific anti-CTLA4 x anti-PDl antibody e.g., XmAb®20717
  • carboplatin or cabazitaxel or docetaxel e.g., XmAb®20717
  • a malignant lymph node baseline assessment is taken between 28 days and 2 days prior to the first administration of the bispecific anti- CTLA4 x anti-PDl antibody (e.g., XmAb®20717) or carboplatin or cabazitaxel or docetaxel.
  • a malignant lymph node response assessment is taken after the first administration of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) or carboplatin or cabazitaxel or docetaxel.
  • a malignant lymph node response assessment is taken between about 52 days and about 56 days after the first administration of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) or carboplatin or cabazitaxel or docetaxel.
  • the bispecific anti-CTLA4 x anti-PDl antibody e.g., XmAb®20717
  • carboplatin or cabazitaxel or docetaxel e.g., XmAb®20717
  • a visceral lesion response assessment is taken after the first administration of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) or carboplatin or cabazitaxel or docetaxel and involves: i) assessing the diameter of the up to 5 target malignant lymph nodes; ii) adding the sum of the diameters together of up to 5 of the target malignant lymph nodes, thereby obtaining the target malignant lymph node response assessment.
  • a malignant lymph node baseline assessment is taken prior to the first administration of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) or olaparib.
  • a malignant lymph node baseline assessment is taken prior to the first administration of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) or olaparib, and involves: assessing the malignant lymph nodes which have a minimum diameter of at least 15 mm in the short axis by CT, thereby assessing the target malignant lymph nodes; ii) adding the sum of the diameters together of up to 5 of the target malignant lymph nodes, thereby obtaining the target malignant lymph node baseline assessment.
  • the bispecific anti-CTLA4 x anti-PDl antibody e.g., XmAb®20717
  • olaparib involves: assessing the malignant lymph nodes which have a minimum diameter of at least 15 mm in the short axis by CT, thereby assessing the target malignant lymph nodes; ii) adding the sum of the diameters together of up to 5 of the target malignant lymph nodes, thereby obtaining the target malignant lymph node baseline assessment
  • a malignant lymph node baseline assessment is taken between 28 days and 2 days prior to the first administration of the bispecific anti- CTLA4 x anti-PDl antibody (e.g., XmAb®20717) or olaparib.
  • a malignant lymph node response assessment is taken after the first administration of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) or olaparib.
  • a malignant lymph node response assessment is taken between about 52 days and about 56 days after the first administration of the bispecific anti-CTLA4 x anti- PDl antibody (e.g., XmAb®20717) or olaparib.
  • a visceral lesion response assessment is taken after the first administration of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) or olaparib and involves: i) assessing the diameter of the up to 5 target malignant lymph nodes; ii) adding the sum of the diameters together of up to 5 of the target malignant lymph nodes, thereby obtaining the target malignant lymph node response assessment.
  • the bispecific anti-CTLA4 x anti-PDl antibody e.g., XmAb®20717
  • olaparib involves: i) assessing the diameter of the up to 5 target malignant lymph nodes; ii) adding the sum of the diameters together of up to 5 of the target malignant lymph nodes, thereby obtaining the target malignant lymph node response assessment.
  • the positive therapeutic response is achieved against the prostate cancer when there are fewer malignant lymph nodes in the response assessment than in the baseline assessment. In an exemplary embodiment, the positive therapeutic response is achieved against the prostate cancer when the malignant lymph nodes are smaller in the response assessment than in the baseline assessment. In an exemplary embodiment, the positive therapeutic response is achieved when the malignant lymph node response assessment is at least 10%, or at least 20%, or at least 30%, or at least 40%, or at least 50%, or at least 60%, or last 70%, or at least 80%, or at least 90%, or 100% below the malignant lymph node baseline assessment. In an exemplary embodiment, the positive therapeutic response is achieved when the malignant lymph node response assessment is at least 30%, below the malignant lymph node baseline assessment.
  • disease or disease progression following treatment using a methods provided herein is determined based on the Response Evaluation Criteria in Solid Tumors (RECIST 1.1).
  • the objective response rate (ORR) or best observed response (BOR) is determined using RECIST 1.1.
  • progression of a disease of the disclosure is determined based on the RECIST guidelines. The following are selected definitions and tables from Revised RECIST Guidelines (Version 1.1; Eisenhauer et al, Eur J Cancer. 2009; 45:228-47; Chalian et al., Rad One. 2011; 31 :2093- 2105, each of which is herein incorporated by reference in its entirety).
  • visceral lesions can be categorized as measurable or non-measurable as follows:
  • visceral lesions can be accurately measured in at least 1 dimension (longest diameter in the plane of measurement is to be recorded) with a minimum size of:
  • CT computed tomography
  • a lymph node for malignant lymph nodes to be considered pathologically enlarged and measurable, can be > 15 mm in short axis when assessed by CT scan (CT scan slice thickness recommended to be no greater than 5 mm). At baseline and in follow-up, the short axis can be measured and followed.
  • Non-measurable lesions are all other lesions, including
  • Lesions considered truly non-measurable include leptomeningeal disease, ascites, pleural or pericardial effusion, inflammatory breast disease, lymphangitic involvement of skin or lung, and abdominal masses/abdominal organomegaly identified by physical exam that is not measurable by reproducible imaging techniques.
  • target lesions may be identified and assessed for response.
  • the following definitions can be used to determine objective tumor response for target lesions:
  • CR Complete Response
  • Partial Response At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.
  • PD Progressive Disease
  • SD Stable Disease
  • nontarget lesions may actually be measurable, they need not be measured and instead should be assessed only qualitatively at the time points specified in the protocol.
  • tumor response definitions apply to the group of nontarget lesions:
  • CR Complete Response
  • Non-CR/Non-PD Persistence of one or more nontarget lesion(s) and/or maintenance of tumor marker level above the normal limit.
  • the appearance of new malignant lesions denotes disease progression.
  • finding of a new lesion should be unequivocal: i.e., not attributable to differences in scanning technique, change in imaging modality or findings thought to represent something other than tumor (for example, some ‘new’ bone lesions may be simply healing or flare of preexisting lesions). This is particularly important when the subject’s baseline lesions show partial or complete response. For example, necrosis of a liver lesion may be reported on a CT scan report as a ‘new’ cystic lesion, which it is not.
  • a lesion identified on a follow-up study in an anatomical location that was not scanned at baseline is considered a new lesion and will indicate disease progression.
  • An example of this is the subject who has visceral disease at baseline and while on study has a CT or magnetic resonance imaging (MRI) brain ordered which reveals metastases. The subject’s brain metastases are considered to be evidence of PD even if he/she did not have brain imaging at baseline.
  • MRI magnetic resonance imaging
  • the best overall response is the best response recorded from the start of the study treatment until the end of treatment, taking into account any requirement for confirmation. Responses after the termination of study drug may be included in the evaluation as long as the subject has not initiated new anticancer therapy.
  • CR complete response
  • PD progressive disease
  • PR partial response
  • SD stable disease.
  • disease or disease progression is determined based on the Prostate Cancer Working Group Guidelines (PCWG3).
  • PCWG3 Prostate Cancer Working Group Guidelines
  • progression of a disease of the disclosure is determined based on the PCWG3 guidelines. The following are selected definitions and tables from PCWG3 Guidelines (Scher et al. J Clin Oncol. 2016;
  • baseline PSA, bone scan, visceral lesions and lymph nodes can be measured as follows: 4.6.2.1.1 PSA
  • PSA can be measured during screening and at baseline.
  • PSA is monitored through early rises for a minimum of 12 weeks (unless there is other evidence of progression).
  • progression in subjects without PSA reduction from baseline is indicated by a rise in PSA > 25% and > 2 ng/mL above baseline value after 12 weeks of treatment.
  • progression in subjects with PSA reduction from baseline is indicated by a rise in PSA of > 25% and > 2 ng/mL above nadir and confirmed by a second value obtained at least 3 weeks later (z.e., a confirmed rising trend).
  • visceral lesions can be accurately measured in at least one dimension (longest diameter in the plane of measurement is to be recorded) with a minimum size of:
  • CT computed tomography
  • visceral lesions considered truly non-measurable include leptomeningeal disease, ascites, pleural or pericardial effusion, inflammatory breast disease, lymphangitic involvement of skin or lung, abdominal masses/abdominal organomegaly identified by physical exam that is not measurable by reproducible imaging techniques.
  • visceral lesions which do not meet the above size criteria are non-measurable.
  • lymph nodes can be measured in the short axis and recorded as follows:
  • a lymph node should be > 15 mm in short axis when assessed by CT scan (CT scan slice thickness recommended to be no greater than 5 mm). At baseline and in followup, only the short axis is measured and followed.
  • Nodes > 10 mm to ⁇ 15 mm in short axis are pathologic, subject to clinical discretion, and non-measurable.
  • pelvic and extrapelvic lymph nodes are recorded separately, and up to five nodal lesions total are recorded.
  • positivity on bone scan defines metastatic disease to bone.
  • the total number of lesions related to metastatic disease can be recorded.
  • serial PSA measurement can be performed and recorded through the study.
  • treatment should be continued through early rises for a minimum of 12 weeks unless there is other evidence of progression.
  • lymph nodes Pelvic and extrapelvic
  • lung liver
  • adrenal central nervous system sites
  • Progression is defined as at least two new lesions with at least
  • PSA response and measurable disease are being evaluated in this study. Both measurable and non-measurable lesions can be evaluated at each restaging to determine whether they have completely resolved or persisted, or whether new lesions have appeared.
  • subjects can be assessed using the following criteria:
  • CR Complete Response
  • Partial Response At least a 30% decrease in the sum of diameter of target lesions taking as reference the baseline sum diameter
  • PD Progressive Disease
  • CR Complete Response
  • Non-CR/Non-PD Persistence of 1 or more nontarget lesions
  • the bispecific anti-CTLA4 x anti-PDl antibody e.g., XmAb®20717
  • efficacy is assessed in a number of ways as described herein.
  • standard assays of efficacy can be run, such as cancer load, size of tumor, evaluation of presence or extent of metastasis, etc.
  • immunooncology treatments can be assessed on the basis of immune status evaluations as well. This can be done in a number of ways, including both in vitro and in vivo assays. For example, evaluation of changes in immune status along with “old fashioned” measurements such as tumor burden, size, invasiveness, LN involvement, metastasis, etc. can be done.
  • any or all of the following can be evaluated: the inhibitory effects of the checkpoints on CD4+ T cell activation or proliferation, CD8+ T (CTL) cell activation or proliferation, CD8+ T cell- mediated cytotoxic activity and/or CTL mediated cell depletion, NK cell activity and NK mediated cell depletion, the potentiating effects of the checkpoints on Treg cell differentiation and proliferation and Treg- or myeloid derived suppressor cell (MDSC)- mediated immunosuppression or immune tolerance, and/or the effects of the checkpoints on proinflammatory cytokine production by immune cells, e.g., IL-2, IFN-y or TNF-a production by T or other immune cells.
  • CTL CD8+ T
  • CTL CD8+ T cell- mediated cytotoxic activity and/or CTL mediated cell depletion
  • NK cell activity and NK mediated cell depletion the potentiating effects of the checkpoints on Treg cell differentiation and proliferation and Treg- or myeloid
  • assessment of treatment is done by evaluating immune cell proliferation, using for example, CFSE dilution method, Ki67 intracellular staining of immune effector cells, and 3H-Thymidine incorporation method.
  • assessment of treatment is done by evaluating the increase in gene expression or increased protein levels of activation-associated markers, including one or more of: CD25, CD69, CD137, ICOS, PD1, GITR, 0X40, and cell degranulation measured by surface expression of CD 107 A.
  • assessment of treatment is done by assessing cytotoxic activity measured by target cell viability detection via estimating numerous cell parameters such as enzyme activity (including protease activity), cell membrane permeability, cell adherence, ATP production, co-enzyme production, and nucleotide uptake activity.
  • enzyme activity including protease activity
  • cell membrane permeability cell permeability
  • cell adherence cell adherence
  • ATP production co-enzyme production
  • nucleotide uptake activity include, but are not limited to, Trypan Blue or PI staining, 51Cr or 35S release method, LDH activity, MTT and/or WST assays, Calcein-AM assay, Luminescent based assay, and others.
  • assessment of treatment is done by assessing T cell activity measured by cytokine production, measure either intracellularly in culture supernatant using cytokines including, but not limited to, TFNy, TNFa, GM-CSF, IL2, IL6, IL4, IL5, IL10, IL13 using well known techniques.
  • cytokines including, but not limited to, TFNy, TNFa, GM-CSF, IL2, IL6, IL4, IL5, IL10, IL13 using well known techniques.
  • assessment of treatment can be done using assays that evaluate one or more of the following: (i) increases in immune response, (ii) increases in activation of aP and/or y5 T cells, (iii) increases in cytotoxic T cell activity, (iv) increases in NK and/or NKT cell activity, (v) alleviation of aP and/or y5 T-cell suppression, (vi) increases in pro- inflammatory cytokine secretion, (vii) increases in IL-2 secretion; (viii) increases in interferon-y production, (ix) increases in Thl response, (x) decreases in Th2 response, (xi) decreases or eliminates cell number and/or activity of at least one of regulatory T cells (Tregs).
  • T cell activation is assessed using a Mixed Lymphocyte Reaction (MLR) assay as is known in the art.
  • MLR Mixed Lymphocyte Reaction
  • An increase in activity indicates immunostimulatory activity. Appropriate increases in activity are outlined herein.
  • the signaling pathway assay measures increases or decreases in immune response as measured for example by phosphorylation or de-phosphorylation of different factors, or by measuring other post translational modifications.
  • An increase in activity indicates immunostimulatory activity. Appropriate increases in activity are outlined herein.
  • the signaling pathway assay measures increases or decreases in activation of aP and/or y5 T cells as measured for example by cytokine secretion or by proliferation or by changes in expression of activation markers like for example CD 137, CD 107a, PD1, etc.
  • An increase in activity indicates immunostimulatory activity. Appropriate increases in activity are outlined herein.
  • the signaling pathway assay measures increases or decreases in cytotoxic T cell activity as measured for example by direct killing of target cells like for example cancer cells or by cytokine secretion or by proliferation or by changes in expression of activation markers like for example CD137, CD107a, PD1, etc. An increase in activity indicates immunostimulatory activity. Appropriate increases in activity are outlined herein.
  • the signaling pathway assay measures increases or decreases in NK and/or NKT cell activity as measured for example by direct killing of target cells like for example cancer cells or by cytokine secretion or by changes in expression of activation markers like for example CD 107a, etc. An increase in activity indicates immunostimulatory activity. Appropriate increases in activity are outlined herein.
  • the signaling pathway assay measures increases or decreases in aP and/or y5 T-cell suppression, as measured for example by cytokine secretion or by proliferation or by changes in expression of activation markers like for example CD 137, CD 107a, PD1, etc. An increase in activity indicates immunostimulatory activity.
  • the signaling pathway assay measures increases or decreases in pro-inflammatory cytokine secretion as measured, for example, by ELISA or by Luminex or by Multiplex bead based methods or by intracellular staining and FACS analysis or by Alispot, etc.
  • An increase in activity indicates immunostimulatory activity. Appropriate increases in activity are outlined herein.
  • the signaling pathway assay measures increases or decreases in IL-2 secretion as measured for example by ELISA or by Luminex or by Multiplex bead based methods or by intracellular staining and FACS analysis or by Alispot etc. An increase in activity indicates immunostimulatory activity. Appropriate increases in activity are outlined herein.
  • the signaling pathway assay measures increases or decreases in interferon-y production as measured for example by ELISA or by Luminex or by Multiplex bead based methods or by intracellular staining and FACS analysis or by Alispot etc.
  • An increase in activity indicates immunostimulatory activity. Appropriate increases in activity are outlined herein.
  • the signaling pathway assay measures increases or decreases in Thl response as measured for example by cytokine secretion or by changes in expression of activation markers.
  • An increase in activity indicates immunostimulatory activity. Appropriate increases in activity are outlined herein.
  • the signaling pathway assay measures increases or decreases in Th2 response as measured for example by cytokine secretion or by changes in expression of activation markers.
  • An increase in activity indicates immunostimulatory activity. Appropriate increases in activity are outlined herein.
  • the signaling pathway assay measures increases or decreases cell number and/or activity of at least one of regulatory T cells (Tregs), as measured for example by flow cytometry or by IHC. A decrease in response indicates immunostimulatory activity. Appropriate decreases are the same as for increases, outlined herein.
  • the signaling pathway assay measures increases or decreases in M2 macrophages cell numbers, as measured for example by flow cytometry or by IHC. A decrease in response indicates immunostimulatory activity. Appropriate decreases are the same as for increases, outlined herein.
  • the signaling pathway assay measures increases or decreases in M2 macrophage pro-tumorigenic activity, as measured for example by cytokine secretion or by changes in expression of activation markers. A decrease in response indicates immunostimulatory activity. Appropriate decreases are the same as for increases, outlined herein.
  • the signaling pathway assay measures increases or decreases in N2 neutrophils increase, as measured for example by flow cytometry or by IHC. A decrease in response indicates immunostimulatory activity. Appropriate decreases are the same as for increases, outlined herein.
  • the signaling pathway assay measures increases or decreases in N2 neutrophils pro-tumorigenic activity, as measured for example by cytokine secretion or by changes in expression of activation markers. A decrease in response indicates immunostimulatory activity. Appropriate decreases are the same as for increases, outlined herein.
  • the signaling pathway assay measures increases or decreases in inhibition of T cell activation, as measured for example by cytokine secretion or by proliferation or by changes in expression of activation markers like for example CD 137, CD 107a, PD1, etc.
  • An increase in activity indicates immunostimulatory activity. Appropriate increases in activity are outlined herein.
  • the signaling pathway assay measures increases or decreases in inhibition of CTL activation as measured for example by direct killing of target cells like for example cancer cells or by cytokine secretion or by proliferation or by changes in expression of activation markers like for example CD137, CD107a, PD1, etc.
  • An increase in activity indicates immunostimulatory activity. Appropriate increases in activity are outlined herein.
  • the signaling pathway assay measures increases or decreases in aP and/or y5 T cell exhaustion as measured for example by changes in expression of activation markers. A decrease in response indicates immunostimulatory activity.
  • the signaling pathway assay measures increases or decreases aP and/or y5 T cell response as measured for example by cytokine secretion or by proliferation or by changes in expression of activation markers like for example CD 137, CD107a, PD1, etc.
  • An increase in activity indicates immunostimulatory activity. Appropriate increases in activity are outlined herein.
  • the signaling pathway assay measures increases or decreases in stimulation of antigen-specific memory responses as measured for example by cytokine secretion or by proliferation or by changes in expression of activation markers like for example CD45RA, CCR7 etc.
  • An increase in activity indicates immunostimulatory activity. Appropriate increases in activity are outlined herein.
  • the signaling pathway assay measures increases or decreases in apoptosis or lysis of cancer cells as measured for example by cytotoxicity assays such as for example MTT, Cr release, Calcine AM, or by flow cytometry based assays like for example CFSE dilution or propidium iodide staining etc.
  • cytotoxicity assays such as for example MTT, Cr release, Calcine AM
  • flow cytometry based assays like for example CFSE dilution or propidium iodide staining etc.
  • An increase in activity indicates immunostimulatory activity.
  • Appropriate increases in activity are outlined herein.
  • the signaling pathway assay measures increases or decreases in stimulation of cytotoxic or cytostatic effect on cancer cells, as measured for example by cytotoxicity assays such as for example MTT, Cr release, Calcine AM, or by flow cytometry based assays like for example CFSE dilution or propidium iodide staining etc.
  • cytotoxicity assays such as for example MTT, Cr release, Calcine AM
  • flow cytometry based assays like for example CFSE dilution or propidium iodide staining etc.
  • An increase in activity indicates immunostimulatory activity.
  • Appropriate increases in activity are outlined herein.
  • the signaling pathway assay measures increases or decreases direct killing of cancer cells as measured for example by cytotoxicity assays such as for example MTT, Cr release, Calcine AM, or by flow cytometry based assays like for example CFSE dilution or propidium iodide staining etc.
  • cytotoxicity assays such as for example MTT, Cr release, Calcine AM
  • flow cytometry based assays like for example CFSE dilution or propidium iodide staining etc.
  • An increase in activity indicates immunostimulatory activity. Appropriate increases in activity are outlined herein.
  • the signaling pathway assay measures increases or decreases Th 17 activity as measured for example by cytokine secretion or by proliferation or by changes in expression of activation markers. An increase in activity indicates immunostimulatory activity. Appropriate increases in activity are outlined herein.
  • the signaling pathway assay measures increases or decreases in induction of complement dependent cytotoxicity and/or antibody dependent cell-mediated cytotoxicity, as measured for example by cytotoxicity assays such as for example MTT, Cr release, Calcine AM, or by flow cytometry based assays like for example CFSE dilution or propidium iodide staining etc.
  • cytotoxicity assays such as for example MTT, Cr release, Calcine AM
  • flow cytometry based assays like for example CFSE dilution or propidium iodide staining etc.
  • An increase in activity indicates immunostimulatory activity.
  • Appropriate increases in activity are outlined herein.
  • T cell activation is measured for example by direct killing of target cells like for example cancer cells or by cytokine secretion or by proliferation or by changes in expression of activation markers like for example CD137, CD107a, PD1, etc.
  • activation markers like for example CD137, CD107a, PD1, etc.
  • increases in proliferation cell surface markers of activation (e.g., CD25, CD69, CD137, and/or PD1), cytotoxicity (ability to kill target cells), and cytokine production (e.g., IL-2, IL-4, IL-6, IFNy, TNF-a, IL-10, and/or IL-17A) would be indicative of immune modulation that would be consistent with enhanced killing of cancer cells.
  • NK cell activation is measured for example by direct killing of target cells like for example cancer cells or by cytokine secretion or by changes in expression of activation markers like for example CD107a, etc.
  • target cells like for example cancer cells
  • cytokine secretion or by changes in expression of activation markers like for example CD107a, etc.
  • increases in proliferation, cytotoxicity (ability to kill target cells and increases CD 107a, granzyme, and perforin expression), cytokine production (e.g., IFNy and TNF), and cell surface receptor expression (e.g., CD25) would be indicative of immune modulation that would be consistent with enhanced killing of cancer cells.
  • y5 T cell activation is measured for example by cytokine secretion or by proliferation or by changes in expression of activation markers.
  • Thl cell activation is measured for example by cytokine secretion or by changes in expression of activation markers.
  • compositions provided herein find use in prostate cancer applications, generally by inhibiting the suppression of T cell activation (e.g., T cells are no longer suppressed).
  • the bispecific anti-CTLA4 x anti-PDl antibody finds use in the treatment of prostate cancers.
  • a dose has a specific amount of antibody that is administered to a human subject over a defined time period.
  • the amount of antibody administered to a human subject is also known as the dose amount.
  • the time over which the dose amount is administered to a human subject is also known as the administration time.
  • the bispecific anti- CTLA4 x anti-PDl antibody (e.g, XmAb®20717) of the disclosure is administered to the human subject according to a dosage regimen described herein. Dosage regimen are adjusted to provide the optimum desired response (e.g, a therapeutic response).
  • the carboplatin, cabazitaxel, prednisone, and/or the bispecific anti-CTLA4 x anti-PDl antibody are administered to the male human subject according to a dosage regimen described herein.
  • the carboplatin, docetaxel, prednisone, and/or the bispecific anti-CTLA4 x anti-PDl antibody are administered to the male human subject according to a dosage regimen described herein.
  • the olaparib and the bispecific anti-CTLA4 x anti- PDl antibody are administered to the male human subject according to a dosage regimen described herein.
  • the efficient dosages and the dosage regimens for the bispecific anti-CTLA4 x anti-PDl antibody depend on the disease or condition to be treated and may be determined by the persons skilled in the art.
  • the efficient dosages and the dosage regimens for the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717), carboplatin, cabazitaxel, docetaxel, and/or prednisone, depend on the disease or condition to be treated and may be determined by the persons skilled in the art.
  • the efficient dosages and the dosage regimens for the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) and olaparib depend on the disease or condition to be treated and may be determined by the persons skilled in the art.
  • the dose amount may be determined or adjusted by measuring the amount of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) in the blood upon administration, for instance taking out a biological sample and using anti -idiotypic antibodies which target the antigen binding region of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717).
  • the dosage may be determined based upon the weight of the human subject, such as by multiplying the weight (in kg, for example) of the human subject by a dose amount (such as those described herein). Prior to the administering of the first cycle, such as the day before the first dose of the first cycle of administration, the weight of the human subject can be assessed.
  • the dosage is the same in at least two administrations, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, at least ten, or more than at least ten administrations.
  • the body weight of the subject is determined prior to Day 1 of a cycle. In some embodiments, the body weight of the subject is determined prior to Day 1 of a 28 day cycle. In some embodiments, the body weight of the subject is determined prior to Day 1 of each cycle. In some embodiments, the body weight of the subject is determined prior to Day 1 of each 28 day cycle. In some embodiments, the body weight of the subject is determined prior to Day 1 of the first cycle.
  • a subject receives a dose of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) on Day 1 of a cycle based on the body weight determined prior to Day 1 of the cycle.
  • the body weight of the subject affects the dosage of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) to the subject and the dose is adjusted.
  • the subject’s weight changes e.g., changes by 10% or more from baseline or from previous measurement
  • subsequent doses can be provided at the new dose level until such a time that the body weight again requires assignment to the another dose level.
  • subsequent doses may be modified if the human subject’s weight changes by a certain amount (for example, more than by about 5%, more than by about 10%, from the weight assessment prior to the first dose assessment or between any two assessments).
  • the weight of the subject may be recalculated for that infusion day or any subsequent infusion days using the current weight.
  • the bispecific anti-CTLA4 x anti-PDl antibody e.g., XmAb®20717
  • the bispecific anti-CTLA4 x anti-PDl antibody is administered every 2 weeks.
  • the bispecific anti-CTLA4 x anti-PDl antibody e.g., XmAb®20717
  • the bispecific anti-CTLA4 x anti-PDl antibody is administered every week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, or more than 10 weeks.
  • the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) is administered every 5 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, or longer than 30 days.
  • the dose of the bispecific anti-CTLA4 x anti-PDl antibody is determined based on Cmax, AUC, and/or Clast.
  • from about 5 to about 15 mg/kg of the bispecific anti-CTLA4 x anti-PDl antibody is administered to a subject every two weeks.
  • from about 5 mg/kg to about 15 mg/kg of the bispecific anti-CTLA4 x anti- PDl antibody is administered to a subject every two weeks.
  • about 10 mg/kg of the bispecific anti-CTLA4 x anti-PDl antibody is administered to a subject (e.g., every two weeks or every three weeks).
  • 10 mg/kg of the bispecific anti-CTLA4 x anti-PDl antibody e.g., XmAb®20717
  • 10 mg/kg of the bispecific anti-CTLA4 x anti-PDl antibody is administered to a subject (e.g., every two weeks).
  • about 15 mg/kg of the bispecific anti-CTLA4 x anti-PDl antibody is administered to a subject (e.g., every two weeks).
  • the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) is administered to the subject on at a dose of about 10 mg/kg on day 1 of a first 28 day treatment cycle, and at a dose of about 10 mg/kg about every two weeks (Q2W) thereafter.
  • the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) is intravenously administered to the subject at a dose of about 10 mg/kg on day 1 of a first 28 day treatment cycle, and at a dose of about 10 mg/kg about every two weeks (Q2W) thereafter.
  • the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) is administered to the subject according to a 28 day treatment cycle.
  • the bi specific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) is intravenously administered to the subject according to a 28 day treatment cycle.
  • the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) is administered to the subject at a dose of about 10 mg/kg according to a 28 day treatment cycle.
  • the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) is intravenously administered to the subject at a dose of about 10 mg/kg according to a 28 day treatment cycle. In other embodiments of the methods provided herein, the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) is administered to the subject on Day 1 and Day 15 of a first 28 day treatment cycle, and about every two weeks (Q2W) thereafter.
  • Q2W two weeks
  • the bispecific anti- CTLA4 x anti-PDl antibody e.g., XmAb®20717
  • the bispecific anti- CTLA4 x anti-PDl antibody is intravenously administered to the subject on Day 1 and Day 15 of a first 28 day treatment cycle, and about every two weeks (Q2W) thereafter.
  • the bispecific anti- CTLA4 x anti-PDl antibody (e.g., XmAb®20717) is administered to the subject at a dose of about 10 mg/kg according to a 28 day treatment cycle, and the bispecific anti-CTLA4 x anti- PDl antibody (e.g., XmAb®20717) is administered to the subject on day 1 of a first 28 day treatment cycle, and about every two weeks (Q2W) thereafter.
  • the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) is intravenously administered to the subject according to a 28 day treatment cycle, and the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) is intravenously administered to the subject on day 1 of a first 28 day treatment cycle, and about every two weeks (Q2W) thereafter.
  • the bispecific anti-CTLA4 x anti-PDl antibody e.g., XmAb®20717
  • the bispecific anti-CTLA4 x anti-PDl antibody is intravenously administered to the subject at a dose of about 10 mg/kg according to a 28 day treatment cycle
  • the bispecific anti-CTLA4 x anti-PDl antibody e.g., XmAb®20717
  • Q2W every two weeks
  • the intravenous dose of the bispecific anti-CTLA4 x anti-PDl antibody is administered once between about 12 and about 17 days.
  • the intravenous dose of the bispecific anti-CTLA4 x anti-PDl antibody is administered once between about 13 and about 15 days.
  • the intravenous dose of the bispecific anti-CTLA4 x anti-PDl antibody is administered once every 13-15 days.
  • the intravenous dose of the bispecific anti-CTLA4 x anti-PDl antibody is administered once between about 12 and about 16 days. In an exemplary embodiment, the intravenous dose of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) is administered once every 12-16 days. In an exemplary embodiment, the intravenous dose of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) is administered once every 14-16 days. In an exemplary embodiment, the intravenous dose of XmAb®20717 is administered once about every 14 days.
  • the intravenous dose of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) is administered once every 14 days. In an exemplary embodiment, the intravenous dose of XmAb®20717 is administered once about every two weeks. In an exemplary embodiment, the intravenous dose of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) is administered once every two weeks. In an exemplary embodiment, the intravenous dose of XmAb®20717 is administered once between about 13 and about 17 days.
  • the intravenous dose of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) is administered once every 13-17 days. In an exemplary embodiment, the intravenous dose of XmAb®20717 is administered once about every 15 days. In an exemplary embodiment, the intravenous dose of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) is administered once every 15 days.
  • the administering of the intravenous dose to the human subject lasts between about 45 minutes and about 75 minutes. In an exemplary embodiment, the administering of the intravenous dose to the human subject lasts between 45 minutes and 75 minutes. In an exemplary embodiment, the administering of the intravenous dose to the human subject lasts about one hour. In an exemplary embodiment, the administering of the intravenous dose to the human subject lasts one hour.
  • the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) is administered for a time period sufficient to treat the prostate cancer.
  • the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) is administered for a time period sufficient to maintain the treatment of the prostate cancer.
  • the time period is between about 1 and about 9 weeks.
  • the time period is between about 2 and about 7 weeks.
  • the time period is between about 3 and about 9 weeks.
  • the time period is between about 1 and about 8 weeks.
  • the time period is between about 3 and about 5 weeks. In an exemplary embodiment, the time period is about 4 weeks. In an exemplary embodiment, the time period is 4 weeks. In an exemplary embodiment, the time period is between about 7 and about 9 weeks. In an exemplary embodiment, the time period is about 8 weeks. In an exemplary embodiment, the time period is 8 weeks. In an exemplary embodiment, the time period is from about 1 week to about 10 years. In an exemplary embodiment, the time period is from about 1 week to about 9.5 years. In an exemplary embodiment, the time period is from about 1 week to about 9 years. In an exemplary embodiment, the time period is from about 1 week to about 8.5 years. In an exemplary embodiment, the time period is from about 1 week to about 8 years.
  • the time period is from about 1 week to about 7.5 years. In an exemplary embodiment, the time period is from about 1 week to about 7 years. In an exemplary embodiment, the time period is from about 1 week to about 6.5 years. In an exemplary embodiment, the time period is from about 1 week to about 6 years. In an exemplary embodiment, the time period is from about 1 week to about 5.5 years. In an exemplary embodiment, the time period is from about 1 week to about 5 years. In an exemplary embodiment, the time period is from about 1 week to about 4.5 years. In an exemplary embodiment, the time period is from about 1 week to about 4 years. In an exemplary embodiment, the time period is from about 1 week to about 3.5 years.
  • the time period is from about 1 week to about 3 years. In an exemplary embodiment, the time period is from about 1 week to about 2.5 years. In an exemplary embodiment, the time period is from about 1 week to about 2 years. In an exemplary embodiment, the time period is from about 1 week to about 1.5 years. In an exemplary embodiment, the time period is from about 1 week to about 1 year. In an exemplary embodiment, the time period is from about 1 week to about 3 months, or about 4 months, or about 5 months, or about 6 months, or about 7 months, or about 8 months, or about 9 months, or about 10 months or about 11 months. In an exemplary embodiment, the time period is until a positive therapeutic response is achieved. In an exemplary embodiment, the time period is as long as a positive therapeutic response is maintained. In an exemplary embodiment, the time period is until a complete response is achieved.
  • the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) is administered once every 13-16 days (e.g., 14 days or 15 days) for a time period lasting between about 1 and about 9 weeks.
  • the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) is administered once every 13-16 days e.g., 14 days or 15 days) for a time period lasting between about 2 and about 7 weeks.
  • the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) is administered once every 13-15 (e.g., 14 days or 15 days) days for a time period lasting between about 3 and about 9 weeks.
  • the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) is administered once every 13-16 days (e.g., 14 days or 15 days) for a time period lasting between about 1 and about 8 weeks.
  • the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) is administered once every 13-16 days (e.g., 14 days or 15 days) for a time period lasting between about 3 and about 5 weeks.
  • the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) is administered once every 13-16 days (e.g., 14 days or 15 days) for a time period lasting about 4 weeks.
  • the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) is administered once every 13-16 days (e.g., 14 days or 15 days) for a time period lasting 4 weeks.
  • the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) is administered once every 13-16 days (e.g., 14 days or 15 days) for a time period lasting between about 7 and about 9 weeks.
  • the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) is administered once every 13-16 days (e.g, 14 days or 15 days) for a time period lasting about 8 weeks.
  • the bispecific anti-CTLA4 x anti-PDl antibody (e.g, XmAb®20717) is administered once every 13-16 days (e.g., 14 days or 15 days) for a time period lasting 8 weeks.
  • the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) is administered once every 13-16 days (e.g., 14 days or 15 days) for a time period lasting until a positive therapeutic response is achieved.
  • the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) is administered once every 13-16 days (e.g., 14 days or 15 days) for a time period sufficient to treat the prostate cancer.
  • the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) is administered once every 13-16 days (e.g., 14 days or 15 days) for a time period sufficient to maintain the treatment of the prostate cancer.
  • the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) is administered to the subject about every two weeks (Q2W).
  • the bispecific anti-CTLA4 x anti-PDl antibody e.g., XmAb®20717
  • Q2W the bispecific anti-CTLA4 x anti-PDl antibody
  • the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) is administered once every about 14 days or 15 days. In certain embodiments, the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) is administered once every 14 days or 15 days.
  • the dosage may be determined or adjusted by measuring the amount of bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) provided herein in the blood upon administration using techniques known in the art, for instance taking out a biological sample and using anti -idiotypic antibodies which target the antigen binding region of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717).
  • bispecific anti-CTLA4 x anti-PDl antibody e.g., XmAb®20717
  • the intravenous dose of the bispecific anti-CTLA4 x anti-PDl antibody is 10 mg/kg.
  • the intravenous dose bispecific anti- CTLA4 x anti-PDl antibody is 10 mg/kg, wherein the bispecific anti-CTLA4 x anti-PDl antibody comprises a first monomer (or a first polypeptide) comprising SEQ ID NO: 1, a second monomer (or a second polypeptide) comprising SEQ ID NO:2, and a light chain (or a third polypeptide) comprising SEQ ID NO:3.
  • the intravenous dose bispecific anti-CTLA4 x anti-PDl antibody is 10 mg/kg, wherein the bispecific anti-CTLA4 x anti-PDl antibody is XmAb®20717.
  • the intravenous dose of 10 mg/.kg of the bispecific anti-CTLA4 x anti-PDl antibody is administered to the subject once about every two weeks (Q2W).
  • carboplatin is administered at a therapeutically effective dose that results in a target area under the serum concentration-time curve of 3 (AUC3). In some embodiments, carboplatin is administered at a therapeutically effective dose that results in a target area under the serum concentration-time curve of 3 (AUC3) for the first treatment cycle. In some embodiments, carboplatin is administered at a therapeutically effective dose that results in a target area under the serum concentration-time curve of 3 (AUC3) for the first administration of the first treatment cycle. In some embodiments, carboplatin is administered at a therapeutically effective dose that results in a target area under the serum concentrationtime curve of 3 (AUC3) for the first and second administrations of the first treatment cycle. In some embodiments, carboplatin is administered at a therapeutically effective dose that results in a target area under the serum concentration-time curve of 3 (AUC3) for the second administrations of the first treatment cycle.
  • AUC3 serum concentration-time curve of 3
  • carboplatin is administered at a therapeutically effective dose that results in a target area under the serum concentration-time curve of 4 (AUC4). In some embodiments, carboplatin is administered at a therapeutically effective dose that results in a target area under the serum concentration-time curve of 4 (AUC4) for the second treatment cycle. In some embodiments, carboplatin is administered at a therapeutically effective dose that results in a target area under the serum concentration-time curve of 4 (AUC4) for the second treatment cycle and any subsequent treatment cycle. In some embodiments, carboplatin is administered at a therapeutically effective dose that results in a target area under the serum concentration-time curve of 4 (AUC4) for the first administration of the second treatment cycle.
  • AUC4 serum concentration-time curve of 4
  • carboplatin is administered at a therapeutically effective dose that results in a target area under the serum concentration-time curve of 4 (AUC4) for the first administration of the second treatment cycle and any subsequent administration. In some embodiments, carboplatin is administered at a therapeutically effective dose that results in a target area under the serum concentration-time curve of 4 (AUC4) for a treatment cycle that is not the first treatment cycle.
  • AUC4 serum concentration-time curve of 4
  • carboplatin is administered for a maximum of about 8 treatment cycles. In some embodiments, carboplatin is administered on Day 1 of the first treatment cycle and every 3 weeks thereafter. In some embodiments, carboplatin is administered on Day 1 of the first treatment cycle and every 19-23 days thereafter. In some embodiments, carboplatin is administered on Day 1 of the first treatment cycle and every 20- 22 days thereafter. In some embodiments, carboplatin is administered on Day 1 of the first treatment cycle and every 21 days thereafter. In some embodiments, carboplatin is administered every 3 weeks.
  • taxane e.g., carbazitaxel or docetaxel
  • carbazitaxel or docetaxel is administered for a maximum of about 8 treatment cycles.
  • carbazitaxel or docetaxel is administered on Day 1 of the first treatment cycle and every 3 weeks thereafter.
  • carbazitaxel or docetaxel is administered on Day 1 of the first treatment cycle and every 19-23 days thereafter.
  • carbazitaxel or docetaxel is administered on Day 1 of the first treatment cycle and every 20-22 days thereafter.
  • carbazitaxel or docetaxel is administered on Day 1 of the first treatment cycle and every 21 days thereafter.
  • carbazitaxel or docetaxel is administered every 3 weeks.
  • taxane e.g., carbazitaxel or docetaxel
  • carbazitaxel or docetaxel is administered in an amount of between about 10 mg/m 2 and about 55 mg/m 2 , between about 15 mg/m 2 and about 65 mg/m 2 , between about 10 mg/m 2 and about 80 mg/m 2 , between about 10 mg/m 2 and about 100 mg/m 2 ,
  • taxane e.g., carbazitaxel or docetaxel
  • taxane is administered in an amount of about 10 mg/m 2 . In some embodiments taxane (e.g., carbazitaxel or docetaxel) is administered in an amount of about 15 mg/m 2 . In some embodiments, taxane (e.g., carbazitaxel or docetaxel) is administered in an amount of about 20 mg/m 2 . In some embodiments, taxane (e.g., carbazitaxel or docetaxel) is administered in an amount of about 50 mg/m 2 .
  • taxane e.g., carbazitaxel or docetaxel
  • taxane is administered in an amount of about 60 mg/m 2 . In some embodiments, taxane (e.g., carbazitaxel or docetaxel) is administered in an amount of about 65 mg/m 2 . In some embodiments, taxane (e.g., carbazitaxel or docetaxel) is administered in an amount of about 55 mg/m 2 . In some embodiments, taxane (e.g., carbazitaxel or docetaxel) is administered in an amount of about 70 mg/m 2 .
  • taxane e.g., carbazitaxel or docetaxel
  • taxane is administered in an amount of about 75 mg/m 2 .
  • taxane e.g., carbazitaxel or docetaxel
  • taxane is administered in an amount of about 80 mg/m 2 .
  • carbazitaxel is administered in an amount of 15 mg/m 2 .
  • carbazitaxel is administered in an amount of 20 mg/m 2 .
  • docetaxel is administered in an amount of 50 mg/m 2 .
  • docetaxel is administered in an amount of 60 mg/m 2 .
  • docetaxel is administered in an amount of 75 mg/m 2 . In some embodiments, the amount of carbazitaxel or docetaxel is different in the first treatment cycle than in a subsequent treatment cycle. In some embodiments, the amount of carbazitaxel or docetaxel is lower in the first treatment cycle than in a subsequent treatment cycle. In some embodiments, the amount of carbazitaxel or docetaxel is different in the first administration of the first treatment cycle than in a subsequent treatment cycle. In some embodiments, the amount of carbazitaxel or docetaxel is lower in the first administration of the first treatment cycle than in a subsequent treatment cycle.
  • carbazitaxel is administered in an amount of 15 mg/m 2 in a first treatment cycle and 20 mg/m 2 in a subsequent treatment cycle (e.g., second cycle and onwards). In some embodiments, carbazitaxel is administered in an amount of about 15 mg/m 2 in a first treatment cycle and about 20 mg/m 2 in a subsequent treatment cycle. In some embodiments, carbazitaxel is administered in an amount of 15 mg/m 2 in a first administration of the first treatment cycle and 20 mg/m 2 in a subsequent treatment cycle. In some embodiments, carbazitaxel is administered in an amount of about 15 mg/m 2 in a first administration of the first treatment cycle and about 20 mg/m 2 in a subsequent treatment cycle.
  • docetaxel is administered in an amount of 50 mg/m 2 in a first treatment cycle and 60 mg/m 2 in a subsequent treatment cycle. In some embodiments, docetaxel is administered in an amount of about 50 mg/m 2 in a first treatment cycle and about 60 mg/m 2 in a subsequent treatment cycle. In some embodiments, docetaxel is administered in an amount of 50 mg/m 2 in a first administration of the first treatment cycle and 60 mg/m 2 in a subsequent treatment cycle. In some embodiments, docetaxel is administered in an amount of about 50 mg/m 2 in a first administration of the first treatment cycle and about 60 mg/m 2 in a subsequent treatment cycle.
  • the amount of carbazitaxel or docetaxel is the same in the first treatment cycle and in a subsequent treatment cycle. In some embodiments, the amount of carbazitaxel or docetaxel is the same in the first administration of the first treatment cycle and in a subsequent treatment cycle. In some embodiments, carbazitaxel is administered in an amount of 15 mg/m 2 in a treatment cycle. In some embodiments, carbazitaxel is administered in an amount of 15 mg/m 2 in all treatment cycles. In some embodiments, carbazitaxel is administered in an amount of about 15 mg/m 2 in a treatment cycle. In some embodiments, carbazitaxel is administered in an amount of about 15 mg/m 2 in all treatment cycles.
  • carbazitaxel is administered in an amount of 20 mg/m 2 in a treatment cycle. In some embodiments, carbazitaxel is administered in an amount of 20 mg/m 2 in all treatment cycles. In some embodiments, carbazitaxel is administered in an amount of about 20 mg/m 2 in a treatment cycle. In some embodiments, carbazitaxel is administered in an amount of about 20 mg/m 2 in all treatment cycles. In some embodiments, docetaxel is administered in an amount of 50 mg/m 2 in a treatment cycle. In some embodiments, docetaxel is administered in an amount of 50 mg/m 2 in all treatment cycles. In some embodiments, docetaxel is administered in an amount of about 50 mg/m 2 in a treatment cycle.
  • docetaxel is administered in an amount of about 50 mg/m 2 in all treatment cycles. In some embodiments, docetaxel is administered in an amount of 60 mg/m 2 in a treatment cycles. In some embodiments, docetaxel is administered in an amount of 60 mg/m 2 in all treatment cycles. In some embodiments, docetaxel is administered in an amount of about 60 mg/m 2 in a treatment cycle. In some embodiments, docetaxel is administered in an amount of about 60 mg/m 2 in all treatment cycles. In some embodiments, docetaxel is administered in an amount of 75 mg/m 2 in a treatment cycles. In some embodiments, docetaxel is administered in an amount of 75 mg/m 2 in all treatment cycles.
  • docetaxel is administered in an amount of about 75 mg/m 2 in a treatment cycle. In some embodiments, docetaxel is administered in an amount of about 75 mg/m 2 in all treatment cycles. In some embodiments, docetaxel is administered to a subject instead of carbazitaxel if the subject is docetaxel naive or has not been treated with docetaxel prior to the first administration of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) of the disclosure. In some embodiments, carbazitaxel or docetaxel is administered every 3 weeks.
  • olaparib (e.g., 300 mg twice daily; 600 mg per day; between about 400-800 mg per day) is administered to a male subject in combination with the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) of the disclosure.
  • the dose of the olaparib is about, at least about, or at most about 600 mg per day.
  • the dose of the olaparib is 600 mg per day.
  • the dose of the olaparib is 300 mg twice daily.
  • the dose of the olaparib is about, at least about, or at most about 300 mg twice daily.
  • olaparib is administered to a male subject with prostate cancer at a dose of between about 500-700 mg on Day 1 of a first treatment cycle. In some embodiments, olaparib is administered to a male subject with prostate cancer at a dose of between about 500-700 mg on Day 1 of a first treatment cycle and every day thereafter. In some embodiments, olaparib is administered to a male subject with prostate cancer at a dose of between about 500-700 mg daily. In some embodiments, olaparib is administered to a male subject with prostate cancer at a dose of between about 500-700 mg as needed. In some embodiments, olaparib is administered to a male subject with prostate cancer two times a day.
  • olaparib is administered to a male subject with prostate cancer three times a day. In some embodiments, olaparib is administered to a male subject with prostate cancer four times a day. In some embodiments, olaparib is administered to a male subject with prostate cancer at a dose of 300 mg two times a day. In some embodiments, olaparib is administered to a male subject with prostate cancer at a dose of 150 mg four times a day. In some embodiments, olaparib is administered to a male subject with prostate cancer at a dose of 200 mg three times a day. In some embodiments, olaparib is administered daily. In some embodiments, olaparib is not administered every day.
  • olaparib is administered every treatment cycle. In some embodiments, olaparib is administered every day of every treatment cycle. In some embodiments, olaparib is not administered every treatment cycle. In some embodiments, olaparib is not administered every day of every treatment cycle. In some embodiments, olaparib is administered at the same dose at each administration. In some embodiments, olaparib is administered at the same dose at each treatment cycle. In some embodiments, olaparib is administered at the same dose at each day. In some embodiments, olaparib is not administered at the same dose at each administration. In some embodiments, olaparib is not administered at the same dose at each treatment cycle.
  • olaparib is not administered at the same dose at each day. In some embodiments, the dose of olaparib is about 600 mg per day. In some embodiments, the dose of olaparib is 600 mg per day. In some embodiments, the dose of olaparib is lower than 600 mg per day. In some embodiments, the dose of olaparib is higher than 600 mg per day.
  • Dosage regimens are adjusted to provide the optimum desired response (e.g., a therapeutic response). For example, a single bolus may be administered, several divided doses may be administered over time or the dose may be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation.
  • Parenteral compositions may be formulated in dosage unit form for ease of administration and uniformity of dosage.
  • Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the subjects to be treated; each unit contains a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.
  • the bispecific anti-CTLA4 x anti-PDl antibody e.g., XmAb®20717
  • XmAb®20717 is administered intravenously.
  • the XmAb®20717 is administered intravenously.
  • the bispecific anti-CTLA4 x anti-PDl antibody is a front line therapy, second line therapy, third line therapy, fourth line therapy, fifth line therapy, or sixth line therapy.
  • the bispecific anti-CTLA4 x anti-PDl antibody treats a refractory prostate cancer.
  • the bispecific anti- CTLA4 x anti-PDl antibody treats a relapsed prostate cancer.
  • the bispecific anti-CTLA4 x anti-PDl antibody treats a refractory and relapsed prostate cancer.
  • the bispecific anti-CTLA4 x anti-PDl antibody is a maintenance therapy.
  • a medical professional having ordinary skill in the art may readily determine and prescribe the effective amount of the antibody composition required. For example, a physician could start doses of the medicament employed in the antibody composition at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.
  • each dosage regimen comprises at least one dose of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) provided to the human subject (per week, per two weeks, per three weeks, or per month/over a set period of day(s) or week(s)). Dosage regimens are adjusted to provide the optimum desired response (e.g., a positive therapeutic response).
  • the efficient dosages and the dosage regimens for the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) used in the present methods depend on the disease or condition to be treated.
  • the bispecific anti-CTLA4 x anti-PDl antibody is XmAb®20717.
  • the subject receives treatment about every 2 weeks (Q2W) for about two years.
  • Human subjects can be selected based on criteria described herein.
  • the human subject is a male adult human subject.
  • the human subject is a male juvenile human subject.
  • the human subject is 18 years or older.
  • the human subject is between the ages of 18 years and 100 years.
  • the human subject is between the ages of 18 years and 80 years.
  • the human subject is between the ages of 45 years and 90 years.
  • the human subject is between the ages of 45 years and 80 years.
  • the human subject is between the ages of 50 years and 90 years.
  • the human subject is between the ages of 55 years and 85 years. In an exemplary embodiment, the human subject is between the ages of 60 years and 80 years. In an exemplary embodiment, the human subject is between the ages of 60 years and 70 years. In an exemplary embodiment, the human subject is 50 years old or older. In an exemplary embodiment, the human subject is between the ages of 50 years and 70 years. [00323] In an exemplary embodiment, the male human subject has progressive metastatic castration-resistant prostate cancer. In an exemplary embodiment, the male human subject has experienced PSA progression. In an exemplary embodiment, the male human subject is able to provide written informed consent.
  • the male subject has an aggressive variant (anaplastic) adenocarcinoma of the prostate (AVPCa).
  • AVPCa adenocarcinoma of the prostate
  • the male subject has a prostate cancer that has progressed after the male subject received a polyadenosine diphosphate ribose polymerase (PARP) inhibitor.
  • PARP polyadenosine diphosphate ribose polymerase
  • the male subject has not been previously treated with a PARP inhibitor.
  • the male subject has a cancer that does not have a targetable mutation.
  • the male human subject has received at least two systemic therapies prior to the first administration of the anti-CTLA4 x anti-PDl bispecific antibody described herein. In an exemplary embodiment, the male subject has received at least three systemic therapies prior to the first administration of the anti-CTLA4 x anti-PDl bispecific antibody described herein. In an exemplary embodiment, the male subject has been treated with chemotherapy prior to the first administration of the anti-CTLA4 x anti-PDl bispecific antibody described herein. In an exemplary embodiment, the male subject has been treated with radiation therapy prior to the first administration of the anti-CTLA4 x anti- PD1 bispecific antibody described herein.
  • the male human subject has histologically confirmed diagnosis of carcinoma of the prostate.
  • the male human subject has progressive mCRPC based on PSA progression, defined as at least 2 rises in PSA with a minimum of a one week interval.
  • the male human subject has progressive mCRPC based on PSA progression, defined as at least 2 rises in PSA with a minimum of a 1 week interval, wherein 1.0 ng/mL is the minimal starting value if confirmed rise is the only indication of progression.
  • the human subject has progressive mCRPC based on soft-tissue progression per RECIST 1.1.
  • the male human subject has progressive mCRPC based on progression of bone disease (evaluable disease) or 2 or more new bone lesions by bone scan.
  • a checkpoint inhibitor prior to the first occurrence of the dosing regimen, a checkpoint inhibitor had been administered to the human subject.
  • the human subject has received treatment with any cytotoxic T-lymphocyte- associated protein (CTLA4), PD1, PDL1, or programmed cell death ligand 2 (PDL2) directed immunotherapy.
  • CTLA4 cytotoxic T-lymphocyte- associated protein
  • PD1, PDL1, or programmed cell death ligand 2 (PDL2) directed immunotherapy In an exemplary embodiment, the human subject has been administered at least one previous prostate cancer treatment, which was a checkpoint inhibitor. In an exemplary embodiment, the human subject has been administered one previous prostate cancer treatment, which was a checkpoint inhibitor.
  • the human subject has been administered at least two previous prostate cancer treatments, one of which was a checkpoint inhibitor, and the other is not the anti-CTLA4 x anti-PDl bispecific antibody described herein.
  • the human subject has been administered two previous prostate cancer treatments, one of which was a checkpoint inhibitor, and the other is not the anti-CTLA4 x anti-PDl bispecific antibody described herein.
  • the previous prostate cancer treatment is selected from the group consisting of a luteinizing hormone-releasing hormone analog, a taxane, a platinum chemotherapeutic, an androgen receptor signaling inhibitor, a bone-targeting radionuclide, sipuleucel-T, and a checkpoint inhibitor antibody.
  • the human subject has progressive mCRPC based on progression after treatment with at least 2 prior lines of anticancer therapy approved for treatment of metastatic prostate cancer.
  • a PARP inhibitor prior to the first occurrence of the dosing regimen, a PARP inhibitor has been administered to the human subject.
  • a PARP inhibitor prior to the first occurrence of the dosing regimen, a PARP inhibitor has been administered to the human subject, and the human subject has progressed.
  • the human subject has been administered at least one previous prostate cancer treatment, which is not the carboplatin, the cabazitaxel, the prednisone, or the anti-CTLA4 x anti-PDl bispecific antibody described herein.
  • the male human subject has been administered one previous prostate cancer treatment, which is not the carboplatin, the cabazitaxel, the prednisone, or the anti-CTLA4 x anti-PDl bispecific antibody described herein.
  • the male human subject has been administered at least two previous prostate cancer treatments, neither of which are the carboplatin, the cabazitaxel, the prednisone, or the anti-CTLA4 x anti-PDl bispecific antibody described herein.
  • the male human subject has been administered two previous prostate cancer treatments, neither of which are the carboplatin, the cabazitaxel, the prednisone, or the anti-CTLA4 x anti-PDl bispecific antibody described herein.
  • the previous prostate cancer treatment is selected from the group consisting of a luteinizing hormone-releasing hormone analog, a taxane, a platinum chemotherapeutic, an androgen receptor signaling inhibitor, a bone-targeting radionuclide, sipuleucel-T, and a checkpoint inhibitor antibody.
  • the male human subject has progressive mCRPC based on progression after treatment with at least 2 prior lines of anticancer therapy approved for treatment of metastatic prostate cancer.
  • the male human subject has progressive mCRPC based on progression after treatment with at least 3 prior lines of anticancer therapy approved for treatment of metastatic prostate cancer. In an exemplary embodiment, the male human subject has progressive mCRPC based on progression after treatment with at least 4 prior lines of anticancer therapy approved for treatment of metastatic prostate cancer.
  • a PARP inhibitor prior to the first occurrence of the dosing regimen, a PARP inhibitor had not been administered to the male human subject.
  • the male human subject has been administered at least one previous prostate cancer treatment, which is neither the olaparib nor the anti-CTLA4 x anti-PDl bispecific antibody described herein.
  • the male human subject has been administered one previous prostate cancer treatment, which is neither the olaparib nor the anti-CTLA4 x anti-PDl bispecific antibody described herein.
  • the male human subject has been administered at least two previous prostate cancer treatments, neither of which are the olaparib or the anti-CTLA4 x anti-PDl bispecific antibody described herein.
  • the male human subject has been administered two previous prostate cancer treatments, neither of which are the olaparib or the anti-CTLA4 x anti-PDl bispecific antibody described herein.
  • the previous prostate cancer treatment is selected from the group consisting of a luteinizing hormone-releasing hormone analog, a taxane, a platinum chemotherapeutic, an androgen receptor signaling inhibitor, a bone-targeting radionuclide, sipuleucel-T, and a checkpoint inhibitor antibody.
  • the male human subject has progressive mCRPC based on progression after treatment with at least 2 prior lines of anticancer therapy approved for treatment of metastatic prostate cancer.
  • the previous prostate cancer treatment is a luteinizing hormone-releasing hormone analog which is a luteinizing hormone-releasing hormone agonist.
  • the luteinizing hormone-releasing hormone agonist is a peptide.
  • the luteinizing hormone-releasing hormone agonist is azagly-nafarelin, buserelin, deslorelin, fertirelin, GnRH, gonadorelin, goserelin, histrelin, lecirelin, leuprorelin, nafarelin, peforelin, or triptorelin.
  • the luteinizing hormone-releasing hormone agonist is buserelin, goserelin, histrelin, leuprorelin, or triptorelin.
  • the previous prostate cancer treatment is a luteinizing hormone-releasing hormone analog which is a luteinizing hormone-releasing hormone antagonist.
  • the luteinizing hormone-releasing hormone antagonist is a peptide.
  • the luteinizing hormone-releasing hormone antagonist is abarelix, cetrorelix, degarelix, ganirelix, or ozarelix.
  • the luteinizing hormone-releasing hormone antagonist is degarelix.
  • the luteinizing hormone-releasing hormone antagonist is not a peptide.
  • the luteinizing hormone-releasing hormone antagonist is elagolix, linzagolix, opigolix, relugolix, or sufugolix.
  • a previous prostate cancer treatment is a platinum chemotherapeutic.
  • the platinum chemotherapeutic is carboplatin, cisplatin, or oxaliplatin.
  • a previous prostate cancer treatment is an androgen receptor signaling inhibitor (ARSI).
  • ARSI is a first generation ARSI.
  • the first generation ARSI is bicalutamide or flutamide.
  • the ARSI is abiraterone, enzalutamide, apalutamide or darolutamide.
  • a previous prostate cancer treatment is a bonetargeting radionuclide.
  • the bone-targeting radionuclide is radium-223.
  • the bone-targeting radionuclide is radium-223 chloride.
  • a previous prostate cancer treatment is sipuleucel-T.
  • a previous prostate cancer treatment is a checkpoint inhibitor antibody.
  • the checkpoint inhibitor antibody is an anti-PDl antibody, an anti-CTLA4 antibody, or an anti-LAG3 antibody.
  • the human subject has recovered from any toxicity related to previous anticancer treatment to ⁇ Grade 2.
  • the human subject is on androgen suppression treatment (e.g., luteinizing hormone-releasing hormone agonist) with castrate level of testosterone ( ⁇ 50 ng/dL).
  • the human subject is on androgen suppression treatment (e.g., luteinizing hormone-releasing hormone agonist) with castrate level of testosterone ( ⁇ 50 ng/dL) and be willing to continue such treatment.
  • the human subject has had a surgical orchiectomy.
  • the male human subject has had a surgical orchiectomy, and is not on androgen suppression treatment (e.g., luteinizing hormone-releasing hormone agonist).
  • the human subject has not had a surgical orchiectomy.
  • the human subject has not had a surgical orchiectomy and is on androgen suppression treatment (e.g., luteinizing hormone- releasing hormone agonist).
  • the human subject has a previously treated brain metastases which is radiologically stable (i.e., are without evidence of progression for at least 4 weeks by repeat imaging (note that the repeat imaging should be performed during study screening), are clinically stable, and are without requirement of steroid treatment for at least 14 days prior to first dose of study treatment.
  • the human subject has had a histologically confirmed diagnosis of a prostate cancer described herein, methods of screening for which are known in the art.
  • the human subject has been diagnosed with a MS H and/or MMRD positive cancer, methods of screening for which are known in the art.
  • the human subject has been diagnosed with a HRD/CDK12 mutation positive prostate cancer, methods of screening for which are known in the art.
  • the human subject has been diagnosed with a prostate cancer which is positive for biallelic loss of CDK12, methods of screening for which are known in the art.
  • the human subject has been diagnosed with a prostate cancer which is HRD positive in at least one gene selected from the group consisting of BRCA1, BRCA2, ATM, PALB2, CHEK2, and FANCA, methods of screening for which are known in the art.
  • the human subject has been diagnosed with a prostate cancer which does not have a targetable mutation, methods of screening for which are known in the art.
  • the human subject has been diagnosed with a prostate cancer which is an aggressive variant prostate cancer, methods of screening for which are known in the art.
  • the human subject has evaluable disease according to Prostate Cancer Working Group (PCWG3) Guidelines.
  • PCWG3 Prostate Cancer Working Group
  • 0 Normal activity— Fully active, able to carry on
  • the human subject has adequate archival metastatic tumor tissue.
  • the human subject agrees to undergo a biopsy of at least 1 metastatic site.
  • the human subject agrees to undergo a fresh biopsy of primary prostate.
  • the human subject agrees to undergo a fresh biopsy of primary prostate, however, such a fresh biopsy is possible if there is clear local disease and no other measurable disease site or biopsiable bone lesion.
  • the human subject is taking prednisone from a previous prostate cancer therapy.
  • the human subject is hepatitis C virus [HCV] antibody positive but HCV RNA negative due to documented, curative prior antiviral treatment or natural resolution.
  • the human subject whose HBsAg is negative and HBcAb is positive may be treated if a hepatitis B virus [HBV] DNA test is negative and the human subject is retested for HBsAg and HBV DNA every 2 months.
  • HBV hepatitis B virus
  • the human subject is not currently receiving anticancer therapies other than androgen deprivation therapy.
  • the human subject has not received treatment with any other anticancer therapy (i.e., other immunotherapy, chemotherapy, radiation therapy, etc.) within 2 weeks of the first administration of the first occurrence of the dosing regimen.
  • the human subject has not received treatment with any cytotoxic T-lymphocyte-associated protein (CTLA4), PD1, PDL1, or programmed cell death ligand 2 (PDL2) directed immunotherapy.
  • CTLA4 cytotoxic T-lymphocyte-associated protein
  • PD1, PDL1, or programmed cell death ligand 2 (PDL2) directed immunotherapy directed immunotherapy.
  • the human subject does not have known active central nervous system metastases and/or carcinomatous meningitis.
  • the human subject does not have a Platelet count ⁇ 100 * 10 9 /L. In an exemplary embodiment, the human subject does not have a Hemoglobin level ⁇ 9.0 g/dL. In an exemplary embodiment, the human subject does not have an absolute neutrophil count ⁇ 1.7 x io 9 for subjects who receive cabazitaxel; ⁇ 1.0 * 10 9 /L for all others. In an exemplary embodiment, the human subject does not have an aspartate aminotransferase at screening > 3 x upper limit of normal (ULN) for subjects without known liver involvement by tumor or > 5 x ULN for subjects with known liver involvement by tumor.
  • UPN upper limit of normal
  • the human subject does not have an alanine aminotransferase at screening > 3 x ULN for subjects without known liver involvement by tumor or > 5 x ULN for subjects with known liver involvement by tumor.
  • the human subject does not have bilirubin > 1.5 x ULN (unless prior diagnosis and documentation of ongoing hemolysis or Gilbert’s syndrome has been made).
  • the human subject does not have an estimated creatinine clearance ⁇ 50 mL/minute calculated by the Cockcroft Gault or Modification of Diet in Renal Disease formulas.
  • the human subject does not have active known or suspected autoimmune disease (except vitiligo; type 1 diabetes mellitus or residual hypothyroidism due to an autoimmune condition that is treatable with hormone replacement therapy only; psoriasis, atopic dermatitis, or another autoimmune skin condition that is managed without systemic therapy; or arthritis that is managed without systemic therapy beyond oral acetaminophen and nonsteroidal anti-inflammatory drugs).
  • active known or suspected autoimmune disease except vitiligo; type 1 diabetes mellitus or residual hypothyroidism due to an autoimmune condition that is treatable with hormone replacement therapy only; psoriasis, atopic dermatitis, or another autoimmune skin condition that is managed without systemic therapy; or arthritis that is managed without systemic therapy beyond oral acetaminophen and nonsteroidal anti-inflammatory drugs).
  • the human subject does not have a condition requiring systemic treatment with corticosteroids, prednisone equivalents, or other immunosuppressive medications within 14 days prior to first dose of the anti-CTLA4 x anti-PDl bispecific antibody described herein (except inhaled or topical corticosteroids or brief courses of corticosteroids given for prophylaxis of contrast dye allergic response).
  • the human subject does not have a condition requiring systemic treatment with corticosteroids, prednisone equivalents, or other immunosuppressive medications within 14 days prior to first dose of the carboplatin, the cabazitaxel, the prednisone, or the anti-CTLA4 x anti-PDl bispecific antibody described herein (except inhaled or topical corticosteroids or brief courses of corticosteroids given for prophylaxis of contrast dye allergic response).
  • the human subject does not have a condition requiring systemic treatment with corticosteroids, prednisone equivalents, or other immunosuppressive medications within 14 days prior to first dose of olaparib or the anti-CTLA4 x anti-PDl bispecific antibody described herein (except inhaled or topical corticosteroids or brief courses of corticosteroids given for prophylaxis of contrast dye allergic response).
  • the human subject has not received an organ allograft.
  • the human subject does not have known history of left ventricular ejection fraction ⁇ 40%.
  • the human subject does not have a history or evidence of any other clinically unstable/uncontrolled disorder, condition, or disease other than their primary malignancy that would pose a risk to patient safety or interfere with study evaluations, procedures, or completion.
  • the human subject does not have evidence of any serious bacterial, viral, parasitic, or systemic fungal infections within the 30 days prior to the first dose of the anti-CTLA4 x anti-PDl bispecific antibody described herein.
  • the human subject has not received a live- virus vaccine within 30 days prior to the first dose of the anti-CTLA4 x anti-PDl bispecific antibody described herein, with the exception of seasonal flu vaccines that do not contain live virus.
  • the human subject does not have evidence of any serious bacterial, viral, parasitic, or systemic fungal infections within the 30 days prior to the first dose of the carboplatin, the cabazitaxel, the prednisone, or the anti-CTLA4 x anti-PDl bispecific antibody described herein.
  • the human subject has not received a live-virus vaccine within 30 days prior to the first dose of the carboplatin, the cabazitaxel, the prednisone, or the anti-CTLA4 x anti-PDl bispecific antibody described herein, with the exception of seasonal flu vaccines that do not contain live virus.
  • the human subject does not have evidence of any serious bacterial, viral, parasitic, or systemic fungal infections within the 30 days prior to the first dose of olaparib or the anti-CTLA4 x anti-PDl bispecific antibody described herein.
  • the human subject has not received a live-virus vaccine within 30 days prior to the first dose of olaparib or the anti-CTLA4 x anti-PDl bispecific antibody described herein, with the exception of seasonal flu vaccines that do not contain live virus.
  • the human subject is not human immunodeficiency virus (HIV) positive subject with CD4+ T-cell (CD4+) counts ⁇ 350 cells/pL.
  • HIV human immunodeficiency virus
  • the human subject does not have an HIV viral load greater than 400 copies/mL. In an exemplary embodiment, the human subject does not have a history of an AIDS (acquired immunodeficiency syndrome)-defining opportunistic infection within the past 12 months. In an exemplary embodiment, the human subject has not been on established antiretroviral therapy (ART) for at least 4 weeks prior to initiation of study drug dosing. (Effective ART is defined as a drug, dosage, and schedule associated with reduction and control of the viral load.). In an exemplary embodiment, the human subject has not had a positive test for hepatitis C RNA. In an exemplary embodiment, the human subject has not had a positive test for hepatitis B surface antigen (HBsAg) or hepatitis B core antibody (HBcAb).
  • HBsAg hepatitis B surface antigen
  • HBcAb hepatitis B core antibody
  • Blood samples can be collected from a human subject using any method known in the art, e.g., by venipuncture or fingerstick. Particular types of blood cells can be isolated, expanded, frozen, and used at a later time. Tissue samples can be obtained from a human subject using any method known in the art, e.g., by biopsy or surgery. CT imaging, ultrasound, or an endoscope can be used to guide this type of procedure. The sample may be flash frozen and stored at -80°C for later use. The sample may also be fixed with a fixative, such as formaldehyde, paraformaldehyde, or acetic acid/ethanol. RNA or protein may be extracted from a fresh, frozen or fixed sample for analysis.
  • a fixative such as formaldehyde, paraformaldehyde, or acetic acid/ethanol.
  • kits comprising a bispecific anti-PDl x CTLA4 antibody, and instructions for administering said bispecific antibody to a subject.
  • a kit comprising a bispecific anti-PDl x CTLA4 antibody, and instructions for use of said bispecific antibody in the treatment of a prostate cancer in a male human subject.
  • the instructions provide that the bispecific antibody is administered to the subject according to a 28 day treatment cycle at a dose of about 10 mg/kg, wherein the dose of the bispecific antibody is intravenously administered to the subject on day 1 of a first 28 day treatment cycle and about every two weeks (Q2W) thereafter.
  • the bispecific antibody comprises a first monomer (or first polypeptide) comprising SEQ ID NO: 1, a second monomer (or second polypeptide) comprising SEQ ID NO:2, and a light chain (or third polypeptide)comprising SEQ ID NO:3.
  • the instructions provide that the subject receive treatment about every 2 weeks (Q2W) for about two years.
  • kits comprising a bispecific anti-PDl x CTLA4 antibody, and instructions for use of said bispecific antibody in the treatment of an aggressive variant (anaplastic) adenocarcinoma of the prostate (AVPCa) in a male human subject.
  • the instructions provide that the bispecific antibody is administered to the subject according to a 28 day treatment cycle at a dose of about 10 mg/kg, wherein the dose of the bispecific antibody is intravenously administered to the subject on day 1 of a first 28 day treatment cycle and about every two weeks (Q2W) thereafter.
  • the bispecific antibody comprises a first monomer (or first polypeptide) comprising SEQ ID NO: 1, a second monomer (or second polypeptide) comprising SEQ ID NO:2, and a light chain (or third polypeptide)comprising SEQ ID NO:3.
  • the instructions further provide that: (a) carboplatin is administered at a therapeutically effective dose that results in a target area under the serum concentration-time curve of 3 (AUC3) in the subject, wherein the dose of the carboplatin is intravenously administered to the subject on day 1 of the first treatment cycle and about three weeks (Q3W) after day 1; (b) cabazitaxel is administered at a dose of about 15 mg/m 2 , wherein the dose of the cabazitaxel is intravenously administered to the subject on day 1 of the first treatment cycle and about three weeks (Q3W) after day 1; (c) carboplatin is administered at a therapeutically effective dose that results in a target area under the serum concentration-time curve of 4 (AUC4) in the subject after cycle 1 is completed or starting on cycle 2 and every 3 weeks thereafter (Q3W); and (d) cabazitaxel is administered at a dose of about 20 mg/m 2 , wherein the dose of the cabazitaxel is
  • the instructions further provide that a steroid is orally administered to the subject.
  • the steroid is prednisone, and the instructions provide that the steroid is administered at a dose of about 5 mg twice per day (b.i.d.) on day 1 of the first treatment cycle, and about twice per day (b.i.d.) thereafter.
  • the cancer has a mutation or other aberrancy in at least two genes independently selected from the group consisting of Rbl, TP53 and PTEN.
  • the subject receives more than one 28 day treatment cycle. In some embodiments, the subject receives up to twenty -four 28 day treatment cycles.
  • kits comprising a bispecific anti-PDl x CTLA4 antibody, and instructions for use of said bispecific antibody in the treatment of an aggressive variant (anaplastic) adenocarcinoma of the prostate (AVPCa) in a male human subject, wherein the subject has not previously been administered docetaxel, and wherein the instructions provide that the bispecific antibody is administered to the subject according to a 28 day treatment cycle at a dose of about 10 mg/kg, wherein the dose of the bispecific antibody is intravenously administered to the subject on day 1 of a first 28 day treatment cycle and about every two weeks (Q2W) thereafter.
  • the instructions provide that the bispecific antibody is administered to the subject according to a 28 day treatment cycle at a dose of about 10 mg/kg, wherein the dose of the bispecific antibody is intravenously administered to the subject on day 1 of a first 28 day treatment cycle and about every two weeks (Q2W) thereafter.
  • the bispecific antibody comprises a first monomer (or first polypeptide) comprising SEQ ID NO: 1, a second monomer (or second polypeptide) comprising SEQ ID NO:2, and a light chain (or third polypeptide)comprising SEQ ID NO:3.
  • the instructions further provide that: (a) carboplatin is administered at a therapeutically effective dose that results in a target area under the serum concentration-time curve of 3 (AUC3) in the subject, wherein the dose of the carboplatin is intravenously administered to the subject on day 1 of the first treatment cycle and about three weeks (Q3W) after day 1; (b) docetaxel is administered at a dose of about 50 mg/m 2 , wherein the dose of the docetaxel is intravenously administered to the subject on day 1 of the first treatment cycle and about three weeks (Q3W) after day 1; (c) carboplatin is administered at a therapeutically effective dose that results in a target area under the serum concentration-time curve of 4 (AUC4) in the subject after cycle 1 is completed or starting on cycle 2 and every 3 weeks thereafter (Q3W); and (d) docetaxel is administered at a dose of about 60 mg/m 2 , wherein the dose of the docetaxel is intravenously administered to the subject after cycle 1 is completed
  • the instructions further provide that a steroid is orally administered to the subject.
  • the steroid is prednisone, and the instructions provide that the steroid is administered at a dose of about 5 mg twice per day (b.i.d.) on day 1 of the first treatment cycle, and about twice per day (b.i.d.) thereafter.
  • the cancer has a mutation or other aberrancy in at least two genes independently selected from the group consisting of Rbl, TP53 and PTEN.
  • the subject receives more than one 28 day treatment cycle. In some embodiments, the subject receives up to twenty -four 28 day treatment cycles.
  • kits comprising a bispecific anti-PDl x CTLA4 antibody, and instructions for use of said bispecific antibody in the treatment of a prostate cancer in a male human subject in need thereof, wherein the instructions provide that the bispecific antibody is administered to the subject according to a 28 day treatment cycle at a dose of about 10 mg/kg, wherein the dose of the bispecific antibody is intravenously administered to the subject on day 1 of a first 28 day treatment cycle and about every two weeks (Q2W) thereafter.
  • Q2W two weeks
  • the bispecific antibody comprises a first monomer (or first polypeptide) comprising SEQ ID NO: 1, a second monomer (or second polypeptide) comprising SEQ ID NO:2, and a light chain (or third polypeptide) comprising SEQ ID NO:3.
  • the instructions further provide that: (a) cabazitaxel is administered at a dose of about 20 mg/m 2 , wherein the dose of the cabazitaxel is intravenously administered to the subject on day 1 of the first treatment cycle and about every three weeks (Q3W) thereafter.
  • the instructions further provide that a steroid is administered to the subject.
  • the steroid is prednisone, and the instructions provide that the steroid is administered at a dose of about 5 mg twice per day (b.i.d.) on day 1 of the first treatment cycle, and about twice per day (b.i.d.) thereafter.
  • kits comprising a bispecific anti-PDl x CTLA4 antibody, and instructions for use of said bispecific antibody in the treatment of a prostate cancer in a male human subject in need thereof, wherein the subject has not previously been administered docetaxel, and wherein the instructions provide that the bispecific antibody is administered to the subject according to a 28 day treatment cycle at a dose of about 10 mg/kg, wherein the dose of the bispecific antibody is intravenously administered to the subject on day 1 of a first 28 day treatment cycle and about every two weeks (Q2W) thereafter.
  • Q2W two weeks
  • the bispecific antibody comprises a first monomer (first polypeptide) comprising SEQ ID NO: 1, a second monomer (second polypeptide) comprising SEQ ID NO:2, and a light chain (third polypeptide) comprising SEQ ID NO:3.
  • the instructions further provide that: (a) docetaxel is administered at a dose of about 60 mg/m 2 wherein the dose of the docetaxel is intravenously administered to the subject on day 1 of the first treatment cycle and about every three weeks (Q3W) thereafter.
  • the instructions further provide that a steroid is administered to the subject.
  • the steroid is prednisone, and the instructions provide that the steroid is administered at a dose of about 5 mg twice per day (b.i.d.) on day 1 of the first treatment cycle, and about twice per day (b.i.d.) thereafter.
  • the subject has received prior treatment with a polyadenosine diphosphate ribose polymerase (PARP) inhibitor.
  • PARP polyadenosine diphosphate ribose polymerase
  • the cancer has a homologous recombination deficiency (HRD).
  • the cancer has a biallelic loss of cyclin-dependent kinase 12 (CDK12).
  • the cancer does not have a targetable mutation.
  • kits comprising a bispecific anti-PDl x CTLA4 antibody, and instructions for use of said bispecific antibody in the treatment of a prostate cancer in a male human subject in need thereof, wherein the subject has not previously been administered a PARP inhibitor, and wherein the instructions provide that the bispecific antibody is administered to the subject according to a 28 day treatment cycle at a dose of about 10 mg/kg, wherein the dose of the bispecific antibody is intravenously administered to the subject on day 1 of a first 28 day treatment cycle and about every two weeks (Q2W) thereafter.
  • Q2W two weeks
  • the bispecific antibody comprises a first monomer (first polypeptide) comprising SEQ ID NO: 1, a second monomer (second polypeptide) comprising SEQ ID NO:2, and a light chain (third polypeptide) comprising SEQ ID NO:3.
  • the instructions further provide that olaparib is administered at a dose of about 300 mg twice a day.
  • the instructions provide that the dose of the olaparib is orally administered twice per day (b.i.d.) to the subject on day 1 of the first treatment cycle, and about twice per day (b.i.d.) thereafter.
  • the cancer has a homologous recombination deficiency (HRD).
  • the cancer has a biallelic loss of cyclin-dependent kinase 12 (CDK12).
  • MTD/RD Maximum Tolerated Dose and/or Recommended Dose
  • XmAb®20717 is a humanized bsAb that binds both PD1 and CTLA4.
  • XmAb®20717 pharmaceutical composition is a sterile liquid supplied in single-use glass vials. Each 10 mL vial is filled with 10.5 mL of pharmaceutical composition containing 10.0 ⁇ 1.0 mg/mL of XmAb®20717, in 20 mM histidine, 250 mM sorbitol, and 0.01% (w/v) polysorbate-80 at pH 6.2. Each product vial is intended to deliver 10.0 mL of drug solution. [00355] Prior to administration, XmAb®20717 is diluted to the final required concentration in an ethylene/polypropylene copolymer infusion bag containing 0.9% Sodium Chloride Injection, USP. After dilution, the bag containing XmAb®20717 should be gently inverted 2 to 3 times to mix the solution. The bag should not be shaken.
  • XmAb®20717 administration should begin as soon as possible after the dosing solution is made. If there is a delay in administration, the dosing solution may be stored at 2 - 8 °C for no more than 24 hours or at room temperature for no more than 4 hours prior to infusion. The full-calculated dose is administered based on the subject’s actual baseline weight measurement in kilograms. Following the first dose, subsequent doses are modified only if the subject’s weight changes by more than 10% from the Day -1 weight, at which point it is recalculated using the current weight. In Part A of the study, subjects were enrolled into escalating dose cohorts to establish an MTD/RD(s) for a dosing regimen consisting of infusions on Days 1 and 15 of each 28-day cycle.
  • the decision to escalate to higher-dose cohorts proceeds according to the Dose Escalation Plan, and the final decision to escalate to a higher dose level is based on review of the aggregate safety data for all subjects through Cycle 1 Day 28.
  • the first subject in the cohort was dosed and observed for a minimum of 24 hours before study drug was administered to the remainder of the cohort. All subjects were assessed for the development of dose-limiting toxicity (DLT) during treatment with XmAb®20717.
  • the assessment period is defined as: Cycle 1, Days 1 to 28.
  • Part B of the study began once the MTD/RD(s) and dosing regimen were established. In Part B, additional subjects with advanced melanoma (excluding uveal), renal cell carcinoma (clear cell predominant type), and non-small cell lung carcinoma are enrolled into disease-specific expansion cohorts of up to 20 subjects each.
  • Each subject was administered XmAb®20717 IV at a constant infusion rate over 1 hour.
  • the initial treatment period for each subject in this study was 2 cycles. Each cycle was 28 days long and consisted of 2 doses of XmAb®20717, on Days 1 and 15.
  • Six dose levels were planned for the dose-escalation phase of the study (Part A). The dose levels are: 0.15, 0.3, 1.0, 3.0, 6.0, and 10.0 mg/kg.
  • a subject’s first dose was based on the Day -1 baseline weight in kilograms. Subsequent doses were modified only if the subject’s weight changed by more than 10% from the Day -1 weight, at which point the dose was recalculated using the subject’s current weight. That dose was continued for the remainder of the trial, unless there was a subsequent 10% weight change.
  • a minimum of 3 subjects were enrolled in each dose-escalation cohort. No 2 subjects within a cohort started treatment with XmAb®20717 on the same day; the first subject was dosed and observed for a minimum of 24 hours before study drug was administered to the remainder of the cohort. All subjects were assessed for the development of dose-limiting toxi cities (DLT) during treatment with XmAb®20717. If none of the first 3 subjects experienced a DLT during the period, escalation to the next dosing level occurred. If any of the first 3 subjects in a dosing cohort experienced a DLT during the period, the cohort was expanded to a total of 6 human subjects or until a second subject in the cohort experienced a DLT.
  • DLT dose-limiting toxi cities
  • Results As of Feb 5, 2020, 34 patients were treated in cohorts 1-6 at fixed doses of 0.15 to 10 mg/kg. Patients had a median age of 57 years (range 32-81), a median time since initial diagnosis of 42 months (range 3 -313) and a median of 4 prior systemic therapies (range 0-9). 68% of patients had a TNM stage of III/ IV and 68% had been exposed to checkpoint therapy.
  • XmAb®20717 treatment was generally well-tolerated through the highest dose cohort tested. Overall rates of Gr3/4 immune-related AEs occurred in 8 (24%) patients including elevations of transaminases 3 (9%), rash 2 (6%), lipase and amylase 1 (3%, without clinical symptoms or radiographic evidence of pancreatitis), lipase (alone) 1 (3%), pruritus 1 (3%), hyperglycemia 1 (3%), arthritis 1 (3%) and colitis 1 (3%), all reversible.
  • Dual PD-l/CTLA-4 blockade has been previously shown to improve outcomes in patients with mCRPC relative to those observed for agents directed at a single checkpoint (Sharma P, et al. Cancer Cell. 2020;38:489-499).
  • Additional strategies to optimize response to immune checkpoint inhibitor (ICI) therapy in patients with mCRPC include: 1) selection of patients with tumors with molecular characteristics that sensitize to ICIs, such as those associated with aggressive variant disease (Lee L, et al. JCO Precis Oncol. 2018: 1-8;
  • Vudalimab (XmAb®20717) is a humanized bispecific monoclonal antibody that simultaneously targets PD-1 and CTLA4, and binds preferentially to PD1/CTLA4 dualpositive cells.
  • XmAb®20717 was associated with complete and partial responses in tumor types typically responsive to single-agent immune checkpoint inhibitor (ICI) therapy (e.g., melanoma, RCC, and NSCLC), as well as those that are not typically responsive to single-agent checkpoint inhibition (e.g., mCRPC and ovarian cancer).
  • ICI immune checkpoint inhibitor
  • mCRPC mCRPC and ovarian cancer
  • potent antitumor immune response was observed in an mCRPC patient with partial response following treatment with XmAb®20717 10 mg/kg Q2W.
  • Multiplex immunofluorescence staining of paired pre-treatment and posttreatment biopsies demonstrated increases in cellular immunity (CD8+ T cells), marked induction of MHC I antigen presenting machinery (B2M), and IFN pathway response (upregulation of PD-L1).
  • the study enrolls subjects in five cohorts (i.e., Cohorts A-E), with up to 20 subjects enrolled in Cohorts A, B, C, and E, and up to 5 subjects enrolled in Cohort D (FIG. 4).
  • Cohorts are molecularly defined as follows based on the results of acceptable, documented prior diagnostic.
  • Cohort A Subjects with aggressive variant (anaplastic) adenocarcinoma of the prostate (AVPCa) receive XmAb®20717 (10 mg/kg infusion every 2 weeks) plus carboplatin target area under the serum concentration-time curve of 4 (AUC 4) intravenously (IV) over 30 minutes every 3 weeks and cabazitaxel 20 mg/m 2 IV (or docetaxel 60 mg/m 2 , if docetaxel naive) every 3 weeks.
  • Cohort B (homologous recombination deficiency [HRD]/cyclin-dependent kinase 12[CDK12] poly-adenosine diphosphate ribose polymerase [PARP] Progressors): Subjects who have progressed on prior PARP inhibitors with at least one of the specified homologous recombination deficiencies receive XmAb®20717 (10 mg/kg infusion every 2 weeks) plus carboplatin AUC 4 IV over 30 minutes every 3 weeks and cabazitaxel 20 mg/m 2 IV (or docetaxel 60 mg/m 2 , if docetaxel naive) every 3 weeks.
  • Cohort C (HRD/CDK12 PARP Naive): Subjects with at least one of the specified molecular abnormalities and who have not yet received a PARP inhibitor receive olaparib 300 mg orally twice daily and XmAb®20717 (10 mg/kg infusion every 2 weeks).
  • Cohort D (MSI-H or MMRD): Subjects whose tumors have been shown to be microsatellite instability-high [MSI-H] or mismatch repair deficient [MMRD] receive XmAb®20717 alone (10 mg/kg infusion every 2 weeks).
  • Cohort E No Targetable Mutations: Subjects receive XmAb®20717 (10 mg/kg infusion every 2 weeks) plus carboplatin AUC 4 IV over 30 minutes every 3 weeks and cabazitaxel 20 mg/m 2 IV (or docetaxel 60 mg/m 2 , if docetaxel naive) every 3 weeks.
  • Subjects with a positive molecular test for one of the following molecular abnormalities are enrolled and receive treatment in Cohort A: Positive for aberrancy in at least 2 of the following genes: Rbl, TP53, and/or PTEN.
  • Subjects with a positive molecular test for one of the following molecular abnormalities are enrolled and receive treatment in Cohort B or C: Positive for HRD in one or more of the following genes: BRCA1, BRCA2, ATM, PALB2, CHEK2, and/or FANCA; and/or positive for biallelic loss of CDK12.
  • XmAb®20717 is a humanized bsAb that binds both CTLA4 and PD1.
  • XmAb®20717 pharmaceutical composition is a sterile liquid supplied in single-use glass vials. Each 10 mL vial is filled with 10.5 mL of pharmaceutical composition containing 10.0 ⁇ 1.0 mg/mL of XmAb®20717, in 20 mM histidine, 250 mM sorbitol, and 0.01% (w/v) polysorbate-80 at pH 6.2. Each product vial is intended to deliver 10.0 mL of drug solution. [00382] Prior to administration, XmAb®20717 is diluted to the final required concentration in an ethylene/polypropylene copolymer infusion bag containing 0.9% Sodium Chloride Injection, USP. After dilution, the bag containing XmAb®20717 should be gently inverted 2 to 3 times to mix the solution. The bag should not be shaken.
  • XmAb®20717 administration should begin as soon as possible after the dosing solution is made. If there is a delay in administration, the dosing solution may be stored at 2 - 8 °C for no more than 24 hours or at room temperature for no more than 4 hours prior to infusion. The full-calculated dose is administered based on the subject’s actual baseline weight measurement in kilograms. Following the first dose, subsequent doses are modified only if the subject’s weight changes by more than 10% from the Day -1 weight, at which point it is recalculated using the current weight.
  • Exploratory Objective Characterize pharmacodynamics, based on cell surface markers on selected immune system cells in peripheral blood; assess changes in immune cell density and intratumoral and juxta-tumoral immune and tumor cell expression of PD-L1, PD- 1, and other immune checkpoint markers; correlate clinical response with tumor and circulating tumor DNA mutation profiles, interferon transcriptional signature, and immune profiling characteristics of cells in the tumor microenvironment by transcriptomic analysis of tumor tissue; and correlate clinical responses with specific genetic defects of molecularly defined cohorts.
  • Subjects are recruited through the clinics at each participating institution. Each subject is assigned a subject screening number at the time of consent.
  • Subjects are consented before undergoing any screening procedures. After consent, subjects must undergo all the assessments listed for the screening period on the Schedule of Assessments (Table 6) to determine preliminary eligibility. The staff at each clinical site arranges the subject’s study visit schedule.
  • site staff submits an enrollment package to Xencor as detailed in the Subject Registration Guidelines.
  • the Xencor Medical Monitor (or designee) reviews the enrollment documents provided and confirm the subject’s eligibility. If eligibility is confirmed, at this time, the subject is assigned a subject enrollment number and a cohort. Study treatment cannot begin until the subject’s eligibility has been confirmed and a subject number and treatment assignment have been provided to the site.
  • Subject Screening Number Subjects who consent for the study are assigned a Subject Screening Number.
  • Subject Enrollment Number Subjects eligible to receive study treatment are assigned a Subject Enrollment Number.
  • XmAb®20717 is administered at a dose of 10 mg/kg on Days 1 and 15 of each 28- day cycle. Subjects are enrolled as follows:
  • Cohort A Subjects with AVPCa receive XmAb®20717 (10 mg/kg infusion every 2 weeks) plus carboplatin target AUC of 4 (AUC 4) IV over 30 minutes every 3 weeks and cabazitaxel 20 mg/m 2 IV (or docetaxel 60 mg/m 2 , if docetaxel naive) every 3 weeks.
  • Cohort B (HRD/CDK12 poly-adenosine diphosphate ribose polymerase [PARP] Progressors): Subjects who have progressed on prior PARP inhibitors with at least one of the specified homologous recombination deficiencies receive XmAb®20717 (10 mg/kg infusion every 2 weeks) plus carboplatin AUC 4 IV over 30 minutes every 3 weeks and cabazitaxel 20 mg/m 2 IV (or docetaxel 60 mg/m 2 , if docetaxel naive) every 3 weeks.
  • Cohort C (HRD/CDK12 PARP Naive): Subjects with at least one of the specified homologous recombination deficiencies and who have not yet received a PARP inhibitor receive olaparib 300 mg orally twice daily and XmAb®20717 (10 mg/kg infusion every 2 weeks).
  • Cohort D Subjects whose tumors have been shown to be MSI-H or MMRD receive XmAb®20717 alone (10 mg/kg infusion every 2 weeks).
  • Cohort E No Targetable Mutations: Subjects receive XmAb®20717 (10 mg/kg infusion every 2 weeks) plus carboplatin AUC 4 IV over 30 minutes every 3 weeks and cabazitaxel 20 mg/m 2 IV (or docetaxel 60 mg/m 2 , if docetaxel naive) every 3 weeks.
  • Subjects in Cohorts A, B, or E may receive up to 8 cycles of carboplatin. Additional cycles of carboplatin may be considered if the Investigator and Medical Monitor agree that a subject is deriving clinical benefit and does not have significant toxicity.
  • Subjects who show signs of progression may continue treatment on study past initial progression if, as determined by the Investigator, they could still clinically benefit from continued treatment, as outlined in the PCWG3 recommendations. If a subject voluntarily withdraws from the study, attempts should be made to contact the subject to determine and record the reason(s) for discontinuation. All subjects who discontinue the study secondary to an AE must be followed until resolution or stabilization of the AE.
  • Dose interruptions of any study drug for AEs may occur at any time and independently at the discretion of the Investigator; • Dose modifications as specified in the United States package insert (USPI) should be followed for each commercial drug administered as part of the combination arms on this study; • If XmAb®20717 is interrupted for more than 12 weeks, treatment should be discontinued unless continuation is approved by the Medical Monitor; • Reductions in the XmAb®20717 dose require approval of the Medical Monitor.
  • USPI United States package insert
  • IrAEs may involve every organ or tissue (Michot, et al. Eur J Cancer.
  • irAEs occur within the first 12 weeks of exposure to an immune- checkpoint inhibitor, but some of them may appear with a delayed onset. Diagnosis of irAEs should be based on exposure to XmAb®20717 and a reasonable immune-based mechanism of the observed AE. Whenever possible, histologic examination or other immune-based diagnostic evaluations should be used to support the diagnosis. Other etiologic causes, including AEs due to tumor progression, should be ruled out.
  • irAEs The spectrum of irAEs is wide and can be general or organ-specific. Examples of general irAEs in subjects treated with immune-checkpoint inhibitors are fatigue, fever, and chills. Organ-specific irAEs consist of pneumonitis, colitis, hepatitis, nephritis and renal dysfunction, skin adverse reactions, encephalitis, myocarditis, and endocrinopathies.
  • Subjects receiving chemotherapy may develop treatment-related neutropenia and thrombocytopenia, despite prophylactic growth factor support.
  • chemotherapy-related myelosuppression refer to the USPI for each specific agent.
  • dosing of XmAb®20717 can be continued, despite myelosuppression, while the chemotherapy is held and/or reduced.
  • XmAb®20717 can be held to enable work-up of chemotherapy -unrelated causes, including immune-related thrombocytopenia, neutropenia, and/or anemia. If chemotherapy cannot be resumed within 21 days due to persistent cytopenia, the subject should be discontinued from all study treatment.
  • the study may be terminated after appropriate consultation among the involved parties.
  • Conditions that prompt such a consultation and may warrant termination of the clinical study include, but are not limited to, the following: • The discovery of an unexpected or unacceptable risk to the subjects enrolled in the clinical study; • Failure to enroll subjects at the required rate; • A decision by the Sponsor to suspend or discontinue development of XmAb®20717; • Sponsor decision. The clinical study may also be terminated at the Sponsor’s discretion for these or any other reasons. Should the study be terminated, and/or a site closed for whatever reason, all documentation pertaining to the study and investigational medicinal product (IMP) must be returned to the Sponsor. Any actions required for assessing or maintaining subject safety continue as required, despite termination of the study or site.
  • IMP investigational medicinal product
  • HBsAg hepatitis B surface antigen
  • HBcAb hepatitis B core antibody
  • HBV human immunodeficiency virus
  • HCVRNA hepatitis C virus
  • Predose PEs and clinical evaluations may be performed up to 24 hours prior to a scheduled infusion of XmAb®20717, except where indicated otherwise: • Abbreviated, symptom-directed PE, including weight; • Vital signs (predose assessments must be performed immediately prior to infusion); • ECOG performance status; • Record AEs; • Record prior and ongoing concomitant medications.
  • Laboratory assessments include: • CBC; • Coagulation panel; • Chemistry panel, including amylase and lipase; • Thyroid function tests: TSH, T3, fT4; • ACTH, cortisol (8 AM); • HgB A1C; • Urinalysis; • Blood for cell surface markers by flow cytometry and similar bioanalytical methods (See Laboratory Manual for detailed instructions); • PK (See Laboratory Manual for detailed instructions); • Blood for peripheral cytokine levels (See Laboratory Manual for detailed instructions); • ADA blood samples (See Laboratory Manual for detailed instructions); • Blood sample stored for potential RNA/transcriptomic profiling (PAXgene); • ECG, standard 12-lead; Tumor assessment by CT/MRI (RECIST 1.1;
  • the Sponsor or designee provides cryotubes, labels, and requisition forms. Serum cryotubes are labeled at the clinical site with the subject enrollment number, date, visit day and time point, and time of sampling. Samples are stored on site at -70°C until the Sponsor notifies the sites to ship the samples on dry ice to the designated lab for sample analysis. Detailed instructions for processing and shipping serum samples are provided in the Laboratory Manual. Venous blood samples for serum analyses of ADA and the cytokine panel are obtained according to the Schedule of Assessments. ADA samples may also be analyzed for soluble factors (including but not limited to sCTLA4, sPDl, and sPDLl) that may interfere with the assay. Blood samples for analyses of PK are obtained according to the Sampling for PK table.
  • a blood sample is collected at baseline and on treatment and stored for potential RNA/transcriptomic profiling.
  • a blood sample is collected for ctDNA mutation profiling.
  • Subjects have their EOT assessments at the end of their last cycle of treatment. If a subject terminates before the end of a cycle, the EOT assessments are performed on the day of study termination. Subjects with a positive ADA at study termination are followed every 28 days ( ⁇ 3 days) until ADA is negative or until administration of another anticancer therapy. Follow-up cease once all scheduled samples have been collected or when the subject begins another anticancer treatment regimen. Subjects are followed for AEs for 70 days after EOT or until the first administration of another anticancer therapy, whichever comes first.
  • Post-Treatment Follow-up Period 14 Days, 28 Days, and 70 Days after EOT
  • Subjects have visits 14 days post-EOT, 28 days post-EOT, and 70 days post-EOT. Scans for subjects who discontinued treatment for reasons other than disease progression should be collected until disease progression. Once these visits and assessments have been completed, the subject is considered as having completed participation in the clinical trial. If a subject enrolls into another trial or requires a change in anticancer treatment before either of these scheduled visits, the visits may be performed earlier. If a subject is unable/unwilling to return for any scheduled visits after the end of treatment, he/she is considered as having completed study requirements at the end of treatment.
  • Subjects are contacted by site staff by telephone, email, or mail at 6 and 12 months after their active participation in the study ends to gather information about disease progression and survival. Scans for subjects who discontinued treatment for reasons other than disease progression should be collected until disease progression. Completion of the long-term follow-up period is not required for a subject to be considered as having completed the clinical trial.
  • Subjects undergo a Screening Visit(s) 2 to 28 days prior to the planned first day of study treatment. Screening procedures and assessments are as follows: Obtain signed informed consent; Obtain documentation of targeted sequencing of metastatic prostate cancer to determine mutational status of MSI-H or MMRD; Review inclusion and exclusion criteria; Collect tissue from formalin-fixed paraffin embedded (FFPE) archival tumor tissue (20 slides, if available, or from fresh pretreatment biopsy); Collect a blood sample for assessment of ctDNA; Demographics; Medical history; Disease-specific history, including any available genomic information on the primary or metastatic tumor and sequencing data; Physical Examination (PE); PSA testing within 14 days of the first dose of drug (except subjects in Cohort A); Computed tomography (CT) or magnetic resonance imaging (MRI) within 28 days prior to the first dose of study drug for baseline tumor assessment per RECIST 1.1 (Eisenhauer et al.
  • FFPE formalin-fixed paraffin embedded
  • Predose PEs and clinical evaluations may be performed up to 24 hours prior to a scheduled infusion of XmAb®20717, except where indicated otherwise: Abbreviated, symptom-directed PE, including weight; Vital signs (predose assessments should be performed immediately prior to infusion); ECOG performance status; Record AEs; Record prior and ongoing concomitant medications.
  • Laboratory assessments include: CBC; Coagulation panel; Chemistry panel, including amylase and lipase; Thyroid function tests: TSH, T3, fT4; ACTH, cortisol (8 AM); HgB A1C; Urinalysis; Blood for cell surface markers by flow cytometry and similar bioanalytical methods; PK; Blood for peripheral cytokine levels; ADA blood samples; Blood sample stored for potential RNA/transcriptomic profiling; ECG, standard 12-lead; Tumor assessment by CT/MRI (RECIST 1.1; Eisenhauer et al, Eur J Cancer. 2009; 45:228-47, as modified by PCWG3 (Scher et al. J Clin Oncol.
  • ACTH adrenocorticotropic hormone
  • ADA anti-drug antibody
  • CBC complete blood count
  • CT computed tomography
  • ctDNA circulating tumor DNA
  • d day
  • ECG electrocardiogram
  • ECOG Eastern Cooperative Oncology Group
  • EOT end of treatment
  • FFPE formalin-fixed paraffinized embedded
  • fT4 free thyroxine
  • HBcAb hepatitis B core antibody
  • HBsAg hepatitis B surface antigen
  • HCV hepatitis C virus
  • Hgb A1C hemoglobin A1C
  • HIV human immunodeficiency virus
  • HRD homologous recombination deficiency
  • IV intravenous
  • MMRD mismatch repair deficient
  • mo month
  • MRI magnetic resonance imaging
  • MSI-H microsatellite instability-high
  • PE physical examination
  • PK pharmacokinetic
  • PSA prostatespecific antigen
  • RECIST Response Evaluation Criteria
  • the procedure can be performed after the subject has consented and registered to the study. Fresh prostate biopsy is acceptable if there is clear local disease and no other measurable disease site or biopsiable bone lesion.
  • c Complete medical history and PE at screening. For all the other time points an abbreviated, symptom-directed PE is to be performed. A thorough diseasespecific history can be recorded at screening, including prior surgery, radiotherapy, and systemic therapy (including duration of treatment, reason for discontinuation, and best overall response), Gleason score at diagnosis, metastatic disease status at diagnosis, PSA levels for the prior 6 months, and any available genomic information on the primary or metastatic tumor and sequencing data.
  • vital signs should be taken predose and 30 minutes ( ⁇ 5 minutes) after start of infusion, immediately before end of infusion, and 30 ( ⁇ 5) and 60 ( ⁇ 5) minutes after end of infusion.
  • vital signs should be taken predose.
  • carboplatin and cabazitaxel or docetaxel
  • vital signs should be taken predose.
  • carboplatin and cabazitaxel or docetaxel
  • vital signs should be taken predose.
  • Baseline body weight to be collected on either Day - 1 or Day 1. f If the assessment is performed or the sample is collected within 3 days prior to dosing on Day 1, it does not need to be repeated on Day 1. g On dosing days in the first 2 cycles of therapy, ECGs should be performed prior to infusion, 2 to 4 hours after end of infusion, and if clinically indicated.
  • ECGs On dosing days after the first 2 cycles of therapy, ECGs should be performed prior to infusion. ECGs should be performed after the subject has been resting supine or semirecumbent for > 5 minutes. All ECGs should be taken with the subject in the same position. h May be performed up to 24 hours prior to infusion. These safety laboratories can be performed by both the central laboratory and local clinical site laboratories to allow review of the results by clinical site personnel before XmAb®20717 infusion.
  • a blood sample can be collected at baseline and on treatment and stored for potential RNA/transcriptomic profiling.
  • m XmAb®20717 can be administered as a 1-hour IV infusion ( ⁇ 10 minutes unless there is approval from the Medical Monitor for a different infusion rate and duration). Subjects are observed for at least 1 hour following the end of infusion.
  • olaparib are administered orally twice daily. See dosing schedules for chemotherapy for subjects in Cohorts A, B, and E.
  • olaparib are administered orally twice daily. See dosing schedules for chemotherapy for subjects in Cohorts A, B, and E.
  • olaparib are administered orally twice daily.
  • ADA sampling is performed prior to infusion on Day 15. Subjects with a positive ADA at termination can be followed every 28 days ( ⁇ 3 days) until ADA reverts to baseline or until the next intervening treatment. p This sampling should be performed predose on Day 1 for those subjects in Cohort D (MSI-H/MMRD) who have received pembrolizumab or nivolumab within 18 weeks prior to the first dose of study drug. q Tumor assessment per RECIST 1.1, as modified by PCWG3. Radiographic evaluations and tumor measurements can be undertaken every 9 weeks ( ⁇ 1 week) for 28 weeks, then every 12 weeks ( ⁇ 1 week) for assessment of both response and disease progression. During post-treatment follow-up, scans for subjects who discontinued treatment for reasons other than disease progression can be collected until disease progression. Radiologic documentation can be provided for subjects removed from study for progressive disease. The date of radiographic evaluations can be calculated from the date of first treatment.
  • Images can be evaluated locally for response and progression. EOT assessment can be performed only if such an assessment has not been performed in the past 60 days.
  • imaging for the Cycle 2 Day 26 time point may be performed within 7 days rather than within 2 days.
  • Pretreatment PSA can be performed within 14 days prior to the first dose of drug.
  • Post-treatment PSA can be performed at the end of Cycle 1 and repeated every 2 cycles (Cycle 3, Cycle 5, Cycle 7, etc.) thereafter in subjects except those in Cohort A.
  • Historical bone scan if performed within 56 days of Cycle 1 Day 1, is acceptable for pretreatment.
  • Inclusion Criteria for Subjects of the Study include:
  • Documented progressive mCRPC based on at least one (or one or more than one) of the following criteria:
  • PSA progression defined as at least 2 rises in PSA with a minimum of a 1 week interval (1.0 ng/mL is the minimal starting value if confirmed rise is the only indication of progression)
  • Prostate cancer must have progressed after treatment with at least 2 prior lines of anticancer therapy approved for treatment of metastatic prostate cancer; prior treatment of subjects in Cohort D (MSI-H or MMRD) should include a checkpoint inhibitor approved by FDA for that indication;
  • Subjects who did not have a surgical orchiectomy should be on androgen suppression treatment (e.g., luteinizing hormone-releasing hormone agonist) with castrate level of testosterone ( ⁇ 50 ng/dL) and be willing to continue the treatment throughout the study;
  • on androgen suppression treatment e.g., luteinizing hormone-releasing hormone agonist
  • castrate level of testosterone ⁇ 50 ng/dL
  • AVPCa Cohort A
  • subjects should be positive for aberrancy of at least 2 of the following: Rbl, TP53, PTEN;
  • HRD Cohort B
  • subjects must meet one of the following criteria: • Positive for HRD in one or more of the following genes: BRCA1, BRCA2, ATM, PALB2, CHEK2, and/or FANCA; • Positive for biallelic loss of CDK12;
  • Cohort C At least one of the following criteria: • Positive for HRD in one or more of the following genes: BRCA1, BRCA2, ATM, PALB2, CHEK2, and/or FANCA; • Positive for biallelic loss of CDK12; Cohort D, subjects must have positive MSI-H/MMRD status;
  • Exclusion Criteria for Subjects of the Study include:
  • Treatment with any other anticancer therapy within 2 weeks of the start of study drug z.e., other immunotherapy, chemotherapy, radiation therapy, etc.
  • Subjects with previously treated brain metastases may participate provided they are radiologically stable, z.e., are without evidence of progression for at least 4 weeks by repeat imaging (note that the repeat imaging should be performed during study screening), are clinically stable, and are without requirement of steroid treatment for at least 14 days prior to first dose of study treatment;
  • autoimmune disease except vitiligo; type 1 diabetes mellitus or residual hypothyroidism due to an autoimmune condition that is treatable with hormone replacement therapy only; psoriasis, atopic dermatitis, or another autoimmune skin condition that is managed without systemic therapy; or arthritis that is managed without systemic therapy beyond oral acetaminophen and nonsteroidal anti-inflammatory drugs);
  • HIV human immunodeficiency virus
  • CD4+ CD4+ T-cell
  • ART antiretroviral therapy
  • hepatitis C RNA a subject who is hepatitis C virus [HCV] antibody positive but HCV RNA negative due to documented, curative prior antiviral treatment or natural resolution is eligible;
  • HBsAg hepatitis B surface antigen
  • HBcAb hepatitis B core antibody
  • a subject whose HBsAg is negative and HBcAb is positive may be enrolled if a hepatitis B virus [HBV] DNA test is negative and the subject is retested for HBsAg and HBV DNA every 2 months.
  • AVPC aggressive variant prostate cancer
  • PARPiN HRD PARPi naive homologous recombination deficient
  • PARPiP HRD PARPi progressor homologous recombination deficient
  • NR not recorded in database
  • NTM no targetable mutation
  • Non-CR/Non-PD refers to persistence of one or more non-target lesion(s) and/or maintenance of tumor marker level above the normal limits
  • PSA prostate specific antigen
  • SAEs treatment-related serious adverse events
  • 5 of the 8 patients treated with vudalimab + chemotherapy included vomiting (Grade 3), maculopapular rash (Grade 2), and colitis (Grade 2) in 1 patient, and sepsis (Grade 3), Guillain-Barre syndrome (Grade 3), and nausea (Grade 3), and diarrhea (Grade 2) in 1 patient each.
  • An additional patient had Grade 3 maculopapular rash and diarrhea, and leukocytosis (not meeting SAE criteria) within the first cycle of therapy.
  • FIG. 8 shows treatment-related adverse events and immunotherapy-related adverse events.
  • Guillain-Barre syndrome a rare event associated with ICI therapy
  • a decision to change the vudalimab and chemotherapy regimen was prompted by the frequency, severity, and incidence in these 8 patients of treatment-related serious and/or severe adverse events leading to discontinuation of treatment - not all of which are clearly irAEs.
  • the decision was made to maintain the vudalimab dose and modify the chemotherapy regimen before proceeding with further enrollment into chemotherapy cohorts.
  • the dosing regimen is changed to restrict carboplatin and carbazitaxel or docetaxel in combination with vudalimab to patients with aggressive variant disease, and use single-agent carbazitaxel or docetaxel therapy in combination with vudalimab in the remaining chemotherapy cohorts (Table 9). Enrollment into chemotherapy cohorts restart following implementation of the amended protocol with the revised regimens. The vudalimab and olaparib and vudalimab monotherapy cohorts remain open for enrollment.
  • the activity of XmAb®20717 was determined in an in vitro assay measuring IL-2 secretion from human lymphocytes stimulated with SEB, a method of assessing in vitro activity that has been used for other checkpoint inhibitors, including nivolumab.
  • SEB- stimulated PBMC were treated with XmAb®20717 or comparators/controls for 24 hours, and lymphocyte function was determined by measuring by ELISA the amount of IL-2 in culture supernatants.
  • XmAb®20717 When compared to an anti-RSV isotype-control bivalent antibody (XENP 15074), XmAb®20717 promoted a 4.1 -fold increase in IL-2 secretion while XENP 16432, a benchmark anti-PDl bivalent antibody derived from the Fv of nivolumab with substitutions in the Fc domain similar to those in the XmAb®20717 Fc domain, promoted a 2.6-fold increase in IL-2 secretion versus control. When compared to PD1 blockade by a bivalent PD1 antibody, XmAb®20717 promoted a 1.5-fold increase in IL-2 secretion.
  • XENP20111 a monovalent anti-PDl scFv-Fc component antibody of XmAb®20717
  • XENP20059 a monovalent anti-CTLA4 Fab-Fc component antibody of XmAb®20717
  • XmAb®20717 promoted a 1.6-fold increase in IL-2 secretion, suggesting that the increased avidity of XmAb®20717 for dual-positive PD1 and CTLA4-expressing T cells contributes to its observed in vitro.

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Abstract

Provided herein, in certain aspects, are methods of treating a prostate cancer in a subject, comprising administering a bispecific anti-CTLA4 x anti-PD1 antibody (e.g., XmAb®20717) in combination with at least one additional agent (e.g., carboplatin, carbazitaxel, docetaxel, and/or olaparib) to the subject. In certain aspects, the bispecific anti- CTLA4 x anti-PD1 antibody comprises a first polypeptide comprising an amino acid sequence of SEQ ID NO: 1, a second polypeptide comprising an amino acid sequence of SEQ ID NO:2, and a third polypeptide comprising an amino acid sequence of SEQ ID NO:3.

Description

COMBINATION TREATMENT WITH A BISPECIFIC ANTIBODY THAT BINDS CTLA4 AND PD1 FOR PROSTATE CANCER
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of U.S. Provisional Patent Application No. 63/423,465, filed November 7, 2022, the disclosure of which is incorporated by reference herein it its entirety.
SEQUENCE LISTING
[0002] This application contains a computer readable Sequence Listing which has been submitted in XML file format with this application, the entire content of which is incorporated by reference herein in its entirety. The Sequence Listing XML file submitted with this application is entitled “14718-048-228_SEQ_LISTING.xml”, was created on November 1, 2023, and is 22,674 bytes in size.
1. FIELD
[0003] Provided herein, in certain aspects, are methods of treating prostate cancer in a subject, comprising administering a bispecific anti-CTLA4 x anti-PDl antibody in combination with at least one additional agent (e.g., carboplatin, carbazitaxel, docetaxel, and/or olaparib) to the subject.
2. SUMMARY
[0004] In one aspect, provided herein is a method of treating a prostate cancer in a male subject in need thereof, the method comprising: (a) administering a bispecific antibody to the male subject at a dose of between about 5-15 mg/kg, wherein the dose of the bispecific antibody is intravenously administered to the male subject on Day 1 of a first treatment cycle and about every two weeks (Q2W) thereafter; (b) administering carboplatin to the male subject at a therapeutically effective dose that results in a target area under the serum concentration-time curve of 3 (AUC3) in the male subject, wherein the dose of the carboplatin is intravenously administered to the male subject twice in the first treatment cycle, wherein the twice is on Day 1 and about three weeks after Day 1 of the first treatment cycle; (c) administering a taxane to the male subject at a dose of between about 10 mg/m2 and about 55 mg/m2, wherein the dose of the taxane is intravenously administered to the male subject twice in the first treatment cycle, wherein the twice is on Day 1 and about three weeks after day 1 of the first treatment cycle; (d) administering carboplatin to the male subject at a therapeutically effective dose that results in a target area under the serum concentration-time curve of 4 (AUC4) in the male subject, wherein the dose of the carboplatin is intravenously administered to the male subject between Day 13 and Day 17 of a second treatment cycle and about every three weeks (Q3W) thereafter; and (e) administering the taxane to the male subject at a dose of between about 15 mg/m2 and about 65 mg/m2, wherein the dose of the taxane is intravenously administered to the male subject between Day 13 and Day 17 of the second treatment cycle and about every three weeks (Q3W) thereafter; wherein each treatment cycle is about 28 days; wherein the prostate cancer is an aggressive variant (anaplastic) adenocarcinoma of the prostate (AVPCa); wherein the dose of the taxane in (e) is higher than the dose of the taxane in (c); and wherein the bispecific antibody comprises a first polypeptide comprising an amino acid sequence of SEQ ID NO: 1, a second polypeptide comprising an amino acid sequence of SEQ ID NO:2, and a third polypeptide comprising an amino acid sequence of SEQ ID NO:3.
[0005] In one aspect, provided herein is a method of treating a prostate cancer in a male subject in need thereof, the method comprising: (a) administering a bispecific antibody to the male subject at a dose of 10 mg/kg, wherein the dose of the bispecific antibody is intravenously administered to the male subject on day 1 of a first treatment cycle and about every two weeks (Q2W) thereafter; (b) administering carboplatin to the male subject at a therapeutically effective dose that results in a target area under the serum concentration-time curve of 3 (AUC3) in the male subject, wherein the dose of the carboplatin is intravenously administered to the male subject twice in the first treatment cycle, wherein the twice is on day 1 and about three weeks after day 1 of the first treatment cycle; (c) administering carbazitaxel to the male subject at a dose of 15 mg/m2, wherein the dose of the carbazitaxel is intravenously administered to the male subject twice in the first treatment cycle, wherein the twice is on day 1 and about three weeks after day 1 of the first treatment cycle; (d) administering carboplatin to the male subject at a therapeutically effective dose that results in a target area under the serum concentration-time curve of 4 (AUC4) in the male subject, wherein the dose of the carboplatin is intravenously administered to the male subject between day 13 and day 17 of a second treatment cycle and about every three weeks (Q3W) thereafter; and (e) administering the carbazitaxel to the male subject at a dose of 20 mg/m2, wherein the dose of the carbazitaxel is intravenously administered to the male subject on day 15 of the second treatment cycle and about every three weeks (Q3W) thereafter; wherein each treatment cycle is 28 days; wherein the prostate cancer is an aggressive variant (anaplastic) adenocarcinoma of the prostate (AVPCa); and wherein the bispecific antibody comprises a first polypeptide comprising an amino acid sequence of SEQ ID NO: 1, a second polypeptide comprising an amino acid sequence of SEQ ID NO:2, and a third polypeptide comprising an amino acid sequence of SEQ ID NO:3.
[0006] In one aspect, provided herein is a method of treating a prostate cancer in a male subject in need thereof, the method comprising: (a) administering a bispecific antibody to the male subject at a dose of 10 mg/kg, wherein the dose of the bispecific antibody is intravenously administered to the male subject on day 1 of a first treatment cycle and about every two weeks (Q2W) thereafter; (b) administering carboplatin to the male subject at a therapeutically effective dose that results in a target area under the serum concentration-time curve of 3 (AUC3) in the male subject, wherein the dose of the carboplatin is intravenously administered to the male subject twice in the first treatment cycle, wherein the twice is on day 1 and about three weeks after day 1 of the first treatment cycle; (c) administering docetaxel to the male subject at a dose of 50 mg/m2, wherein the dose of the docetaxel is intravenously administered to the male subject twice in the first treatment cycle, wherein the twice is on day 1 and about three weeks after day 1 of the first treatment cycle; (d) administering carboplatin to the male subject at a therapeutically effective dose that results in a target area under the serum concentration-time curve of 4 (AUC4) in the male subject, wherein the dose of the carboplatin is intravenously administered to the male subject between day 13 and day 17 of a second treatment cycle and about every three weeks (Q3W) thereafter; and (e) administering the docetaxel to the male subject at a dose of 60 mg/m2, wherein the dose of the docetaxel is intravenously administered to the male subject on day 15 of the second treatment cycle and about every three weeks (Q3W) thereafter; wherein each treatment cycle is 28 days; wherein the prostate cancer is an aggressive variant (anaplastic) adenocarcinoma of the prostate (AVPCa); and wherein the bispecific antibody comprises a first polypeptide comprising an amino acid sequence of SEQ ID NO: 1, a second polypeptide comprising an amino acid sequence of SEQ ID NO:2, and a third polypeptide comprising an amino acid sequence of SEQ ID NO:3.
[0007] In one aspect, provided herein is a method of treating a prostate cancer in a male subject in need thereof, the method comprising: (a) administering a bispecific antibody to the male subject at a dose of between about 5-15 mg/kg, wherein the dose of the bispecific antibody is intravenously administered to the male subject on Day 1 of a first treatment cycle and about every two weeks (Q2W) thereafter; and (b) administering a taxane to the male subject at a dose of between about 10 mg/m2 and about 80 mg/m2, wherein the dose of the taxane is intravenously administered to the male subject on Day 1 of the first treatment cycle and about every three weeks (Q3W) thereafter; wherein each treatment cycle is about 28 days; wherein the prostate cancer progressed after the male subject received a polyadenosine diphosphate ribose polymerase (PARP) inhibitor prior to the administering of (a) and/or wherein the prostate cancer does not have a targetable mutation; and wherein the bispecific antibody comprises a first polypeptide comprising an amino acid sequence of SEQ ID NO: 1, a second polypeptide comprising an amino acid sequence of SEQ ID NO:2, and a third polypeptide comprising an amino acid sequence of SEQ ID NO:3.
[0008] In one aspect, provided herein is a method of treating a prostate cancer in a male subject in need thereof, the method comprising: (a) administering a bispecific antibody to the male subject at a dose of 10 mg/kg, wherein the dose of the bispecific antibody is intravenously administered to the male subject on day 1 of a first treatment cycle and about every two weeks (Q2W) thereafter; and (b) administering carbazitaxel to the male subject at a dose of 20 mg/m2, wherein the dose of the carbazitaxel is intravenously administered to the male subject on day 1 of the first treatment cycle and about every three weeks (Q3W) thereafter; wherein each treatment cycle is 28 days; wherein the prostate cancer progressed after the male subject received a polyadenosine diphosphate ribose polymerase (PARP) inhibitor prior to the administering of (a) and/or wherein the prostate cancer does not have a targetable mutation; and wherein the bispecific antibody comprises a first polypeptide comprising an amino acid sequence of SEQ ID NO: 1, a second polypeptide comprising an amino acid sequence of SEQ ID NO:2, and a third polypeptide comprising an amino acid sequence of SEQ ID NO:3.
[0009] In one aspect, provided herein is a method of treating a prostate cancer in a male subject in need thereof, the method comprising: (a) administering a bispecific antibody to the male subject at a dose of 10 mg/kg, wherein the dose of the bispecific antibody is intravenously administered to the male subject on day 1 of a first treatment cycle and about every two weeks (Q2W) thereafter; and (b) administering docetaxel to the male subject at a dose of 75 mg/m2, wherein the dose of the docetaxel is intravenously administered to the male subject on day 1 of the first treatment cycle and about every three weeks (Q3W) thereafter; wherein each treatment cycle is 28 days; wherein the prostate cancer progressed after the male subject received a polyadenosine diphosphate ribose polymerase (PARP) inhibitor prior to the administering of (a) and/or wherein the prostate cancer does not have a targetable mutation; and wherein the bispecific antibody comprises a first polypeptide comprising an amino acid sequence of SEQ ID NO: 1, a second polypeptide comprising an amino acid sequence of SEQ ID NO:2, and a third polypeptide comprising an amino acid sequence of SEQ ID NO:3. [0010] In one aspect, provided herein is a method of treating prostate cancer in a male subject in need thereof, the method comprising: (a) administering a bispecific antibody to the male subject at a dose of between about 5-15 mg/kg, wherein the dose of the bispecific antibody is intravenously administered to the male subject on day 1 of a first treatment cycle and about every two weeks (Q2W) thereafter; and (b) administering olaparib to the male subject at a dose of between about 500 to about 700 mg per day on day 1 of a first treatment cycle and every day thereafter; wherein each treatment cycle is about 28 days; wherein the male subject has not been previously treated with a polyadenosine diphosphate ribose polymerase (PARP) inhibitor; and wherein the bispecific antibody comprises a first polypeptide comprising an amino acid sequence of SEQ ID NO: 1, a second polypeptide comprising an amino acid sequence of SEQ ID NO:2, and a third polypeptide comprising an amino acid sequence of SEQ ID NO:3.
[0011] In one embodiment, the AVPCa has a mutation or other aberrancy in at least two genes independently selected from the group consisting of Rbl, TP53 and PTEN. In one embodiment, the prostate cancer is not an aggressive variant (anaplastic) adenocarcinoma of the prostate (AVPCa). In one embodiment, the prostate cancer has a homologous recombination deficiency (HRD). In one embodiment, the prostate cancer has a biallelic loss of cyclin-dependent kinase 12 (CDK12). In one embodiment, the male subject has been previously treated with a polyadenosine diphosphate ribose polymerase (PARP) inhibitor. In one embodiment, the prostate cancer does not have a targetable mutation.
[0012] In one embodiment, the dose of the olaparib is 600 mg per day. In one embodiment, the 600 mg per day is administered twice per day in an amount of 300 mg each. In one embodiment, the dose of the bispecific antibody is 10 mg/kg. In one embodiment, the taxane is carbazitaxel. In one embodiment, the taxane is carbazitaxel and the dose is 15 mg/m2 for (c) and 20 mg/m2 for (e). In one embodiment, the taxane is carbazitaxel and the dose is 20 mg/m2. In one embodiment, the taxane is docetaxel if the male subject has not been treated with docetaxel prior to the first treatment cycle. In one embodiment, the taxane is docetaxel if the male subject has not been treated with docetaxel prior to the first treatment cycle, and the dose is 50 mg/ m2 for (c) and 60 mg/ m2 for (e). In one embodiment, the taxane is docetaxel if the male subject has not been treated with docetaxel prior to the first treatment cycle, and the dose is 75 mg/m2.
[0013] In one embodiment, the male subject has not been treated with docetaxel prior to the first treatment cycle. In one embodiment, the carboplatin is intravenously administered on administered on day 15 of the second treatment cycle. In one embodiment, the male subject has received at least two systemic therapies prior to the first treatment cycle. In one embodiment, the male subject has received at least three systemic therapies prior to the first treatment cycle. In one embodiment, the male subject has been treated with chemotherapy prior to the first treatment cycle. In one embodiment, the male subject has been treated with radiation therapy prior to the first treatment cycle. In one embodiment, the male subject is an adult male subject. In one embodiment, the adult male subject is 50 years of age or older. [0014] In one embodiment, the method results in a decrease in prostate specific antigen (PSA) in a biological sample obtained from the male subject compared to a reference. In one embodiment, the decrease in PSA is a decrease of about or at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or more than 95% as compared to the reference. In one embodiment, the decrease is about or at least about 50% as compared to the reference. In one embodiment, the reference is the level of PSA in a biological sample obtained from the male subject prior to the first treatment cycle. In one embodiment, the reference is the level of PSA at baseline. In one embodiment, the level of PSA in a biological sample obtained from the male subject in a previous time point. In one embodiment, the biological sample is blood, plasma, and/or serum.
[0015] In one embodiment, the method further comprises orally administering a steroid to the male subject. In one embodiment, the carboplatin is administered for about 8 treatment cycles. In one embodiment, the male subject has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. In one embodiment, the method results in stable disease classification of the prostate cancer as determined by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. In one embodiment, the method results in partial response classification of the prostate cancer as determined by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. In one embodiment, the method is for about or at least about 3 treatment cycles. In one embodiment, the method is for about or at least about 6 treatment cycles. In one embodiment, the method is for about or at least about 8 treatment cycles.
3. BRIEF DESCRIPTION OF THE DRAWINGS
[0016] FIG. 1 depicts the structure of the antibody described herein. The XmAb®20717 has a “bottle opener” format (also referred to as the “triple F” format). Bottle opener format antibodies include a) a first monomer that includes a first Fc domain and an scFv region, wherein the scFv includes a first variable heavy chain and a first variable light chain (also referred herein as a “scFv-Fc heavy chain;” b) a second monomer that includes a VH-CH1- hinge-CH2-CH3, wherein VH is a second variable heavy chain and CH2 and CH3 is a second Fc domain (also referred herein as a “Fab-Fc heavy chain;” and c) a light chain that includes a second variable light chain. As shown in FIG 1, the scFv is the PD1 binding domain and the second variable heavy chain and second variable light chain for the CTLA4 binding domain. It should be noted that the scFv and Fab domains can be switched (e.g., anti-PDl as a Fab and anti-CTLA4 as a scFv).
[0017] FIG. 2 depicts the amino acid sequences of the XmAb®20717 antibody. The antibody is named using the Fab variable region first and the scFv variable region second, separated by a dash, followed by the chain designation (Fab-Fc heavy chain, scFv-Fc heavy chain or light chain). CDRs are underlined and slashes indicate the border(s) of the variable regions.
[0018] FIG. 3 shows potent antitumor immune response in a mCRPC patient following XmAb®20717 treatment, as shown by multiplex immunofluorescence staining of paited pretreatment and post-treatment biopsies.
[0019] FIG. 4 depicts a study design showing the study population, cohorts, and their respective treatments with the XmAb®20717 antibody.
[0020] FIG. 5 depicts the study schema for subjects treated with the XmAb®20717 antibody.
[0021] FIG. 6 depicts a graph showing duration of treatment with the XmAb®20717 antibody, carboplatin, and taxane (cabazitaxel or docetaxel), or the XmAb®20717 antibody with olaparib (data cutoff date of September 7, 2022). FIG. 6 shows treatment-related adverse events (TRAE; z.e., events attributed to any component of combination therapy) reported for > 2 of the 8 patients treated with XmAb®20717 and chemotherapy or any immunotherapy-related adverse event (irAE) by maximum Common Terminology Criteria for Adverse Events (CTCAE) grade. No irAEs or TRAEs were reported for the patient who received XmAb®20717 and olaparib. Arrows indicate treatment ongoing as of September 7, 2022. AVPC = aggressive variant prostate cancer; PARPiN HRD = PARPi naive homologous recombination deficient; PARPiP HRD = PARPi progressor homologous recombination deficient; NTM = no targetable mutation.
[0022] FIG. 7 depicts a graph showing percent change from baseline in prostate specific antigen (PSA) (data cutoff date of September 7, 2022). AVPC = aggressive variant prostate cancer; PARPiN HRD = PARPi naive homologous recombination deficient; PARPiP HRD = PARPi progressor homologous recombination deficient; NTM = no targetable mutation. [0023] FIG. 8 depicts a graph showing treatment-related adverse events (TRAE; i.e., events attributed by the investigator to any component of combination therapy) reported for > 2 of the 8 patients treated with the XmAb®20717 antibody and chemotherapy or any immunotherapy-related adverse event (irAE; as determined by the sponsor) by maximum Common Terminology Criteria for Adverse Events (CTCAE) grade (data cutoff date of September 7, 2022). No irAEs or TRAEs were reported for the patient who received the XmAb®20717 antibody and olaparib.
4. DETAILED DESCRIPTION
[0024] All publications, patents, patent applications and other documents cited in this application are hereby incorporated by reference in their entireties for all purposes to the same extent as if each individual publication, patent, patent application or other document were individually indicated to be incorporated by reference for all purposes. In the event that there is an inconsistency between the teachings of one or more of the references incorporated herein and the present disclosure, the teachings of the present specification controls.
4.1 Definitions
[0025] In order that the application may be more completely understood, several definitions are set forth below. Such definitions are meant to encompass grammatical equivalents.
[0026] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood to one of ordinary skill in the art to which this invention pertains. Otherwise, certain terms used herein have the meanings as set forth in the specification.
[0027] As used herein, and unless expressly stated to the contrary, “or” refers to an inclusive or and not to an exclusive or. For example, a condition A or B is satisfied by any one of the following: A is true (or present) and B is false (or not present), A is false (or not present) and B is true (or present), and both A and B are true (or present).
[0028] As used herein, the conjunctive term “and/or” between multiple recited elements is understood as encompassing both individual and combined options. For instance, where two elements are conjoined by “and/or,” a first option refers to the applicability of the first element without the second. A second option refers to the applicability of the second element without the first. A third option refers to the applicability of the first and second elements together. Any one of these options is understood to fall within the meaning, and therefore satisfy the requirement of the term “and/or” as used herein. Concurrent applicability of more than one of the options is also understood to fall within the meaning, and therefore satisfy the requirement of the term “and/or.”
[0029] The term “about” in relation to a reference numerical value can include the numerical value itself and a range of values plus or minus 10% from that numerical value. For example, the amount “about 10” includes 10 and any amounts from 9 to 11. For example, the term “about” in relation to a reference numerical value can also include a range of values plus or minus 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% from that value. In some cases, the numerical disclosed throughout can be “about” that numerical value even without specifically mentioning the term “about.”
[0030] Unless otherwise indicated, the term “at least” preceding a series of elements is to be understood to refer to every element in the series.
[0031] The terms “a,” “an,” “the” and similar referents used in the context of describing the disclosure (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context.
[0032] By “CTLA4,” “CTLA4,” “cytotoxic T-lymphocyte-associated protein 4,” “CD 152,” or “cluster of differentiation 152” (e.g., GenBank Accession Number NP_001032720 (human isoform without transmembrane) and NP_005205 (human isoform with transmembrane)) as used herein is meant a coinhibitory receptor that is present on the surface of CD4+ and CD8+ T cells that is upregulated in inflammatory environments in which activated T cells are present. Unless otherwise stated herein, the bispecific antibodies provided herein bind to the extracellular domain of human CTLA4. CTLA4 is a member of the immunoglobulin superfamily. CTLA4 contains an extracellular V domain, a transmembrane domain, and a cytoplasmic tail. Alternate splice variants, encoding different isoforms, have been characterized. The membrane-bound isoform functions as a homodimer interconnected by a disulfide bond, while the soluble isoform functions as a monomer. CTLA4 is capable of providing a physiological counterbalance to immune cell activation and thereby to control the intensity of the immune response. It exerts this effect by outcompeting CD28, a costimulatory molecule necessary for T-cell activation, for binding to CD80 and CD86 on antigen-presenting cells and tumor cells. The net effect of CTLA4 up-regulation is down-modulation of T-cell activation (Postow et al., J Clin Oncol. 2015;33(17): 1974-1982). CTLA4 can also inhibit T cell responses directly via SHP-2 and PP2A dephosphorylation of TCR-proximal signaling proteins such as CD3 and LAT. CTLA4 is also known to bind PI3K. [0033] By “PD1,” “PD1,” “Programmed cell death protein 1,” “CD279,” and “cluster of differentiation 279” (e.g., GenBank Accession Number NP_0015009 (human)) as used herein is meant a type I membrane protein that is a member of the extended CD28/CTLA4 family of T cell regulators. Unless otherwise stated herein, the bispecific antibodies provided herein bind to the extracellular domain of human PD1. PD1 includes an extracellular IgV domain followed by a transmembrane region and an intracellular tail PD1 is expressed on the surface of activated T cells, B cells and macrophage and is upregulated in the context of chronic and persistent antigen stimulation. In human subjects with cancer, PD1 is upregulated on the surface of activated tumor-infiltrating CD8+ T cells, as well as activated B cells and myeloid cells. Its primary ligands, PDL1 and PDL2, may be expressed on a wide range of cell types including antigen-presenting cells and tumor cells, and the overall effect of engagement of the ligands is to limit, terminate, or attenuate the cytotoxic and cytokine-producing capacity of cytotoxic T cells. This, in turn, results in an ineffective antitumor immune response and the persistence of tumors (Postow et al., J Clin Oncol. 2015;33(17): 1974-1982).
[0034] By “bispecific” or “bispecific antibody” herein is meant any non-native or alternate antibody formats, including those described herein, that bind to two different antigens (e.g., PD1 x CTLA4 bispecific antibodies, such as XmAb®20717).
[0035] By “modification” herein is meant an amino acid substitution, insertion, and/or deletion in a polypeptide sequence or an alteration to a moiety chemically linked to a protein. For example, a modification may be an altered carbohydrate or PEG structure attached to a protein. By “amino acid modification” herein is meant an amino acid substitution, insertion, and/or deletion in a polypeptide sequence. For clarity, unless otherwise noted, the amino acid modification is always to an amino acid coded for by DNA, e.g., the 20 amino acids that have codons in DNA and RNA.
[0036] By “amino acid substitution” or “substitution” herein is meant the replacement of an amino acid at a particular position in a parent polypeptide sequence with a different amino acid. In particular, in some embodiments, the substitution is to an amino acid that is not naturally occurring at the particular position, either not naturally occurring within the organism or in any organism. For example, the substitution E272Y refers to a variant polypeptide, in this case an Fc variant, in which the glutamic acid at position 272 is replaced with tyrosine. In some cases, any amino acid substitution is always to an amino acid coded for by DNA, e.g, the 20 amino acids that have codons in DNA and RNA. For clarity, a protein which has been engineered to change the nucleic acid coding sequence but not change the starting amino acid (for example exchanging CGG (encoding arginine) to CGA (still encoding arginine) to increase host organism expression levels) is not an “amino acid substitution”; that is, despite the creation of a new gene encoding the same protein, if the protein has the same amino acid at the particular position that it started with, it is not an amino acid substitution.
[0037] By “amino acid insertion” or “insertion” as used herein is meant the addition of an amino acid sequence at a particular position in a parent polypeptide sequence. For example, - 233E or 233E designates an insertion of glutamic acid after position 233 and before position 234. Additionally, -233ADE or A233ADE designates an insertion of AlaAspGlu after position 233 and before position 234. In this case, any amino acid insertion is to an amino acid coded for by DNA, e.g., the 20 amino acids that have codons in DNA and RNA.
[0038] By “amino acid deletion” or “deletion” as used herein is meant the removal of an amino acid sequence at a particular position in a parent polypeptide sequence. For example, K447-, K447_, K447del or K447# designates a deletion of lysine at position 447. As is known in the art and more fully disclosed below, N- or C-terminal clipping can occur during production, including the lysine at position 447, the glycine at position 446, or additional amino acids. In some cases, the nucleic acids encoding the heavy chains herein can terminate at position 447, 446, 445, 444, etc.
[0039] By “variant protein” or “protein variant”, or “variant” as used herein is meant a protein that differs from that of a parent protein by virtue of at least one amino acid modification. Protein variant may refer to the protein itself, a composition comprising the protein, or the amino sequence that encodes it. Preferably, the protein variant has at least one amino acid modification compared to the parent protein, e.g., from about one to about seventy amino acid modifications, and preferably from about one to about twenty amino acid modifications compared to the parent. For example, the variant Fc domains of XmAb®717 can have 14 amino acid variants as compared to a human IgGl. As described below, in some embodiments the parent polypeptide, for example an Fc parent polypeptide, is a human wild type sequence, such as the Fc region from IgGl, IgG2, IgG4, although human sequences with variants can also serve as “parent polypeptides”. The protein variant sequence herein can preferably possess at least about 80% identity with a parent protein sequence, and most preferably at least about 90% identity, more preferably at least about 95-98-99% identity. Variant protein can refer to the variant protein itself, compositions comprising the protein variant, or the DNA sequence that encodes it. Accordingly, by “antibody variant” or “variant antibody” as used herein is meant an antibody that differs from a parent antibody by virtue of at least one amino acid modification, “IgG variant” or “variant IgG” as used herein is meant an antibody that differs from a parent IgG (again, in many cases, from a human IgG sequence) by virtue of at least one amino acid modification, and “immunoglobulin variant” or “variant immunoglobulin” as used herein is meant an immunoglobulin sequence that differs from that of a parent immunoglobulin sequence by virtue of at least one amino acid modification. “Fc variant” or “variant Fc” as used herein is meant a protein comprising an amino acid modification in an Fc domain. The Fc variants provided herein are defined according to the amino acid modifications that compose them. Thus, for example, N434S or 434S is an Fc variant with the substitution serine at position 434 relative to the parent Fc polypeptide, where the numbering is according to the EU index. Likewise, M428L/N434S defines an Fc variant with the substitutions M428L and N434S relative to the parent Fc polypeptide. The identity of the WT amino acid may be unspecified, in which case the aforementioned variant is referred to as 428L/434S. It is noted that the order in which substitutions are provided is arbitrary, that is to say that, for example, N434S/M428L is the same Fc variant as M428L/N434S, and so on. For all positions discussed herein that relate to antibodies, unless otherwise noted, amino acid position numbering is according to the EU index. The EU index or EU index as in Kabat or EU numbering scheme refers to the numbering of the EU antibody (Edelman et al., 1969, Proc Natl Acad Sci USA 63:78-85, hereby entirely incorporated by reference.) The modification can be an addition, deletion, or substitution. For clarity, variant proteins within the scope of the present disclosure retain the biological activity of the parent protein, although it can differ in scale or scope. Thus, for example, amino acid substitutions can be made in the anti-CTLA4 antigen binding domains provided herein as long as they retain the ability to bind to human CTLA4 as measured by a BIOCORE or Octet assay.
[0040] As used herein, “protein” is meant at least two covalently attached amino acids, which includes proteins, polypeptides, oligopeptides and peptides. The peptidyl group may comprise naturally occurring amino acids and peptide bonds, or synthetic peptidomimetic structures, i.e. “analogs”, such as peptoids (see Simon et al., PNAS USA 89(20):9367 (1992), entirely incorporated by reference). The amino acids may either be naturally occurring or synthetic (e.g., not an amino acid that is coded for by DNA); as will be appreciated by those in the art. For example, homo-phenylalanine, citrulline, ornithine and noreleucine are considered synthetic amino acids herein, and both D- and L-(R or S) configured amino acids may be utilized. The variants herein may comprise modifications that include the use of synthetic amino acids incorporated using, for example, the technologies developed by Schultz and colleagues, including but not limited to methods described by Cropp & Shultz, 2004, Trends Genet. 20(12):625-30, Anderson et al., 2004, Proc Natl Acad Sci USA 101 (2):7566- 71, Zhang et al., 2003, 303(5656):371-3, and Chin et al., 2003, Science 301(5635):964-7, all entirely incorporated by reference. In addition, polypeptides may include synthetic derivatization of one or more side chains or termini, glycosylation, PEGylation, circular permutation, cyclization, linkers to other molecules, fusion to proteins or protein domains, and addition of peptide tags or labels.
[0041] By “residue” as used herein is meant a position in a protein and its associated amino acid identity. For example, Asparagine 297 (also referred to as Asn297 or N297) is a residue at position 297 in the human antibody IgGl .
[0042] As used herein, the term “antibody” is used in a broad sense and includes immunoglobulin or antibody molecules. In general, antibodies are proteins or peptide chains that exhibit binding specificity to a specific antigen. In specific embodiments, the antibodies provided herein are based on IgGl, IgG2, or IgG4. In some embodiments, the antibodies provided herein are based on IgGl, IgG2, or IgG4 and contain amino acid variants. In many preferred embodiments, the antibodies provided herein are based on human IgGl, and contain amino acid variants as outlined herein. Antibody light chains of vertebrate species can be assigned to one of two clearly distinct types, namely kappa and lambda, based on the amino acid sequences of their constant domains. In one embodiment, an antibody provided herein comprises a kappa light chain. In other embodiments, an antibody provided herein comprises a lambda light chain. In certain embodiments, an antibody provided herein comprises a kappa light chain and a lambda light chain. Accordingly, the antibodies provided herein can, in certain embodiments, contain a kappa light chain constant domain. In other embodiments, antibodies provided herein can, in certain embodiments, contain lambda light chain constant domains. In some embodiments, the antibodies provided herein can contain kappa light chain and lambda light chain constant domains.
[0043] In addition to the heavy and light constant domains, antibodies contain an antigenbinding region that is made up of a light chain variable (VL) domain (or region) and a heavy chain variable (VH) domain (or region). The term “hypervariable region”, such as a VH or VL, when used herein refers to the regions of an antibody variable region that are hypervariable in sequence and/or form structurally defined loops. Generally, antibodies comprise six hypervariable regions; three in the VH (HCDR1, HCDR2, HCDR3), and three in the VL (LCDR1, LCDR2, LCDR3). A “CDR” refers to one of three hypervariable regions (VH CDR1, VH CDR2 or VH CDR3) within the non-framework region of the immunoglobulin (Ig or antibody) VH P-sheet framework, or one of three hypervariable regions (VL CDR1, VL CDR2 or VL CDR3) within the non-framework region of the antibody VL P-sheet framework. Accordingly, CDRs are variable region sequences interspersed within the framework region sequences. The light chain variable region CDR1 domain is interchangeably referred to herein as LCDR1 or VL CDR1. The light chain variable region CDR2 domain is interchangeably referred to herein as LCDR2 or VL CDR2. The light chain variable region CDR3 domain is interchangeably referred to herein as LCDR3 or VL CDR3. The heavy chain variable region CDR1 domain is interchangeably referred to herein as HCDR1 or VH CDR1. The heavy chain variable region CDR2 domain is interchangeably referred to herein as HCDR2 or VH CDR2. The heavy chain variable region CDR1 domain is interchangeably referred to herein as HCDR3 or VH CDR3.
[0044] A number of hypervariable region delineations are in use and are encompassed herein, for example, in the tables and/or Examples provided below. The “Kabaf ’ CDRs are based on sequence variability and are the most commonly used (see, e.g., Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD. (1991)). “Chothia” refers instead to the location of the structural loops (see, e.g., Chothia and Lesk, J. Mol. Biol. 196:901-917 (1987)). The end of the Chothia CDR-HCDR1 loop when numbered using the Kabat numbering convention varies between H32 and H34 depending on the length of the loop (this is because the Kabat numbering scheme places the insertions at H35A and H35B; if neither 35 A nor 35B is present, the loop ends at 32; if only 35A is present, the loop ends at 33; if both 35A and 35B are present, the loop ends at 34). The “AbM” hypervariable regions represent a compromise between the Kabat CDRs and Chothia structural loops, and are used by Oxford Molecular’s AbM antibody modeling software (see, e.g., Martin, in Antibody Engineering, Vol. 2, Chapter 3, Springer Verlag). “Contact” hypervariable regions are based on an analysis of the available complex crystal structures. An additional a universal numbering system can also be used, ImMunoGeneTics (IMGT) Information System® (Lafranc et al., Dev. Comp. Immunol. 27(l):55-77 (2003)). IMGT is an integrated information system specializing in immunoglobulins (IG), T cell receptors (TR) and major histocompatibility complex (MHC) of human and other vertebrates. Herein, the CDRs are referred to in terms of both the amino acid sequence and the location within the light or heavy chain. As the “location” of the CDRs within the structure of the immunoglobulin variable domain is conserved between species and present in structures called loops, by using numbering systems that align variable domain sequences according to structural features, CDR and framework residues and are readily identified. This information can be used in grafting and replacement of CDR residues from immunoglobulins of one species into an acceptor framework from, typically, a human antibody. An additional numbering system (AHon) has been developed by Honegger and Pliickthun, J. Mol. Biol. 309: 657-670 (2001). Correspondence between the numbering system, including, for example, the Kabat numbering and the IMGT unique numbering system, is well known to one skilled in the art (see, e.g., Kabat, supra, Chothia and Lesk, supra, Martin, supra, Lafranc el al., supra). An Exemplary system may also be used that combines Kabat and Chothia.
Figure imgf000016_0001
[0045] Hypervariable regions may comprise “extended hypervariable regions” as follows: 24-36 or 24-34 (LCDR1), 46-56 or 50-56 (LCDR2) and 89-97 or 89-96 (LCDR3) in the VL and 26-35 or 26-35A (HCDR1), 50-65 or 49-65 (HCDR2) and 93-102, 94-102, or 95-102 (HCDR3) in the VH. CDR sequences, reflecting each of the above numbering schemes, are provided herein.
[0046] The term “constant region” or “constant domain” refers to a carboxy terminal portion of the light and heavy chain which is not directly involved in binding of the antibody to antigen but exhibits various effector function, such as interaction with the Fc receptor. The terms refer to the portion of an immunoglobulin molecule having a more conserved amino acid sequence relative to the other portion of the immunoglobulin, the variable region, which contains the antigen binding site. The constant region may contain the CHI, hinge, CH2 and CH3 regions of the heavy chain and the CL region of the light chain.
[0047] The term “framework” or “FR” residues are those variable region residues flanking the CDRs. FR residues are those variable domain residues other than the hypervariable region residues or CDR residues.
[0048] By “antigen binding domain” or “ABD” herein is meant a set of six Complementary Determining Regions (CDRs) that, when present as part of a polypeptide sequence, specifically binds a target antigen as discussed herein. Thus, a “CTLA4 antigen binding domain” binds human CTLA4. A “checkpoint antigen binding domain” binds a target checkpoint antigen as outlined herein. As is known in the art, these CDRs are generally present as a first set of variable heavy CDRs (vhCDRs or VHCDRs) and a second set of variable light CDRs (vlCDRs or VLCDRs), each comprising three CDRs: vhCDRl, vhCDR2, vhCDR3 for the heavy chain and vlCDRl, vlCDR2 and vlCDR3 for the light. The CDRs are present in the variable heavy and variable light domains, respectively, and together form an Fv region. Thus, in some cases, the six CDRs of the antigen binding domain are contributed by a variable heavy and a variable light domain. In a “Fab” format, the set of 6 CDRs are contributed by two different polypeptide sequences, the variable heavy domain (vh or VH; containing the vhCDRl, vhCDR2 and vhCDR3) and the variable light domain (vl or VL; containing the vlCDRl, vlCDR2 and vlCDR3), with the C-terminus of the vh domain being attached to the N-terminus of the CHI domain of the heavy chain and the C-terminus of the vl domain being attached to the N-terminus of the constant light domain (and thus forming the light chain). In a scFv format, the vh and vl domains are covalently attached, generally through the use of a linker (a “scFv linker”) as outlined herein, into a single polypeptide sequence, which can be either (starting from the N-terminus) vh-linker-vl or vl- linker-vh (including optional domain linkers on each side, depending on the format used (e.g., from FIG. 1). In general, the C-terminus of the scFv domain is attached to the N- terminus of the hinge in the second monomer.
[0049] By “Fab” or “Fab region” as used herein is meant the polypeptide that comprises the VH, CHI, VL, and CL immunoglobulin domains, generally on two different polypeptide chains (e.g., VH-CH1 on one chain and VL-CL on the other). Fab may refer to this region in isolation, or this region in the context of a bispecific antibody provided herein. In the context of a Fab, the Fab comprises an Fv region in addition to the CHI and CL domains.
[0050] By “Fv” or “Fv fragment” or “Fv region” as used herein is meant a polypeptide that comprises the VL and VH domains of an ABD. Fv regions can be formatted as both Fabs (as discussed above, generally two different polypeptides that also include the constant regions as outlined above) and scFvs, where the VL and VH domains are combined (generally with a linker as discussed herein) to form an scFv.
[0051] By “single chain Fv” or “scFv” herein is meant a variable heavy domain covalently attached to a variable light domain, generally using a scFv linker as discussed herein, to form a scFv or scFv domain. A scFv domain can be in either orientation from N- to C-terminus (vh-linker-vl or vl-linker-vh). In the sequences depicted in the sequence listing and in the figures, the order of the vh and vl domain is indicated in the name, e.g., H.X L.Y means N- to C-terminal is vh-linker-vl, and L.Y H.X is vl-linker-vh.
[0052] By “ amino acid” and “amino acid identity” as used herein is meant one of the 20 naturally occurring amino acids that are coded for by DNA and RNA.
[0053] By “IgG Fc ligand” as used herein is meant a molecule, preferably a polypeptide, from any organism that binds to the Fc region of an IgG antibody to form an Fc/Fc ligand complex. Fc ligands include but are not limited to FcyRIs, FcyRIIs, FcyRIIIs, FcRn, Clq, C3, mannan binding lectin, mannose receptor, staphylococcal protein A, streptococcal protein G, and viral FcyR. Fc ligands also include Fc receptor homologs (FcRH), which are a family of Fc receptors that are homologous to the FcyRs (Davis et al., 2002, Immunological Reviews 190: 123-136, entirely incorporated by reference). Fc ligands may include undiscovered molecules that bind Fc. Particular IgG Fc ligands are FcRn and Fc gamma receptors. By “Fc ligand” as used herein is meant a molecule, preferably a polypeptide, from any organism that binds to the Fc region of an antibody to form an Fc/Fc ligand complex.
[0054] By “Fc gamma receptor”, “FcyR” or “FcgammaR” as used herein is meant any member of the family of proteins that bind the IgG antibody Fc region and is encoded by an FcyR gene. In humans this family includes but is not limited to FcyRI (CD64), including isoforms FcyRIa, FcyRIb, and FcyRIc; FcyRII (CD32), including isoforms FcyRIIa (including allotypes H131 and R131), FcyRIIb (including FcyRIIb-1 and FcyRIIb-2), and FcyRIIc; and FcyRIII (CD16), including isoforms FcyRIIIa (including allotypes V158 and Fl 58) and FcyRIIIb (including allotypes FcyRIIb-NAl and FcyRIIb-NA2) (Jefferis et al., 2002, Immunol Lett 82:57-65, entirely incorporated by reference), as well as any undiscovered human FcyRs or FcyR isoforms or allotypes. An FcyR may be from any organism, including but not limited to humans, mice, rats, rabbits, and monkeys. Mouse FcyRs include but are not limited to FcyRI (CD64), FcyRII (CD32), FcyRIII (CD16), and FcyRIII-2 (CD16-2), as well as any undiscovered mouse FcyRs or FcyR isoforms or allotypes.
[0055] By “FcRn” or “neonatal Fc Receptor” as used herein is meant a protein that binds the IgG antibody Fc region and is encoded at least in part by an FcRn gene. As is known in the art, the functional FcRn protein comprises two polypeptides, often referred to as the heavy chain and light chain. The light chain is beta-2-microglobulin and the heavy chain is encoded by the FcRn gene. Unless otherwise noted herein, FcRn or an FcRn protein refers to the complex of FcRn heavy chain with beta-2-microglobulin. A variety of FcRn variants can be used to increase binding to the FcRn receptor, and in some cases, to increase serum halflife.
[0056] By “parent polypeptide” as used herein is meant a starting polypeptide that is subsequently modified to generate a variant. The parent polypeptide may be a naturally occurring polypeptide, or a variant or engineered version of a naturally occurring polypeptide. Parent polypeptide may refer to the polypeptide itself, compositions that comprise the parent polypeptide, or the amino acid sequence that encodes it. Accordingly, by “parent immunoglobulin” as used herein is meant an unmodified immunoglobulin, polypeptide that is modified to generate a variant, and by “parent antibody” as used herein is meant an unmodified antibody that is modified to generate a variant antibody.
[0057] By “Fc” or “Fc region” or “Fc domain” as used herein is meant the polypeptide comprising the CH2-CH3 domains of an IgG molecule, and in some cases, inclusive of the hinge. In EU numbering for human IgGl, the CH2-CH3 domain comprises amino acids 231 to 447, and the hinge is 216 to 230. Thus, the definition of “Fc domain” includes both amino acids 231-447 (CH2-CH3) or 216-447 (hinge-CH2-CH3), or fragments thereof. An “Fc fragment” in this context may contain fewer amino acids from either or both of the N- and C- termini but still retains the ability to form a dimer with another Fc domain or Fc fragment as can be detected using standard methods, generally based on size (e.g., non-denaturing chromatography, size exclusion chromatography, etc.) Human IgG Fc domains are of particular use in the methods provided herein, and can be the Fc domain from human IgGl, IgG2 or IgG4.
[0058] By “heavy chain constant region” herein is meant the CHl-hinge-CH2-CH3 portion of an antibody (or fragments thereof), excluding the variable heavy domain; in EU numbering of human IgGl this is amino acids 118-447. By “heavy chain constant region fragment” herein is meant a heavy chain constant region that contains fewer amino acids from either or both of the N- and C-termini but still retains the ability to form a dimer with another heavy chain constant region.
[0059] By “position” as used herein is meant a location in the sequence of a protein. Positions may be numbered sequentially, or according to an established format, for example the EU index for antibody numbering.
[0060] By “target antigen” as used herein is meant the molecule that is bound specifically by the antigen binding domain comprising the variable regions of a given antibody. As discussed below, in the present case the target antigens are CTLA4 and PD1. [0061] By “strandedness” in the context of the monomers of the heterodimeric antibodies provided herein is meant that, similar to the two strands of DNA that “match”, heterodimerization variants are incorporated into each monomer so as to preserve the ability to “match” to form heterodimers. For example, if some pl variants are engineered into monomer A (e.g., making the pl higher) then steric variants that are “charge pairs” that can be utilized as well do not interfere with the pl variants, e.g., the charge variants that make a pl higher are put on the same “strand” or “monomer” to preserve both functionalities. Similarly, for “skew” variants that come in pairs of a set as more fully outlined below, the skilled artisan will consider pl in deciding into which strand or monomer that incorporates one set of the pair will go, such that pl separation is maximized using the pl of the skews as well.
[0062] By “target cell” as used herein is meant a cell that expresses a target antigen. [0063] By “host cell” in the context of producing a bispecific antibody provided herein is meant a cell that contains the exogeneous nucleic acids encoding the components of the bispecific antibody and is capable of expressing the bispecific antibody under suitable conditions. Suitable host cells are discussed herein.
[0064] By “variable region” or “variable domain” as used herein is meant the region of an immunoglobulin that comprises one or more Ig domains substantially encoded by any of the VK, V , and/or VH genes that make up the kappa, lambda, and heavy chain immunoglobulin genetic loci respectively, and contains the CDRs that confer antigen specificity. Thus, a “variable heavy domain” pairs with a “variable light domain” to form an antigen binding domain (“ABD”). In addition, each variable domain comprises three hypervariable regions (“complementary determining regions,” “CDRs”) (vhCDRl, vhCDR2 and vhCDR3 for the variable heavy domain and vlCDRl, vlCDR2 and vlCDR3 for the variable light domain) and four framework (FR) regions, arranged from amino-terminus to carboxy -terminus in the following order: FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4.
[0065] Also provided is a number of antibody domains that have sequence identity to human antibody domains, or to the anti-CTLA4 domains, PD1 domains, or Fc domains of XmAb®717. Sequence identity between two similar sequences (e.g., antibody variable domains) can be measured by algorithms such as that of Smith, T.F. & Waterman, M.S. (1981) “Comparison of Biosequences,” Adv. Appl. Math. 2:482 [local homology algorithm]; Needleman, S.B. & Wunsch, CD. (1970) “A General Method Applicable To The Search For Similarities In The Amino Acid Sequence Of Two Proteins,” J. Mol. Biol. 48:443 [homology alignment algorithm], Pearson, W.R. & Lipman, D.J. (1988) “Improved Tools For Biological Sequence Comparison,” Proc. Natl. Acad. Sci. (U.S.A.) 85:2444 [search for similarity method]; or Altschul, S.F. et al, (1990) “Basic Local Alignment Search Tool,” J. Mol. Biol. 215:403-10 , the “BLAST” algorithm, see https://blast.ncbi.nlm.nih.gov/Blast.cgi. When using any of the aforementioned algorithms, the default parameters (for Window length, gap penalty, etc.) are used. In one embodiment, sequence identity is done using the BLAST algorithm, using default parameters. Accordingly, suitable Fv or Fc domains can be, e.g., 90%, 95%, 98%, 99%, or 100% identical to the parental domains.
[0066] By “wild type or WT” herein is meant an amino acid sequence or a nucleotide sequence that is found in nature, including allelic variations. A WT protein has an amino acid sequence or a nucleotide sequence that has not been intentionally modified.
[0067] The antibodies provided herein are generally isolated or recombinant. “Isolated,” when used to describe the various polypeptides disclosed herein, means a polypeptide that has been identified and separated and/or recovered from a cell or cell culture from which it was expressed. Ordinarily, an isolated polypeptide can be prepared by at least one purification step. An “isolated antibody,” refers to an antibody which is substantially free of other antibodies having different antigenic specificities. “Recombinant” means the antibodies are generated using recombinant nucleic acid techniques in exogeneous host cells, and they can be isolated as well.
[0068] “Specific binding” or “specifically binds to” or is “specific for” a particular antigen or an epitope means binding that is measurably different from a non-specific interaction. Specific binding can be measured, for example, by determining binding of a molecule compared to binding of a control molecule, which generally is a molecule of similar structure that does not have binding activity. For example, specific binding can be determined by competition with a control molecule that is similar to the target.
[0069] Specific binding for a particular antigen or an epitope can be exhibited, for example, by an antibody having a KD for an antigen or epitope of at least about 10'4 M, at least about 10'5 M, at least about 10'6 M, at least about 10'7 M, at least about 10'8 M, at least about 10'9 M, alternatively at least about 10'10 M, at least about 10'11 M, at least about 10'12 M, or greater, where KD refers to a dissociation rate of a particular antibody-antigen interaction. Typically, an antibody that specifically binds an antigen can have a KD that is 20-, 50-, 100-, 500-, 1000-, 5,000-, 10,000- or more times greater for a control molecule relative to the antigen or epitope.
[0070] Also, specific binding for a particular antigen or an epitope can be exhibited, for example, by an antibody having a KA or Ka for an antigen or epitope of at least 20-, 50-, 100-, 500-, 1000-, 5,000-, 10,000- or more times greater for the epitope relative to a control, where KA or Ka refers to an association rate of a particular antibody-antigen interaction. Binding affinity is generally measured using a Biacore, SPR or BLI assay.
[0071] By “refractory” in the context of a cancer is intended the particular cancer is resistant to, or non-responsive to, therapy with a particular therapeutic agent. A cancer can be refractory to therapy with a particular therapeutic agent either from the onset of treatment with the particular therapeutic agent (z.e., non-responsive to initial exposure to the therapeutic agent), or as a result of developing resistance to the therapeutic agent, either over the course of a first treatment period with the therapeutic agent or during a subsequent treatment period with the therapeutic agent.
[0072] As used herein, the terms “positive therapeutic response,” “treat,” “treatment,” and/or “treating” refer to the reduction or amelioration or elimination of the progression, severity and/or effect associated with a prostate cancer described herein, or the improvement in the prostate cancer condition, or the improvement in the disease associated with the prostate cancer, or the increase in the immune system response of the human subject (e.g., male subject for prostate cancer), or the amelioration of one or more symptoms (preferably, one or more discernible symptoms) of a prostate cancer described herein resulting from the administration of one or more therapies. In specific embodiments, the terms “positive therapeutic response,” “treat,” “treatment,” and/or “treating” refer to the amelioration of at least one measurable physical parameter of a prostate cancer described herein, such as tumor size, rate of tumor growth, number of tumor cells, tumor invasiveness, presence of metastasis, or extent of metastasis. In other embodiments the terms “positive therapeutic response,” “treat,” “treatment,” and/or “treating” refer to the inhibition of the progression of a prostate cancer described herein, either physically by, e.g., stabilization of a discernible symptom, physiologically by, e.g., stabilization of a physical parameter, or both. In an exemplary embodiment, achieving a positive therapeutic response against a prostate cancer provides an improvement, or a lack of progression, in the disease associated with the tumor or the tumor condition, and/or an improvement, or a lack of progression, in the symptoms associated with the disease or condition.
[0073] For example, achieving a positive therapeutic response against a prostate cancer refers to one or more of the following: (1) a reduction in the number of cancer cells (e.g., prostate cancer cells); (2) an increase in cell death (e.g., prostate cancer cell death); (3) inhibition of cell survival (e.g., prostate cancer cell survival); (5) inhibition (z.e., slowing to some extent, preferably lack of progression) of cancer growth (e.g., prostate cancer growth), such as stable disease; (6) inhibition of cancer cell metastasis (e.g., prostate cancer cell metastasis); (7) an increase in progression-free survival; (8) an increase in overall survival rate; and (9) some relief from one or more symptoms associated with the disease or condition. [0074] Additional descriptions regarding positive therapeutic responses can be found in the RECIST criteria (Eisenhauer et al. Eur J Can. 2009; 45:228-47; Chalian et al. One. 2011; 31 :2093-105); the imRECIST criteria (Hodi et al. J Clin Oncol. 2018: JCO2017751644. doi: 10.1200/JC0.2017.75.1644); the modified IrRC criteria (Wolchok et al. Clin Cancer Res. 2009;15(23):7412-20); and the PCWG3 criteria (Scher et al. Clin Oncol. 2016;34(12): 1402- 18). Each of the aforementioned references is herein incorporated by reference in its entirety for disclosures relating to the respective criteria. Exemplary embodiments for the assessment of prostate cancer treatment using the RECIST guidelines are also provided elsewhere herein. [0075] In some embodiments, achieving a positive therapeutic response against a prostate cancer involves administering the compositions described herein for a pre-specified period of time, discontinuing administration for another specific period of time, and resuming administration of the compositions described herein for yet another specific period of time. In some embodiments, achieving a positive therapeutic response against a prostate cancer involves administering the compositions described herein until one of the responses described herein is achieved, pausing administration of the compositions described herein while this positive therapeutic response continues to be observed, and resuming administration of the compositions described herein if this positive therapeutic response ceases to be observed. [0076] Positive therapeutic responses against a prostate cancer can be determined by standardized response criteria specific to the disease associated with the prostate cancer. Prostate cancer response can be assessed for changes in tumor morphology (ie., with neoadjuvant use of a therapy, such as assessment of pathological response) or tumor metrics (z.e., overall tumor burden, tumor size, and the like) using screening techniques such as magnetic resonance imaging (MRI) scan, positron emission tomography (PET) scan, x-radiographic imaging, radionuclide scan, computed tomographic (CT) scan, bone scan imaging, endoscopy, tumor sampling including bone marrow aspiration (BMA), and counting of tumor marker levels and/or tumor cells in the circulation.
[0077] A positive therapeutic response or treating according to the present disclosure can include an improvement in one or more symptoms associated with a prostate cancer of the disclosure. In some embodiments, a symptom includes feeling less tired, feeling less weak, feeling less dizzy or lightheaded, reduction in shortness of breath, reduction in fever, fewer infections, quicker recovery from infections, reduction in ease of bruising, reduction in bleeding episodes, weight gain, reduction in night sweats, gain of appetite, reduction in abdominal swelling, reduction in lymph node swelling, reduction in bone or joint pain, and reduction in thymus swelling.
[0078] In certain embodiments, the positive therapeutic response is as compared to the response in the subject prior to treatment with the bispecific anti-CTLA4 x anti-PDl antibody.
[0079] A positive therapeutic response or treating according to the present disclosure includes a “therapeutically effective amount” of the medicaments used. A “therapeutically effective amount” refers to an amount effective, at dosages and for periods of time necessary, to achieve a desired therapeutic result. In some embodiments, the desired therapeutic result is a complete response, partial response or stable disease. In specific embodiments, the desired therapeutic result is an improvement in response according to the RECIST guidelines (v. 1.1) as outlined in Eisenhauer et al. Eur. J. Cancer, 2009, 45:228-247, which is incorporated herein by reference in its entirety regarding, e.g., tumor response evaluation criteria. For example, in the case of evaluation of target lesions, for example, a “Complete Response” (CR) refers to the disappearance of all target lesions, where any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. A “Partial Response” (PR) refers to at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. “Progressive Disease” (PD) refers to at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progression). “Stable Disease” (SD) refers to neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. In the case of evaluation of non-target lesions, a “Complete Response” (CR) refers to the disappearance of all non-target lesions and normalization of tumor marker level. All lymph nodes must be non-pathological in size (<10mm short axis). A “Non-CR/Non-PD” refers to persistence of one or more non-target lesion(s) and/or maintenance of tumor marker level above the normal limits. A “Progressive Disease” (PD) refers to the unequivocal progression of existing non-target lesions. (Note: the appearance of one or more new lesions is also considered progression).
[0080] A therapeutically effective amount may vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of the medicaments to elicit a desired response in the individual. A therapeutically effective amount is also one in which any toxic or detrimental effects of the antibody or antibody portion are outweighed by the therapeutically beneficial effects.
[0081] A “therapeutically effective amount” for tumor therapy may also be measured by its ability to stabilize the progression of disease. The ability of the compositions described herein to achieve a positive therapeutic response against a prostate cancer may be evaluated in an animal model system predictive of efficacy in human tumors.
[0082] Alternatively, this property of a composition may be evaluated by examining the ability of its components to inhibit cell growth or to induce apoptosis by in vitro assays known to the skilled practitioner. A therapeutically effective amount of a composition described herein may decrease tumor size, or otherwise ameliorate symptoms in a subject. One of ordinary skill in the art would be able to determine such amounts based on such factors as the human subject’s size, the severity of the human subject’s symptoms, and the particular composition or route of administration selected.
[0083] The terms “patient,” “subject,” and “human subject” can be used interchangeably herein.
4.2 Overview
[0084] Disclosed herein are methods of treating a prostate cancer that include cells expressing CTLA4 (“CTLA4-expressing cancer”), for example, a prostate cancer of the disclosure, through the administration of certain bispecific anti-PDl x CTLA4 antibodies at particular dosages in combination with an additional agent (e.g., carboplatin, carbazitaxel, docetaxel, and/or olaparib). The term “CTLA4-expressing cancer” can refer to a cancer that expresses CTLA4 or a cancer that overexpresses CTLA4 as compared to normal tissue. The term “PD1 -expressing cancer” can refer to a cancer that expresses PD1 or a cancer that overexpresses PD1. Thus, the methods provided herein include treating a prostate cancer that expresses both CTLA4 and PD1, through the administration of certain bispecific anti-PDl x CTLA4 antibodies at particular dosages in combination with an additional agent (e.g., carboplatin, carbazitaxel, docetaxel, and/or olaparib).
[0085] In some aspects, the methods provided herein are directed to the administration of the bispecific anti-PDl x CTLA4 antibodies (e.g., XmAb®20717) in combination with an additional agent (e.g., carboplatin, carbazitaxel, docetaxel, and/or olaparib) for the treatment of prostate cancer as outlined herein. The disclosure provides methods of achieving a positive therapeutic response against a prostate cancer through the administration of XmAb®20717 according to a dosage regimen described herein in combination with an additional agent (e.g., carboplatin, carbazitaxel, docetaxel, and/or olaparib). The present disclosure also provides methods of treating prostate cancer through the administration of XmAb®20717 according to a dosage regimen described herein in combination with an additional agent (e.g., carboplatin, carbazitaxel, docetaxel, and/or olaparib). Also provided herein are methods of achieving a positive therapeutic response against prostate cancer through the administration of XmAb®20717, carboplatin, and cabazitaxel, according to a dosage regimen described herein. Also provided herein are methods of achieving a positive therapeutic response against prostate cancer through the administration of XmAb®20717, carboplatin, and docetaxel, according to a dosage regimen described herein. The disclosure also provides methods of achieving a positive therapeutic response against prostate cancer through the administration of XmAb®20717 and olaparib according to a dosage regimen described herein.
[0086] It will be understood that XmAb®20717 can be used as the bispecific anti-CTLA4 x anti-PDl antibody in all methods of the invention provided herein.
[0087] It will also be understood that that a biosimilar of XmAb®20717 can be used as the bispecific anti-CTLA4 x anti-PDl antibody in all methods of the invention provided herein.
[0088] It will further be understood that a bioequivalent of XmAb®20717 can be used as the bispecific anti-CTLA4 x anti-PDl antibody in all methods of the invention provided herein.
[0089] It will further be understood that a biobetter of XmAb®20717 can be used as the bispecific anti-CTLA4 x anti-PDl antibody in all methods of the invention provided herein.
4.3 Antibodies
[0090] Provided herein are methods directed to the administration of XmAb®20717 to achieve a positive therapeutic response against a prostate cancer in combination with at least one additional agent (e.g., carboplatin, carbazitaxel, docetaxel, and/or olaparib). The present disclosure is directed to the administration of XmAb®20717 for the treatment of a prostate cancer, as described herein and in U.S. Pat. App. No. 15/623,314, US Publication No. 2018/0118836, U.S. Prov. Pat. App. Nos. 62/350,145, 62/355,511, and 62/420,500, all of which are expressly incorporated herein by reference, particularly for the bispecific formats of the figures, as well as all sequences, Figures and accompanying Legends therein.
[0091] Amino acid sequences of exemplary bispecific anti-CTL4 x anti-PDl antibodies useful in the methods provided herein are shown in Table 1 below. Table 1. Amino Acid Sequences of Exemplary Bispecific anti-CTLA4 x anti-PDl
Antibodies (underlining refers to CDRs)
Figure imgf000027_0001
Figure imgf000028_0001
[0092] In some embodiments, the bispecific anti-CTLA4 x anti-PDl antibodies (e.g., XmAb®20717) have a “bottle opener” format (also referred to as the “triple F” format) as is generally depicted in FIG. 1. In this embodiment, the PD1 antigen binding domain is the scFv in the bottle opener format and the CTLA4 antigen binding domain is the Fab in the bottle opener format (terms as used in US Publication No. 20180118836 Al, all of which are expressly incorporated by reference in their entirety and specifically for all the definitions, sequences of CTLA4 antigen binding domains and sequences of PD1 antigen binding domains). [0093] The anti-PDl scFv antigen binding domain can have the sequence depicted in FIG. 2, Table 1. The anti-CTLA4 Fab binding domain can have the sequence depicted in FIG. 2, Table 1
[0094] One bispecific antibody of particular use in the methods provided herein, XmAb®20717, is shown in FIG. 2 and Table 1. In certain embodiments, XmAb®20717 includes a first monomer (or a first polypeptide) comprising SEQ ID NO: 1, a second monomer (or a second polypeptide) comprising SEQ ID NO: 2, and a light chain (or a third polypeptide) comprising SEQ ID NO: 3. In certain embodiments, XmAb®20717 includes a first polypeptide comprising an amino acid sequence of SEQ ID NO: 1, a second polypeptide comprising an amino acid sequence of SEQ ID NO: 2, and a third polypeptide comprising an amino acid sequence of SEQ ID NO: 3. XmAb®20717 can be made as known in the art. In certain embodiments, XmAb®20717 is made by expressing a nucleic acid composition that includes a) a first nucleic that encodes a first amino acid monomer comprising “Fab-Fc Heavy Chain;” b) a second nucleic that encodes a second amino acid monomer comprising “scFv-Fc Heavy Chain;” and c) a third nucleic that encodes a “light chain,” as depicted in FIG 2
[0095] Additionally, as is known in the art, N- and/or C-terminal clipping can occur during protein synthesis, whereby the heavy chains depicted herein may have the C-terminal lysine (K447) removed, as well as the penultimate glycine (G446), and optionally additional amino acids residues (e.g., from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more C-terminal amino acids can be removed). Alternatively, the nucleic acids encoding the heavy chains of the bispecific antibodies can be engineered such that these terminal residues are eliminated entirely to facilitate additional homogeneity. Thus, included within the definition of XmAb717 are C- terminally truncated versions. As is known in the art, this C-terminal clipping can also occur in vivo in the patient.
[0096] In some embodiments, the nucleic acids that encode for each of these three amino acid sequences can be incorporated into one or more expression vectors for expression. In certain embodiments, XmAb®20717 consists of a first monomer (or a first polypeptide) comprising SEQ ID NO: 1, a second monomer (or a second polypeptide) comprising SEQ ID NO: 2, and a light chain (or a third polypeptide) comprising SEQ ID NO: 3. In certain embodiments, XmAb®20717 includes a first monomer (or a first polypeptide) consisting of SEQ ID NO: 1, a second monomer (or a second polypeptide) comprising SEQ ID NO: 2, and a light chain (or a third polypeptide) comprising SEQ ID NO: 3. In certain embodiments, XmAb®20717 includes a first monomer (or a first polypeptide) comprising SEQ ID NO: 1, a second monomer (or a second polypeptide) consisting of SEQ ID NO: 2, and a light chain (or a third polypeptide) comprising SEQ ID NO: 3. In certain embodiments, XmAb®20717 includes a first monomer (or a first polypeptide) comprising SEQ ID NO: 1, a second monomer (or a second polypeptide) comprising SEQ ID NO: 2, and a light chain (or a third polypeptide) consisting of SEQ ID NO: 3. In certain embodiments, XmAb®20717 includes a first monomer (or a first polypeptide) consisting of SEQ ID NO: 1, a second monomer (or a second polypeptide) consisting of SEQ ID NO: 2, and a light chain (or a third polypeptide) comprising SEQ ID NO: 3. In certain embodiments, XmAb®20717 includes a first monomer (or a first polypeptide) consisting of SEQ ID NO: 1, a second monomer (or a second polypeptide) comprising SEQ ID NO: 2, and a light chain (or a third polypeptide) consisting of SEQ ID NO: 3. In certain embodiments, XmAb®20717 includes a first monomer (or a first polypeptide) comprising SEQ ID NO: 1, a second monomer (or a second polypeptide) consisting of SEQ ID NO: 2, and a light chain (or a third polypeptide) consisting of SEQ ID NO: 3. In certain embodiments, XmAb®20717 includes a first monomer (or a first polypeptide) consisting of SEQ ID NO: 1, a second monomer (or a second polypeptide) consisting of SEQ ID NO: 2, and a light chain (or a third polypeptide) consisting of SEQ ID NO: 3.
[0097] In some embodiments, the VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3 sequences are according to the Kabat numbering system. In some embodiments, the VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3 sequences are according to the Chothia numbering system. In some embodiments, the VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3 sequences are according to the Exemplary numbering system. In some embodiments, the VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3 sequences are according to the Contact numbering system. In some embodiments, the VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3 sequences are according to the IMGT numbering system. In some embodiments, the VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3 sequences are according to the AbM numbering system. Exemplary sets of 6 CDRs (VH CDR1-3 and VL CDR1-3) of certain antibody embodiments are provided herein. Other sets of CDRs are contemplated and within the scope of the antibody embodiments provided herein.
[0098] In one embodiment, the bispecific anti-CTLA4 x anti-PDl antibody comprises a first antigen binding domain that binds to PD1, wherein the first antigen binding domain comprises a VH comprising a VH CDR1, VH CDR2 and VH CDR3 having an amino acid sequence of a VH CDR1, VH CDR2 and VH CDR3, respectively, of a VH having an amino acid sequence provided in Table 1.
[0099] In one embodiment, the bispecific anti-CTLA4 x anti-PDl antibody comprises a first antigen binding domain that binds to PD1, wherein the first antigen binding domain comprises a VL comprising a VL CDR1, VL CDR2 and VL CDR3 having an amino acid sequence of a VL CDR1, VL CDR2 and VL CDR3, respectively, of a VL having an amino acid sequence provided in Table 1.
[00100] In one embodiment, the bispecific anti-CTLA4 x anti-PDl antibody comprises a first antigen binding domain that binds to PD1, wherein the first antigen binding domain comprises a VH comprising a VH CDR1, VH CDR2 and VH CDR3 having an amino acid sequence of a VH CDR1, VH CDR2 and VH CDR3, respectively, of a VH having an amino acid sequence provided in Table 1, and a VL comprising a VL comprising a VL CDR1, VL CDR2 and VL CDR3 having an amino acid sequence of a VL CDR1, VL CDR2 and VL CDR3, respectively, of a VL having an amino acid sequence provided in Table 1.
[00101] In one embodiment, the bispecific anti-CTLA4 x anti-PDl antibody comprises a second antigen binding domain that binds to CTLA4, wherein the second antigen binding domain comprises a VH comprising a VH CDR1, VH CDR2 and VH CDR3 having an amino acid sequence of a VH CDR1, VH CDR2 and VH CDR3, respectively, of a VH having an amino acid sequence provided in Table 1.
[00102] In one embodiment, the bispecific anti-CTLA4 x anti-PDl antibody comprises a second antigen binding domain that binds to CTLA4, wherein the second antigen binding domain comprises a VL comprising a VL CDR1, VL CDR2 and VL CDR3 having an amino acid sequence of a VL CDR1, VL CDR2 and VL CDR3, respectively, of a VL having an amino acid sequence provided in Table 1.
[00103] In one embodiment, the bispecific anti-CTLA4 x anti-PDl antibody comprises a second antigen binding domain that binds to CTLA4, wherein the second antigen binding domain comprises a VH comprising a VH CDR1, VH CDR2 and VH CDR3 having an amino acid sequence of a VH CDR1, VH CDR2 and VH CDR3, respectively, of a VH having an amino acid sequence provided in Table 1, and a VL comprising a VL CDR1, VL CDR2 and VL CDR3 having an amino acid sequence of a VL CDR1, VL CDR2 and VL CDR3, respectively, of a VL having an amino acid sequence provided in Table 1.
[00104] In one embodiment, the bispecific anti-CTLA4 x anti-PDl antibody comprises a first antigen binding domain that binds to PD1, wherein the first antigen binding domain comprises a VH comprising a VH CDR1, VH CDR2 and VH CDR3 having an amino acid sequence of a VH CDR1, VH CDR2 and VH CDR3, respectively, of a VH having an amino acid sequence provided in Table 1, and a VL comprising a VL CDR1, VL CDR2 and VL CDR3 having an amino acid sequence of a VL CDR1, VL CDR2 and VL CDR3, respectively, of a VL having an amino acid sequence provided in Table 1, and a second antigen binding domain that binds to CTLA4, wherein the second antigen binding domain comprises a VH comprising a VH CDR1, VH CDR2 and VH CDR3 having an amino acid sequence of a VH CDR1, VH CDR2 and VH CDR3, respectively, of a VH having an amino acid sequence provided in Table 1, and a VL comprising a VL CDR1, VL CDR2 and VL CDR3 having an amino acid sequence of a VL CDR1, VL CDR2 and VL CDR3, respectively, of a VL having an amino acid sequence provided in Table 1.
[00105] In one embodiment, the bispecific anti-CTLA4 x anti-PDl antibody comprises a first antigen binding domain that binds to PD1, wherein the first antigen binding domain comprises a VH comprising a VH CDR1, VH CDR2 and VH CDR3 having an amino acid sequence of a VH CDR1, VH CDR2 and VH CDR3, respectively, of a VH having an amino acid sequence of SEQ ID NO: 16.
[00106] In one embodiment, the bispecific anti-CTLA4 x anti-PDl antibody comprises a first antigen binding domain that binds to PD1, wherein the first antigen binding domain comprises a VL comprising a VL CDR1, VL CDR2 and VL CDR3 having an amino acid sequence of a VL CDR1, VL CDR2 and VL CDR3, respectively, of a VL having an amino acid sequence of SEQ ID NO: 17.
[00107] In one embodiment, the bispecific anti-CTLA4 x anti-PDl antibody comprises a first antigen binding domain that binds to PD1, wherein the first antigen binding domain comprises a VH comprising a VH CDR1, VH CDR2 and VH CDR3 having an amino acid sequence of a VH CDR1, VH CDR2 and VH CDR3, respectively, of a VH having an amino acid sequence of SEQ ID NO: 16, and a VL comprising a VL CDR1, VL CDR2 and VL CDR3 having an amino acid sequence of a VL CDR1, VL CDR2 and VL CDR3, respectively, of a VL having an amino acid sequence of SEQ ID NO: 17.
[00108] In one embodiment, the bispecific anti-CTLA4 x anti-PDl antibody comprises a second antigen binding domain that binds to CTLA4, wherein the second antigen binding domain comprises a VH comprising a VH CDR1, VH CDR2 and VH CDR3 having an amino acid sequence of a VH CDR1, VH CDR2 and VH CDR3, respectively, of a VH having an amino acid sequence of SEQ ID NO: 18.
[00109] In one embodiment, the bispecific anti-CTLA4 x anti-PDl antibody comprises a second antigen binding domain that binds to CTLA4, wherein the first antigen binding domain comprises a VL comprising a VL CDR1, VL CDR2 and VL CDR3 having an amino acid sequence of a VL CDR1, VL CDR2 and VL CDR3, respectively, of a VL having an amino acid sequence of SEQ ID NO: 19.
[00110] In one embodiment, the bispecific anti-CTLA4 x anti-PDl antibody comprises a second antigen binding domain that binds to CTLA4, wherein the second antigen binding domain comprises a VH comprising a VH CDR1, VH CDR2 and VH CDR3 having an amino acid sequence of a VH CDR1, VH CDR2 and VH CDR3, respectively, of a VH having an amino acid sequence of SEQ ID NO: 18, and a VL comprising a VL CDR1, VL CDR2 and VL CDR3 having an amino acid sequence of a VL CDR1, VL CDR2 and VL CDR3, respectively, of a VL having an amino acid sequence of SEQ ID NO: 19.
[00111] In one embodiment, the bispecific anti-CTLA4 x anti-PDl antibody comprises a first antigen binding domain that binds to PD1, wherein the first antigen binding domain comprises a VH comprising a VH CDR1, VH CDR2 and VH CDR3 having an amino acid sequence of a VH CDR1, VH CDR2 and VH CDR3, respectively, of a VH having an amino acid sequence of SEQ ID NO: 16, and a VL comprising a VL CDR1, VL CDR2 and VL CDR3 having an amino acid sequence of a VL CDR1, VL CDR2 and VL CDR3, respectively, of a VL having an amino acid sequence of SEQ ID NO: 17, and a second antigen binding domain that binds to CTLA4, wherein the second antigen binding domain comprises a VH comprising a VH CDR1, VH CDR2 and VH CDR3 having an amino acid sequence of a VH CDR1, VH CDR2 and VH CDR3, respectively, of a VH having an amino acid sequence of SEQ ID NO: 18, and a VL comprising a VL CDR1, VL CDR2 and VL CDR3 having an amino acid sequence of a VL CDR1, VL CDR2 and VL CDR3, respectively, of a VL having an amino acid sequence of SEQ ID NO: 19.
[00112] In one embodiment, the bispecific anti-CTLA4 x anti-PDl antibody comprises a first antigen binding domain that binds to PD1, wherein the first antigen binding domain comprises a VH domain comprising a VH CDR1, a VH CDR2, and a VH CDR3 having an amino acid sequence of SEQ ID NO:4, SEQ ID NO:5, and SEQ ID NO:6, respectively. [00113] In one embodiment, the bispecific anti-CTLA4 x anti-PDl antibody comprises a first antigen binding domain that binds to PD1, wherein the first antigen binding domain comprises a VL domain comprising a VL CDR1, a VL CDR2, and a VL CDR3 having an amino acid sequence of SEQ ID NO:7, SEQ ID NO:8, and SEQ ID NOV, respectively. [00114] In one embodiment, the bispecific anti-CTLA4 x anti-PDl antibody comprises a first antigen binding domain that binds to PD1, wherein the first antigen binding domain comprises a VH domain comprising a VH CDR1, a VH CDR2, and a VH CDR3 having the amino acid sequence of SEQ ID NO:4, SEQ ID NO:5, and SEQ ID NO:6, respectively, and a VL domain comprising a VL CDR1, a VL CDR2, and a VL CDR3 having an amino acid sequence of SEQ ID NO:7, SEQ ID NO:8, and SEQ ID NO:9, respectively.
[00115] In one embodiment, the bispecific anti-CTLA4 x anti-PDl antibody comprises a second antigen binding domain that binds to CTLA4, wherein the second antigen binding domain comprises a VH domain comprising a VH CDR1, a VH CDR2, and a VH CDR3 having an amino acid sequence of SEQ ID NO: 10, SEQ ID NO: 11, and SEQ ID NO: 12, respectively.
[00116] In one embodiment, the bispecific anti-CTLA4 x anti-PDl antibody comprises a second antigen binding domain that binds to CTLA4, wherein the second antigen binding domain comprises a VL domain comprising a VL CDR1, a VL CDR2, and a VL CDR3 having an amino acid sequence of SEQ ID NO: 13, SEQ ID NO: 14, and SEQ ID NO: 15, respectively.
[00117] In one embodiment, the bispecific anti-CTLA4 x anti-PDl antibody comprises a second antigen binding domain that binds to CTLA4, wherein the second antigen binding domain comprises a VH domain comprising a VH CDR1, a VH CDR2, and a VH CDR3 having an amino acid sequence of SEQ ID NO: 10, SEQ ID NO: 11, and SEQ ID NO: 12, respectively, and a VL domain comprising a VL CDR1, a VL CDR2, and a VL CDR3 having an amino acid sequence of SEQ ID NO: 13, SEQ ID NO: 14, and SEQ ID NO: 15, respectively.
[00118] In one embodiment, the bispecific anti-CTLA4 x anti-PDl antibody comprises a first antigen binding domain that binds to PD1 and a second antigen binding domain that binds to CTLA4, wherein the first antigen binding domain comprises a VH domain comprising a VH CDR1, a VH CDR2, and a VH CDR3 having an amino acid sequence of SEQ ID NO:4, SEQ ID NO:5, and SEQ ID NO:6, respectively, and a VL domain comprising a VL CDR1, a VL CDR2, and a VL CDR3 having an amino acid sequence of SEQ ID NO:7, SEQ ID NO: 8, and SEQ ID NOV, respectively, and the second antigen binding domain comprises a VH domain comprising a VH CDR1, a VH CDR2, and a VH CDR3 having an amino acid sequence of SEQ ID NO: 10, SEQ ID NO: 11, and SEQ ID NO: 12, respectively, and a VL domain comprising a VL CDR1, a VL CDR2, and a VL CDR3 having an amino acid sequence of SEQ ID NO: 13, SEQ ID NO: 14, and SEQ ID NO: 15, respectively.
[00119] In one embodiment, the bispecific anti-CTLA4 x anti-PDl antibody comprises a first antigen binding domain that binds to PD1, wherein the first antigen binding domain comprises a VH domain having an amino acid sequence that is about 90%, 95%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 16. In one embodiment, the first antigen binding domain comprises a VH domain having an amino acid sequence that is about 90% identical to the amino acid sequence of SEQ ID NO: 16. In another embodiment, the first antigen binding domain comprises a VH domain having an amino acid sequence that is about 95% identical to the amino acid sequence of SEQ ID NO: 16. In another embodiment, the first antigen binding domain comprises a VH domain having an amino acid sequence that is about 98% identical to the amino acid sequence of SEQ ID NO: 16. In another embodiment, the first antigen binding domain comprises a VH domain having an amino acid sequence that is about 99% identical to the amino acid sequence of SEQ ID NO: 16. In one embodiment, the first antigen binding domain comprises a VH domain having an amino acid sequence that is about 100% identical to the amino acid sequence of SEQ ID NO: 16.
[00120] In one embodiment, the bispecific anti-CTLA4 x anti-PDl antibody comprises a first antigen binding domain that binds to PD1, wherein the first antigen binding domain comprises a VL domain having an amino acid sequence that is about 90%, 95%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 17. In one embodiment, the first antigen binding domain comprises a VL domain having an amino acid sequence that is about 90% identical to the amino acid sequence of SEQ ID NO: 17. In another embodiment, the first antigen binding domain comprises a VL domain having an amino acid sequence that is about 95% identical to the amino acid sequence of SEQ ID NO: 17. In another embodiment, the first antigen binding domain comprises a VL domain having an amino acid sequence that is about 98% identical to the amino acid sequence of SEQ ID NO: 17. In another embodiment, the first antigen binding domain comprises a VL domain having an amino acid sequence that is about 99% identical to the amino acid sequence of SEQ ID NO: 17. In another embodiment, the first antigen binding domain comprises a VL domain having an amino acid sequence that is about 100% identical to the amino acid sequence of SEQ ID NO: 17.
[00121] In one embodiment, the bispecific anti-CTLA4 x anti-PDl antibody comprises a first antigen binding domain that binds to PD1, wherein the first antigen binding domain comprises a VH domain having an amino acid sequence that is about 90%, 95%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 16 and a VL domain having an amino acid sequence that is about 90%, 95%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 17. In one embodiment, the first antigen binding domain comprises a VH domain having an amino acid sequence that is about 90%, identical to the amino acid sequence of SEQ ID NO: 16 and a VL domain having an amino acid sequence that is about 90% identical to the amino acid sequence of SEQ ID NO: 17. In another embodiment, the first antigen binding domain comprises a VH domain having an amino acid sequence that is about 95%, identical to the amino acid sequence of SEQ ID NO: 16 and a VL domain having an amino acid sequence that is about 95% identical to the amino acid sequence of SEQ ID NO: 17. In another embodiment, the first antigen binding domain comprises a VH domain having an amino acid sequence that is about 98%, identical to the amino acid sequence of SEQ ID NO: 16 and a VL domain having an amino acid sequence that is about 98% identical to the amino acid sequence of SEQ ID NO: 17. In another embodiment, the first antigen binding domain comprises a VH domain having an amino acid sequence that is about 99%, identical to the amino acid sequence of SEQ ID NO: 16 and a VL domain having an amino acid sequence that is about 99% identical to the amino acid sequence of SEQ ID NO: 17. In another embodiment, the first antigen binding domain comprises a VH domain having an amino acid sequence that is about 100%, identical to the amino acid sequence of SEQ ID NO: 16 and a VL domain having an amino acid sequence that is about 100% identical to the amino acid sequence of SEQ ID NO: 17.
[00122] In one embodiment, the bispecific anti-CTLA4 x anti-PDl antibody comprises a second antigen binding domain that binds to CTLA4, wherein the second antigen binding domain comprises a VH domain having an amino acid sequence that is about 90%, 95%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 18. In one embodiment, the second antigen binding domain comprises a VH domain having an amino acid sequence that is about 90% identical to the amino acid sequence of SEQ ID NO: 18. In another embodiment, the second antigen binding domain comprises a VH domain having an amino acid sequence that is about 95% identical to the amino acid sequence of SEQ ID NO: 18. In another embodiment, the second antigen binding domain comprises a VH domain having an amino acid sequence that is about 98% identical to the amino acid sequence of SEQ ID NO: 18. In another embodiment, the second antigen binding domain comprises a VH domain having an amino acid sequence that is about 99% identical to the amino acid sequence of SEQ ID NO: 18. In another embodiment, the second antigen binding domain comprises a VH domain having an amino acid sequence that is about 100% identical to the amino acid sequence of SEQ ID NO: 18.
[00123] In one embodiment, the bispecific anti-CTLA4 x anti-PDl antibody comprises a second antigen binding domain that binds to CTLA4, wherein the second antigen binding domain comprises a VL domain having an amino acid sequence that is about 90%, 95%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 19. In one embodiment, the second antigen binding domain comprises a VL domain having an amino acid sequence that is about 90% identical to the amino acid sequence of SEQ ID NO: 19. In another embodiment, the second antigen binding domain comprises a VL domain having an amino acid sequence that is about 95% identical to the amino acid sequence of SEQ ID NO: 19. In another embodiment, the second antigen binding domain comprises a VL domain having an amino acid sequence that is about 98% identical to the amino acid sequence of SEQ ID NO: 19. In another embodiment, the second antigen binding domain comprises a VL domain having an amino acid sequence that is about 99% identical to the amino acid sequence of SEQ ID NO: 19. In another embodiment, the second antigen binding domain comprises a VL domain having an amino acid sequence that is about 100% identical to the amino acid sequence of SEQ ID NO: 19.
[00124] In one embodiment, the bispecific anti-CTLA4 x anti-PDl antibody comprises a second antigen binding domain that binds to CTLA4, wherein the second antigen binding domain comprises a VH domain having an amino acid sequence that is about 90%, 95%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 18 and a VL domain having an amino acid sequence that is about 90%, 95%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 19. In one embodiment, the second antigen binding domain comprises a VH domain having an amino acid sequence that is about 90%, identical to the amino acid sequence of SEQ ID NO: 18 and a VL domain having an amino acid sequence that is about 90% identical to the amino acid sequence of SEQ ID NO: 19. In another embodiment, the second antigen binding domain comprises a VH domain having an amino acid sequence that is about 95%, identical to the amino acid sequence of SEQ ID NO: 18 and a VL domain having an amino acid sequence that is about 95% identical to the amino acid sequence of SEQ ID NO: 19. In another embodiment, the second antigen binding domain comprises a VH domain having an amino acid sequence that is about 98%, identical to the amino acid sequence of SEQ ID NO: 18 and a VL domain having an amino acid sequence that is about 98% identical to the amino acid sequence of SEQ ID NO: 19. In another embodiment, the second antigen binding domain comprises a VH domain having an amino acid sequence that is about 99%, identical to the amino acid sequence of SEQ ID NO: 18 and a VL domain having an amino acid sequence that is about 99% identical to the amino acid sequence of SEQ ID NO: 19. In another embodiment, the second antigen binding domain comprises a VH domain having an amino acid sequence that is about 100%, identical to the amino acid sequence of SEQ ID NO: 18 and a VL domain having an amino acid sequence that is about 100% identical to the amino acid sequence of SEQ ID NO: 19. [00125] In one embodiment, the bispecific anti-CTLA4 x anti-PDl antibody comprises a first antigen binding domain that binds to PD1 and a second antigen binding domain that binds to CTLA4, wherein the first antigen binding domain comprises a VH domain having an amino acid sequence that is about 90%, 95%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 16 and a VL domain having an amino acid sequence that is about 90%, 95%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 17, and the second antigen binding domain comprises a VH domain having an amino acid sequence that is about 90%, 95%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 18 and a VL domain having an amino acid sequence that is about 90%, 95%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 19. In one embodiment, the first antigen binding domain comprises a VH domain having an amino acid sequence that is about 90%, identical to the amino acid sequence of SEQ ID NO: 16 and a VL domain having an amino acid sequence that is about 90% identical to the amino acid sequence of SEQ ID NO: 17, and the second antigen binding domain comprises a VH domain having an amino acid sequence that is about 90%, identical to the amino acid sequence of SEQ ID NO: 18 and a VL domain having an amino acid sequence that is about 90% identical to the amino acid sequence of SEQ ID NO: 19. In another embodiment, the first antigen binding domain comprises a VH domain having an amino acid sequence that is about 95%, identical to the amino acid sequence of SEQ ID NO: 16 and a VL domain having an amino acid sequence that is about 95% identical to the amino acid sequence of SEQ ID NO: 17, and the second antigen binding domain comprises a VH domain having an amino acid sequence that is about 95%, identical to the amino acid sequence of SEQ ID NO: 18 and a VL domain having an amino acid sequence that is about 95% identical to the amino acid sequence of SEQ ID NO: 19. In another embodiment, the first antigen binding domain comprises a VH domain having an amino acid sequence that is about 98%, identical to the amino acid sequence of SEQ ID NO: 16 and a VL domain having an amino acid sequence that is about 98% identical to the amino acid sequence of SEQ ID NO: 17, and the second antigen binding domain comprises a VH domain having an amino acid sequence that is about 98%, identical to the amino acid sequence of SEQ ID NO: 18 and a VL domain having an amino acid sequence that is about 98% identical to the amino acid sequence of SEQ ID NO: 19. In another embodiment, the first antigen binding domain comprises a VH domain having an amino acid sequence that is about 99%, identical to the amino acid sequence of SEQ ID NO: 16 and a VL domain having an amino acid sequence that is about 99% identical to the amino acid sequence of SEQ ID NO: 17, and the second antigen binding domain comprises a VH domain having an amino acid sequence that is about 99%, identical to the amino acid sequence of SEQ ID NO: 18 and a VL domain having an amino acid sequence that is about 99% identical to the amino acid sequence of SEQ ID NO: 19. In another embodiment, the first antigen binding domain comprises a VH domain having an amino acid sequence that is about 100% identical to the amino acid sequence of SEQ ID NO: 16 and a VL domain having an amino acid sequence that is about 100% identical to the amino acid sequence of SEQ ID NO: 17, and the second antigen binding domain comprises a VH domain having an amino acid sequence that is about 100% identical to the amino acid sequence of SEQ ID NO: 18 and a VL domain having an amino acid sequence that is about 100% identical to the amino acid sequence of SEQ ID NO: 19.
[00126] In some embodiments, the first monomer (or a first polypeptide) is about 90% identical to the amino acid sequence of SEQ ID NO: 1. In some embodiments, the first monomer (or a first polypeptide) is about 95% identical to the amino acid sequence of SEQ ID NO: 1. In some embodiments, the first monomer (or a first polypeptide) is about 97% identical to the amino acid sequence of SEQ ID NO: 1. In some embodiments, the first monomer (or a first polypeptide) is about 98% identical to the amino acid sequence of SEQ ID NO: 1. In some embodiments, the first monomer (or a first polypeptide) is about 99% identical to the amino acid sequence of SEQ ID NO: 1. In some embodiments, the first monomer (or a first polypeptide) is about 100% identical to the amino acid sequence of SEQ ID NO: 1.
[00127] In some embodiments, the second monomer (or a second polypeptide) is about 90% identical to the amino acid sequence of SEQ ID NO:2. In some embodiments, the second monomer (or a second polypeptide) is about 95% identical to the amino acid sequence of SEQ ID NO:2. In some embodiments, the second monomer (or a second polypeptide) is about 97% identical to the amino acid sequence of SEQ ID NO:2. In some embodiments, the second monomer (or a second polypeptide) is about 98% identical to the amino acid sequence of SEQ ID NO:2. In some embodiments, the second monomer (or a second polypeptide) is about 99% identical to the amino acid sequence of SEQ ID NO:2. In some embodiments, the second monomer (or a second polypeptide) is about 100% identical to the amino acid sequence of SEQ ID NO:2.
[00128] In some embodiments, the third monomer (or a third polypeptide) is about 90% identical to the amino acid sequence of SEQ ID NO:3. In some embodiments, the third monomer (or a third polypeptide) is about 95% identical to the amino acid sequence of SEQ ID NO:3. In some embodiments, the third monomer (or a third polypeptide) is about 97% identical to the amino acid sequence of SEQ ID NO:3. In some embodiments, the third monomer (or a third polypeptide) is about 98% identical to the amino acid sequence of SEQ ID NO:3. In some embodiments, the third monomer (or a third polypeptide) is about 99% identical to the amino acid sequence of SEQ ID NO:3. In some embodiments, the third monomer (or a third polypeptide) is about 100% identical to the amino acid sequence of SEQ ID NO:3.
[00129] In some embodiments, the first monomer (or first polypeptide) is about 90% identical to the amino acid sequence of SEQ ID NO: 1, and the second monomer (or second polypeptide) is about 90% identical to the amino acid sequence of SEQ ID NO:2. In some embodiments, the first monomer (or first polypeptide) is about 95% identical to the amino acid sequence of SEQ ID NO: 1, and the second monomer (or second polypeptide) is about 95% identical to the amino acid sequence of SEQ ID NO:2. In some embodiments, the first monomer (or first polypeptide) is about 97% identical to the amino acid sequence of SEQ ID NO: 1, and the second monomer (or second polypeptide) is about 97% identical to the amino acid sequence of SEQ ID NO:2. In some embodiments, the first monomer (or first polypeptide) is about 98% identical to the amino acid sequence of SEQ ID NO: 1, and the second monomer (or second polypeptide) is about 98% identical to the amino acid sequence of SEQ ID NO:2. In some embodiments, the first monomer (or first polypeptide) is about 99% identical to the amino acid sequence of SEQ ID NO: 1, and the second monomer (or second polypeptide) is about 99% identical to the amino acid sequence of SEQ ID NO:2. In some embodiments, the first monomer (or first polypeptide) is about 100% identical to the amino acid sequence of SEQ ID NO: 1, and the second monomer (or second polypeptide) is about 100% identical to the amino acid sequence of SEQ ID NO:2.
[00130] In some embodiments, the first monomer (or first polypeptide) is about 90% identical to the amino acid sequence of SEQ ID NO: 1, and the third monomer (or third polypeptide) is about 90% identical to the amino acid sequence of SEQ ID NO:3. In some embodiments, the first monomer (or first polypeptide) is about 95% identical to the amino acid sequence of SEQ ID NO: 1, and the third monomer (or third polypeptide) is about 95% identical to the amino acid sequence of SEQ ID NO:3. In some embodiments, the first monomer (or first polypeptide) is about 97% identical to the amino acid sequence of SEQ ID NO: 1, and the third monomer (or third polypeptide) is about 97% identical to the amino acid sequence of SEQ ID NO:3. In some embodiments, the first monomer (or first polypeptide) is about 98% identical to the amino acid sequence of SEQ ID NO: 1, and the third monomer (or third polypeptide) is about 98% identical to the amino acid sequence of SEQ ID NO:3. In some embodiments, the first monomer (or first polypeptide) is about 99% identical to the amino acid sequence of SEQ ID NO: 1, and the third monomer (or third polypeptide) is about 99% identical to the amino acid sequence of SEQ ID NO:3. In some embodiments, the first monomer (or first polypeptide) is about 100% identical to the amino acid sequence of SEQ ID NO: 1, and the third monomer (or third polypeptide) is about 100% identical to the amino acid sequence of SEQ ID NO:3.
[00131] In some embodiments, the second monomer (or second polypeptide) is about 90% identical to the amino acid sequence of SEQ ID NO:2, and the third monomer (or third polypeptide) is about 90% identical to the amino acid sequence of SEQ ID NO:3. In some embodiments, the second monomer (or second polypeptide) is about 95% identical to the amino acid sequence of SEQ ID NO:2, and the third monomer (or third polypeptide) is about 95% identical to the amino acid sequence of SEQ ID NO:3. In some embodiments, the second monomer (or second polypeptide) is about 97% identical to the amino acid sequence of SEQ ID NO:2, and the third monomer (or third polypeptide) is about 97% identical to the amino acid sequence of SEQ ID NO:3. In some embodiments, the second monomer (or second polypeptide) is about 98% identical to the amino acid sequence of SEQ ID NO:2, and the third monomer (or third polypeptide) is about 98% identical to the amino acid sequence of SEQ ID NO:3. In some embodiments, the second monomer (or second polypeptide) is about 99% identical to the amino acid sequence of SEQ ID NO: 2, and the third monomer (or third polypeptide) is about 99% identical to the amino acid sequence of SEQ ID NO:3. In some embodiments, the second monomer (or second polypeptide) is about 100% identical to the amino acid sequence of SEQ ID NO:2, and the third monomer (or third polypeptide) is about 100% identical to the amino acid sequence of SEQ ID NO:3.
[00132] In some embodiments, the first monomer (or first polypeptide) is about 90% identical to the amino acid sequence of SEQ ID NO: 1, the second monomer (or second polypeptide) is about 90% identical to the amino acid sequence of SEQ ID NO:2, and the third monomer (or third polypeptide) is about 90% identical to the amino acid sequence of SEQ ID NO:3. In some embodiments, the first monomer (or first polypeptide) is about 95% identical to the amino acid sequence of SEQ ID NO: 1, the second monomer (or second polypeptide) is about 95% identical to the amino acid sequence of SEQ ID NO:2, and the third monomer (or third polypeptide) is about 95% identical to the amino acid sequence of SEQ ID NO:3. In some embodiments, the first monomer (or first polypeptide) is about 97% identical to the amino acid sequence of SEQ ID NO: 1, the second monomer (or second polypeptide) is about 97% identical to the amino acid sequence of SEQ ID NO:2, and the third monomer (or third polypeptide) is about 97% identical to the amino acid sequence of SEQ ID NO:3. In some embodiments, the first monomer (or first polypeptide) is about 98% identical to the amino acid sequence of SEQ ID NO: 1, the second monomer (or second polypeptide) is about 98% identical to the amino acid sequence of SEQ ID NO:2, and the third monomer (or third polypeptide) is about 98% identical to the amino acid sequence of SEQ ID NO:3. In some embodiments, the first monomer (or first polypeptide) is about 99% identical to the amino acid sequence of SEQ ID NO: 1, the second monomer (or second polypeptide) is about 99% identical to the amino acid sequence of SEQ ID NO:2, and the third monomer (or third polypeptide) is about 99% identical to the amino acid sequence of SEQ ID NO:3. In some embodiments, the first monomer (or first polypeptide) is about 100% identical to the amino acid sequence of SEQ ID NO: 1, the second monomer (or second polypeptide) is about 100% identical to the amino acid sequence of SEQ ID NO:2, and the third monomer (or third polypeptide) is about 100% identical to the amino acid sequence of SEQ ID NO:3.
[00133] As is known in the art, the nucleic acids encoding the components provided herein can be incorporated into expression vectors as is known in the art, and depending on the host cells used to produce an antibody of the disclosure (e.g., XmAb®20717). Generally, the nucleic acids are operably linked to any number of regulatory elements (promoters, origin of replication, selectable markers, ribosomal binding sites, inducers, etc.). The expression vectors can be extra-chromosomal or integrating vectors.
[00134] The nucleic acids and/or expression vectors provided herein are then transformed into any number of different types of host cells as is well known in the art, including mammalian, bacterial, yeast, insect and/or fungal cells, with mammalian cells (e.g., CHO cells), finding use in many embodiments.
[00135] In some embodiments, nucleic acids encoding each monomer (polypeptide) and the nucleic acid encoding a light chain, as applicable depending on the format, are each contained within a single expression vector, generally under different or the same promoter controls. In embodiments of particular use in the methods provided herein, each of these two or three nucleic acids are contained on a different expression vector. That is, in certain embodiments, a first expression vector comprises the nucleic acid encoding the first monomer (or first polypeptide), a second expression vector comprises the nucleic acid encoding the second monomer (or second polypeptide), and a third expression vector comprises the nucleic acid encoding the light chain (or a third polypeptide).
[00136] XmAb®20717 can be made by culturing host cells comprising the expression vector(s) as is well known in the art. Once produced, traditional antibody purification steps are done, including an ion exchange chromatography step. As discussed in U.S. Pat. App. No. 15/623,314 and US Publication No. 2018/0118836, hereby incorporated by reference in their entirety and particularly for the discussions concerning purification, having the pls of the two monomers differ by at least 0.5 can allow separation by ion exchange chromatography or isoelectric focusing, or other methods sensitive to isoelectric point. That is, the inclusion of pl substitutions that alter the isoelectric point (pl) of each monomer so that such that each monomer has a different pl and the heterodimer also has a distinct pl, thus facilitating isoelectric purification of the “triple F” heterodimer (e.g., anionic exchange columns, cationic exchange columns). These substitutions also aid in the determination and monitoring of any contaminating dual scFv-Fc and mAb homodimers post-purification (e.g., IEF gels, cIEF, and analytical IEX columns).
[00137] Once made, XmAb®20717 can be administered to human subjects according to a dosage regimen described herein.
4.4 Pharmaceutical Compositions and Pharmaceutical Administration [00138] Bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) provided herein can be incorporated into pharmaceutical compositions suitable for administration to a human subject according to a dosage regimen described herein. In some embodiments, XmAb®20717 is incorporated into pharmaceutical compositions suitable for administration to a human subject according to a dosage regimen described herein. As used herein, “dosage regimen” refers to a systematic plan of drug administration regarding formulation, route of administration, drug dose, dosing interval and/or treatment duration. Typically, the pharmaceutical composition comprises a anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) and a pharmaceutically acceptable carrier. As used herein, “pharmaceutically acceptable carrier” includes any and all solvents, dispersion media, coatings, isotonic and absorption delaying agents, and the like that are physiologically compatible and are suitable for administration to a subject for the methods described herein. Examples of pharmaceutically acceptable carriers include one or more of water, saline, phosphate buffered saline, dextrose, glycerol, ethanol and the like, as well as combinations thereof. In many cases, it is preferable to include isotonic agents, for example, sugars, polyalcohols such as mannitol, sorbitol, or sodium chloride in the composition. Pharmaceutically acceptable carriers may further comprise minor amounts of auxiliary substances such as surfactants (such as nonionic surfactants) wetting or emulsifying agents (such as a polysorbate), preservatives or buffers (such as an organic acid, which as a citrate or an acetate), which enhance the shelf life or effectiveness of the bispecific anti-CTLA4 x anti-PDl antibodies (e.g., XmAb®20717). Examples of pharmaceutically acceptable carriers include polysorbates (polysorbate-80).
[00139] In an exemplary embodiment, the pharmaceutical composition comprises a bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717), and a preservative or buffer. In an exemplary embodiment, the pharmaceutical composition comprises a bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717), and histidine. In an exemplary embodiment, the pharmaceutical composition comprises a bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717), and an acetate. In an exemplary embodiment, the pharmaceutical composition comprises a bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717), and sodium acetate. In an exemplary embodiment, the pharmaceutical composition comprises a bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) and a citrate. In an exemplary embodiment, the pharmaceutical composition comprises a bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) and sodium citrate. In one embodiment, the pharmaceutical composition comprises a bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) and a succinate. In one embodiment, the pharmaceutical composition comprises a bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) and sodium succinate.
[00140] In an exemplary embodiment, the pharmaceutical composition comprises a bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) and an isotonic agent. In an exemplary embodiment, the pharmaceutical composition comprises a bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) and a polyalcohol. In an exemplary embodiment, the pharmaceutical composition comprises a bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) and mannitol. In an exemplary embodiment, the pharmaceutical composition comprises a bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) and sorbitol. In an exemplary embodiment, the pharmaceutical composition comprises a bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) and sodium chloride. In an exemplary embodiment, the pharmaceutical composition comprises a bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) and potassium chloride. [00141] In an exemplary embodiment, the pharmaceutical composition comprises a bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) and a wetting or emulsifying agent. In an exemplary embodiment, the pharmaceutical composition comprises a bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) and a polysorbate. In an exemplary embodiment, the pharmaceutical composition comprises a bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) and polysorbate-80.
[00142] In an exemplary embodiment, the pharmaceutical composition comprises a bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) and an intravenous solution stabilizer. In an exemplary embodiment, the intravenous solution stabilizer comprises a polysorbate and a citrate. In an exemplary embodiment, the pharmaceutical composition comprises a bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) and sodium citrate and polysorbate-80. In one embodiment, the intravenous solution stabilizer comprises a polysorbate and a succinate. In one embodiment, the pharmaceutical composition comprises a bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) and sodium succinate and polysorbate-80.
[00143] In an exemplary embodiment, the pharmaceutical composition comprises a bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) and a buffer and an isotonic agent. In an exemplary embodiment, the pharmaceutical composition comprises a bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) and a buffer and sorbitol. In an exemplary embodiment, the pharmaceutical composition comprises a bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) and an acetate and an isotonic agent. In an exemplary embodiment, the pharmaceutical composition comprises a bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) and histidine and an isotonic agent. In an exemplary embodiment, the pharmaceutical composition comprises a bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) and an acetate and sorbitol. In an exemplary embodiment, the pharmaceutical composition comprises a bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) and sodium acetate and sorbitol. In an exemplary embodiment, the pharmaceutical composition comprises a bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) and histidine and sorbitol. In one embodiment, the pharmaceutical composition comprises a bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) and a buffer and sodium chloride. In one embodiment, the pharmaceutical composition comprises a bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) and a succinate and an isotonic agent. In one embodiment, the pharmaceutical composition comprises a bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) and a succinate and sodium chloride. In one embodiment, the pharmaceutical composition comprises a bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) and sodium succinate and sodium chloride.
[00144] In an exemplary embodiment, the pharmaceutical composition comprises a bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) and a buffer and an isotonic agent and an intravenous solution stabilizer. In an exemplary embodiment, the pharmaceutical composition comprises a bispecific anti-CTLA4 x anti-PDl antibody e.g., XmAb®20717) and a buffer and sorbitol and an intravenous solution stabilizer. In an exemplary embodiment, the pharmaceutical composition comprises a bispecific anti-CTLA4 x anti-PDl antibody e.g., XmAb®20717) and an acetate and an isotonic agent and an intravenous solution stabilizer. In an exemplary embodiment, the pharmaceutical composition comprises a bispecific anti-CTLA4 x anti-PDl antibody e.g., XmAb®20717) and histidine and an isotonic agent and an intravenous solution stabilizer. In an exemplary embodiment, the pharmaceutical composition comprises a bispecific anti-CTLA4 x anti-PDl antibody e.g., XmAb®20717) and an acetate and sorbitol and an intravenous solution stabilizer. In an exemplary embodiment, the pharmaceutical composition comprises a bispecific anti-CTLA4 x anti-PDl antibody e.g., XmAb®20717) and sodium acetate and sorbitol and an intravenous solution stabilizer. In an exemplary embodiment, the pharmaceutical composition comprises a bispecific anti-CTLA4 x anti-PDl antibody e.g., XmAb®20717) and histidine and sorbitol and an intravenous solution stabilizer.
[00145] In an exemplary embodiment, the pharmaceutical composition comprises a bispecific anti-CTLA4 x anti-PDl antibody e.g., XmAb®20717) and sodium chloride. In an exemplary embodiment, the pharmaceutical composition comprises a bispecific anti-CTLA4 x anti-PDl antibody e.g., XmAb®20717) and sodium chloride and polysorbate-80. In an exemplary embodiment, the pharmaceutical composition comprises a bispecific anti-CTLA4 x anti-PDl antibody e.g., XmAb®20717) and sodium citrate and sodium chloride. In an exemplary embodiment, the pharmaceutical composition comprises a bispecific anti-CTLA4 x anti-PDl antibody e.g., XmAb®20717) and sodium citrate, sodium chloride, and polysorbate-80. In an exemplary embodiment, the pharmaceutical composition comprises a bispecific anti-CTLA4 x anti-PDl antibody e.g., XmAb®20717) and sodium citrate, sodium chloride, sodium acetate, sorbitol and polysorbate-80. In an exemplary embodiment, the pharmaceutical composition comprises a bispecific anti-CTLA4 x anti-PDl antibody e.g., XmAb®20717) and sodium citrate, sodium chloride, histidine, sorbitol and polysorbate-80. [00146] In one embodiment, the pharmaceutical composition comprises a bispecific anti- CTLA4 x anti-PDl antibody (e.g., XmAb®20717) and sodium succinate and sucrose. In one embodiment, the pharmaceutical composition comprises a bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) and sodium succinate and polysorbate-80. In one embodiment, the pharmaceutical composition comprises a bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) and sodium succinate and sodium chloride. In one embodiment, the pharmaceutical composition comprises a bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) and sucrose and polysorbate-80. In one embodiment, the pharmaceutical composition comprises a bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) and sucrose and sodium chloride. In one embodiment, the pharmaceutical composition comprises a bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) and sucrose and polysorbate-80. In one embodiment, the pharmaceutical composition comprises a bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) and polysorbate-80 and sodium chloride. In one embodiment, the pharmaceutical composition comprises a bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) and sodium succinate and sucrose and polysorbate-80. In one embodiment, the pharmaceutical composition comprises a bispecific anti-CTLA4 x anti-PDl antibody (e.g, XmAb®20717) and sodium succinate and sucrose and sodium chloride. In one embodiment, the pharmaceutical composition comprises a bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) and sucrose and polysorbate-80 and sodium chloride. In one embodiment, the pharmaceutical composition comprises a bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) and sucrose and polysorbate-80 and sodium chloride and sodium succinate.
[00147] The pharmaceutical compositions provided herein may be in a variety of forms. These include, for example, liquid, semi-solid and solid dosage forms, such as liquid solutions (e.g., injectable and infusible solutions), dispersions or suspensions. The form depends on the intended mode of administration and therapeutic application. Exemplary compositions are in the form of injectable or infusible solutions, such as compositions similar to those used for passive immunization of humans with other antibodies. In an exemplary embodiment, the mode of administration is intravenous. In an exemplary embodiment, the antibody is administered by intravenous infusion or injection.
[00148] Pharmaceutical compositions typically must be sterile and stable under the conditions of manufacture and storage. Sterile injectable solutions can be prepared by incorporating the antibody in the required amount in an appropriate solvent with one or a combination of ingredients enumerated herein, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the antibody into a sterile vehicle that contains a basic dispersion medium and the required other ingredients from those enumerated herein.
[00149] In some embodiments, prophylactic premedication can be administered to a subject to reduce infusion related reactions. In some embodiments, acetaminophen (e.g., 650 mg orally), diphenhydramine hydrochloride (e.g., 25 - 50 mg IV) and/or dexamethasone (e.g., 10 mg IV) is administered to a subject to reduce infusion related reactions. In some embodiments, diphenhydramine hydrochloride (e.g., 50 mg IV) and/ or dexamethasone (e.g., 10 - 20 mg IV) is administered to a subject to reduce infusion related reactions. In some embodiments, epinephrine and/or bronchodilators is administered to a subject to reduce infusion related reactions. In some embodiments, epinephrine, antihistamines, corticosteroids, IV fluids, vasopressors, oxygen, bronchodilators, and/or acetaminophen is administered to a subject to reduce infusion related reactions. In some embodiments, one or more medications to reduce infusion related reactions is administered to a subject prior to the administration of a bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) to the subject. In some embodiments, one or more medications to reduce infusion related reactions is administered to a subject prior to but on the same day as the administration of a bispecific anti-CTLA4 x anti- PDl antibody (e.g., XmAb®20717) to the subject. In some embodiments, one or more medications to reduce infusion related reactions is administered to a subject after the administration of a bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) to the subject.
[00150] The anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) can be administered by a variety of methods known in the art. In an exemplary embodiment, the route/mode of administration is intravenous injection. As will be appreciated by the skilled artisan, the route and/or mode of administration will vary depending upon the desired results.
[00151] In some embodiments, the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) is a front line therapy, second line therapy, third line therapy, fourth line therapy, fifth line therapy, or sixth line therapy.
[00152] A medical professional can readily determine and prescribe the effective amount of the antibody composition required. For example, a physician could start doses of the medicament employed in the antibody composition at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved. 4.5 Methods of Treatment and Combination Therapy
[00153] In an exemplary embodiment, provided are methods for treating CTLA4 expressing cancers. In an exemplary embodiment, provided are methods for treating PD1 expressing cancers. In an exemplary embodiment, provided are methods for treating CTLA4 and/or PD1 expressing cancers. In an exemplary embodiment, provided are methods for treating a prostate cancer. The compositions of the disclosure can be used to treat certain prostate cancers, for example, as described herein. In some embodiments, a composition of the disclosure is administered according to a method of the disclosure to treat a prostate cancer. In some embodiments, the prostate cancer is receptive to treatment by an antibody which binds to PD1. In some embodiments, the prostate cancer is receptive to treatment by an antibody which binds to CTLA4. In some embodiments, the prostate cancer is receptive to treatment by an antibody which binds to PD1 and CTLA4. In some embodiments, the prostate cancer is refractory. In some embodiments, the prostate cancer is relapsed. In some embodiments, the prostate cancer is refractory and relapsed. In some embodiments, a bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717; 5-15 mg/kg; or 10 mg/kg) is used in a method of the disclosure. In some embodiments, the bispecific anti-CTLA4 x anti- PDl antibody (e.g, XmAb®20717) that is used in a method of the disclosure is described throughout the disclosure and in Section 4.3. In some embodiments, any dosage described in this disclosure can be used in a method of the disclosure. In some embodiments, any dosage described in Section 4.8 can be used in a method of the disclosure
[00154] In one aspect, provided herein are methods of treating an aggressive variant (anaplastic) adenocarcinoma of the prostate (AVPCa) in a male subject comprising (a) administering a bispecific anti-CTLA4 x anti-PDl antibody (e.g, XmAb®20717; 5-15 mg/kg; or 10 mg/kg), (b) administering carboplatin in a therapeutically effective dose that results in a target area under the serum concentration-time curve of 3 (AUC3), (c) administering taxane (e.g., carbazitaxel or docetaxel) (e.g., between about 10 mg/m2 and about 55 mg/m2, between about 10 mg/m2 and about 20 mg/m2, or between about 40 mg/m2 and about 60 mg/m2; carbazitaxel at 15 mg/m2; or docetaxel at 50 mg/m2), (d) administering carboplatin in a therapeutically effective dose that results in a target area under the serum concentration-time curve of 4 (AUC4), and (e) administering taxane (e.g., carbazitaxel or docetaxel) (e.g., between about 15 mg/m2 and about 65 mg/m2, between about 10 mg/m2 and about 30 mg/m2, between about 15 mg/m2 and about 25 mg/m2, between about 55 mg/m2 and about 65 mg/m2, or between about 50 mg/m2 and about 70 mg/m2; carbazitaxel at 20 mg/m2; or docetaxel at 60 mg/m2). In some embodiments, the dose of the carbazitaxel or docetaxel in (e) is higher than the dose of the carbazitaxel or docetaxel in (c). In some embodiments, carbazitaxel or docetaxel is intravenously administered on Day 15 of the second treatment cycle. In some embodiments, carboplatin is intravenously administered on Day 15 of the second treatment cycle. In some embodiments, the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) of the disclosure is intravenously administered to the male subject on day 1 of a first treatment cycle and about every two weeks (Q2W) thereafter. In some embodiments, the dose of the carboplatin of (b) is intravenously administered to the male subject twice in the first treatment cycle, wherein the twice is on Day 1 and about three weeks after Day 1 of the first treatment cycle. In some embodiments, the dose of carbazitaxel or docetaxel of (c) is intravenously administered to the male subject twice in a first treatment cycle, wherein the twice is on Day 1 and about three weeks after Day 1 of the first treatment cycle. In some embodiments, the dose of the carboplatin of (d) is intravenously administered to the male subject between Day 13 and Day 17 of a second treatment cycle and about every three weeks (Q3W) thereafter. In some embodiments, the dose of carbazitaxel or docetaxel of (e) is intravenously administered to the male subject between Day 13 and Day 17 of the second treatment cycle and about every three weeks (Q3W) thereafter. In some embodiments, each treatment cycle is about 28 days. In some embodiments, each treatment cycle is 28 days. In some embodiments, each treatment cycle is between about 26-30 days. In some embodiments, the dose of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) of the disclosure in (a) is 10 mg/kg. In some embodiments, carbazitaxel in (c) is administered at a dose of 15 mg/m2. In some embodiments, docetaxel in (c) is administered at a dose of 50 mg/m2 (e.g., if the subject has not been administered with docetaxel previously, or prior to the first administration of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) of the disclosure, or prior to the start of the method of the disclosure). In some embodiments, carbazitaxel in (e) is administered at a dose of 20 mg/m2. In some embodiments, docetaxel in (e) is administered at a dose of 60 mg/m2 (e.g., if the subject has not been administered with docetaxel previously, or prior to the first administration of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) of the disclosure, or prior to the start of the method of the disclosure). In some embodiments, carbazitaxel in (c) is administered at a dose of between about 5-20 mg/m2. In some embodiments, docetaxel in (c) is administered at a dose of between about 40-60 mg/m2 or 45- 55 mg/m2 (e.g., if the subject has not been administered with docetaxel previously, or prior to the first administration of the bispecific anti-CTLA4 x anti-PDl antibody (e.g, XmAb®20717) of the disclosure, or prior to the start of the method of the disclosure). In some embodiments, carbazitaxel in (e) is administered at a dose of between about 15-25 mg/m2. In some embodiments, docetaxel in (e) is administered at a dose of between about 50- 70 mg/m2 or about 55-65 mg/m2 (e.g., if the subject has not been administered with docetaxel previously, or prior to the first administration of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) of the disclosure, or prior to the start of the method of the disclosure). In some embodiments, (b) and (c) are administered during the first treatment cycle. In some embodiments, (b) and (c) are for the starting dose. In some embodiments, (b) and (c) are administered for the first administration of the first treatment cycle. In some embodiments, (b) and (c) are administered for the first two administrations of the first treatment cycle. In some embodiments, (b) and (c) are administered on Day 1 of the first treatment cycle. In some embodiments, (b) and (c) are administered on Day 1 of the first treatment cycle and about 3 weeks thereafter. In some embodiments, (b) and (c) are administered on Day 1 of the first treatment cycle and in one day about 3 weeks after (e.g., about Day 21 of the first treatment cycle). In some embodiments, (b) and (c) are administered on Day 1 of the first treatment cycle and in one day between about Day 20 to Day 28 of the first treatment cycle. In some embodiments, (b) and (c) are administered on Day 1 of the first treatment cycle and in one day between about Day 20 to Day 23 of the first treatment cycle. In some embodiments, (b) and (c) are administered on Day 1 of the first treatment cycle and about Day 21 of the first treatment cycle. In some embodiments, (b) and (c) are administered on Day 1 of the first treatment cycle and on Day 21 of the first treatment cycle. In some embodiments, (d) and (e) start on the second treatment cycle. In some embodiments, (d) and (e) start on the second treatment cycle and continues to a subsequence cycle and/or for the duration of treatment (e.g., third treatment cycle, fourth treatment cycle, fifth treatment cycle, and/or any subsequent cycle). In some embodiments, (d) and (e) start on the first administration of the second treatment cycle and every 3 weeks (Q3W) thereafter. In some embodiments, (d) and (e) are administered on Day 15 of the second treatment cycle and about every 3 weeks thereafter. In some embodiments, (d) and (e) are administered between about Day 14 to Day 16 of the second treatment cycle and about every 3 weeks thereafter. In some embodiments, (d) and (e) are administered on the second week of the second treatment cycle and about every 3 weeks thereafter. In some embodiments, (d) and (e) are administered on Day 15 of the second treatment cycle, fifth treatment cycle, eight treatment cycle, and/or any other suitable treatment cycle. In some embodiments, (d) and (e) are administered between about Day 14 to Day 16 of the second treatment cycle, fifth treatment cycle, eight treatment cycle, and/or any other suitable treatment cycle. In some embodiments, (d) and (e) are administered on Day 8 of the third treatment cycle, sixth treatment cycle, ninth treatment cycle, and/or any other suitable treatment cycle. In some embodiments, (d) and (e) are administered between about Day 7 to Day 9 of the third treatment cycle, sixth treatment cycle, ninth treatment cycle, and/or any other suitable treatment cycle. In some embodiments, (b) and (c) are administered on Day 1 of the first treatment cycle and Day 21 of the first treatment cycle, and (d) and (e) are administered every three weeks after Day 21 of the first treatment cycle. In some embodiments, (a) is administered on Day 1 of the first treatment cycle and about every two weeks thereafter (e.g., Day 1 and Day 15 of each treatment cycle; between about Days 1-3 of each treatment cycle and/or Days 14-17 of each treatment cycle); (b) and (c) are administered on Day 1 of the first treatment cycle and about three weeks after Day 1 (e.g., Day 21 of the first treatment cycle; between about Days 19-23 of the first treatment cycle); and (d) and (e) are administered every three weeks thereafter (e.g., every three weeks after Day 21 or after Days 19-23 of the first treatment cycle). In some embodiments, (a) is administered on Day 1 and Day 15 of each treatment cycle; (b) and (c) are administered on Day 1 of the first treatment cycle and Day 21 of the first treatment cycle; and (d) and (e) are administered every three weeks after Day 21 of the first treatment cycle. In some embodiments, (b) and (c) are administered on Day 1 of the first treatment cycle and Day 21 of the first treatment cycle, and (d) and (e) are administered on Day 15 of the second treatment cycle, Day 8 of the third treatment cycle, and every three weeks thereafter for the duration of treatment and/or for any other suitable time. In some embodiments, (a) is administered on Day 1 and Day 15 of each treatment cycle; (b) and (c) are administered on Day 1 of the first treatment cycle and Day 21 of the first treatment cycle; and (d) and (e) are administered on Day 15 of the second treatment cycle, Day 8 of the third treatment cycle, and every three weeks thereafter for the duration of treatment and/or for any other suitable time. In some embodiments, the carboplatin is administered for about or at most about 7-9 cycles. In some embodiments, the carboplatin is administered for about or at most about 8 cycles. In some embodiments, carboplatin is administered for about or at most about 8 cycles. In some embodiments, (d) is administered for about or at most about 7 cycles. In some embodiments, (d) is administered for about or at most about 8 cycles. In some embodiments, the method of the disclosure includes stopping administration of (d) after the carboplatin is administered to a subject for a total of 8 treatment cycles. In some embodiments, the method of the disclosure includes (b) and (c) for the first treatment cycle, (d) and (e) for the following seven treatment cycles, and (e) for any subsequent treatment cycle. In some embodiments, the method of the disclosure includes (a), (b) and (c) for the first treatment cycle; (a), (d) and (e) for the following eigth treatment cycles; and (a) and (e) for any subsequent treatment cycle. In some embodiments, the method of the disclosure includes (a), (b) and (c) for the first treatment cycle; (a), (d) and (e) for following seven treatment cycles; and (a) and (e) for any subsequent treatment cycle. In some embodiments, the prostate cancer is an aggressive variant (anaplastic) adenocarcinoma of the prostate (AVPCa). In some embodiments, the AVPCa has a mutation or other aberrancy in at least two genes independently selected from the group consisting of Rbl, TP53, and PTEN. In some embodiments, the prostate cancer is metastatic castration-resistant prostate cancer.
[00155] In one aspect, provided herein are methods of treating a prostate cancer in a male subject comprising administering a bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717; 5-15 mg/kg; or 10 mg/kg) of the disclosure and administering taxane (e.g., carbazitaxel or docetaxel) (e.g., between about 10 mg/m2 and about 80 mg/m2, between about 15 mg/m2 and about 25 mg/m2, or between about 70 mg/m2 and about 80 mg/m2; carbazitaxel at 20 mg/m2; or docetaxel at 75 mg/m2 or 60 mg/m2). In some embodiments, the dose of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) of the disclosure is 10 mg/kg. In some embodiments, carbazitaxel is administered at a dose of 20 mg/m2. In some embodiments, carbazitaxel is administered at a dose of about 20 mg/m2. In some embodiments, docetaxel is administered at a dose of 75 mg/m2 (e.g., if the subject has not been administered with docetaxel previously, or prior to the first administration of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) of the disclosure, or prior to the start of the method of the disclosure). In some embodiments, docetaxel is administered at a dose of about 75 mg/m2 (e.g., if the subject has not been administered with docetaxel previously, or prior to the first administration of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) of the disclosure, or prior to the start of the method of the disclosure). In some embodiments, docetaxel is administered at a dose of 60 mg/m2 (e.g., if the subject has not been administered with docetaxel previously, or prior to the first administration of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) of the disclosure, or prior to the start of the method of the disclosure). In some embodiments, carbazitaxel is administered at a dose of between about 5-25 mg/m2 or between about 15-25 mg/m2. In some embodiments, docetaxel is administered at a dose of between about 50-80 mg/m2 or between about 70-90 mg/m2 or between about 70-80 mg/m2 or between about 65-85 mg/m2 (e.g., if the subject has not been administered with docetaxel previously, or prior to the first administration of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) of the disclosure, or prior to the start of the method of the disclosure). In some embodiments, the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717; 5-15 mg/kg; or 10 mg/kg) of the disclosure is administered on Day 1 of the first treatment cycle and about every two weeks thereafter for the duration of treatment and/or for any suitable period of time. In some embodiments, the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717; 5-15 mg/kg; or 10 mg/kg) of the disclosure is administered on Day 1 of the first treatment cycle and about Day 15 of the first treatment cycle and about every two weeks thereafter for the duration of treatment and/or for any suitable period of time. In some embodiments, the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717; 5-15 mg/kg; or 10 mg/kg) of the disclosure is administered on Day 1 of the first treatment cycle and between about Day 13-17 of the first treatment cycle and about every two weeks thereafter for the duration of treatment and/or for any suitable period of time. In some embodiments, the bispecific anti- CTLA4 x anti-PDl antibody (e.g., XmAb®20717; 5-15 mg/kg; or 10 mg/kg) of the disclosure is administered on Day 1 of each treatment cycle and between about Day 13-17 of each treatment cycle. In some embodiments, the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717; 5-15 mg/kg; or 10 mg/kg) of the disclosure is administered on Day 1 of each treatment cycle and Day 15 of each treatment cycle. In some embodiments, the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717; 5-15 mg/kg; or 10 mg/kg) of the disclosure is administered on Day 1 of the first treatment cycle and every two weeks thereafter and carbazitaxel or docetaxel is administered on Day 1 of the first treatment cycle and every three weeks thereafter. In some embodiments, the bispecific anti-CTLA4 x anti- PDl antibody (e.g., XmAb®20717; 5-15 mg/kg; or 10 mg/kg) of the disclosure is administered on Day 1 of each treatment cycle and Day 15 of each treatment cycle and carbazitaxel or docetaxel is administered on Day 1 of the first treatment cycle, on Day 21 of the first treatment cycle, and about every two weeks thereafter. In some embodiments, the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717; 5-15 mg/kg; or 10 mg/kg) of the disclosure is administered on Day 1 of each treatment cycle and between Day 13-17 of each treatment cycle and carbazitaxel or docetaxel is administered on Day 1 of the first treatment cycle, between about Day 19-22 of the first treatment cycle, and about every two weeks thereafter (e.g., between about every 19-23 days). In some embodiments, the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717; 5-15 mg/kg; or 10 mg/kg) of the disclosure is administered on Day 1 and Day 15 of each treatment cycle; and carbazitaxel or docetaxel is administered on Day 1 of the first treatment cycle and Day 21 of the first treatment cycle, on Day 15 of the second treatment cycle, on Day 8 of the third treatment cycle, and every three weeks thereafter for the duration of treatment and/or for any other suitable time. In some embodiments, carbazitaxel or docetaxel is administered on Day 1 of the first treatment cycle and about every 3 weeks thereafter. In some embodiments, carbazitaxel or docetaxel is administered on Day 1 and Day 21 of the first treatment cycle and about every 3 weeks thereafter. In some embodiments, carbazitaxel or docetaxel is administered on Day 15 of the second treatment cycle and about every 3 weeks thereafter. In some embodiments, carbazitaxel or docetaxel is administered between about Day 1 to Day 3 of the first treatment cycle and about every 3 weeks thereafter. In some embodiments, carbazitaxel or docetaxel is administered between about Day 19 to Day 23 of the first treatment cycle and about every 3 weeks thereafter. In some embodiments, carbazitaxel or docetaxel is administered between about Day 14 to Day 16 of the second treatment cycle and about every 3 weeks thereafter. In some embodiments, carbazitaxel or docetaxel is administered on the first week of the first treatment cycle and about every 3 weeks thereafter. In some embodiments, carbazitaxel or docetaxel is administered on the third week of the first treatment cycle and about every 3 weeks thereafter. In some embodiments, carbazitaxel or docetaxel is administered on the second week of the second treatment cycle and about every 3 weeks thereafter. In some embodiments, carbazitaxel or docetaxel is administered on Day 15 of the second treatment cycle, fifth treatment cycle, eight treatment cycle, and/or any other suitable treatment cycle. In some embodiments, carbazitaxel or docetaxel is administered between about Day 14 to Day 16 of the second treatment cycle, fifth treatment cycle, eight treatment cycle, and/or any other suitable treatment cycle. In some embodiments, carbazitaxel or docetaxel is administered on Day 8 of the third treatment cycle, sixth treatment cycle, ninth treatment cycle, and/or any other suitable treatment cycle. In some embodiments, carbazitaxel or docetaxel is administered between about Day 7 to Day 9 of the third treatment cycle, sixth treatment cycle, ninth treatment cycle, and/or any other suitable treatment cycle. In some embodiments, the prostate cancer is not an aggressive variant (anaplastic) adenocarcinoma of the prostate (AVPCa). In some embodiments, the prostate cancer has a homologous recombination deficiency (HRD). In some embodiments, the prostate cancer has a biallelic loss of cyclin-dependent kinase 12 (CDK12). In some embodiments, the male subject has been previously treated with a polyadenosine diphosphate ribose polymerase (PARP) inhibitor. In some embodiments, the prostate cancer does not have a targetable mutation. In some embodiments, the prostate cancer is metastatic castration-resistant prostate cancer. In some embodiments, the prostate cancer progressed after the male subject received a polyadenosine diphosphate ribose polymerase (PARP) inhibitor prior to the start of the method or prior to the first administration of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) of the disclosure; and/or the prostate cancer does not have a targetable mutation. In some embodiments, each treatment cycle is about 28 days. In some embodiments, each treatment cycle is 28 days. In some embodiments, each treatment cycle is between about 26-30 days.
[00156] In one aspect, provided herein are methods of treating a prostate cancer in a male subject comprising administering a bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717; 5-15 mg/kg; or 10 mg/kg) and administering olaparib to the subject (e.g., 300 mg per day; 300 mg twice daily; 600 mg per day; between about 400-800 mg per day; or between about 250 to 650 mg per day). In some embodiments, the dose of the olaparib is about, at least about, or at most about 600 mg per day. In some embodiments, the dose of the olaparib is 600 mg per day. In some embodiments, the dose of the olaparib is 300 mg twice daily. In some embodiments, the dose of the olaparib is about, at least about, or at most about 300 mg twice daily. In some embodiments, olaparib is administered to a male subject with prostate cancer at a dose of between about 500-700 mg on Day 1 of a first treatment cycle. In some embodiments, olaparib is administered to a male subject with prostate cancer at a dose of between about 500-700 mg on Day 1 of a first treatment cycle and every day thereafter. In some embodiments, olaparib is administered to a male subject with prostate cancer at a dose of between about 500-700 mg daily. In some embodiments, olaparib is administered to a male subject with prostate cancer at a dose of between about 500-700 mg as needed. In some embodiments, olaparib is administered to a male subject with prostate cancer two times a day. In some embodiments, olaparib is administered to a male subject with prostate cancer three times a day. In some embodiments, olaparib is administered to a male subject with prostate cancer four times a day. In some embodiments, olaparib is administered to a male subject with prostate cancer at a dose of 300 mg two times a day. In some embodiments, olaparib is administered to a male subject with prostate cancer at a dose of 150 mg four times a day. In some embodiments, olaparib is administered to a male subject with prostate cancer at a dose of 200 mg three times a day. In some embodiments, the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717; 5-15 mg/kg; or 10 mg/kg) of the disclosure is administered on Day 1 of the first treatment cycle and about every two weeks thereafter for the duration of treatment and/or for any suitable period of time. In some embodiments, the bispecific anti- CTLA4 x anti-PDl antibody (e.g., XmAb®20717; 5-15 mg/kg; or 10 mg/kg) of the disclosure is administered on Day 1 of the first treatment cycle and about Day 15 of the first treatment cycle and about every two weeks thereafter for the duration of treatment and/or for any suitable period of time. In some embodiments, the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717; 5-15 mg/kg; or 10 mg/kg) of the disclosure is administered on Day 1 of the first treatment cycle and between about Day 13-17 of the first treatment cycle and about every two weeks thereafter for the duration of treatment and/or for any suitable period of time. In some embodiments, the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717; 5-15 mg/kg; or 10 mg/kg) of the disclosure is administered on Day 1 of each treatment cycle and between about Day 13-17 of each treatment cycle. In some embodiments, the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717; 5-15 mg/kg; or 10 mg/kg) of the disclosure is administered on Day 1 of each treatment cycle and Day 15 of each treatment cycle. In some embodiments, the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717; 5-15 mg/kg; or 10 mg/kg) of the disclosure is administered on Day 1 of the first treatment cycle and every two weeks thereafter and olaparib is administered to the subject on Day 1 of the first treatment cycle and every day thereafter. In some embodiments, the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717; 5-15 mg/kg; or 10 mg/kg) of the disclosure is administered on Day 1 of the first treatment cycle and every two weeks thereafter and olaparib is administered to the subject on Day 1 of the first treatment cycle. In some embodiments, the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717; 5-15 mg/kg; or 10 mg/kg) of the disclosure is administered on Day 1 of the first treatment cycle and every two weeks thereafter and olaparib is administered to the subject on about Day 1 of the first treatment cycle and about every day thereafter. In some embodiments, the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717; 5-15 mg/kg; or 10 mg/kg) of the disclosure is administered on Day 1 of the first treatment cycle and every two weeks thereafter and olaparib is administered to the subject during every treatment cycle. In some embodiments, olaparib is not administered during every treatment cycle. In some embodiments, olaparib is administered to a subject daily. In some embodiments, olaparib is administered to a subject at least once (or one day), 2 times (or days), 3 times (or days), 4 times (or days), 5 times (or days), 6 times (or days), 7 times (or days), 8 times (or days), 9 times (or days), 10 times (or days), 11 times (or days), 12 times (or days), 13 times (or days), 14 times (or days), 15 times (or days), 16 times (or days), 17 times (or days), 18 times (or days), 19 times (or days), 20 times (or days), 21 times (or days), 22 times (or days), 23 times (or days), 24 times (or days), 25 times (or days), 26 times (or days), 27 times (or days), and/or 28 times (or days) in a treatment cycle. In some embodiments, the prostate cancer is not an aggressive variant (anaplastic) adenocarcinoma of the prostate (AVPCa). In some embodiments, the prostate cancer has a homologous recombination deficiency (HRD). In some embodiments, the prostate cancer has a biallelic loss of cyclin- dependent kinase 12 (CDK12). In some embodiments, the male subject has not been previously treated with a polyadenosine diphosphate ribose polymerase (PARP) inhibitor. In some embodiments, the prostate cancer does not have a targetable mutation. In some embodiments, the prostate cancer is metastatic castration-resistant prostate cancer. In some embodiments, each treatment cycle is about 28 days. In some embodiments, each treatment cycle is 28 days. In some embodiments, each treatment cycle is between about 26-30 days. [00157] In one aspect, provided herein is a method of treating a prostate cancer in a male human subject in need thereof, the method comprising: administering to the subject according to a 28 day treatment cycle, a bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717; 5-15 mg/kg; or 10 mg/kg) of the disclosure at a dose of about 5-15 mg/kg or about 10 mg/kg, wherein the dose of the bispecific antibody is intravenously administered to the subject on day 1 of a first 28 day treatment cycle and about every two weeks (Q2W) thereafter. In one embodiment, the prostate cancer is microsatellite instability-high (MSI-H) prostate cancer. In one embodiment, the prostate cancer is mismatch repair deficient (MMRD) prostate cancer. In one embodiment, the subject receives treatment about every 2 weeks (Q2W) for about two years.
[00158] In an exemplary embodiment, the prostate cancer is mCRPC. In an exemplary embodiment, the prostate cancer is microsatellite instability-high [MSI-H], In an exemplary embodiment, the prostate cancer is mismatch repair deficient [MMRD], In an exemplary embodiment, the mCRPC is microsatellite instability -high [MSI-H], In an exemplary embodiment, the mCRPC is mismatch repair deficient [MMRD],
[00159] In an exemplary embodiment, the prostate cancer is MSI-H positive. In an exemplary embodiment, the prostate cancer is MMRD positive. In an exemplary embodiment, the mCRPC is MSI-H positive. In an exemplary embodiment, the mCRPC is MMRD positive.
[00160] In an exemplary embodiment, the prostate cancer is aggressive variant (anaplastic) adenocarcinoma of the prostate (AVPCa). In an exemplary embodiment, the mCRPC is aggressive variant (anaplastic) adenocarcinoma of the prostate (AVPCa). In an exemplary embodiment, the prostate cancer is neuroendocrine prostate cancer. In an exemplary embodiment, the mCRPC is neuroendocrine prostate cancer.
[00161] In an exemplary embodiment, the prostate cancer is positive for Rbl. In an exemplary embodiment, the prostate cancer is positive for TP53. In an exemplary embodiment, the prostate cancer is positive for PTENb. In an exemplary embodiment, the mCRPC is positive for aberrancy for at least two of Rbl, TP53, and PTENb. In an exemplary embodiment, the mCRPC is positive for Rbl. In an exemplary embodiment, the mCRPC is positive for TP53. In an exemplary embodiment, the mCRPC is positive for PTENb. In an exemplary embodiment, the mCRPC is positive for aberrancy for at least two of Rbl, TP53, and PTENb.
[00162] In an exemplary embodiment, the prostate cancer has a homologous recombination deficiency (HRD). In an exemplary embodiment, the prostate cancer is mCRPC with a homologous recombination deficiency. In an exemplary embodiment, the prostate cancer has a cyclin-dependent kinase 12 (CDK12) mutation. In an exemplary embodiment, the prostate cancer is mCRPC with a CDK12 mutation.
[00163] In an exemplary embodiment, the prostate cancer is HRD positive in at least one gene selected from the group consisting of BRCA1, BRCA2, ATM, PALB2, CHEK2, and FANCA. In an exemplary embodiment, the prostate cancer is mCRPC and is HRD positive in at least one gene selected from the group consisting of BRCA1, BRCA2, ATM, PALB2, CHEK2, and FANCA. In an exemplary embodiment, the prostate cancer is positive for biallelic loss of CDK12. In an exemplary embodiment, the prostate cancer is mCRPC and is positive for biallelic loss of CDK12.
[00164] In an exemplary embodiment, the prostate cancer is positive for HRD in one or more of the following genes: BRCA1, BRCA2, ATM, PALB2, CHEK2, FANCA; and/or positive for biallelic loss of CDK12. In an exemplary embodiment, the prostate cancer is mCRPC which is a HRD/CDK12 mutation positive cancer which is one of the following: Positive for HRD in one or more of the following genes: BRCA1, BRCA2, ATM, PALB2, CHEK2, FANCA; and/or Positive for biallelic loss of CDK12.
[00165] In an exemplary embodiment, the prostate cancer is not positive for aberrancy for at least two of Rbl, TP53, and PTENb; not positive for HRD in one or more of the following genes: BRCA1, BRCA2, ATM, PALB2, CHEK2, FANCA; not positive for biallelic loss of CDK12; and not positive for microsatellite instability-high [MSI-H] or mismatch repair deficient [MMRD], In an exemplary embodiment, the mCRPC is not positive for aberrancy for at least two of Rbl, TP53, and PTENb; not positive for HRD in one or more of the following genes: BRCA1, BRCA2, ATM, PALB2, CHEK2, FANCA; not positive for biallelic loss of CDK12; and not positive for microsatellite instability-high [MSI-H] or mismatch repair deficient [MMRD],
[00166] In an exemplary embodiment, the human male subject with prostate cancer, prior to the dosing regimen, or the first occurrence of the dosing regimen, had not been administered a PARP inhibitor. In an exemplary embodiment, the human male subject with mCRPC, prior to the dosing regimen, or the first occurrence of the dosing regimen, had not been administered a PARP inhibitor.
[00167] In an exemplary embodiment, the prostate cancer is a HRD/CDK12 mutation positive cancer, and the human male subject with prostate cancer, prior to the dosing regimen, or the first occurrence of the dosing regimen, had not been administered a PARP inhibitor. In an exemplary embodiment, the prostate cancer is mCRPC and is a HRD/CDK12 mutation positive cancer, and the human male subject with prostate cancer, prior to the dosing regimen, or the first occurrence of the dosing regimen, had not been administered a PARP inhibitor. In an exemplary embodiment, the prostate cancer is a HRD/CDK12 mutation positive cancer which is one of the following: positive for HRD in one or more of the following genes: BRCA1, BRCA2, ATM, PALB2, CHEK2, FANCA; and/or positive for biallelic loss of CDK12, and the human male subject with prostate cancer, prior to the dosing regimen, or the first occurrence of the dosing regimen, had not been administered a PARP inhibitor. In an exemplary embodiment, the prostate cancer is mCRPC which is a HRD/CDK12 mutation positive cancer which is one of the following: Positive for HRD in one or more of the following genes: BRCA1, BRCA2, ATM, PALB2, CHEK2, FANCA; and/or Positive for biallelic loss of CDK12, and the human male subject with prostate cancer, prior to the dosing regimen, or the first occurrence of the dosing regimen, had not been administered a PARP inhibitor.
[00168] In an exemplary embodiment, the prostate cancer described herein is a primary tumor. In an exemplary embodiment, the prostate cancer described herein is a locally advanced primary tumor. In an exemplary embodiment, the prostate cancer described herein is a locally advanced primary tumor. In an exemplary embodiment, the prostate cancer described herein is a metastatic tumor.
[00169] In some embodiments, the prostate cancer is treated according to a method described herein. In one embodiment, the cancer is treated (such as by achieving a positive therapeutic response) by administering a bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) to the human subject in one or more cycles. Each cycle comprises dose amount(s) of a bispecific anti-CTLA4 x anti-PDl antibody e.g., XmAb®20717) provided according to a dosage regimen described herein. Each cycle can last for one or more weeks or months, or until a positive therapeutic response is achieved, or so long as there is a positive therapeutic response. In one embodiment, administration of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) stops after the positive therapeutic response is achieved, and the administration of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) begins again once the positive therapeutic response diminishes or disappears. In one embodiment, the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) is administered until partial remission. In one embodiment, the bispecific anti-CTLA4 x anti- PDl antibody (e.g., XmAb®20717) is administered until complete remission.
[00170] In some embodiments, the method of treatment comprises a bispecific anti- CTLA4 x anti-PDl antibody (e.g., XmAb®20717) being administered in one to twenty cycles in combination with at least one additional agent of the disclosure. In one embodiment, the method of treatment comprises a bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) being administered in one, or two, or three, or four, or five, or six, or seven, or eight, or nine, or ten, or more than ten cycles. In one embodiment, the dosage regimen has a dose amount (quantity of an antibody) and an administration time (the length of time in which the dose amount is administered).
[00171] In one embodiment, the method comprises a first cycle. In one embodiment, the method comprises a first cycle and a second cycle. In one embodiment, the method comprises a first cycle and a second cycle, where each cycle is different or wherein each cycle is the same. In one embodiment, the method comprises a first cycle and a second cycle and a third cycle. In one embodiment, the method comprises a first cycle and a second cycle and a third cycle, where each cycle is different or wherein each cycle is the same. In one embodiment, the method comprises a first cycle and a second cycle and a third cycle and a fourth cycle. In one embodiment, the method comprises a first cycle and a second cycle and a third cycle and a fourth cycle, where each cycle is different or wherein each cycle is the same. In one embodiment, the method comprises a first cycle and a second cycle and a third cycle and a fourth cycle and a fifth cycle. In one embodiment, the method comprises a first cycle and a second cycle and a third cycle and a fourth cycle and a fifth cycle, where each cycle is different or wherein each cycle is the same. In one embodiment, the method comprises a first cycle and a second cycle and a third cycle and a fourth cycle and a fifth cycle and a sixth cycle. In one embodiment, the method comprises a first cycle and a second cycle and a third cycle and a fourth cycle and a fifth cycle and a sixth cycle, where each cycle is different or wherein each cycle is the same. In one embodiment, the method comprises a first cycle and a second cycle and a third cycle and a fourth cycle and a fifth cycle and a sixth cycle and a seventh cycle. In one embodiment, the method comprises a first cycle and a second cycle and a third cycle and a fourth cycle and a fifth cycle and a sixth cycle and a seventh cycle, where each cycle is different or wherein each cycle is the same. In one embodiment, the method comprises a first cycle and a second cycle and a third cycle and a fourth cycle and a fifth cycle and a sixth cycle and a seventh cycle and an eighth cycle. In one embodiment, the method comprises a first cycle and a second cycle and a third cycle and a fourth cycle and a fifth cycle and a sixth cycle and a seventh cycle and an eighth cycle, where each cycle is different or wherein each cycle is the same. In one embodiment, the method comprises a first cycle and a second cycle and a third cycle and a fourth cycle and a fifth cycle and a sixth cycle and a seventh cycle and an eighth cycle and a ninth cycle. In one embodiment, the method comprises a first cycle and a second cycle and a third cycle and a fourth cycle and a fifth cycle and a sixth cycle and a seventh cycle and an eighth cycle and a ninth cycle, where each cycle is different or wherein each cycle is the same. In some embodiments, different dosages (e.g., of the bispecific anti-CTLA4 x anti-PDl antibody) are used in each cycle or in each administration. In some embodiments, the same dosage (e.g., of the bispecific anti-CTLA4 x anti-PDl antibody) is used between administrations in the same cycle. In some embodiments, the same dosage (e.g., of the bispecific anti-CTLA4 x anti-PDl antibody) is used between any two cycles, any three cycles, any four cycles, or more than any four cycles. In some embodiments, different dosage (e.g., of the bispecific anti-CTLA4 x anti-PDl antibody) is used between administrations in the same cycle. In some embodiments, different dosage (e.g., of the bispecific anti-CTLA4 x anti-PDl antibody) is used between any two cycles, any three cycles, any four cycles, or more than any four cycles.
[00172] It will be understood that XmAb®20717 can be used as the bispecific anti-CTLA4 x anti-PDl antibody in all methods of the invention provided herein. It will be understood that a biosimilar or XmAb®20717 can be used as the bispecific anti-CTLA4 x anti-PDl antibody in all methods of the invention provided herein. It will be understood that a bioequivalent or XmAb®20717 can be used as the bispecific anti-CTLA4 x anti-PDl antibody in all methods of the invention provided herein. It will be understood that a biobetter or XmAb®20717 can be used as the bispecific anti-CTLA4 x anti-PDl antibody in all methods of the invention provided herein.
[00173] In some embodiments, a steroid is administered to a male subject of the disclosure. In some embodiments, the steroid is prednisone administered at a dose of about 5 mg twice per day (b.i.d.) on day 1 of the first treatment cycle, and about twice per day (b.i.d.) thereafter.
[00174] In some embodiments, a method of the disclosure includes about, at least about, or at most about 1 treatment cycle, 2 treatment cycles, 3 treatment cycles, 4 treatment cycles, 5 treatment cycles, 6 treatment cycles, 7 treatment cycles, 8 treatment cycles, 9 treatment cycles, 10 treatment cycles, 11 treatment cycles, 12 treatment cycles, 13 treatment cycles, 14 treatment cycles, 15 treatment cycles, 16 treatment cycles, 17 treatment cycles, 18 treatment cycles, 19 treatment cycles, 20 treatment cycles, 21 treatment cycles, 22 treatment cycles, 23 treatment cycles, 24 treatment cycles, 25 treatment cycles, 26 treatment cycles, 27 treatment cycles, 28 treatment cycles, 29 treatment cycles, 30 treatment cycles, or more than 30 treatment cycles. In some embodiments, each treatment cycle is about 28 days. In some embodiments, each treatment cycle is 28 days. In some embodiments, each treatment cycle is between about 26-30 days. In some embodiments, a method of the disclosure results in stable disease classification of the prostate cancer as determined by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. In some embodiments, a method of the disclosure results in partial response classification of the prostate cancer as determined by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. In some embodiments, a method of the disclosure results in less or a reduced number of adverse events as compared to the average adverse events observed for an approved therapy (e.g., FDA approved) for treating the same prostate cancer that the male subject has.
[00175] In some embodiments, the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) is administered with Carboplatin (e.g., prior to, after, or at the same time or same day). In some embodiments, the methods of the present disclosure comprises administration of Carboplatin to a subject. In some embodiments, a pharmaceutical composition of the disclosure comprises Carboplatin. Carboplatin can be obtained through purchase from companies such as Sagent Pharma, Meitheal Pharmaceuticals, AdooQ Bioscience or Accord BioPharma (as Paraplatin®). Carboplatin is available in 10 mg/mL solutions. Calvert's formula can be utilized to calculate the dose of carboplatin.
[00176] In some embodiments, the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) is administered with Cabazitaxel (e.g., prior to, after, or at the same time or same day). In some embodiments, the methods of the present disclosure comprises administration of Cabazitaxel to a subject. In some embodiments, a pharmaceutical composition of the disclosure comprises Cabazitaxel. Cabazitaxel (Jevtana®, Sanofi -Aventis) can be obtained through purchase in 60 mg/1.5 mL solutions.
[00177] In some embodiments, the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) is administered with Docetaxel (e.g., prior to, after, or at the same time or same day). In some embodiments, the methods of the present disclosure comprises administration of Docetaxel to a subject. In some embodiments, a pharmaceutical composition of the disclosure comprises Docetaxel. Docetaxel (Taxotere®, Sanofi -Aventis) can be obtained through purchase in 20 mg/mL and 80 mg/4 mL solutions.
[00178] In some embodiments, the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) is administered with Olaparib (e.g., prior to, after, or at the same time or same day). In some embodiments, the methods of the present disclosure comprises administration of Olaparib to a subject. In some embodiments, a pharmaceutical composition of the disclosure comprises Olaparib. Olaparib (Lynparza®, AstraZeneca) can be obtained through purchase in 100 mg or 150 mg tablets. In an exemplary embodiment, a 300 mg oral dosage of olaparib is provided by the administration of two 150 mg tablets to the male human subject. In an exemplary embodiment, a 300 mg oral dosage of olaparib is provided by the administration of three 100 mg tablets to the male human subject. In an exemplary embodiment, a twice daily 300 mg oral dosage of olaparib is provided by the administration of two administrations per day of two 150 mg tablets to the male human subject, or two administrations per day of three 100 mg tablets to the male human subject or a combination thereof. In some embodiments, 300 mg twice a day is administered to a male subject for a total daily dosage of 600 mg. In some embodiments, between about 400-700 mg of Olaparib is administered to a subject. In some embodiments, between about 300-900 mg of Olaparib is administered to a subject. In some embodiments, between about 550-650 mg of Olaparib is administered to a subject.
[00179] In some embodiments, the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) is administered with Prednisone (e.g., prior to, after, or at the same time or same day). In some embodiments, the methods of the present disclosure comprises administration of Prednisone to a subject. In some embodiments, a pharmaceutical composition of the disclosure comprises Prednisone. Prednisone can be obtained through purchase from companies such as Roxane Laboratories in 5 mg/mL solutions.
[00180] In specific embodiments the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) is the only therapeutic antibody administered to the subject during the treatment methods provided herein. In some embodiments, the male subject has received one or at least one systemic therapy prior to the start of a method of the disclosure. In some embodiments, the male subject has received one or at least one systemic therapy prior to the first administration of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) of the disclosure. In some embodiments, the male subject has received two or at least two systemic therapies prior to the start of a method of the disclosure. In some embodiments, the male subject has received two or at least two systemic therapies prior to the first administration of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) of the disclosure. In some embodiments, the male subject has received three or at least three systemic therapies prior to the start of a method of the disclosure. In some embodiments, the male subject has received three or at least three systemic therapies prior to the first administration of the bispecific anti-CTLA4 x anti-PDl antibody (e.g, XmAb®20717) of the disclosure. In some embodiments, the male subject has received four or at least four systemic therapies prior to the start of a method of the disclosure. In some embodiments, the male subject has received four or at least four systemic therapies prior to the first administration of the bispecific anti-CTLA4 x anti-PDl antibody (e.g, XmAb®20717) of the disclosure. In some embodiments, the male subject has been treated with chemotherapy prior to the start of a method of the disclosure. In some embodiments, the male subject has been treated with chemotherapy prior to the first administration of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) of the disclosure. In some embodiments, the male subject has been treated with radiation therapy prior to the start of a method of the disclosure. In some embodiments, the male subject has been treated with radiation therapy prior to the first administration of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) of the disclosure.
[00181] In some embodiments, a bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) described herein can be used in combination with another therapeutic agent (e.g., Carboplatin, Cabazitaxel, Docetaxel, Prednisone, Olaparib, or any other appropriate therapeutic agent). Administered “in combination”, as used herein, means that two (or more) different treatments are delivered to the subject during the course of the subject’s affliction with the disorder, e.g.., the two or more treatments are delivered after the subject has been diagnosed with the disorder and before the disorder has been cured or eliminated or treatment has ceased for other reasons. In certain embodiments, the two or more treatments are delivered during the maintenance period following administration of the bispecific anti- CTLA4 x anti-PDl antibody and after the disorder has been cured or eliminated. In some embodiments, combination with another therapeutic agent refers to another therapeutic agent that is known to treat or is used to treat the same disease or disorder that the bispecific anti- CTLA4 x anti-PDl antibody (e.g., XmAb®20717) of the disclosure is being used to treat in the subject. In some embodiments, the delivery of one treatment is still occurring when the delivery of the second begins, so that there is overlap in terms of administration. This is sometimes referred to herein as “simultaneous” or “concurrent delivery”. In other embodiments, the delivery of one treatment ends before the delivery of the other treatment begins. In some embodiments of either case, the treatment is more effective because of combined administration. For example, the second treatment is more effective, e.g., an equivalent effect is seen with less of the second treatment, or the second treatment reduces one or more symptoms to a greater extent, than would be seen if the second treatment were administered in the absence of the first treatment, or the analogous situation is seen with the first treatment. In some embodiments, delivery is such that the reduction in a symptom, or other parameter related to the disorder is greater than what would be observed with one treatment delivered in the absence of the other. The effect of the two treatments can be partially additive, wholly additive, or greater than additive. The delivery can be such that an effect of the first treatment delivered is still detectable when the second is delivered.
[00182] The bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) and at least one additional therapeutic agent can be administered simultaneously, in the same or in separate compositions, or sequentially. For sequential administration, the bispecific anti- CTLA4 x anti-PDl antibody (e.g., XmAb®20717) described herein can be administered first, and the additional agent can be administered second, or vice versa.
[00183] The bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) and/or one or more additional therapeutic agents, procedures or modalities can be administered during periods of active disorder, or during a period of positive therapeutic response or less active disease. The bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) can be administered before the other treatment, concurrently with the treatment, post-treatment, or during a positive therapeutic response to the disorder.
[00184] When administered in combination, the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) and the one or more additional agents (e.g., second or third agent) can be administered in an amount or dose that is higher, lower or the same than the amount or dosage of each agent used individually, e.g., as a monotherapy. In some embodiments, the administered amount or dosage of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) and the one or more additional agents (e.g., second or third agent), is lower (e.g., at least about 10%, at least about 20%, at least about 30%, at least about 40%, or at least about 50%) than the amount or dosage of each agent used individually, e.g., as a monotherapy. In other embodiments, the amount or dosage of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) and the one or more additional agents (e.g., second or third agent, that results in a desired effect (e.g., treatment of cancer) is lower (e.g., at least about 10%, at least about 20%, at least about 30%, at least about 40%, or at least about 50%) than the amount or dosage of each agent used individually, e.g., as a monotherapy, required to achieve the same therapeutic effect.
4.5.1. Combination Therapy: Side-effect ameliorating agent
[00185] In some embodiments, a bispecific antibody is administered to a human subject in combination with one or more side-effect ameliorating agent(s). In an exemplary embodiment, the one or more side-effect ameliorating agent(s) is administered prior to the first administration of the bispecific antibody. In an exemplary embodiment, the one or more side-effect ameliorating agent(s) is administered prior to each administration of the bispecific antibody.
[00186] Possible side effects include, but are not limited to, increased amounts of alanine transaminase (ALT) in the blood, increased amounts of aspartate transaminase (AST) in the blood, fever, vomiting, nausea, diarrhea, hypotension, hypoxia, rash, dysphagia, gastroparesis, capillary leak syndrome, hypophosphatemia, anemia, fatigue, and increased lipase in the blood. Symptoms of treatment with the bispecific anti-CTLA4 x anti-PDl antibody e.g., XmAb®20717) of the disclosure can include high fevers, nausea, transient hypotension, hypoxia, and the like. Symptoms can also include clinical constitutional signs and symptoms such as fever, fatigue, anorexia, myalgias, arthralgias, nausea, vomiting, headache, clinical skin signs, and rash. Symptoms can include clinical gastrointestinal signs and symptoms such as nausea, vomiting and diarrhea. Symptoms can include clinical respiratory signs and symptoms such as tachypnea and hypoxemia. Symptoms can include clinical cardiovascular signs and symptoms such as tachycardia, widened pulse pressure, hypotension, increased cardiac output (early) and potentially diminished cardiac output. Symptoms can include clinical coagulation signs and symptoms such as elevated d-dimer, hypofibrinogenemia with or without bleeding. Symptoms can include clinical renal signs and symptoms such as azotemia. Symptoms can include clinical hepatic signs and symptoms such as transaminitis and hyperbilirubinemia. Symptoms can include clinical neurologic signs and symptoms such as headache, mental status changes, confusion, delirium, word finding difficulty or frank aphasia, hallucinations, tremor, dysmetria, altered gait, and seizures.
[00187] In an exemplary embodiment, the administration of XmAb®20717 described herein to the human subject produces a low rate of one or more symptoms described herein. In an exemplary embodiment, the administration of XmAb®20717 described herein to the human subject produces a low level of one or more symptoms described herein. In an exemplary embodiment, the administration of XmAb®20717 described herein to the human subject produces a low Grade (such as Grade 1 or Grade 2) of one or more symptoms described herein. In an exemplary embodiment, the administration of XmAb®20717 described herein to the human subject produces a low Grade (such as Grade 1 or Grade 2) of at least one symptom.
[00188] In one embodiment, the one or more side-effect ameliorating agent(s) include steroids, antihistamines, anti-allergic agents, antinausea agents (or anti-emetics), analgesic agents, antipyretic agents, cytoprotective agents, vasopressor agents, anticonvulsant agents, anti-inflammatories, or any combination thereof. In some embodiments, epinephrine, antihistamines, corticosteroids, IV fluids, vasopressors, oxygen, bronchodilators, and/or acetaminophen is administered to a subject. In some embodiments, at least one of epinephrine, antihistamines, corticosteroids, IV fluids, vasopressors, oxygen, bronchodilators, and/or acetaminophen is administered to a subject prior to administration of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) to the subject. In some embodiments, at least one of epinephrine, antihistamines, corticosteroids, IV fluids, vasopressors, oxygen, bronchodilators, and/or acetaminophen is administered to a subject after administration of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) to the subject. In some embodiments, at least one of epinephrine, antihistamines, corticosteroids, IV fluids, vasopressors, oxygen, bronchodilators, and/or acetaminophen is administered to a subject on the same day as the administration of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) to the subject.
4.5.2. Combination Therapy: Side-effect ameliorating agent, Steroid
[00189] In one embodiment, the side-effect ameliorating agent is a steroid. In one embodiment, the steroid is a corticosteroid. In one embodiment, the corticosteroid is a glucocorticoid. In one embodiment, the corticosteroid is betamethasone, dexamethasone, prednisone, prednisolone, methylprednisolone (e.g., 0.5-1 mg/kg/day or 1-2 mg/kg/day), triamcinolone, or any combination thereof. In one embodiment, the corticosteroid is hydrocortisone, cortisone, betamethasone, or any combination thereof. In one embodiment, the steroid is fludrocortisone. In one embodiment, the steroid is dexamethasone.
4.5.3. Combination Therapy: Side-effect ameliorating agent, Antihistamine
[00190] In one embodiment, the side-effect ameliorating agent is an antihistamine. In one embodiment, the antihistamine is an Hi antagonist. In one embodiment, the Hi antagonist is acrivastine, azelastine, bilastine, bromodiphenhydramine, brompheniramine, buclizine, carbinoxamine, cetirizine (Zyrtec®), chlorodiphenhydramine, chlorphenamine, clemastine, cyclizine, cyproheptadine, dexbrompheniramine, dexchlorpheniramine, dimenhydrinate, dimetindene, diphenhydramine, doxylamine, ebastine, embramine, fexofenadine (Allegra®), hydroxyzine (Vistaril®), loratadine (Claritin®), meclizine, mirtazapine, olopatadine, orphenadrine, phenindamine, pheniramine, phenyltoloxamine, promethazine, quetiapine (Seroquel®), rupatadine (Alergoliber®), tripelennamine, triprolidine, or any combination thereof.
[00191] In one embodiment, the antihistamine is acrivastine. In one embodiment, the antihistamine is cetirizine. In one embodiment, the antihistamine is diphenhydramine. In one embodiment, the antihistamine is Benadryl®.
[00192] In one embodiment, the antihistamine is an Hi inverse agonist. In one embodiment, the Hi inverse agonist is acrivastine, cetirizine, levocetirizine, desloratadine, pyrilamine, or any combination thereof.
[00193] In one embodiment, the antihistamine is an H2 antihistamine. In one embodiment, the H2 antihistamine is an H2 antagonist. In one embodiment, the H2 antihistamine is an H2 inverse agonist. In one embodiment, the H2 antihistamine is cimetidine, famotidine, lafutidine, nizatidine, ranitidine, roxatidine, tiotidine, or any combination thereof.
4.5.4. Combination Therapy: Side-effect ameliorating agent, Antiallergy agent
[00194] In one embodiment, the side-effect ameliorating agent is an antiallergy agent. In one embodiment, the side-effect ameliorating agent is antihistamines, glucocorticoids, epinephrine (adrenaline), mast cell stabilizers, antileukotriene agents, anti-cholinergics, decongestants, or any combination thereof. In one embodiment, the side-effect ameliorating agent is a decongestant. In one embodiment, the side-effect ameliorating agent is an adrenaline releasing agent. In one embodiment, the side-effect ameliorating agent is levomethamphetamine, phenylpropanolamine, propylhexedrine (Benzedrex®), loratadine, or any combination thereof. In one embodiment, the side-effect ameliorating agent is an a- adrenergic receptor agonist. In one embodiment, the side-effect ameliorating agent is naphazoline, oxymetazoline, phenylephrine, synephrine, tetryzoline, tramazoline, xylometazoline, or any combination thereof. 4.5.5. Combination Therapy: Side-effect ameliorating agent, Antinausea agents (or anti-emetic)
[00195] In one embodiment, the side-effect ameliorating agent is an antinausea agent. In one embodiment, the side-effect ameliorating agent is an antiemetic agent. In one embodiment, the side-effect ameliorating agent is a 5-HT3 receptor antagonist. In one embodiment, the side-effect ameliorating agent is a dolasetron (Anzemet®), granisetron (Kytril®, Sancuso®), ondansetron (Zofran®), tropisetron (Setrovel®, Navoban®), palonosetron (Aloxi®), mirtazapine (Remeron®), or any combination thereof. In one embodiment, the sideeffect ameliorating agent is a dopamine antagonist. In one embodiment, the side-effect ameliorating agent is a 5-HT3 receptor antagonist. In one embodiment, the side-effect ameliorating agent is domperidone (Motilium®), olanzapine (Zyprexa®), droperidol, haloperidol, chlorpromazine, prochlorperazine, alizapride, prochlorperazine (Compazine®, Stemzine®, Buccastem®, Stemetil®, Phenotil®), metoclopramide (Reglan®), or any combination thereof. In one embodiment, the side-effect ameliorating agent is a NK1 receptor antagonist. In one embodiment, the side-effect ameliorating agent is aprepitant or fosaprepitant (Emend®), casopitant, rolapitant (Varubi®), or any combination thereof. In one embodiment, the side-effect ameliorating agent is an anticholinergic. In one embodiment, the side-effect ameliorating agent is scopolamine.
4.5.6. Combination Therapy: Side-effect ameliorating agent, Analgesic and/or antipyretic agent
[00196] In one embodiment, the side-effect ameliorating agent is an analgesic agent. In one embodiment, the side-effect ameliorating agent is an antipyretic agent. In one embodiment, the side-effect ameliorating agent is a salicylate, any derivative thereof, or any combination thereof. In one embodiment, the salicylate is selected from the group consisting of aspirin, diflunisal, salsalate, salicylic acid, any derivative thereof, or any combination thereof. In one embodiment, the salicylate is choline salicylate, magnesium salicylate, sodium salicylate, or any combination thereof. In one embodiment, the side-effect ameliorating agent is aspirin. In one embodiment, the side-effect ameliorating agent is acetaminophen, any derivative thereof. In one embodiment, the side-effect ameliorating agent is an NSAID, any derivative thereof. In one embodiment, the NSAID is a propionic acid derivative. In one embodiment, the NSAID is ibuprofen, dexibuprofen, naproxen, fenoprofen, ketoprofen, dexketoprofen, flurbiprofen, oxaprozin, loxoprofen, any derivative thereof, or any combination thereof. In one embodiment, the NSAID is ibuprofen. In one embodiment, the NSAID is naproxen. In one embodiment, the NSAID is an acetic acid derivative. In one embodiment, the NSAID is indomethacin, tolmetin, sulindac, etodolac, ketorolac, diclofenac, aceclofenac, nabumetone, any derivative thereof, or any combination thereof. In one embodiment, the NSAID is an enolic acid derivative. In one embodiment, the NSAID is piroxicam, meloxicam, tenoxicam, droxicam, lornoxicam, phenylbutazone, any derivative thereof, or any combination thereof. In one embodiment, the NSAID is an anthranilic acid derivative. In one embodiment, the NSAID is mefenamic acid, meclofenamic acid, flufenamic acid, tolfenamic acid, any derivative thereof, or any combination thereof. In one embodiment, the side-effect ameliorating agent is phenazone, metamizole, nabumetone, any derivative thereof, or any combination thereof. In one embodiment, the side-effect ameliorating agent is an opiate. In one embodiment, the sideeffect ameliorating agent is codeine, morphine, thebaine, fentanyl, or any combination thereof. In one embodiment, the side-effect ameliorating agent is dihydrocodeine, oxymorphol, oxycodone, oxymorphone, metopon, or any combination thereof.
4.5.7. Combination Therapy: Side-effect ameliorating agent, Vasopressor agent
[00197] In one embodiment, the side-effect ameliorating agent is a vasopressor agent. In one embodiment, the vasopressor agent is norepinephrine, phenylephrine, epinephrine, ephedrine, dopamine, vasopressin, or any combination thereof. In one embodiment, the vasopressor agent is dobutamine, midodrine, amezinium, or any combination thereof.
4.5.8. Combination Therapy: Side-effect ameliorating agent, Anticonvulsant agent
[00198] In one embodiment, the side-effect ameliorating agent is an anticonvulsant agent. In one embodiment, the anticonvulsant is an aldehyde. In one embodiment, the aldehyde is paraldehyde. In one embodiment, the anticonvulsant is an aromatic allylic alcohol. In one embodiment, the aromatic allylic alcohol is stiripentol. In one embodiment, the anticonvulsant is a barbiturate. In one embodiment, the barbiturate is phenobarbital, primidone, methylphenobarbital, barbexaclone, or any combination thereof. In one embodiment, the anticonvulsant is a benzodiazepine. In one embodiment, the benzodiazepine is clobazam, clonazepam, clorazepate, diazepam, midazolam, lorazepam, nitrazepam, temazepam, nimetazepam, or any combination thereof. In one embodiment, the anticonvulsant is a carboxamide. In one embodiment, the carboxamide is carbamazepine, oxcarbazepine, eslicarbazepine acetate or any combination thereof. In one embodiment, the anticonvulsant is a fatty acid. In one embodiment, the fatty acid is a valproate. In one embodiment, the valproate is valproic acid, sodium valproate, divalproex sodium, or any combination thereof. In one embodiment, the valproate is vigabatrin, progabide, and tiagabine. In one embodiment, the anticonvulsant is a fructose derivative. In one embodiment, the fructose derivative is topiramate. In one embodiment, the anticonvulsant is a GABA analog. In one embodiment, the GABA analog is gabapentin, pregabalin, or any combination thereof. In one embodiment, the anticonvulsant is a hydantoin. In one embodiment, the hydantoin is ethotoin, phenytoin, mephenytoin, fosphenytoin, or any combination thereof. In one embodiment, the anticonvulsant is an oxazolidinedione. In one embodiment, the oxazolidinedione is paramethadione, trimethadione, ethadione, or any combination thereof. In one embodiment, the anticonvulsant is a propionate. In one embodiment, the anticonvulsant is a pyrimidinedione. In one embodiment, the anticonvulsant is a pyrrolidine. In one embodiment, the pyrrolidine is brivaracetam, etiracetam, levetiracetam, seletracetam, or any combination thereof. In one embodiment, the anticonvulsant is levetiracetam. In one embodiment, the anticonvulsant is a succinimide. In one embodiment, the succinimide is ethosuximide, phensuximide, mesuximide, or any combination thereof. In one embodiment, the anticonvulsant is a sulfonamide. In one embodiment, the succinimide is acetazolamide, sultiame, methazolamide, zonisamide, or any combination thereof. In one embodiment, the anticonvulsant is a triazine. In one embodiment, the triazine is lamotrigine. In one embodiment, the anticonvulsant is a urea. In one embodiment, the urea is pheneturide, phenacemide, or any combination thereof. In one embodiment, the anticonvulsant is a valproylamide. In one embodiment, the anticonvulsant is a valproylamide. In one embodiment, the valproylamide is valpromide, valnoctamide, or any combination thereof. In one embodiment, the anticonvulsant is perampanel, stiripentol, pyridoxine, or any combination thereof.
4.5.9. Combination Therapy: Side-effect ameliorating agent, TNFa inhibitor
[00199] In one embodiment, the side-effect ameliorating agent is an anti-inflammatory agent. In one embodiment, the side-effect ameliorating agent is a TNF-a inhibitor. In one embodiment, the TNF-a inhibitor is an antibody. Examples of an anti-TNFa antibody molecule such as, infliximab (Remicade®) (e.g., 5 mg/kg), adalimumab (Humira®), certolizumab pegol (Cimzia®), golimumab (Simponi®), or any combination thereof. Another example of a TNFa inhibitor is a fusion protein such as entanercept (Enbrel®). In one embodiment, the TNF-a inhibitor is a small molecule. Small molecule inhibitor of TNFa include, but are not limited to, xanthine derivatives (e.g., pentoxifylline), bupropion, or any combination thereof. 4.5.10. Combination Therapy: Side-effect ameliorating agent, IL6 inhibitor
[00200] In one embodiment, the side-effect ameliorating agent is an anti-inflammatory agent. In one embodiment, the side-effect ameliorating agent is a IL-6 inhibitor. An example of an IL-6 inhibitor is an anti-IL-6 antibody molecule such as tocilizumab (toe), sarilumab, elsilimomab, CNTO 328, ALD518/BMS-945429, CNTO 136, CPSL2364, CDP6038, VX30, ARGX-109, FE301, FM101, or any combination thereof. In one embodiment, the anti -IL-6 antibody molecule is tocilizumab.
[00201] The methods described herein can comprise administering a bispecific antibody described herein to a human subject and further administering one or more agents to manage elevated levels of a soluble factor resulting from treatment with a bispecific antibody. In one embodiment, the soluble factor elevated in the human subject is one or more of IFN-y, TNFa, IL-2 and IL-6. In an embodiment t, the factor elevated in the human subject is one or more of IL-1, GM-CSF, IL- 10, IL-8, IL-5 and fraktalkine. Therefore, an agent administered to treat this side effect can be an agent that neutralizes one or more of these soluble factors. In one embodiment, the agent that neutralizes one or more of these soluble forms is an antibody or antigen binding fragment thereof. Examples of such agents include, but are not limited to a steroid (e.g., corticosteroid), an inhibitor of TNFa, and inhibitor of IL-1R, and an inhibitor of IL-6. Examples include anakinra or rilonacept or canakinumab.
[00202] In one embodiment, the side-effect ameliorating agent is one that reduces an immune-mediated side effect. Exemplary immune-mediated side effects include, but are not limited to pneumonitis, colitis, hepatitis, nephritis and renal dysfunction, hypothyroidism, hyperthyroidism, and endocrinopathies (e.g., hypophysitis, Type 1 diabetes mellitus and thyroid disorders such as hypothyroidism and hyperthyroidism). In one embodiment, the side-effect ameliorating agent reduces embryofetal toxicity.
[00203] In an embodiment, the human subject can be administered an antipyretic agent. In an embodiment, the human subject can be administered an analgesic agent.
4.5.11. Side-effect combinations and amounts
[00204] In one embodiment, a steroid is administered prior to the bispecific antibody. In one embodiment, the steroid is administered in an amount between about 5 mg and about 30 mg. In one embodiment, the steroid described herein is administered in an amount between about 5 mg and about 25 mg. In one embodiment, the steroid is administered in an amount between about 5 mg and about 15 mg. In one embodiment, the steroid is administered in an amount between about 8 mg and about 12 mg. In one embodiment, the steroid is administered in an amount between about 10 mg and about 20 mg. In one embodiment, the steroid is administered in an amount of about 10 mg. In one embodiment, the steroid is administered in an amount of 10 mg. In one embodiment, the steroid is administered in an amount between about 18 mg and about 22 mg. In one embodiment, the steroid is administered in an amount of about 20 mg. In one embodiment, the steroid is administered in an amount of 20 mg. In one embodiment, the steroid is dexamethasone. In one embodiment, the steroid is dexamethasone and is administered in an amount between about 10 mg and about 20 mg. In one embodiment, the steroid is dexamethasone and is administered in an amount of about 10 mg. In one embodiment, the steroid is dexamethasone. In one embodiment, the steroid is dexamethasone and is administered in an amount of about 20 mg. In one embodiment, the steroid is dexamethasone and is administered between about 45 minutes and 75 minutes before each administration of a bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717). In one embodiment, the steroid is dexamethasone and is administered about 60 minutes before each administration of a bispecific anti-CTLA4 x anti- PDl antibody (e.g., XmAb®20717). In one embodiment, the steroid is dexamethasone and is administered about 60 minutes before an administration of bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717). In one embodiment, about 20 mg of dexamethasone is administered about 60 minutes before each administration of a bispecific anti-CTLA4 x anti- PDl antibody (e.g., XmAb®20717). In one embodiment, about 20 mg of dexamethasone is administered about 60 minutes before an administration of a bispecific anti-CTLA4 x anti- PDl antibody (e.g., XmAb®20717).
[00205] In one embodiment, an antihistamine is administered prior to the bispecific antibody. In one embodiment, the antihistamine is an Hi antagonist. In one embodiment, the Hi antagonist is a first generation Hi antagonist. In one embodiment, the antihistamine is an ethanolamine. In one embodiment, the ethanolamine is diphenhydramine, carbinoxamine, doxylamine, orphenadrine, bromazine, clemastine, dimenhydrinate, or any combination thereof. In one embodiment, the antihistamine is diphenhydramine. In one embodiment, the antihistamine is administered in an amount between about 20 mg and 60 mg. In one embodiment, the antihistamine is administered in an amount between about 20 mg and 30 mg. In one embodiment, the antihistamine is administered in an amount of about 25 mg. In one embodiment, the antihistamine is administered in an amount of 25 mg. In one embodiment, the antihistamine is administered in an amount between about 40 mg and 60 mg. In one embodiment, the antihistamine is administered in an amount between about 45 mg and 55 mg. In one embodiment, the antihistamine is administered in an amount of about 50 mg. In one embodiment, the antihistamine is administered in an amount of 50 mg. In one embodiment, the antihistamine is diphenhydramine and the amount between about 20 mg and about 30 mg. In one embodiment, the antihistamine is diphenhydramine and the amount is about 25 mg. In one embodiment, the antihistamine is diphenhydramine and is administered between about 20 minutes and 70 minutes before each administration of a bispecific anti- CTLA4 x anti-PDl antibody (e.g., XmAb®20717). In one embodiment, the antihistamine is diphenhydramine and is administered between about 30 minutes and 60 minutes before each administration of a bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717). In one embodiment, the antihistamine is diphenhydramine and is administered between about 30 minutes and 60 minutes before an administration of a bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717). In one embodiment, about 25 mg of diphenhydramine is administered between about 30 minutes and 60 minutes before each administration of a bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717). In one embodiment, about 25 mg of diphenhydramine is administered between about 30 minutes and 60 minutes before an administration of a bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717). [00206] In one embodiment, acetaminophen is administered prior to the bispecific antibody. In one embodiment, acetaminophen is administered in an amount between about 100 mg and 1000 mg. In one embodiment, acetaminophen is administered in an amount between about 400 mg and 600 mg. In one embodiment, acetaminophen is administered in an amount of about 500 mg. In one embodiment, acetaminophen is administered in an amount of 500 mg. In one embodiment, acetaminophen is administered in an amount between about 500 mg and 800 mg. In one embodiment, acetaminophen is administered in an amount between about 550 mg and 750 mg. In one embodiment, acetaminophen is administered in an amount between about 600 mg and 700 mg. In one embodiment, acetaminophen is administered in an amount of about 650 mg. In one embodiment, acetaminophen is administered in an amount of 650 mg. In one embodiment, the acetaminophen is administered between about 15 minutes and about 45 minutes before each administration of a bispecific anti-CTLA4 x anti-PDl antibody (e.g, XmAb®20717). In one embodiment, the acetaminophen is administered about 30 minutes before each administration of a bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717). In one embodiment, the acetaminophen is administered between about 60 minutes and about 30 minutes before an administration of a bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717). In one embodiment, the acetaminophen is administered between about 60 minutes and about 30 minutes before each administration of a bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717). In one embodiment, about 650 mg of acetaminophen is administered about 30 minutes before each administration of a bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717).
[00207] In one embodiment, a steroid, an Hi antagonist, and acetaminophen are administered prior to the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717). In one embodiment, dexamethasone, an Hi antagonist, and acetaminophen are administered prior to the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717). In one embodiment, a steroid, diphenhydramine, and acetaminophen are administered prior to the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717). In one embodiment, dexamethasone, diphenhydramine, and acetaminophen are administered prior to the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717). In one embodiment, dexamethasone is administered in an amount of about 10 mg or about 20 mg, diphenhydramine is administered in an amount of about 25 mg, and acetaminophen is administered in an amount of about 650 mg prior to the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717). In an exemplary embodiment, if the human subject is not experiencing a symptom after 1 or 2 or 3 or 4 consecutive doses of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717), then administration of a side-effect ameliorating agent described herein does not occur.
[00208] In one embodiment, an antinausea agent is administered prior to the bispecific antibody. In one embodiment, the antinausea agent is a 5-HT3 receptor antagonist. In one embodiment, the 5-HT3 receptor antagonist is administered in an amount between about 5 mg and 30 mg. In one embodiment, the 5-HT3 receptor antagonist is administered in an amount between about 5 mg and 15 mg. In one embodiment, the 5-HT3 receptor antagonist is administered in an amount between about 5 mg and 10 mg. In one embodiment, the 5-HT3 receptor antagonist is administered in an amount of about 8 mg. In one embodiment, the 5- HT3 receptor antagonist is administered in an amount of 8 mg. In one embodiment, the 5- HT3 receptor antagonist is ondansetron.
[00209] In one embodiment, an NK1 receptor antagonist is administered prior to the bispecific antibody. In one embodiment, the NK1 receptor antagonist is administered in an amount between about 100 mg and 300 mg. In one embodiment, the NK1 receptor antagonist is administered in an amount between about 125 mg and 200 mg. In one embodiment, the NK1 receptor antagonist is administered in an amount between about 125 mg and 175 mg. In one embodiment, the NK1 receptor antagonist is administered in an amount of about 150 mg. In one embodiment, the NK1 receptor antagonist is administered in an amount of 150 mg. In one embodiment, the NK1 receptor antagonist is aprepitant, fosaprepitant, or combination thereof. In one embodiment, the NK1 receptor antagonist is fosaprepitant dimeglumine.
4.6 Assessment of Positive Therapeutic Response
[00210] The compositions of the disclosure can be used to achieve a positive therapeutic response against prostate cancer. In an exemplary embodiment, a bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) composition is administered according to a method described herein to achieve a positive therapeutic response against prostate cancer. In an exemplary embodiment, a bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) composition and a carboplatin composition and a cabazitaxel composition are administered according to a method described herein to achieve a positive therapeutic response against prostate cancer. In an exemplary embodiment, a bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) composition and a carboplatin composition and a docetaxel composition are administered according to a method described herein to achieve a positive therapeutic response against prostate cancer. In an exemplary embodiment, a bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) composition and a cabazitaxel composition are administered according to a method described herein to achieve a positive therapeutic response against prostate cancer. In an exemplary embodiment, a bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) composition and a docetaxel composition are administered according to a method described herein to achieve a positive therapeutic response against prostate cancer. In an exemplary embodiment, a bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) composition and an olaparib composition are administered according to a method described herein to achieve a positive therapeutic response against prostate cancer. In an exemplary embodiment, the prostate cancer is receptive to treatment by an antibody which binds to CTLA4. In an exemplary embodiment, the prostate cancer is receptive to treatment by an antibody which binds to PD1. In an exemplary embodiment, the prostate cancer is receptive to treatment by an antibody which binds to CTLA4 and PD1. In an exemplary embodiment, the prostate cancer is receptive to treatment by carboplatin. In an exemplary embodiment, the prostate cancer is receptive to treatment by cabazitaxel. In an exemplary embodiment, the prostate cancer is receptive to treatment by docetaxel. In an exemplary embodiment, the prostate cancer is receptive to treatment by olaparib. [00211] In an exemplary embodiment, the positive therapeutic response can be assessed by assays or tools described herein. In an exemplary embodiment, the positive therapeutic response is a reduction in cancer tumor size, a reduction in the rate of cancer tumor growth, a reduction in the number of cancer-associated cells, an increase in cancer-associated cell death, an inhibition of cancer-associated cell survival, and/or an inhibition (z.e., slowing to some extent, preferably halting) of cancer-associated proliferation. In an exemplary embodiment, the positive therapeutic response is a reduction in prostate cancer tumor size, a reduction in the rate of prostate cancer tumor growth, a reduction in the number of prostate cancer-associated cells, an increase in prostate cancer-associated cell death, an inhibition of prostate cancer-associated cell survival, an inhibition (z.e., slowing to some extent, preferably halting) of prostate cancer-associated proliferation, and/or a lowering of prostate-specific antigen (PSA) levels in the male human subject.
[00212] In some embodiments, the desired therapeutic result is a complete response, partial response or stable disease. In specific embodiments, the desired therapeutic result is an improvement in response according to the RECIST guidelines (v. 1.1) as outlined in Eisenhauer et al. Eur. J. Cancer, 2009, 45:228-247, which is incorporated herein by reference in its entirety regarding, e.g., tumor response evaluation criteria.
[00213] In certain embodiments, the positive therapeutic response is assessed by the size of the target lesion(s). In some embodiments, the positive therapeutic response is a complete response as compared to baseline. In other embodiments, the positive therapeutic response is a partial response as compared to baseline. In some embodiments, the subject does not have progressive disease as compared to baseline. In other embodiments, the subject has stable disease as compared to baseline.
[00214] In certain embodiments, the positive therapeutic response is assessed by the size of the non-target lesion(s). In some embodiments, the positive therapeutic response is a complete response as compared to baseline. In other embodiments, the positive therapeutic response is a partial response as compared to baseline. In some embodiments, the subject does not have progressive disease as compared to baseline. In other embodiments, the subject has stable disease as compared to baseline.
[00215] In an exemplary embodiment, measuring of visceral lesions are used to assess the positive therapeutic response. Visceral lesions can be measured by computed tomography, or by caliper measurement by clinical examination, or by chest X-ray. The measurement methods are standardized and known to one of skill in the art. In an exemplary embodiment, a visceral lesion baseline assessment is taken prior to the first administration of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717). In an exemplary embodiment, a visceral lesion baseline assessment is taken prior to the first administration of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717), and involves: i) assessing the visceral lesions which have a minimum diameter along the longest plane of measurement of at least 10 mm by CT, 10 mm by caliper measurement by clinical examination, and 20 mm by chest X-ray, thereby assessing the target visceral lesions; ii) adding the sum of the diameters together of up to 5 of the target visceral lesions, thereby obtaining the visceral lesion baseline assessment. In an exemplary embodiment, a visceral lesion baseline assessment is taken between 28 days and 2 days prior to the first administration of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717). In an exemplary embodiment, a visceral lesion response assessment is taken after the first administration of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717). In an exemplary embodiment, a visceral lesion response assessment is taken between about 52 days and about 56 days after the first administration of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717). In an exemplary embodiment, a visceral lesion response assessment is taken after the first administration of the bispecific anti-CTLA4 x anti-PDl antibody e.g., XmAb®20717) and involves: i) assessing the diameter of the up to 5 target visceral lesions; ii) adding the sum of the diameters together of up to 5 of the target visceral lesions, thereby obtaining the visceral lesion response assessment. In an exemplary embodiment, a visceral lesion baseline assessment is taken prior to the first administration of the bispecific anti- CTLA4 x anti-PDl antibody (e.g., XmAb®20717) or carboplatin or cabazitaxel or docetaxel. In an exemplary embodiment, a visceral lesion baseline assessment is taken prior to the first administration of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) or carboplatin or cabazitaxel or docetaxel, and involves: i) assessing the visceral lesions which have a minimum diameter along the longest plane of measurement of at least 10 mm by CT, 10 mm by caliper measurement by clinical examination, and 20 mm by chest X-ray, thereby assessing the target visceral lesions; ii) adding the sum of the diameters together of up to 5 of the target visceral lesions, thereby obtaining the visceral lesion baseline assessment. In an exemplary embodiment, a visceral lesion baseline assessment is taken between 28 days and 2 days prior to the first administration of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) or carboplatin or cabazitaxel or docetaxel. In an exemplary embodiment, a visceral lesion response assessment is taken after the first administration of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) or carboplatin or cabazitaxel or docetaxel. In an exemplary embodiment, a visceral lesion response assessment is taken between about 52 days and about 56 days (about 8 weeks) after the first administration of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) or carboplatin or cabazitaxel or docetaxel. In an exemplary embodiment, a visceral lesion response assessment is taken after the first administration of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) or carboplatin or cabazitaxel or docetaxel and involves: i) assessing the diameter of the up to 5 target visceral lesions; ii) adding the sum of the diameters together of up to 5 of the target visceral lesions, thereby obtaining the visceral lesion response assessment. In an exemplary embodiment, a visceral lesion baseline assessment is taken prior to the first administration of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) or olaparib. In an exemplary embodiment, a visceral lesion baseline assessment is taken prior to the first administration of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) or olaparib, and involves: i) assessing the visceral lesions which have a minimum diameter along the longest plane of measurement of at least 10 mm by CT, 10 mm by caliper measurement by clinical examination, and 20 mm by chest X-ray, thereby assessing the target visceral lesions; ii) adding the sum of the diameters together of up to 5 of the target visceral lesions, thereby obtaining the visceral lesion baseline assessment. In an exemplary embodiment, a visceral lesion baseline assessment is taken between 28 days and 2 days prior to the first administration of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) or olaparib. In an exemplary embodiment, a visceral lesion response assessment is taken after the first administration of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) or olaparib. In an exemplary embodiment, a visceral lesion response assessment is taken between about 52 days and about 56 days (about 8 weeks) after the first administration of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) or olaparib. In an exemplary embodiment, a visceral lesion response assessment is taken after the first administration of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) or olaparib and involves: i) assessing the diameter of the up to 5 target visceral lesions; ii) adding the sum of the diameters together of up to 5 of the target visceral lesions, thereby obtaining the visceral lesion response assessment.
[00216] In an exemplary embodiment, the positive therapeutic response is achieved against the prostate cancer when there are fewer visceral lesions in the response assessment than in the baseline assessment. In an exemplary embodiment, the positive therapeutic response is achieved against the prostate cancer when the visceral lesions are smaller in the response assessment than in the baseline assessment. In an exemplary embodiment, the positive therapeutic response is achieved when the visceral lesion response assessment is at least 10%, or at least 20%, or at least 30%, or at least 40%, or at least 50%, or at least 60%, or last 70%, or at least 80%, or at least 90%, or 100% below the visceral lesion baseline assessment. In an exemplary embodiment, the positive therapeutic response is achieved when the visceral lesion response assessment is at least 30%, below the visceral lesion baseline assessment.
[00217] In an exemplary embodiment, the prostate cancer can be assessed for positive therapeutic purposes by assessing one or more properties of the prostate cancer in the patient prior to the administration of the compositions described herein, thereby obtaining a baseline assessment or evaluation. After the first administration of at least one of the compositions described herein, the prostate cancer property is assessed or evaluated again, thereby obtaining a response assessment. By comparing the baseline assessment and the response assessment, a determination can be made if the positive therapeutic response has been achieved. If the response assessment is an improvement over the baseline assessment, then the positive therapeutic response against prostate cancer is achieved. In an exemplary embodiment, more than one response assessment is made at different times during the course of treatment (during one or more of the times in which the dosing regimen is implemented). In an exemplary embodiment, assessing the prostate cancer is done by assessing one or more oncologic markers of the human subject. In an exemplary embodiment, the oncologic marker is selected from the group consisting of prostate-specific antigen (PSA) levels (for prostate cancer), bone lesions, visceral lesions, and malignant lymph nodes. For clarity, a positive therapeutic response can be in one oncologic marker category or more than one. That is, for example, a combination of lowered PSA level and/or reduced number of bone lesions and/or reduced diameter sum of target visceral lesions and/or reduced diameter sum of target malignant lymph nodes marks the achievement of the positive therapeutic response.
[00218] In an exemplary embodiment, the methods of the disclosure results in a decrease in prostate specific antigen (PSA) compared to a reference. In an exemplary embodiment, the decrease in PSA is a decrease of about or at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or more than 95% as compared to the reference. In an exemplary embodiment, the decrease is about or at least about 50% as compared to the reference. In an exemplary embodiment, the reference is the level of PSA in a biological sample obtained from the male subject prior to the first administration of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717). In an exemplary embodiment, the reference is the level of PSA of the male subject at baseline. In an exemplary embodiment, the reference is the level of PSA in a biological sample obtained from the male subject at a previous timepoint. In an exemplary embodiment, the reference is the level of PSA of at least one male subject with the same stage and/or disease progression of the prostate cancer and/or age group classification of the subject being treated with a method of the disclosure. In an exemplary embodiment, the reference is the level of PSA is a predetermined number. In some embodiments, a reference is the PSA level obtained from a biological sample from a male subject. In some embodiments, a reference is the PSA level obtained from a biological sample from a male subject with prostate cancer. In some embodiments, a reference is the PSA level obtained from a biological sample from one or more male subjects with prostate cancer. In some embodiments, a reference is the PSA level obtained from a biological sample from a male subject with prostate cancer before the first administration of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) of the disclosure. In some embodiments, a reference is the PSA level obtained from a biological sample from a male subject with prostate cancer from a previous time point. In some embodiments, a reference is the PSA level obtained from a biological sample from a male subject with prostate cancer before an administration of the bispecific anti-CTLA4 x anti- PDl antibody (e.g., XmAb®20717) of the disclosure. In some embodiments, a reference is the PSA level obtained from a biological sample from a male subject with prostate cancer obtained from an earlier treatment cycle.
[00219] In an exemplary embodiment, PSA levels are used to assess a positive therapeutic response. PSA levels are obtained by PSA tests, and PSA tests are standardized and known to one of skill in the art. In an exemplary embodiment, a PSA level baseline assessment is taken prior to the first administration of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717). In an exemplary embodiment, a PSA level baseline assessment is taken between 28 days and 2 days prior to the first administration of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717). In an exemplary embodiment, a PSA level baseline assessment is taken the day prior to the first administration of bispecific anti-CTLA4 x anti- PDl antibody (e.g., XmAb®20717). In an exemplary embodiment, a PSA level response assessment is taken after the first administration of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717). In an exemplary embodiment, a PSA level response assessment is taken between about 21 days and about 28 days after the intravenous dose of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717). In an exemplary embodiment, a PSA level baseline assessment is taken prior to the first administration of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) or carboplatin or cabazitaxel or docetaxel. In an exemplary embodiment, a PSA level baseline assessment is taken between 28 days and 2 days prior to the first administration of the bispecific anti- CTLA4 x anti-PDl antibody (e.g., XmAb®20717) or carboplatin or cabazitaxel or docetaxel. In an exemplary embodiment, a PSA level baseline assessment is taken the day prior to the first administration of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) or carboplatin or cabazitaxel or docetaxel. In an exemplary embodiment, a PSA level response assessment is taken after the first administration of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) or carboplatin or cabazitaxel or docetaxel. In an exemplary embodiment, a PSA level response assessment is taken between about 21 days and about 28 days after the intravenous dose of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717). In an exemplary embodiment, a PSA level response assessment is taken between about 26 days and about 30 days, or between about 54 days and about 58 days, or between about 82 days and about 86 days, or between about 110 days and about 114 days, after the first administration of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) or carboplatin or cabazitaxel or docetaxel. In an exemplary embodiment, a PSA level response assessment is taken between about 82 days and about 86 days after the first administration of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) or carboplatin or cabazitaxel or docetaxel. In an exemplary embodiment, a PSA level baseline assessment is taken prior to the first administration of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) or olaparib. In an exemplary embodiment, a PSA level baseline assessment is taken between 28 days and 2 days prior to the first administration of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) or olaparib. In an exemplary embodiment, a PSA level baseline assessment is taken the day prior to the first administration of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) or olaparib. In an exemplary embodiment, a PSA level response assessment is taken after the first administration of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) or olaparib. In an exemplary embodiment, a PSA level response assessment is taken between about 21 days and about 28 days after the intravenous dose of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717). In an exemplary embodiment, a PSA level response assessment is taken between about 26 days and about 30 days (about 4 weeks), or between about 54 days and about 58 days (about 7 weeks), or between about 82 days and about 86 days (about 12 weeks), or between about 110 days and about 114 days, after the first administration of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) or olaparib. In an exemplary embodiment, a PSA level response assessment is taken between about 82 days and about 86 days (about 12 weeks) after the first administration of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) or olaparib.
[00220] In an exemplary embodiment, the positive therapeutic response is achieved when the PSA level in the response assessment is below the PSA level in the baseline assessment. In an exemplary embodiment, the positive therapeutic response is achieved when the PSA level in the response assessment is at least 10%, or at least 20%, or at least 30%, or at least 40%, or at least 50%, or at least 60%, or last 70%, or at least 80%, or at least 90% below the PSA level in the baseline assessment. In an exemplary embodiment, the positive therapeutic response is achieved when the PSA level in the response assessment is at least 50% below the PSA level in the baseline assessment.
[00221] In an exemplary embodiment, measuring of bone lesions are used to assess the positive therapeutic response. Bone lesions can be measured by a bone scan, and these are standardized and known to one of skill in the art. In an exemplary embodiment, a bone lesion baseline assessment is taken prior to the first administration of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717). In an exemplary embodiment, a bone lesion baseline assessment is taken between 28 days and 2 days prior to the first administration of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717). In an exemplary embodiment, a bone lesion response assessment is taken after the first administration of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717). In an exemplary embodiment, a bone lesion response assessment is taken between about 52 days and about 56 days (about 8 weeks) after the first administration of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717). In an exemplary embodiment, a bone lesion response assessment involves counting the number of bone lesions in a bone scan taken between about 52 days and about 56 days (about 8 weeks) after the first administration of the bispecific anti- CTLA4 x anti-PDl antibody (e.g., XmAb®20717). In an exemplary embodiment, a bone lesion baseline assessment is taken prior to the first administration of the bispecific anti- CTLA4 x anti-PDl antibody (e.g., XmAb®20717) or carboplatin or cabazitaxel or docetaxel. In an exemplary embodiment, a bone lesion baseline assessment involves counting the number of bone lesions in a bone scan taken prior to the first administration of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) or carboplatin or cabazitaxel or docetaxel. In an exemplary embodiment, a bone lesion baseline assessment is taken between 28 days and 2 days prior to the first administration of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) or carboplatin or cabazitaxel or docetaxel. In an exemplary embodiment, a bone lesion response assessment is taken after the first administration of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) or carboplatin or cabazitaxel or docetaxel. In an exemplary embodiment, a bone lesion response assessment is taken between about 52 days and about 56 days (about 8 weeks) after the first administration of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) or carboplatin or cabazitaxel or docetaxel. In an exemplary embodiment, a bone lesion response assessment involves counting the number of bone lesions in a bone scan taken between about 52 days and about 56 days (about 8 weeks) after the first administration of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) or carboplatin or cabazitaxel or docetaxel. In an exemplary embodiment, a bone lesion baseline assessment is taken prior to the first administration of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) or olaparib. In an exemplary embodiment, a bone lesion baseline assessment involves counting the number of bone lesions in a bone scan taken prior to the first administration of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) or olaparib. In an exemplary embodiment, a bone lesion baseline assessment is taken between 28 days and 2 days prior to the first administration of the bispecific anti-CTLA4 x anti-PDl antibody (e.g, XmAb®20717) or olaparib. In an exemplary embodiment, a bone lesion response assessment is taken after the first administration of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) or olaparib. In an exemplary embodiment, a bone lesion response assessment is taken between about 52 days and about 56 days (about 8 weeks) after the first administration of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) or olaparib. In an exemplary embodiment, a bone lesion response assessment involves counting the number of bone lesions in a bone scan taken between about 52 days and about 56 days (about 8 weeks) after the first administration of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) or olaparib.
[00222] In an exemplary embodiment, the positive therapeutic response is achieved against the prostate cancer when there are fewer bone lesions in the response assessment than in the baseline assessment. In an exemplary embodiment, the positive therapeutic response is achieved against the prostate cancer when the number of bone lesions in the response assessment is lower than the number of bone lesions in the baseline assessment. In an exemplary embodiment, the positive therapeutic response is achieved when the number of bone lesions in the bone scan in the response assessment is at least 1 fewer, or at least 2 fewer, or at least 3 fewer, or at least 4 fewer, or at least 5 fewer than the number of bone lesions in the bone scan in the baseline assessment. In an exemplary embodiment, the positive therapeutic response is achieved against the prostate cancer when the bone lesions are smaller in the response assessment than in the baseline assessment.
[00223] In an exemplary embodiment, measuring of malignant lymph nodes are used to assess the positive therapeutic response. Malignant lymph nodes can be measured by computed tomography. The measurement method is standardized and known to one of skill in the art. In an exemplary embodiment, a malignant lymph node baseline assessment is taken prior to the first administration of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717). In an exemplary embodiment, a malignant lymph node baseline assessment is taken prior to the first administration of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717), and involves: assessing the malignant lymph nodes which have a minimum diameter of at least 15 mm in the short axis by CT, thereby assessing the target malignant lymph nodes; ii) adding the sum of the diameters together of up to 5 of the target malignant lymph nodes, thereby obtaining the target malignant lymph node baseline assessment. In an exemplary embodiment, a malignant lymph node baseline assessment is taken between 28 days and 2 days prior to the first administration of the bispecific anti- CTLA4 x anti-PDl antibody (e.g., XmAb®20717). In an exemplary embodiment, a malignant lymph node response assessment is taken after the first administration of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717). In an exemplary embodiment, a malignant lymph node response assessment is taken between about 52 days and about 56 days after the first administration of the bispecific anti-CTLA4 x anti-PDl antibody (e.g, XmAb®20717). In an exemplary embodiment, a visceral lesion response assessment is taken after the first administration of the bispecific anti-CTLA4 x anti-PDl antibody (e.g, XmAb®20717) and involves: i) assessing the diameter of the up to 5 target malignant lymph nodes; ii) adding the sum of the diameters together of up to 5 of the target malignant lymph nodes, thereby obtaining the target malignant lymph node response assessment. In an exemplary embodiment, a malignant lymph node baseline assessment is taken prior to the first administration of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) or carboplatin or cabazitaxel or docetaxel. In an exemplary embodiment, a malignant lymph node baseline assessment is taken prior to the first administration of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) or carboplatin or cabazitaxel or docetaxel, and involves: assessing the malignant lymph nodes which have a minimum diameter of at least 15 mm in the short axis by CT, thereby assessing the target malignant lymph nodes; ii) adding the sum of the diameters together of up to 5 of the target malignant lymph nodes, thereby obtaining the target malignant lymph node baseline assessment. In an exemplary embodiment, a malignant lymph node baseline assessment is taken between 28 days and 2 days prior to the first administration of the bispecific anti- CTLA4 x anti-PDl antibody (e.g., XmAb®20717) or carboplatin or cabazitaxel or docetaxel. In an exemplary embodiment, a malignant lymph node response assessment is taken after the first administration of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) or carboplatin or cabazitaxel or docetaxel. In an exemplary embodiment, a malignant lymph node response assessment is taken between about 52 days and about 56 days after the first administration of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) or carboplatin or cabazitaxel or docetaxel. In an exemplary embodiment, a visceral lesion response assessment is taken after the first administration of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) or carboplatin or cabazitaxel or docetaxel and involves: i) assessing the diameter of the up to 5 target malignant lymph nodes; ii) adding the sum of the diameters together of up to 5 of the target malignant lymph nodes, thereby obtaining the target malignant lymph node response assessment. In an exemplary embodiment, a malignant lymph node baseline assessment is taken prior to the first administration of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) or olaparib. In an exemplary embodiment, a malignant lymph node baseline assessment is taken prior to the first administration of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) or olaparib, and involves: assessing the malignant lymph nodes which have a minimum diameter of at least 15 mm in the short axis by CT, thereby assessing the target malignant lymph nodes; ii) adding the sum of the diameters together of up to 5 of the target malignant lymph nodes, thereby obtaining the target malignant lymph node baseline assessment. In an exemplary embodiment, a malignant lymph node baseline assessment is taken between 28 days and 2 days prior to the first administration of the bispecific anti- CTLA4 x anti-PDl antibody (e.g., XmAb®20717) or olaparib. In an exemplary embodiment, a malignant lymph node response assessment is taken after the first administration of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) or olaparib. In an exemplary embodiment, a malignant lymph node response assessment is taken between about 52 days and about 56 days after the first administration of the bispecific anti-CTLA4 x anti- PDl antibody (e.g., XmAb®20717) or olaparib. In an exemplary embodiment, a visceral lesion response assessment is taken after the first administration of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) or olaparib and involves: i) assessing the diameter of the up to 5 target malignant lymph nodes; ii) adding the sum of the diameters together of up to 5 of the target malignant lymph nodes, thereby obtaining the target malignant lymph node response assessment.
[00224] In an exemplary embodiment, the positive therapeutic response is achieved against the prostate cancer when there are fewer malignant lymph nodes in the response assessment than in the baseline assessment. In an exemplary embodiment, the positive therapeutic response is achieved against the prostate cancer when the malignant lymph nodes are smaller in the response assessment than in the baseline assessment. In an exemplary embodiment, the positive therapeutic response is achieved when the malignant lymph node response assessment is at least 10%, or at least 20%, or at least 30%, or at least 40%, or at least 50%, or at least 60%, or last 70%, or at least 80%, or at least 90%, or 100% below the malignant lymph node baseline assessment. In an exemplary embodiment, the positive therapeutic response is achieved when the malignant lymph node response assessment is at least 30%, below the malignant lymph node baseline assessment.
4.6.1. RECIST Guidelines
[00225] In some embodiments, disease or disease progression following treatment using a methods provided herein is determined based on the Response Evaluation Criteria in Solid Tumors (RECIST 1.1). In some embodiments, the objective response rate (ORR) or best observed response (BOR) is determined using RECIST 1.1. In some embodiments, progression of a disease of the disclosure is determined based on the RECIST guidelines. The following are selected definitions and tables from Revised RECIST Guidelines (Version 1.1; Eisenhauer et al, Eur J Cancer. 2009; 45:228-47; Chalian et al., Rad One. 2011; 31 :2093- 2105, each of which is herein incorporated by reference in its entirety).
4.6.1.1 Measurability of Visceral Lesion at Baseline
[00226] In an exemplary embodiment, at baseline, visceral lesions can be categorized as measurable or non-measurable as follows:
4.6.1.1.1 Measurable Visceral Lesions
[00227] In an exemplary embodiment, visceral lesions can be accurately measured in at least 1 dimension (longest diameter in the plane of measurement is to be recorded) with a minimum size of:
• 10 mm by computed tomography (CT) scan (CT scan slice thickness no greater than 5 mm)
• 10 mm caliper measurement by clinical exam (lesions which cannot be accurately measured with calipers should be recorded as non-measurable) 20 mm by chest X-ray
4.6.1.2 Measurability of Lymph Nodes at Baseline
[00228] In an exemplary embodiment, for malignant lymph nodes to be considered pathologically enlarged and measurable, a lymph node can be > 15 mm in short axis when assessed by CT scan (CT scan slice thickness recommended to be no greater than 5 mm). At baseline and in follow-up, the short axis can be measured and followed.
4.6.1.3 Non-measurable Lesions
[00229] In an exemplary embodiment, Non-measurable lesions are all other lesions, including
• Small lesions (longest diameter < 10 mm or pathological lymph nodes with P10 to < 15 mm short axis) as well as truly non-measurable lesions
• Lesions considered truly non-measurable include leptomeningeal disease, ascites, pleural or pericardial effusion, inflammatory breast disease, lymphangitic involvement of skin or lung, and abdominal masses/abdominal organomegaly identified by physical exam that is not measurable by reproducible imaging techniques.
4.6.1.4 Response Criteria
4.6.1.4.1 Target Lesions
[00230] In an exemplary embodiment, up to 5 target lesions may be identified and assessed for response. The following definitions can be used to determine objective tumor response for target lesions:
• Complete Response (CR): Disappearance of all target lesions. - Any pathological lymph nodes (whether target or nontarget) should have reduction in short axis to < 10 mm.
• Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.
• Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum should also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progression.) • Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum of diameters while on study.
4.6.1.4.2 Nontarget Lesions
[00231] In an exemplary embodiment, while some nontarget lesions may actually be measurable, they need not be measured and instead should be assessed only qualitatively at the time points specified in the protocol. In an exemplary embodiment, the following tumor response definitions apply to the group of nontarget lesions:
• Complete Response (CR): Disappearance of all nontarget lesions and normalization of tumor marker level. All lymph nodes should be nonpathological in size (< 10 mm short axis).
• Non-CR/Non-PD: Persistence of one or more nontarget lesion(s) and/or maintenance of tumor marker level above the normal limit.
• Progressive Disease (PD): Unequivocal progression of existing nontarget lesions. (Note: the appearance of one or more new lesions is also considered progression.)
4.6.1.4.3 New Lesions
[00232] In an exemplary embodiment, the appearance of new malignant lesions denotes disease progression. There are no specific criteria for the identification of new radiographic lesions; however, the finding of a new lesion should be unequivocal: i.e., not attributable to differences in scanning technique, change in imaging modality or findings thought to represent something other than tumor (for example, some ‘new’ bone lesions may be simply healing or flare of preexisting lesions). This is particularly important when the subject’s baseline lesions show partial or complete response. For example, necrosis of a liver lesion may be reported on a CT scan report as a ‘new’ cystic lesion, which it is not.
[00233] In an exemplary embodiment, a lesion identified on a follow-up study in an anatomical location that was not scanned at baseline is considered a new lesion and will indicate disease progression. An example of this is the subject who has visceral disease at baseline and while on study has a CT or magnetic resonance imaging (MRI) brain ordered which reveals metastases. The subject’s brain metastases are considered to be evidence of PD even if he/she did not have brain imaging at baseline.
[00234] In an exemplary embodiment, if a new lesion is equivocal, for example, because of its small size, continued therapy and follow-up evaluation will clarify if it represents truly new disease. If repeat scans confirm there is definitely a new lesion, then progression should be declared using the date of the initial scan.
4.6.1.5 Evaluation of Overall Response
[00235] The best overall response is the best response recorded from the start of the study treatment until the end of treatment, taking into account any requirement for confirmation. Responses after the termination of study drug may be included in the evaluation as long as the subject has not initiated new anticancer therapy.
[00236] The subject’s overall response assignment will depend on the findings of both target and nontarget disease and will also take into consideration the appearance of new lesions. This is captured in Table 2.
Table 2. Assessment of Overall Response in Subjects with Target (± Nontarget Disease)
Figure imgf000091_0001
CR = complete response, PD = progressive disease; PR = partial response, SD = stable disease.
4.6.2. Prostate Cancer Working Group Guidelines (PCWG3)
[00237] In some embodiments, disease or disease progression is determined based on the Prostate Cancer Working Group Guidelines (PCWG3). In some embodiments, progression of a disease of the disclosure is determined based on the PCWG3 guidelines. The following are selected definitions and tables from PCWG3 Guidelines (Scher et al. J Clin Oncol. 2016;
34(12): 1402-18).
4.6.2.1 Baseline Assessments
[00238] In an exemplary embodiment, baseline PSA, bone scan, visceral lesions and lymph nodes can be measured as follows: 4.6.2.1.1 PSA
[00239] In an exemplary embodiment, PSA can be measured during screening and at baseline. In some embodiments, PSA is monitored through early rises for a minimum of 12 weeks (unless there is other evidence of progression). In some embodiments, progression in subjects without PSA reduction from baseline is indicated by a rise in PSA > 25% and > 2 ng/mL above baseline value after 12 weeks of treatment. In some embodiments, progression in subjects with PSA reduction from baseline is indicated by a rise in PSA of > 25% and > 2 ng/mL above nadir and confirmed by a second value obtained at least 3 weeks later (z.e., a confirmed rising trend).
4.6.2.1.2 Visceral Lesions at Baseline
[00240] In an exemplary embodiment, visceral lesions can be accurately measured in at least one dimension (longest diameter in the plane of measurement is to be recorded) with a minimum size of:
• 10 mm by computed tomography (CT) scan (CT scan slice thickness no greater than 5 mm)
• 10 mm caliper measurement by clinical exam (lesions which cannot be accurately measured with calipers should be recorded as non-measurable)
• 20 mm by chest X-ray
[00241] In an exemplary embodiment, up to 5 lesions per site of disease (lungs, liver, adrenal, and central nervous system) are measured and recorded separately as measurable disease.
[00242] In an exemplary embodiment, visceral lesions considered truly non-measurable include leptomeningeal disease, ascites, pleural or pericardial effusion, inflammatory breast disease, lymphangitic involvement of skin or lung, abdominal masses/abdominal organomegaly identified by physical exam that is not measurable by reproducible imaging techniques.
[00243] In an exemplary embodiment, visceral lesions which do not meet the above size criteria are non-measurable.
4.6.2.1.3 Lymph Nodes at Baseline
[00244] In an exemplary embodiment, lymph nodes can be measured in the short axis and recorded as follows:
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a lymph node should be > 15 mm in short axis when assessed by CT scan (CT scan slice thickness recommended to be no greater than 5 mm). At baseline and in followup, only the short axis is measured and followed.
• Nodes > 10 mm to < 15 mm in short axis are pathologic, subject to clinical discretion, and non-measurable.
• Nodes < 10 mm are normal.
[00245] In an exemplary embodiment, pelvic and extrapelvic lymph nodes are recorded separately, and up to five nodal lesions total are recorded.
4.6.2.1.4 Bone Scan
[00246] In an exemplary embodiment, positivity on bone scan defines metastatic disease to bone. In an exemplary embodiment, the total number of lesions related to metastatic disease can be recorded.
4.6.2.2 Response Assessments
4.6.2.2.1 PSA
[00247] In an exemplary embodiment, serial PSA measurement can be performed and recorded through the study. In an exemplary embodiment, because a favorable effect on PSA may be delayed, treatment should be continued through early rises for a minimum of 12 weeks unless there is other evidence of progression.
[00248] In an exemplary embodiment, early rises in PSA (before 12 weeks) are not considered progression unless there is other evidence of disease progression.
4.6.2.2.2 Visceral and Nodal Lesions
[00249] In an exemplary embodiment, changes in lymph nodes (pelvic and extrapelvic), lung, liver, adrenal, and central nervous system sites are recorded separately.
• Up to 5 target lesions per site of disease can be measured
• Changes in visceral (lung, liver, adrenal, central nervous system) lesions > 10 mm in longest dimension can be recorded. The type of progression (growth of existing lesions versus development of new lesions) should be recorded by site.
• Previously normal lymph nodes (< 10 mm) should have grown by > 5 mm in the short axis and be 10 mm in the short axis to be considered to have progressed
• Nodes that have progressed to > 10 mm to < 15 mm are pathologic, subject to clinical discretion, and nonmeasurable
• For existing pathologic adenopathy (> 15 mm), progression is defined per RECIST 1.1 4.6.2.23 Bone Scan
[00250] In an exemplary embodiment, exclude pseudoprogression in the absence of symptoms or other signs of progression.
• First post-treatment scan: Progression is defined as at least two new lesions with at least
2 additional lesions on the next scan (2 + 2 rule)
• All scans after the first post-treatment scan: At least 2 new lesions relative to the first post-treatment scan, confirmed on a subsequent scan
4.6.2.3 Evaluation of Overall Response
[00251] In an exemplary embodiment, PSA response and measurable disease are being evaluated in this study. Both measurable and non-measurable lesions can be evaluated at each restaging to determine whether they have completely resolved or persisted, or whether new lesions have appeared.
4.6.2.3.1 Response Criteria:
[00252] In an exemplary embodiment, subjects can be assessed using the following criteria:
4.6.2.3.2 Evaluation of Target Lesions
• Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or nontarget) should have reduction in short axis to < 10 mm
• Partial Response (PR): At least a 30% decrease in the sum of diameter of target lesions taking as reference the baseline sum diameter
• Progressive Disease (PD): At least a 20% increase in the sum diameter of target lesions taking as references the smallest sum diameter on the study (including baseline sum if that is the smallest sum on study). The sum should also demonstrate an absolute increase of at least 5 mm.
• Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD
4.6.2.3.3 Evaluation of Nontarget Lesions
• Complete Response (CR): Disappearance of all nontarget lesions. All lymph nodes should be nonpathological in nature (< 10 mm short axis).
• Non-CR/Non-PD: Persistence of 1 or more nontarget lesions
• Progressive Disease (PD): Unequivocal progression. Note that the designation of overall progression solely on the basis of a change in nontarget disease in the face of stable or responding target disease is extremely rare. Examples of progression when the subject has only non-measurable disease include an increase in pleural effusion from “trace” to “large” or an increase in lymphangitic disease from localized to widespread. Refer to Section 4.6.1 of the RECIST guidelines for further guidance on progression in nontarget disease (Eisenhauer el at. Eur J Cancer. 2009; 45:228-47).
4.7 Biological and Biochemical Functionality of the Heterodimeric Checkpoint Antibodies
[00253] Generally, the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) is administered to human subjects with prostate cancer, and efficacy is assessed in a number of ways as described herein. Thus, while standard assays of efficacy can be run, such as cancer load, size of tumor, evaluation of presence or extent of metastasis, etc., immunooncology treatments can be assessed on the basis of immune status evaluations as well. This can be done in a number of ways, including both in vitro and in vivo assays. For example, evaluation of changes in immune status along with “old fashioned” measurements such as tumor burden, size, invasiveness, LN involvement, metastasis, etc. can be done. Thus, any or all of the following can be evaluated: the inhibitory effects of the checkpoints on CD4+ T cell activation or proliferation, CD8+ T (CTL) cell activation or proliferation, CD8+ T cell- mediated cytotoxic activity and/or CTL mediated cell depletion, NK cell activity and NK mediated cell depletion, the potentiating effects of the checkpoints on Treg cell differentiation and proliferation and Treg- or myeloid derived suppressor cell (MDSC)- mediated immunosuppression or immune tolerance, and/or the effects of the checkpoints on proinflammatory cytokine production by immune cells, e.g., IL-2, IFN-y or TNF-a production by T or other immune cells.
[00254] In some embodiments, assessment of treatment is done by evaluating immune cell proliferation, using for example, CFSE dilution method, Ki67 intracellular staining of immune effector cells, and 3H-Thymidine incorporation method.
[00255] In some embodiments, assessment of treatment is done by evaluating the increase in gene expression or increased protein levels of activation-associated markers, including one or more of: CD25, CD69, CD137, ICOS, PD1, GITR, 0X40, and cell degranulation measured by surface expression of CD 107 A.
[00256] In general, gene expression assays are done as is known in the art. In general, protein expression measurements are also similarly done as is known in the art.
[00257] In some embodiments, assessment of treatment is done by assessing cytotoxic activity measured by target cell viability detection via estimating numerous cell parameters such as enzyme activity (including protease activity), cell membrane permeability, cell adherence, ATP production, co-enzyme production, and nucleotide uptake activity. Specific examples of these assays include, but are not limited to, Trypan Blue or PI staining, 51Cr or 35S release method, LDH activity, MTT and/or WST assays, Calcein-AM assay, Luminescent based assay, and others.
[00258] In some embodiments, assessment of treatment is done by assessing T cell activity measured by cytokine production, measure either intracellularly in culture supernatant using cytokines including, but not limited to, TFNy, TNFa, GM-CSF, IL2, IL6, IL4, IL5, IL10, IL13 using well known techniques.
[00259] Accordingly, assessment of treatment can be done using assays that evaluate one or more of the following: (i) increases in immune response, (ii) increases in activation of aP and/or y5 T cells, (iii) increases in cytotoxic T cell activity, (iv) increases in NK and/or NKT cell activity, (v) alleviation of aP and/or y5 T-cell suppression, (vi) increases in pro- inflammatory cytokine secretion, (vii) increases in IL-2 secretion; (viii) increases in interferon-y production, (ix) increases in Thl response, (x) decreases in Th2 response, (xi) decreases or eliminates cell number and/or activity of at least one of regulatory T cells (Tregs).
4.7.1. Assays to measure efficacy
[00260] In some embodiments, T cell activation is assessed using a Mixed Lymphocyte Reaction (MLR) assay as is known in the art. An increase in activity indicates immunostimulatory activity. Appropriate increases in activity are outlined herein.
[00261] In one embodiment, the signaling pathway assay measures increases or decreases in immune response as measured for example by phosphorylation or de-phosphorylation of different factors, or by measuring other post translational modifications. An increase in activity indicates immunostimulatory activity. Appropriate increases in activity are outlined herein.
[00262] In one embodiment, the signaling pathway assay measures increases or decreases in activation of aP and/or y5 T cells as measured for example by cytokine secretion or by proliferation or by changes in expression of activation markers like for example CD 137, CD 107a, PD1, etc. An increase in activity indicates immunostimulatory activity. Appropriate increases in activity are outlined herein.
[00263] In one embodiment, the signaling pathway assay measures increases or decreases in cytotoxic T cell activity as measured for example by direct killing of target cells like for example cancer cells or by cytokine secretion or by proliferation or by changes in expression of activation markers like for example CD137, CD107a, PD1, etc. An increase in activity indicates immunostimulatory activity. Appropriate increases in activity are outlined herein. [00264] In one embodiment, the signaling pathway assay measures increases or decreases in NK and/or NKT cell activity as measured for example by direct killing of target cells like for example cancer cells or by cytokine secretion or by changes in expression of activation markers like for example CD 107a, etc. An increase in activity indicates immunostimulatory activity. Appropriate increases in activity are outlined herein.
[00265] In one embodiment, the signaling pathway assay measures increases or decreases in aP and/or y5 T-cell suppression, as measured for example by cytokine secretion or by proliferation or by changes in expression of activation markers like for example CD 137, CD 107a, PD1, etc. An increase in activity indicates immunostimulatory activity.
[00266] Appropriate increases in activity are outlined herein.
[00267] In one embodiment, the signaling pathway assay measures increases or decreases in pro-inflammatory cytokine secretion as measured, for example, by ELISA or by Luminex or by Multiplex bead based methods or by intracellular staining and FACS analysis or by Alispot, etc. An increase in activity indicates immunostimulatory activity. Appropriate increases in activity are outlined herein.
[00268] In one embodiment, the signaling pathway assay measures increases or decreases in IL-2 secretion as measured for example by ELISA or by Luminex or by Multiplex bead based methods or by intracellular staining and FACS analysis or by Alispot etc. An increase in activity indicates immunostimulatory activity. Appropriate increases in activity are outlined herein.
[00269] In one embodiment, the signaling pathway assay measures increases or decreases in interferon-y production as measured for example by ELISA or by Luminex or by Multiplex bead based methods or by intracellular staining and FACS analysis or by Alispot etc. An increase in activity indicates immunostimulatory activity. Appropriate increases in activity are outlined herein.
[00270] In one embodiment, the signaling pathway assay measures increases or decreases in Thl response as measured for example by cytokine secretion or by changes in expression of activation markers. An increase in activity indicates immunostimulatory activity. Appropriate increases in activity are outlined herein.
[00271] In one embodiment, the signaling pathway assay measures increases or decreases in Th2 response as measured for example by cytokine secretion or by changes in expression of activation markers. An increase in activity indicates immunostimulatory activity. Appropriate increases in activity are outlined herein.
[00272] In one embodiment, the signaling pathway assay measures increases or decreases cell number and/or activity of at least one of regulatory T cells (Tregs), as measured for example by flow cytometry or by IHC. A decrease in response indicates immunostimulatory activity. Appropriate decreases are the same as for increases, outlined herein.
[00273] In one embodiment, the signaling pathway assay measures increases or decreases in M2 macrophages cell numbers, as measured for example by flow cytometry or by IHC. A decrease in response indicates immunostimulatory activity. Appropriate decreases are the same as for increases, outlined herein.
[00274] In one embodiment, the signaling pathway assay measures increases or decreases in M2 macrophage pro-tumorigenic activity, as measured for example by cytokine secretion or by changes in expression of activation markers. A decrease in response indicates immunostimulatory activity. Appropriate decreases are the same as for increases, outlined herein.
[00275] In one embodiment, the signaling pathway assay measures increases or decreases in N2 neutrophils increase, as measured for example by flow cytometry or by IHC. A decrease in response indicates immunostimulatory activity. Appropriate decreases are the same as for increases, outlined herein.
[00276] In one embodiment, the signaling pathway assay measures increases or decreases in N2 neutrophils pro-tumorigenic activity, as measured for example by cytokine secretion or by changes in expression of activation markers. A decrease in response indicates immunostimulatory activity. Appropriate decreases are the same as for increases, outlined herein.
[00277] In one embodiment, the signaling pathway assay measures increases or decreases in inhibition of T cell activation, as measured for example by cytokine secretion or by proliferation or by changes in expression of activation markers like for example CD 137, CD 107a, PD1, etc. An increase in activity indicates immunostimulatory activity. Appropriate increases in activity are outlined herein.
[00278] In one embodiment, the signaling pathway assay measures increases or decreases in inhibition of CTL activation as measured for example by direct killing of target cells like for example cancer cells or by cytokine secretion or by proliferation or by changes in expression of activation markers like for example CD137, CD107a, PD1, etc. An increase in activity indicates immunostimulatory activity. Appropriate increases in activity are outlined herein.
[00279] In one embodiment, the signaling pathway assay measures increases or decreases in aP and/or y5 T cell exhaustion as measured for example by changes in expression of activation markers. A decrease in response indicates immunostimulatory activity.
[00280] Appropriate decreases are the same as for increases, outlined herein.
[00281] In one embodiment, the signaling pathway assay measures increases or decreases aP and/or y5 T cell response as measured for example by cytokine secretion or by proliferation or by changes in expression of activation markers like for example CD 137, CD107a, PD1, etc. An increase in activity indicates immunostimulatory activity. Appropriate increases in activity are outlined herein.
[00282] In one embodiment, the signaling pathway assay measures increases or decreases in stimulation of antigen-specific memory responses as measured for example by cytokine secretion or by proliferation or by changes in expression of activation markers like for example CD45RA, CCR7 etc. An increase in activity indicates immunostimulatory activity. Appropriate increases in activity are outlined herein.
[00283] In one embodiment, the signaling pathway assay measures increases or decreases in apoptosis or lysis of cancer cells as measured for example by cytotoxicity assays such as for example MTT, Cr release, Calcine AM, or by flow cytometry based assays like for example CFSE dilution or propidium iodide staining etc. An increase in activity indicates immunostimulatory activity. Appropriate increases in activity are outlined herein.
[00284] In one embodiment, the signaling pathway assay measures increases or decreases in stimulation of cytotoxic or cytostatic effect on cancer cells, as measured for example by cytotoxicity assays such as for example MTT, Cr release, Calcine AM, or by flow cytometry based assays like for example CFSE dilution or propidium iodide staining etc. An increase in activity indicates immunostimulatory activity. Appropriate increases in activity are outlined herein.
[00285] In one embodiment, the signaling pathway assay measures increases or decreases direct killing of cancer cells as measured for example by cytotoxicity assays such as for example MTT, Cr release, Calcine AM, or by flow cytometry based assays like for example CFSE dilution or propidium iodide staining etc. An increase in activity indicates immunostimulatory activity. Appropriate increases in activity are outlined herein.
[00286] In one embodiment, the signaling pathway assay measures increases or decreases Th 17 activity as measured for example by cytokine secretion or by proliferation or by changes in expression of activation markers. An increase in activity indicates immunostimulatory activity. Appropriate increases in activity are outlined herein.
[00287] In one embodiment, the signaling pathway assay measures increases or decreases in induction of complement dependent cytotoxicity and/or antibody dependent cell-mediated cytotoxicity, as measured for example by cytotoxicity assays such as for example MTT, Cr release, Calcine AM, or by flow cytometry based assays like for example CFSE dilution or propidium iodide staining etc. An increase in activity indicates immunostimulatory activity. Appropriate increases in activity are outlined herein.
[00288] In one embodiment, T cell activation is measured for example by direct killing of target cells like for example cancer cells or by cytokine secretion or by proliferation or by changes in expression of activation markers like for example CD137, CD107a, PD1, etc. For T-cells, increases in proliferation, cell surface markers of activation (e.g., CD25, CD69, CD137, and/or PD1), cytotoxicity (ability to kill target cells), and cytokine production (e.g., IL-2, IL-4, IL-6, IFNy, TNF-a, IL-10, and/or IL-17A) would be indicative of immune modulation that would be consistent with enhanced killing of cancer cells.
[00289] In one embodiment, NK cell activation is measured for example by direct killing of target cells like for example cancer cells or by cytokine secretion or by changes in expression of activation markers like for example CD107a, etc. For NK cells, increases in proliferation, cytotoxicity (ability to kill target cells and increases CD 107a, granzyme, and perforin expression), cytokine production (e.g., IFNy and TNF), and cell surface receptor expression (e.g., CD25) would be indicative of immune modulation that would be consistent with enhanced killing of cancer cells.
[00290] In one embodiment, y5 T cell activation is measured for example by cytokine secretion or by proliferation or by changes in expression of activation markers.
[00291] In one embodiment, Thl cell activation is measured for example by cytokine secretion or by changes in expression of activation markers.
[00292] Appropriate increases in activity or response (or decreases, as appropriate as outlined above), are increases of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or 98 to 99% percent over the signal in either a reference sample or in control samples, for example test samples that do not contain an antibody provided herein. Similarly, increases of at least one-, two-, three-, four- or five-fold as compared to reference or control samples show efficacy. 4.7.2. Treatments
[00293] Once made, the compositions provided herein find use in prostate cancer applications, generally by inhibiting the suppression of T cell activation (e.g., T cells are no longer suppressed).
[00294] Accordingly, the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) finds use in the treatment of prostate cancers.
4.8 Dosage Regimen
[00295] A dose has a specific amount of antibody that is administered to a human subject over a defined time period. The amount of antibody administered to a human subject is also known as the dose amount. The time over which the dose amount is administered to a human subject is also known as the administration time. In some embodiments, the bispecific anti- CTLA4 x anti-PDl antibody (e.g, XmAb®20717) of the disclosure is administered to the human subject according to a dosage regimen described herein. Dosage regimen are adjusted to provide the optimum desired response (e.g, a therapeutic response). In some embodiments, the carboplatin, cabazitaxel, prednisone, and/or the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) are administered to the male human subject according to a dosage regimen described herein. In some embodiments, the carboplatin, docetaxel, prednisone, and/or the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) are administered to the male human subject according to a dosage regimen described herein. In some embodiments, the olaparib and the bispecific anti-CTLA4 x anti- PDl antibody (e.g., XmAb®20717) are administered to the male human subject according to a dosage regimen described herein. The efficient dosages and the dosage regimens for the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) depend on the disease or condition to be treated and may be determined by the persons skilled in the art. The efficient dosages and the dosage regimens for the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717), carboplatin, cabazitaxel, docetaxel, and/or prednisone, depend on the disease or condition to be treated and may be determined by the persons skilled in the art. The efficient dosages and the dosage regimens for the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) and olaparib depend on the disease or condition to be treated and may be determined by the persons skilled in the art.
[00296] The dose amount may be determined or adjusted by measuring the amount of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) in the blood upon administration, for instance taking out a biological sample and using anti -idiotypic antibodies which target the antigen binding region of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717). The dosage may be determined based upon the weight of the human subject, such as by multiplying the weight (in kg, for example) of the human subject by a dose amount (such as those described herein). Prior to the administering of the first cycle, such as the day before the first dose of the first cycle of administration, the weight of the human subject can be assessed. In some embodiments, the dosage is the same in at least two administrations, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, at least ten, or more than at least ten administrations.
[00297] In some embodiments, the body weight of the subject is determined prior to Day 1 of a cycle. In some embodiments, the body weight of the subject is determined prior to Day 1 of a 28 day cycle. In some embodiments, the body weight of the subject is determined prior to Day 1 of each cycle. In some embodiments, the body weight of the subject is determined prior to Day 1 of each 28 day cycle. In some embodiments, the body weight of the subject is determined prior to Day 1 of the first cycle.
[00298] In some embodiments, a subject receives a dose of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) on Day 1 of a cycle based on the body weight determined prior to Day 1 of the cycle. In some embodiments, the body weight of the subject affects the dosage of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) to the subject and the dose is adjusted. For example, if at any time after treatment with the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) begins, the subject’s weight changes (e.g., changes by 10% or more from baseline or from previous measurement) and the new weight requires reassignment to a different dose, subsequent doses can be provided at the new dose level until such a time that the body weight again requires assignment to the another dose level. Following the first dose of the first cycle administration, subsequent doses may be modified if the human subject’s weight changes by a certain amount (for example, more than by about 5%, more than by about 10%, from the weight assessment prior to the first dose assessment or between any two assessments). In some embodiments, the weight of the subject may be recalculated for that infusion day or any subsequent infusion days using the current weight. In some embodiments, the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) is administered every 2 weeks. In some embodiments, the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) is administered every 3 weeks. In some embodiments, the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) is administered every week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, or more than 10 weeks. In some embodiments, the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) is administered every 5 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, or longer than 30 days. In some embodiments, the dose of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) is determined based on Cmax, AUC, and/or Clast.
[00299] In some embodiments of the various methods provided herein, from about 5 to about 15 mg/kg of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) is administered to a subject every two weeks. In some embodiments of the various methods provided herein, from about 5 mg/kg to about 15 mg/kg of the bispecific anti-CTLA4 x anti- PDl antibody (e.g., XmAb®20717) is administered to a subject every two weeks. In some embodiments, about 10 mg/kg of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) is administered to a subject (e.g., every two weeks or every three weeks). In some embodiments, 10 mg/kg of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) is administered to a subject (e.g., every two weeks). In some embodiments, about 15 mg/kg of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) is administered to a subject (e.g., every two weeks).
[00300] In other embodiments of the methods provided herein, the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) is administered to the subject on at a dose of about 10 mg/kg on day 1 of a first 28 day treatment cycle, and at a dose of about 10 mg/kg about every two weeks (Q2W) thereafter. In other embodiments of the methods provided herein, the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) is intravenously administered to the subject at a dose of about 10 mg/kg on day 1 of a first 28 day treatment cycle, and at a dose of about 10 mg/kg about every two weeks (Q2W) thereafter. In certain embodiments of the methods provided herein, the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) is administered to the subject according to a 28 day treatment cycle. In certain embodiments of the methods provided herein, the bi specific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) is intravenously administered to the subject according to a 28 day treatment cycle. In certain embodiments of the methods provided herein, the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) is administered to the subject at a dose of about 10 mg/kg according to a 28 day treatment cycle. In certain embodiments of the methods provided herein, the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) is intravenously administered to the subject at a dose of about 10 mg/kg according to a 28 day treatment cycle. In other embodiments of the methods provided herein, the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) is administered to the subject on Day 1 and Day 15 of a first 28 day treatment cycle, and about every two weeks (Q2W) thereafter. In other embodiments of the methods provided herein, the bispecific anti- CTLA4 x anti-PDl antibody (e.g., XmAb®20717) is intravenously administered to the subject on Day 1 and Day 15 of a first 28 day treatment cycle, and about every two weeks (Q2W) thereafter. In other embodiments of the methods provided herein, the bispecific anti- CTLA4 x anti-PDl antibody (e.g., XmAb®20717) is administered to the subject at a dose of about 10 mg/kg according to a 28 day treatment cycle, and the bispecific anti-CTLA4 x anti- PDl antibody (e.g., XmAb®20717) is administered to the subject on day 1 of a first 28 day treatment cycle, and about every two weeks (Q2W) thereafter. In some embodiments of the methods provided herein, the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) is intravenously administered to the subject according to a 28 day treatment cycle, and the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) is intravenously administered to the subject on day 1 of a first 28 day treatment cycle, and about every two weeks (Q2W) thereafter. In some embodiments of the methods provided herein, the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) is intravenously administered to the subject at a dose of about 10 mg/kg according to a 28 day treatment cycle, and the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) is intravenously administered to the subject on day 1 of a first 28 day treatment cycle, and about every two weeks (Q2W) thereafter.
[00301] In an exemplary embodiment, the intravenous dose of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) is administered once between about 12 and about 17 days. In an exemplary embodiment, the intravenous dose of the bispecific anti-CTLA4 x anti-PDl antibody (e.g, XmAb®20717) is administered once between about 13 and about 15 days. In an exemplary embodiment, the intravenous dose of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) is administered once every 13-15 days. In an exemplary embodiment, the intravenous dose of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) is administered once between about 12 and about 16 days. In an exemplary embodiment, the intravenous dose of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) is administered once every 12-16 days. In an exemplary embodiment, the intravenous dose of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) is administered once every 14-16 days. In an exemplary embodiment, the intravenous dose of XmAb®20717 is administered once about every 14 days. In an exemplary embodiment, the intravenous dose of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) is administered once every 14 days. In an exemplary embodiment, the intravenous dose of XmAb®20717 is administered once about every two weeks. In an exemplary embodiment, the intravenous dose of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) is administered once every two weeks. In an exemplary embodiment, the intravenous dose of XmAb®20717 is administered once between about 13 and about 17 days. In an exemplary embodiment, the intravenous dose of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) is administered once every 13-17 days. In an exemplary embodiment, the intravenous dose of XmAb®20717 is administered once about every 15 days. In an exemplary embodiment, the intravenous dose of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) is administered once every 15 days.
[00302] In an exemplary embodiment, the administering of the intravenous dose to the human subject lasts between about 45 minutes and about 75 minutes. In an exemplary embodiment, the administering of the intravenous dose to the human subject lasts between 45 minutes and 75 minutes. In an exemplary embodiment, the administering of the intravenous dose to the human subject lasts about one hour. In an exemplary embodiment, the administering of the intravenous dose to the human subject lasts one hour.
[00303] In an exemplary embodiment, the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) is administered for a time period sufficient to treat the prostate cancer. In an exemplary embodiment, the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) is administered for a time period sufficient to maintain the treatment of the prostate cancer. In an exemplary embodiment, the time period is between about 1 and about 9 weeks. In an exemplary embodiment, the time period is between about 2 and about 7 weeks. In an exemplary embodiment, the time period is between about 3 and about 9 weeks. In an exemplary embodiment, the time period is between about 1 and about 8 weeks. In an exemplary embodiment, the time period is between about 3 and about 5 weeks. In an exemplary embodiment, the time period is about 4 weeks. In an exemplary embodiment, the time period is 4 weeks. In an exemplary embodiment, the time period is between about 7 and about 9 weeks. In an exemplary embodiment, the time period is about 8 weeks. In an exemplary embodiment, the time period is 8 weeks. In an exemplary embodiment, the time period is from about 1 week to about 10 years. In an exemplary embodiment, the time period is from about 1 week to about 9.5 years. In an exemplary embodiment, the time period is from about 1 week to about 9 years. In an exemplary embodiment, the time period is from about 1 week to about 8.5 years. In an exemplary embodiment, the time period is from about 1 week to about 8 years. In an exemplary embodiment, the time period is from about 1 week to about 7.5 years. In an exemplary embodiment, the time period is from about 1 week to about 7 years. In an exemplary embodiment, the time period is from about 1 week to about 6.5 years. In an exemplary embodiment, the time period is from about 1 week to about 6 years. In an exemplary embodiment, the time period is from about 1 week to about 5.5 years. In an exemplary embodiment, the time period is from about 1 week to about 5 years. In an exemplary embodiment, the time period is from about 1 week to about 4.5 years. In an exemplary embodiment, the time period is from about 1 week to about 4 years. In an exemplary embodiment, the time period is from about 1 week to about 3.5 years. In an exemplary embodiment, the time period is from about 1 week to about 3 years. In an exemplary embodiment, the time period is from about 1 week to about 2.5 years. In an exemplary embodiment, the time period is from about 1 week to about 2 years. In an exemplary embodiment, the time period is from about 1 week to about 1.5 years. In an exemplary embodiment, the time period is from about 1 week to about 1 year. In an exemplary embodiment, the time period is from about 1 week to about 3 months, or about 4 months, or about 5 months, or about 6 months, or about 7 months, or about 8 months, or about 9 months, or about 10 months or about 11 months. In an exemplary embodiment, the time period is until a positive therapeutic response is achieved. In an exemplary embodiment, the time period is as long as a positive therapeutic response is maintained. In an exemplary embodiment, the time period is until a complete response is achieved.
[00304] In an exemplary embodiment, the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) is administered once every 13-16 days (e.g., 14 days or 15 days) for a time period lasting between about 1 and about 9 weeks. In an exemplary embodiment, the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) is administered once every 13-16 days e.g., 14 days or 15 days) for a time period lasting between about 2 and about 7 weeks. In an exemplary embodiment, the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) is administered once every 13-15 (e.g., 14 days or 15 days) days for a time period lasting between about 3 and about 9 weeks. In an exemplary embodiment, the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) is administered once every 13-16 days (e.g., 14 days or 15 days) for a time period lasting between about 1 and about 8 weeks. In an exemplary embodiment, the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) is administered once every 13-16 days (e.g., 14 days or 15 days) for a time period lasting between about 3 and about 5 weeks. In an exemplary embodiment, the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) is administered once every 13-16 days (e.g., 14 days or 15 days) for a time period lasting about 4 weeks. In an exemplary embodiment, the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) is administered once every 13-16 days (e.g., 14 days or 15 days) for a time period lasting 4 weeks. In an exemplary embodiment, the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) is administered once every 13-16 days (e.g., 14 days or 15 days) for a time period lasting between about 7 and about 9 weeks. In an exemplary embodiment, the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) is administered once every 13-16 days (e.g, 14 days or 15 days) for a time period lasting about 8 weeks. In an exemplary embodiment, the bispecific anti-CTLA4 x anti-PDl antibody (e.g, XmAb®20717) is administered once every 13-16 days (e.g., 14 days or 15 days) for a time period lasting 8 weeks. In an exemplary embodiment, the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) is administered once every 13-16 days (e.g., 14 days or 15 days) for a time period lasting until a positive therapeutic response is achieved. In an exemplary embodiment, the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) is administered once every 13-16 days (e.g., 14 days or 15 days) for a time period sufficient to treat the prostate cancer. In an exemplary embodiment, the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) is administered once every 13-16 days (e.g., 14 days or 15 days) for a time period sufficient to maintain the treatment of the prostate cancer. In specific embodiments, the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) is administered to the subject about every two weeks (Q2W). In specific embodiments, the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) is administered to the subject every two weeks (Q2W). In certain embodiments, the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) is administered once every about 14 days or 15 days. In certain embodiments, the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) is administered once every 14 days or 15 days.
[00305] The dosage may be determined or adjusted by measuring the amount of bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) provided herein in the blood upon administration using techniques known in the art, for instance taking out a biological sample and using anti -idiotypic antibodies which target the antigen binding region of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717).
[00306] In a specific embodiment, the intravenous dose of the bispecific anti-CTLA4 x anti-PDl antibody is 10 mg/kg. In certain embodiments, the intravenous dose bispecific anti- CTLA4 x anti-PDl antibody is 10 mg/kg, wherein the bispecific anti-CTLA4 x anti-PDl antibody comprises a first monomer (or a first polypeptide) comprising SEQ ID NO: 1, a second monomer (or a second polypeptide) comprising SEQ ID NO:2, and a light chain (or a third polypeptide) comprising SEQ ID NO:3. In certain embodiments, the intravenous dose bispecific anti-CTLA4 x anti-PDl antibody is 10 mg/kg, wherein the bispecific anti-CTLA4 x anti-PDl antibody is XmAb®20717. In specific embodiment, the intravenous dose of 10 mg/.kg of the bispecific anti-CTLA4 x anti-PDl antibody is administered to the subject once about every two weeks (Q2W).
[00307] In some embodiments, carboplatin is administered at a therapeutically effective dose that results in a target area under the serum concentration-time curve of 3 (AUC3). In some embodiments, carboplatin is administered at a therapeutically effective dose that results in a target area under the serum concentration-time curve of 3 (AUC3) for the first treatment cycle. In some embodiments, carboplatin is administered at a therapeutically effective dose that results in a target area under the serum concentration-time curve of 3 (AUC3) for the first administration of the first treatment cycle. In some embodiments, carboplatin is administered at a therapeutically effective dose that results in a target area under the serum concentrationtime curve of 3 (AUC3) for the first and second administrations of the first treatment cycle. In some embodiments, carboplatin is administered at a therapeutically effective dose that results in a target area under the serum concentration-time curve of 3 (AUC3) for the second administrations of the first treatment cycle.
[00308] In some embodiments, carboplatin is administered at a therapeutically effective dose that results in a target area under the serum concentration-time curve of 4 (AUC4). In some embodiments, carboplatin is administered at a therapeutically effective dose that results in a target area under the serum concentration-time curve of 4 (AUC4) for the second treatment cycle. In some embodiments, carboplatin is administered at a therapeutically effective dose that results in a target area under the serum concentration-time curve of 4 (AUC4) for the second treatment cycle and any subsequent treatment cycle. In some embodiments, carboplatin is administered at a therapeutically effective dose that results in a target area under the serum concentration-time curve of 4 (AUC4) for the first administration of the second treatment cycle. In some embodiments, carboplatin is administered at a therapeutically effective dose that results in a target area under the serum concentration-time curve of 4 (AUC4) for the first administration of the second treatment cycle and any subsequent administration. In some embodiments, carboplatin is administered at a therapeutically effective dose that results in a target area under the serum concentration-time curve of 4 (AUC4) for a treatment cycle that is not the first treatment cycle.
[00309] In some embodiments, carboplatin is administered for a maximum of about 8 treatment cycles. In some embodiments, carboplatin is administered on Day 1 of the first treatment cycle and every 3 weeks thereafter. In some embodiments, carboplatin is administered on Day 1 of the first treatment cycle and every 19-23 days thereafter. In some embodiments, carboplatin is administered on Day 1 of the first treatment cycle and every 20- 22 days thereafter. In some embodiments, carboplatin is administered on Day 1 of the first treatment cycle and every 21 days thereafter. In some embodiments, carboplatin is administered every 3 weeks.
[00310] In some embodiments, taxane (e.g., carbazitaxel or docetaxel) is administered for a maximum of about 8 treatment cycles. In some embodiments, carbazitaxel or docetaxel is administered on Day 1 of the first treatment cycle and every 3 weeks thereafter. In some embodiments, carbazitaxel or docetaxel is administered on Day 1 of the first treatment cycle and every 19-23 days thereafter. In some embodiments, carbazitaxel or docetaxel is administered on Day 1 of the first treatment cycle and every 20-22 days thereafter. In some embodiments, carbazitaxel or docetaxel is administered on Day 1 of the first treatment cycle and every 21 days thereafter. In some embodiments, carbazitaxel or docetaxel is administered every 3 weeks.
[00311] In some embodiments, taxane (e.g., carbazitaxel or docetaxel) is administered in an amount of between about 10 mg/m2 and about 55 mg/m2, between about 15 mg/m2 and about 65 mg/m2, between about 10 mg/m2 and about 80 mg/m2, between about 10 mg/m2 and about 100 mg/m2, between about 10 mg/m2 and about 20 mg/m2, between about 15 mg/m2 and about 25 mg/m2, between about 45 mg/m2 and about 55 mg/m2, between about 70 mg/m2 and about 80 mg/m2, between about 55 mg/m2 and about 65 mg/m2. In some embodiments, taxane (e.g., carbazitaxel or docetaxel) is administered in an amount of about 10 mg/m2. In some embodiments taxane (e.g., carbazitaxel or docetaxel) is administered in an amount of about 15 mg/m2. In some embodiments, taxane (e.g., carbazitaxel or docetaxel) is administered in an amount of about 20 mg/m2. In some embodiments, taxane (e.g., carbazitaxel or docetaxel) is administered in an amount of about 50 mg/m2. In some embodiments, taxane (e.g., carbazitaxel or docetaxel) is administered in an amount of about 60 mg/m2. In some embodiments, taxane (e.g., carbazitaxel or docetaxel) is administered in an amount of about 65 mg/m2. In some embodiments, taxane (e.g., carbazitaxel or docetaxel) is administered in an amount of about 55 mg/m2. In some embodiments, taxane (e.g., carbazitaxel or docetaxel) is administered in an amount of about 70 mg/m2. In some embodiments, taxane (e.g., carbazitaxel or docetaxel) is administered in an amount of about 75 mg/m2. In some embodiments, taxane (e.g., carbazitaxel or docetaxel) is administered in an amount of about 80 mg/m2. In some embodiments, carbazitaxel is administered in an amount of 15 mg/m2. In some embodiments, carbazitaxel is administered in an amount of 20 mg/m2. In some embodiments, docetaxel is administered in an amount of 50 mg/m2. In some embodiments, docetaxel is administered in an amount of 60 mg/m2. In some embodiments, docetaxel is administered in an amount of 75 mg/m2. In some embodiments, the amount of carbazitaxel or docetaxel is different in the first treatment cycle than in a subsequent treatment cycle. In some embodiments, the amount of carbazitaxel or docetaxel is lower in the first treatment cycle than in a subsequent treatment cycle. In some embodiments, the amount of carbazitaxel or docetaxel is different in the first administration of the first treatment cycle than in a subsequent treatment cycle. In some embodiments, the amount of carbazitaxel or docetaxel is lower in the first administration of the first treatment cycle than in a subsequent treatment cycle. In some embodiments, carbazitaxel is administered in an amount of 15 mg/m2 in a first treatment cycle and 20 mg/m2 in a subsequent treatment cycle (e.g., second cycle and onwards). In some embodiments, carbazitaxel is administered in an amount of about 15 mg/m2 in a first treatment cycle and about 20 mg/m2 in a subsequent treatment cycle. In some embodiments, carbazitaxel is administered in an amount of 15 mg/m2 in a first administration of the first treatment cycle and 20 mg/m2 in a subsequent treatment cycle. In some embodiments, carbazitaxel is administered in an amount of about 15 mg/m2 in a first administration of the first treatment cycle and about 20 mg/m2 in a subsequent treatment cycle. In some embodiments, docetaxel is administered in an amount of 50 mg/m2 in a first treatment cycle and 60 mg/m2 in a subsequent treatment cycle. In some embodiments, docetaxel is administered in an amount of about 50 mg/m2 in a first treatment cycle and about 60 mg/m2 in a subsequent treatment cycle. In some embodiments, docetaxel is administered in an amount of 50 mg/m2 in a first administration of the first treatment cycle and 60 mg/m2 in a subsequent treatment cycle. In some embodiments, docetaxel is administered in an amount of about 50 mg/m2 in a first administration of the first treatment cycle and about 60 mg/m2 in a subsequent treatment cycle. In some embodiments, the amount of carbazitaxel or docetaxel is the same in the first treatment cycle and in a subsequent treatment cycle. In some embodiments, the amount of carbazitaxel or docetaxel is the same in the first administration of the first treatment cycle and in a subsequent treatment cycle. In some embodiments, carbazitaxel is administered in an amount of 15 mg/m2 in a treatment cycle. In some embodiments, carbazitaxel is administered in an amount of 15 mg/m2 in all treatment cycles. In some embodiments, carbazitaxel is administered in an amount of about 15 mg/m2 in a treatment cycle. In some embodiments, carbazitaxel is administered in an amount of about 15 mg/m2 in all treatment cycles. In some embodiments, carbazitaxel is administered in an amount of 20 mg/m2 in a treatment cycle. In some embodiments, carbazitaxel is administered in an amount of 20 mg/m2 in all treatment cycles. In some embodiments, carbazitaxel is administered in an amount of about 20 mg/m2 in a treatment cycle. In some embodiments, carbazitaxel is administered in an amount of about 20 mg/m2 in all treatment cycles. In some embodiments, docetaxel is administered in an amount of 50 mg/m2 in a treatment cycle. In some embodiments, docetaxel is administered in an amount of 50 mg/m2 in all treatment cycles. In some embodiments, docetaxel is administered in an amount of about 50 mg/m2 in a treatment cycle. In some embodiments, docetaxel is administered in an amount of about 50 mg/m2 in all treatment cycles. In some embodiments, docetaxel is administered in an amount of 60 mg/m2 in a treatment cycles. In some embodiments, docetaxel is administered in an amount of 60 mg/m2 in all treatment cycles. In some embodiments, docetaxel is administered in an amount of about 60 mg/m2 in a treatment cycle. In some embodiments, docetaxel is administered in an amount of about 60 mg/m2 in all treatment cycles. In some embodiments, docetaxel is administered in an amount of 75 mg/m2 in a treatment cycles. In some embodiments, docetaxel is administered in an amount of 75 mg/m2 in all treatment cycles. In some embodiments, docetaxel is administered in an amount of about 75 mg/m2 in a treatment cycle. In some embodiments, docetaxel is administered in an amount of about 75 mg/m2 in all treatment cycles. In some embodiments, docetaxel is administered to a subject instead of carbazitaxel if the subject is docetaxel naive or has not been treated with docetaxel prior to the first administration of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) of the disclosure. In some embodiments, carbazitaxel or docetaxel is administered every 3 weeks.
[00312] In some embodiments, olaparib (e.g., 300 mg twice daily; 600 mg per day; between about 400-800 mg per day) is administered to a male subject in combination with the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) of the disclosure. In some embodiments, the dose of the olaparib is about, at least about, or at most about 600 mg per day. In some embodiments, the dose of the olaparib is 600 mg per day. In some embodiments, the dose of the olaparib is 300 mg twice daily. In some embodiments, the dose of the olaparib is about, at least about, or at most about 300 mg twice daily. In some embodiments, olaparib is administered to a male subject with prostate cancer at a dose of between about 500-700 mg on Day 1 of a first treatment cycle. In some embodiments, olaparib is administered to a male subject with prostate cancer at a dose of between about 500-700 mg on Day 1 of a first treatment cycle and every day thereafter. In some embodiments, olaparib is administered to a male subject with prostate cancer at a dose of between about 500-700 mg daily. In some embodiments, olaparib is administered to a male subject with prostate cancer at a dose of between about 500-700 mg as needed. In some embodiments, olaparib is administered to a male subject with prostate cancer two times a day. In some embodiments, olaparib is administered to a male subject with prostate cancer three times a day. In some embodiments, olaparib is administered to a male subject with prostate cancer four times a day. In some embodiments, olaparib is administered to a male subject with prostate cancer at a dose of 300 mg two times a day. In some embodiments, olaparib is administered to a male subject with prostate cancer at a dose of 150 mg four times a day. In some embodiments, olaparib is administered to a male subject with prostate cancer at a dose of 200 mg three times a day. In some embodiments, olaparib is administered daily. In some embodiments, olaparib is not administered every day. In some embodiments, olaparib is administered every treatment cycle. In some embodiments, olaparib is administered every day of every treatment cycle. In some embodiments, olaparib is not administered every treatment cycle. In some embodiments, olaparib is not administered every day of every treatment cycle. In some embodiments, olaparib is administered at the same dose at each administration. In some embodiments, olaparib is administered at the same dose at each treatment cycle. In some embodiments, olaparib is administered at the same dose at each day. In some embodiments, olaparib is not administered at the same dose at each administration. In some embodiments, olaparib is not administered at the same dose at each treatment cycle. In some embodiments, olaparib is not administered at the same dose at each day. In some embodiments, the dose of olaparib is about 600 mg per day. In some embodiments, the dose of olaparib is 600 mg per day. In some embodiments, the dose of olaparib is lower than 600 mg per day. In some embodiments, the dose of olaparib is higher than 600 mg per day.
[00313] Dosage regimens are adjusted to provide the optimum desired response (e.g., a therapeutic response). For example, a single bolus may be administered, several divided doses may be administered over time or the dose may be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation. Parenteral compositions may be formulated in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the subjects to be treated; each unit contains a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.
[00314] In some embodiments, the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) is administered intravenously. In some embodiments, the XmAb®20717 is
I l l administered once-every-two-weeks until disease progression, unacceptable toxicity, or individual choice.
[00315] In some embodiments, the bispecific anti-CTLA4 x anti-PDl antibody (e.g, XmAb®20717) is a front line therapy, second line therapy, third line therapy, fourth line therapy, fifth line therapy, or sixth line therapy.
[00316] In some embodiments, the bispecific anti-CTLA4 x anti-PDl antibody (e.g, XmAb®20717) treats a refractory prostate cancer. In some embodiments, the bispecific anti- CTLA4 x anti-PDl antibody (e.g., XmAb®20717) treats a relapsed prostate cancer. In some embodiments, the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) treats a refractory and relapsed prostate cancer. In some embodiments, the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) is a maintenance therapy.
[00317] A medical professional having ordinary skill in the art may readily determine and prescribe the effective amount of the antibody composition required. For example, a physician could start doses of the medicament employed in the antibody composition at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.
[00318] Specific dosing regimens are also contemplated and encompassed by embodiments of the various methods provided herein for the treatment of a prostate cancer in a human male subject.
[00319] The specification for the dosage unit forms provided herein are dictated by and directly dependent on (a) the unique characteristics of the active compound and the particular therapeutic effect to be achieved, and (b) the limitations inherent in the art of compounding such an active compound for the treatment of sensitivity in individuals.
[00320] In one embodiment, each dosage regimen comprises at least one dose of the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) provided to the human subject (per week, per two weeks, per three weeks, or per month/over a set period of day(s) or week(s)). Dosage regimens are adjusted to provide the optimum desired response (e.g., a positive therapeutic response). The efficient dosages and the dosage regimens for the bispecific anti-CTLA4 x anti-PDl antibody (e.g., XmAb®20717) used in the present methods depend on the disease or condition to be treated. In a specific embodiment, the bispecific anti-CTLA4 x anti-PDl antibody is XmAb®20717.
[00321] In one embodiment, the subject receives treatment about every 2 weeks (Q2W) for about two years. 4.9 Selection of Human Subjects
[00322] Human subjects can be selected based on criteria described herein. In an exemplary embodiment, the human subject is a male adult human subject. In an exemplary embodiment, the human subject is a male juvenile human subject. In an exemplary embodiment, the human subject is 18 years or older. In an exemplary embodiment, the human subject is between the ages of 18 years and 100 years. In an exemplary embodiment, the human subject is between the ages of 18 years and 80 years. In an exemplary embodiment, the human subject is between the ages of 45 years and 90 years. In an exemplary embodiment, the human subject is between the ages of 45 years and 80 years. In an exemplary embodiment, the human subject is between the ages of 50 years and 90 years. In an exemplary embodiment, the human subject is between the ages of 55 years and 85 years. In an exemplary embodiment, the human subject is between the ages of 60 years and 80 years. In an exemplary embodiment, the human subject is between the ages of 60 years and 70 years. In an exemplary embodiment, the human subject is 50 years old or older. In an exemplary embodiment, the human subject is between the ages of 50 years and 70 years. [00323] In an exemplary embodiment, the male human subject has progressive metastatic castration-resistant prostate cancer. In an exemplary embodiment, the male human subject has experienced PSA progression. In an exemplary embodiment, the male human subject is able to provide written informed consent. In an exemplary embodiment, the male subject has an aggressive variant (anaplastic) adenocarcinoma of the prostate (AVPCa). In an exemplary embodiment, the male subject has a prostate cancer that has progressed after the male subject received a polyadenosine diphosphate ribose polymerase (PARP) inhibitor. In an exemplary embodiment, the male subject has not been previously treated with a PARP inhibitor. In an exemplary embodiment, the male subject has a cancer that does not have a targetable mutation.
[00324] In an exemplary embodiment, the male human subject has received at least two systemic therapies prior to the first administration of the anti-CTLA4 x anti-PDl bispecific antibody described herein. In an exemplary embodiment, the male subject has received at least three systemic therapies prior to the first administration of the anti-CTLA4 x anti-PDl bispecific antibody described herein. In an exemplary embodiment, the male subject has been treated with chemotherapy prior to the first administration of the anti-CTLA4 x anti-PDl bispecific antibody described herein. In an exemplary embodiment, the male subject has been treated with radiation therapy prior to the first administration of the anti-CTLA4 x anti- PD1 bispecific antibody described herein.
[00325] In an exemplary embodiment, the male human subject has histologically confirmed diagnosis of carcinoma of the prostate. In an exemplary embodiment, the male human subject has progressive mCRPC based on PSA progression, defined as at least 2 rises in PSA with a minimum of a one week interval. In an exemplary embodiment, the male human subject has progressive mCRPC based on PSA progression, defined as at least 2 rises in PSA with a minimum of a 1 week interval, wherein 1.0 ng/mL is the minimal starting value if confirmed rise is the only indication of progression. In an exemplary embodiment, the human subject has progressive mCRPC based on soft-tissue progression per RECIST 1.1. In an exemplary embodiment, the male human subject has progressive mCRPC based on progression of bone disease (evaluable disease) or 2 or more new bone lesions by bone scan. [00326] In an exemplary embodiment, prior to the first occurrence of the dosing regimen, a checkpoint inhibitor had been administered to the human subject. In an exemplary embodiment, the human subject has received treatment with any cytotoxic T-lymphocyte- associated protein (CTLA4), PD1, PDL1, or programmed cell death ligand 2 (PDL2) directed immunotherapy. In an exemplary embodiment, the human subject has been administered at least one previous prostate cancer treatment, which was a checkpoint inhibitor. In an exemplary embodiment, the human subject has been administered one previous prostate cancer treatment, which was a checkpoint inhibitor. In an exemplary embodiment, the human subject has been administered at least two previous prostate cancer treatments, one of which was a checkpoint inhibitor, and the other is not the anti-CTLA4 x anti-PDl bispecific antibody described herein. In an exemplary embodiment, the human subject has been administered two previous prostate cancer treatments, one of which was a checkpoint inhibitor, and the other is not the anti-CTLA4 x anti-PDl bispecific antibody described herein. In an exemplary embodiment, the previous prostate cancer treatment is selected from the group consisting of a luteinizing hormone-releasing hormone analog, a taxane, a platinum chemotherapeutic, an androgen receptor signaling inhibitor, a bone-targeting radionuclide, sipuleucel-T, and a checkpoint inhibitor antibody. In an exemplary embodiment, the human subject has progressive mCRPC based on progression after treatment with at least 2 prior lines of anticancer therapy approved for treatment of metastatic prostate cancer.
[00327] In an exemplary embodiment, prior to the first occurrence of the dosing regimen, a PARP inhibitor has been administered to the human subject. In an exemplary embodiment, prior to the first occurrence of the dosing regimen, a PARP inhibitor has been administered to the human subject, and the human subject has progressed. In an exemplary embodiment, the human subject has been administered at least one previous prostate cancer treatment, which is not the carboplatin, the cabazitaxel, the prednisone, or the anti-CTLA4 x anti-PDl bispecific antibody described herein. In an exemplary embodiment, the male human subject has been administered one previous prostate cancer treatment, which is not the carboplatin, the cabazitaxel, the prednisone, or the anti-CTLA4 x anti-PDl bispecific antibody described herein. In an exemplary embodiment, the male human subject has been administered at least two previous prostate cancer treatments, neither of which are the carboplatin, the cabazitaxel, the prednisone, or the anti-CTLA4 x anti-PDl bispecific antibody described herein. In an exemplary embodiment, the male human subject has been administered two previous prostate cancer treatments, neither of which are the carboplatin, the cabazitaxel, the prednisone, or the anti-CTLA4 x anti-PDl bispecific antibody described herein. In an exemplary embodiment, the previous prostate cancer treatment is selected from the group consisting of a luteinizing hormone-releasing hormone analog, a taxane, a platinum chemotherapeutic, an androgen receptor signaling inhibitor, a bone-targeting radionuclide, sipuleucel-T, and a checkpoint inhibitor antibody. In an exemplary embodiment, the male human subject has progressive mCRPC based on progression after treatment with at least 2 prior lines of anticancer therapy approved for treatment of metastatic prostate cancer. In an exemplary embodiment, the male human subject has progressive mCRPC based on progression after treatment with at least 3 prior lines of anticancer therapy approved for treatment of metastatic prostate cancer. In an exemplary embodiment, the male human subject has progressive mCRPC based on progression after treatment with at least 4 prior lines of anticancer therapy approved for treatment of metastatic prostate cancer.
[00328] In an exemplary embodiment, prior to the first occurrence of the dosing regimen, a PARP inhibitor had not been administered to the male human subject. In an exemplary embodiment, the male human subject has been administered at least one previous prostate cancer treatment, which is neither the olaparib nor the anti-CTLA4 x anti-PDl bispecific antibody described herein. In an exemplary embodiment, the male human subject has been administered one previous prostate cancer treatment, which is neither the olaparib nor the anti-CTLA4 x anti-PDl bispecific antibody described herein. In an exemplary embodiment, the male human subject has been administered at least two previous prostate cancer treatments, neither of which are the olaparib or the anti-CTLA4 x anti-PDl bispecific antibody described herein. In an exemplary embodiment, the male human subject has been administered two previous prostate cancer treatments, neither of which are the olaparib or the anti-CTLA4 x anti-PDl bispecific antibody described herein. In an exemplary embodiment, the previous prostate cancer treatment is selected from the group consisting of a luteinizing hormone-releasing hormone analog, a taxane, a platinum chemotherapeutic, an androgen receptor signaling inhibitor, a bone-targeting radionuclide, sipuleucel-T, and a checkpoint inhibitor antibody. In an exemplary embodiment, the male human subject has progressive mCRPC based on progression after treatment with at least 2 prior lines of anticancer therapy approved for treatment of metastatic prostate cancer.
[00329] In an exemplary embodiment, the previous prostate cancer treatment is a luteinizing hormone-releasing hormone analog which is a luteinizing hormone-releasing hormone agonist. In an exemplary embodiment, the luteinizing hormone-releasing hormone agonist is a peptide. In an exemplary embodiment, the luteinizing hormone-releasing hormone agonist is azagly-nafarelin, buserelin, deslorelin, fertirelin, GnRH, gonadorelin, goserelin, histrelin, lecirelin, leuprorelin, nafarelin, peforelin, or triptorelin. In an exemplary embodiment, the luteinizing hormone-releasing hormone agonist is buserelin, goserelin, histrelin, leuprorelin, or triptorelin.
[00330] In an exemplary embodiment, the previous prostate cancer treatment is a luteinizing hormone-releasing hormone analog which is a luteinizing hormone-releasing hormone antagonist. In an exemplary embodiment, the luteinizing hormone-releasing hormone antagonist is a peptide. In an exemplary embodiment, the luteinizing hormone- releasing hormone antagonist is abarelix, cetrorelix, degarelix, ganirelix, or ozarelix. In an exemplary embodiment, the luteinizing hormone-releasing hormone antagonist is degarelix. In an exemplary embodiment, the luteinizing hormone-releasing hormone antagonist is not a peptide. In an exemplary embodiment, the luteinizing hormone-releasing hormone antagonist is elagolix, linzagolix, opigolix, relugolix, or sufugolix.
[00331] In an exemplary embodiment, a previous prostate cancer treatment is a platinum chemotherapeutic. In an exemplary embodiment, the platinum chemotherapeutic is carboplatin, cisplatin, or oxaliplatin.
[00332] In an exemplary embodiment, a previous prostate cancer treatment is an androgen receptor signaling inhibitor (ARSI). In an exemplary embodiment, the ARSI is a first generation ARSI. In an exemplary embodiment, the first generation ARSI is bicalutamide or flutamide. In an exemplary embodiment, the ARSI is abiraterone, enzalutamide, apalutamide or darolutamide.
[00333] In an exemplary embodiment, a previous prostate cancer treatment is a bonetargeting radionuclide. In an exemplary embodiment, the bone-targeting radionuclide is radium-223. In an exemplary embodiment, the bone-targeting radionuclide is radium-223 chloride.
[00334] In an exemplary embodiment, a previous prostate cancer treatment is sipuleucel-T.
[00335] In an exemplary embodiment, a previous prostate cancer treatment is a checkpoint inhibitor antibody. In an exemplary embodiment, the checkpoint inhibitor antibody is an anti-PDl antibody, an anti-CTLA4 antibody, or an anti-LAG3 antibody.
[00336] In an exemplary embodiment, the human subject has recovered from any toxicity related to previous anticancer treatment to < Grade 2. In an exemplary embodiment, the human subject is on androgen suppression treatment (e.g., luteinizing hormone-releasing hormone agonist) with castrate level of testosterone (< 50 ng/dL). In an exemplary embodiment, the human subject is on androgen suppression treatment (e.g., luteinizing hormone-releasing hormone agonist) with castrate level of testosterone (< 50 ng/dL) and be willing to continue such treatment. In an exemplary embodiment, the human subject has had a surgical orchiectomy. In an exemplary embodiment, the male human subject has had a surgical orchiectomy, and is not on androgen suppression treatment (e.g., luteinizing hormone-releasing hormone agonist). In an exemplary embodiment, the human subject has not had a surgical orchiectomy. In an exemplary embodiment, the human subject has not had a surgical orchiectomy and is on androgen suppression treatment (e.g., luteinizing hormone- releasing hormone agonist). In an exemplary embodiment, the human subject has a previously treated brain metastases which is radiologically stable (i.e., are without evidence of progression for at least 4 weeks by repeat imaging (note that the repeat imaging should be performed during study screening), are clinically stable, and are without requirement of steroid treatment for at least 14 days prior to first dose of study treatment.
[00337] In an exemplary embodiment, the human subject has had a histologically confirmed diagnosis of a prostate cancer described herein, methods of screening for which are known in the art. In an exemplary embodiment, the human subject has been diagnosed with a MS H and/or MMRD positive cancer, methods of screening for which are known in the art. In an exemplary embodiment, the human subject has been diagnosed with a HRD/CDK12 mutation positive prostate cancer, methods of screening for which are known in the art. In an exemplary embodiment, the human subject has been diagnosed with a prostate cancer which is positive for biallelic loss of CDK12, methods of screening for which are known in the art. In an exemplary embodiment, the human subject has been diagnosed with a prostate cancer which is HRD positive in at least one gene selected from the group consisting of BRCA1, BRCA2, ATM, PALB2, CHEK2, and FANCA, methods of screening for which are known in the art. In an exemplary embodiment, the human subject has been diagnosed with a prostate cancer which does not have a targetable mutation, methods of screening for which are known in the art. In an exemplary embodiment, the human subject has been diagnosed with a prostate cancer which is an aggressive variant prostate cancer, methods of screening for which are known in the art.
[00338] In an exemplary embodiment, the human subject has evaluable disease according to Prostate Cancer Working Group (PCWG3) Guidelines. In an exemplary embodiment, the human subject has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, wherein 0 = Normal activity— Fully active, able to carry on all predisease performance without restriction; 1 = Symptoms, but ambulatory, restricted in physically strenuous activity, but ambulatory and able to carry out work of a light or sedentary nature (e.g., light housework, office work); 2 = In bed < 50% of the time, ambulatory and capable of all self- care, but unable to carry out any work activities, up and about more than 50% of waking hours; 3 = In bed > 50% of the time, capable of only limited self-care, confined to bed or chair more than 50% of waking hours; 4 = 100% bedridden, completely disabled, cannot carry on any self-care, totally confined to bed or chair; 5 = Dead. In an exemplary embodiment, the human subject has adequate archival metastatic tumor tissue. In an exemplary embodiment, the human subject agrees to undergo a biopsy of at least 1 metastatic site. In an exemplary embodiment, the human subject agrees to undergo a fresh biopsy of primary prostate. In an exemplary embodiment, the human subject agrees to undergo a fresh biopsy of primary prostate, however, such a fresh biopsy is possible if there is clear local disease and no other measurable disease site or biopsiable bone lesion. In an exemplary embodiment, the human subject is taking prednisone from a previous prostate cancer therapy. In an exemplary embodiment, the human subject is hepatitis C virus [HCV] antibody positive but HCV RNA negative due to documented, curative prior antiviral treatment or natural resolution. In an exemplary embodiment, the human subject whose HBsAg is negative and HBcAb is positive may be treated if a hepatitis B virus [HBV] DNA test is negative and the human subject is retested for HBsAg and HBV DNA every 2 months.
[00339] In an exemplary embodiment, the human subject is not currently receiving anticancer therapies other than androgen deprivation therapy. In an exemplary embodiment, the human subject has not received treatment with any other anticancer therapy (i.e., other immunotherapy, chemotherapy, radiation therapy, etc.) within 2 weeks of the first administration of the first occurrence of the dosing regimen. In an exemplary embodiment, the human subject has not received treatment with any cytotoxic T-lymphocyte-associated protein (CTLA4), PD1, PDL1, or programmed cell death ligand 2 (PDL2) directed immunotherapy. In an exemplary embodiment, the human subject does not have known active central nervous system metastases and/or carcinomatous meningitis. In an exemplary embodiment, the human subject does not have a Platelet count < 100 * 109/L. In an exemplary embodiment, the human subject does not have a Hemoglobin level < 9.0 g/dL. In an exemplary embodiment, the human subject does not have an absolute neutrophil count < 1.7 x io9 for subjects who receive cabazitaxel; < 1.0 * 109/L for all others. In an exemplary embodiment, the human subject does not have an aspartate aminotransferase at screening > 3 x upper limit of normal (ULN) for subjects without known liver involvement by tumor or > 5 x ULN for subjects with known liver involvement by tumor. In an exemplary embodiment, the human subject does not have an alanine aminotransferase at screening > 3 x ULN for subjects without known liver involvement by tumor or > 5 x ULN for subjects with known liver involvement by tumor. In an exemplary embodiment, the human subject does not have bilirubin > 1.5 x ULN (unless prior diagnosis and documentation of ongoing hemolysis or Gilbert’s syndrome has been made). In an exemplary embodiment, the human subject does not have an estimated creatinine clearance < 50 mL/minute calculated by the Cockcroft Gault or Modification of Diet in Renal Disease formulas. In an exemplary embodiment, the human subject does not have active known or suspected autoimmune disease (except vitiligo; type 1 diabetes mellitus or residual hypothyroidism due to an autoimmune condition that is treatable with hormone replacement therapy only; psoriasis, atopic dermatitis, or another autoimmune skin condition that is managed without systemic therapy; or arthritis that is managed without systemic therapy beyond oral acetaminophen and nonsteroidal anti-inflammatory drugs). In an exemplary embodiment, the human subject does not have a condition requiring systemic treatment with corticosteroids, prednisone equivalents, or other immunosuppressive medications within 14 days prior to first dose of the anti-CTLA4 x anti-PDl bispecific antibody described herein (except inhaled or topical corticosteroids or brief courses of corticosteroids given for prophylaxis of contrast dye allergic response). In an exemplary embodiment, the human subject does not have a condition requiring systemic treatment with corticosteroids, prednisone equivalents, or other immunosuppressive medications within 14 days prior to first dose of the carboplatin, the cabazitaxel, the prednisone, or the anti-CTLA4 x anti-PDl bispecific antibody described herein (except inhaled or topical corticosteroids or brief courses of corticosteroids given for prophylaxis of contrast dye allergic response). In an exemplary embodiment, the human subject does not have a condition requiring systemic treatment with corticosteroids, prednisone equivalents, or other immunosuppressive medications within 14 days prior to first dose of olaparib or the anti-CTLA4 x anti-PDl bispecific antibody described herein (except inhaled or topical corticosteroids or brief courses of corticosteroids given for prophylaxis of contrast dye allergic response). In an exemplary embodiment, the human subject has not received an organ allograft. In an exemplary embodiment, the human subject does not have known history of left ventricular ejection fraction < 40%. In an exemplary embodiment, the human subject does not have a history or evidence of any other clinically unstable/uncontrolled disorder, condition, or disease other than their primary malignancy that would pose a risk to patient safety or interfere with study evaluations, procedures, or completion. In an exemplary embodiment, the human subject does not have evidence of any serious bacterial, viral, parasitic, or systemic fungal infections within the 30 days prior to the first dose of the anti-CTLA4 x anti-PDl bispecific antibody described herein. In an exemplary embodiment, the human subject has not received a live- virus vaccine within 30 days prior to the first dose of the anti-CTLA4 x anti-PDl bispecific antibody described herein, with the exception of seasonal flu vaccines that do not contain live virus. In an exemplary embodiment, the human subject does not have evidence of any serious bacterial, viral, parasitic, or systemic fungal infections within the 30 days prior to the first dose of the carboplatin, the cabazitaxel, the prednisone, or the anti-CTLA4 x anti-PDl bispecific antibody described herein. In an exemplary embodiment, the human subject has not received a live-virus vaccine within 30 days prior to the first dose of the carboplatin, the cabazitaxel, the prednisone, or the anti-CTLA4 x anti-PDl bispecific antibody described herein, with the exception of seasonal flu vaccines that do not contain live virus. In an exemplary embodiment, the human subject does not have evidence of any serious bacterial, viral, parasitic, or systemic fungal infections within the 30 days prior to the first dose of olaparib or the anti-CTLA4 x anti-PDl bispecific antibody described herein. In an exemplary embodiment, the human subject has not received a live-virus vaccine within 30 days prior to the first dose of olaparib or the anti-CTLA4 x anti-PDl bispecific antibody described herein, with the exception of seasonal flu vaccines that do not contain live virus. In an exemplary embodiment, the human subject is not human immunodeficiency virus (HIV) positive subject with CD4+ T-cell (CD4+) counts < 350 cells/pL. In an exemplary embodiment, the human subject does not have an HIV viral load greater than 400 copies/mL. In an exemplary embodiment, the human subject does not have a history of an AIDS (acquired immunodeficiency syndrome)-defining opportunistic infection within the past 12 months. In an exemplary embodiment, the human subject has not been on established antiretroviral therapy (ART) for at least 4 weeks prior to initiation of study drug dosing. (Effective ART is defined as a drug, dosage, and schedule associated with reduction and control of the viral load.). In an exemplary embodiment, the human subject has not had a positive test for hepatitis C RNA. In an exemplary embodiment, the human subject has not had a positive test for hepatitis B surface antigen (HBsAg) or hepatitis B core antibody (HBcAb).
[00340] Blood samples can be collected from a human subject using any method known in the art, e.g., by venipuncture or fingerstick. Particular types of blood cells can be isolated, expanded, frozen, and used at a later time. Tissue samples can be obtained from a human subject using any method known in the art, e.g., by biopsy or surgery. CT imaging, ultrasound, or an endoscope can be used to guide this type of procedure. The sample may be flash frozen and stored at -80°C for later use. The sample may also be fixed with a fixative, such as formaldehyde, paraformaldehyde, or acetic acid/ethanol. RNA or protein may be extracted from a fresh, frozen or fixed sample for analysis.
4.10 Kits
[00341] In another aspect, provided herein is a kit comprising a bispecific anti-PDl x CTLA4 antibody, and instructions for administering said bispecific antibody to a subject. [00342] In another aspect, provided herein is a kit comprising a bispecific anti-PDl x CTLA4 antibody, and instructions for use of said bispecific antibody in the treatment of a prostate cancer in a male human subject. In some embodiments, the instructions provide that the bispecific antibody is administered to the subject according to a 28 day treatment cycle at a dose of about 10 mg/kg, wherein the dose of the bispecific antibody is intravenously administered to the subject on day 1 of a first 28 day treatment cycle and about every two weeks (Q2W) thereafter. In a specific embodiment, the bispecific antibody comprises a first monomer (or first polypeptide) comprising SEQ ID NO: 1, a second monomer (or second polypeptide) comprising SEQ ID NO:2, and a light chain (or third polypeptide)comprising SEQ ID NO:3. In one embodiment, the instructions provide that the subject receive treatment about every 2 weeks (Q2W) for about two years.
[00343] In another aspect, provided herein is a kit comprising a bispecific anti-PDl x CTLA4 antibody, and instructions for use of said bispecific antibody in the treatment of an aggressive variant (anaplastic) adenocarcinoma of the prostate (AVPCa) in a male human subject. In some embodiments, the instructions provide that the bispecific antibody is administered to the subject according to a 28 day treatment cycle at a dose of about 10 mg/kg, wherein the dose of the bispecific antibody is intravenously administered to the subject on day 1 of a first 28 day treatment cycle and about every two weeks (Q2W) thereafter. In a specific embodiment, the bispecific antibody comprises a first monomer (or first polypeptide) comprising SEQ ID NO: 1, a second monomer (or second polypeptide) comprising SEQ ID NO:2, and a light chain (or third polypeptide)comprising SEQ ID NO:3. In one embodiment, the instructions further provide that: (a) carboplatin is administered at a therapeutically effective dose that results in a target area under the serum concentration-time curve of 3 (AUC3) in the subject, wherein the dose of the carboplatin is intravenously administered to the subject on day 1 of the first treatment cycle and about three weeks (Q3W) after day 1; (b) cabazitaxel is administered at a dose of about 15 mg/m2, wherein the dose of the cabazitaxel is intravenously administered to the subject on day 1 of the first treatment cycle and about three weeks (Q3W) after day 1; (c) carboplatin is administered at a therapeutically effective dose that results in a target area under the serum concentration-time curve of 4 (AUC4) in the subject after cycle 1 is completed or starting on cycle 2 and every 3 weeks thereafter (Q3W); and (d) cabazitaxel is administered at a dose of about 20 mg/m2, wherein the dose of the cabazitaxel is intravenously administered to the subject after cycle 1 is completed or starting on cycle 2 and every 3 weeks thereafter (Q3W). In one embodiment, the instructions further provide that a steroid is orally administered to the subject. In one embodiment, the steroid is prednisone, and the instructions provide that the steroid is administered at a dose of about 5 mg twice per day (b.i.d.) on day 1 of the first treatment cycle, and about twice per day (b.i.d.) thereafter. In some embodiments, the cancer has a mutation or other aberrancy in at least two genes independently selected from the group consisting of Rbl, TP53 and PTEN. In some embodiments, the subject receives more than one 28 day treatment cycle. In some embodiments, the subject receives up to twenty -four 28 day treatment cycles.
[00344] In another aspect, provided herein is a kit comprising a bispecific anti-PDl x CTLA4 antibody, and instructions for use of said bispecific antibody in the treatment of an aggressive variant (anaplastic) adenocarcinoma of the prostate (AVPCa) in a male human subject, wherein the subject has not previously been administered docetaxel, and wherein the instructions provide that the bispecific antibody is administered to the subject according to a 28 day treatment cycle at a dose of about 10 mg/kg, wherein the dose of the bispecific antibody is intravenously administered to the subject on day 1 of a first 28 day treatment cycle and about every two weeks (Q2W) thereafter. In a specific embodiment, the bispecific antibody comprises a first monomer (or first polypeptide) comprising SEQ ID NO: 1, a second monomer (or second polypeptide) comprising SEQ ID NO:2, and a light chain (or third polypeptide)comprising SEQ ID NO:3. In one embodiment, the instructions further provide that: (a) carboplatin is administered at a therapeutically effective dose that results in a target area under the serum concentration-time curve of 3 (AUC3) in the subject, wherein the dose of the carboplatin is intravenously administered to the subject on day 1 of the first treatment cycle and about three weeks (Q3W) after day 1; (b) docetaxel is administered at a dose of about 50 mg/m2, wherein the dose of the docetaxel is intravenously administered to the subject on day 1 of the first treatment cycle and about three weeks (Q3W) after day 1; (c) carboplatin is administered at a therapeutically effective dose that results in a target area under the serum concentration-time curve of 4 (AUC4) in the subject after cycle 1 is completed or starting on cycle 2 and every 3 weeks thereafter (Q3W); and (d) docetaxel is administered at a dose of about 60 mg/m2, wherein the dose of the docetaxel is intravenously administered to the subject after cycle 1 is completed or starting on cycle 2 and every 3 weeks thereafter (Q3W). In one embodiment, the instructions further provide that a steroid is orally administered to the subject. In one embodiment, the steroid is prednisone, and the instructions provide that the steroid is administered at a dose of about 5 mg twice per day (b.i.d.) on day 1 of the first treatment cycle, and about twice per day (b.i.d.) thereafter. In some embodiments, the cancer has a mutation or other aberrancy in at least two genes independently selected from the group consisting of Rbl, TP53 and PTEN. In some embodiments, the subject receives more than one 28 day treatment cycle. In some embodiments, the subject receives up to twenty -four 28 day treatment cycles.
[00345] In another aspect, provided herein is a kit comprising a bispecific anti-PDl x CTLA4 antibody, and instructions for use of said bispecific antibody in the treatment of a prostate cancer in a male human subject in need thereof, wherein the instructions provide that the bispecific antibody is administered to the subject according to a 28 day treatment cycle at a dose of about 10 mg/kg, wherein the dose of the bispecific antibody is intravenously administered to the subject on day 1 of a first 28 day treatment cycle and about every two weeks (Q2W) thereafter. In some embodiments, the bispecific antibody comprises a first monomer (or first polypeptide) comprising SEQ ID NO: 1, a second monomer (or second polypeptide) comprising SEQ ID NO:2, and a light chain (or third polypeptide) comprising SEQ ID NO:3. In certain embodiments, the instructions further provide that: (a) cabazitaxel is administered at a dose of about 20 mg/m2, wherein the dose of the cabazitaxel is intravenously administered to the subject on day 1 of the first treatment cycle and about every three weeks (Q3W) thereafter. In some embodiments, the instructions further provide that a steroid is administered to the subject. In one embodiment, the steroid is prednisone, and the instructions provide that the steroid is administered at a dose of about 5 mg twice per day (b.i.d.) on day 1 of the first treatment cycle, and about twice per day (b.i.d.) thereafter. [00346] In another aspect, provided herein is a kit comprising a bispecific anti-PDl x CTLA4 antibody, and instructions for use of said bispecific antibody in the treatment of a prostate cancer in a male human subject in need thereof, wherein the subject has not previously been administered docetaxel, and wherein the instructions provide that the bispecific antibody is administered to the subject according to a 28 day treatment cycle at a dose of about 10 mg/kg, wherein the dose of the bispecific antibody is intravenously administered to the subject on day 1 of a first 28 day treatment cycle and about every two weeks (Q2W) thereafter. In some embodiments, the bispecific antibody comprises a first monomer (first polypeptide) comprising SEQ ID NO: 1, a second monomer (second polypeptide) comprising SEQ ID NO:2, and a light chain (third polypeptide) comprising SEQ ID NO:3. In certain embodiments, the instructions further provide that: (a) docetaxel is administered at a dose of about 60 mg/m2 wherein the dose of the docetaxel is intravenously administered to the subject on day 1 of the first treatment cycle and about every three weeks (Q3W) thereafter. In some embodiments, the instructions further provide that a steroid is administered to the subject. In one embodiment, the steroid is prednisone, and the instructions provide that the steroid is administered at a dose of about 5 mg twice per day (b.i.d.) on day 1 of the first treatment cycle, and about twice per day (b.i.d.) thereafter. In some embodiments, the subject has received prior treatment with a polyadenosine diphosphate ribose polymerase (PARP) inhibitor. In some embodiments, the cancer has a homologous recombination deficiency (HRD). In some embodiments, the cancer has a biallelic loss of cyclin-dependent kinase 12 (CDK12). In some embodiments, the cancer does not have a targetable mutation. [00347] In another aspect, provided herein is a kit comprising a bispecific anti-PDl x CTLA4 antibody, and instructions for use of said bispecific antibody in the treatment of a prostate cancer in a male human subject in need thereof, wherein the subject has not previously been administered a PARP inhibitor, and wherein the instructions provide that the bispecific antibody is administered to the subject according to a 28 day treatment cycle at a dose of about 10 mg/kg, wherein the dose of the bispecific antibody is intravenously administered to the subject on day 1 of a first 28 day treatment cycle and about every two weeks (Q2W) thereafter. In certain embodiments, the bispecific antibody comprises a first monomer (first polypeptide) comprising SEQ ID NO: 1, a second monomer (second polypeptide) comprising SEQ ID NO:2, and a light chain (third polypeptide) comprising SEQ ID NO:3. In some embodiments, the instructions further provide that olaparib is administered at a dose of about 300 mg twice a day. In some embodiments, the instructions provide that the dose of the olaparib is orally administered twice per day (b.i.d.) to the subject on day 1 of the first treatment cycle, and about twice per day (b.i.d.) thereafter. In some embodiments, the cancer has a homologous recombination deficiency (HRD). In some embodiments, the cancer has a biallelic loss of cyclin-dependent kinase 12 (CDK12).
[00348] All cited references are herein expressly incorporated by reference in their entirety.
[00349] Whereas particular embodiments of the invention have been described above for purposes of illustration, it will be appreciated by those skilled in the art that numerous variations of the details may be made without departing from the invention as described in the appended claims.
[00350] All publications, patents, patent applications and other documents cited in this application are hereby incorporated by reference in their entireties for all purposes to the same extent as if each individual publication, patent, patent application or other document were individually indicated to be incorporated by reference for all purposes. In the event that there is an inconsistency between the teachings of one or more of the references incorporated herein and the present disclosure, the teachings of the present specification controls.
5. EXAMPLES
[00351] Examples are provided below to illustrate the present invention. These examples are not meant to constrain the present invention to any particular application or theory of operation. For all constant region positions discussed in the present invention, numbering is according to the EU index as in Kabat (Kabat et al., 1991, Sequences of Proteins of Immunological Interest, 5th Ed., United States Public Health Service, National Institutes of Health, Bethesda, entirely incorporated by reference). Those skilled in the art of antibodies will appreciate that this convention consists of nonsequential numbering in specific regions of an immunoglobulin sequence, enabling a normalized reference to conserved positions in immunoglobulin families. Accordingly, the positions of any given immunoglobulin as defined by the EU index will not necessarily correspond to its sequential sequence.
[00352] General and specific scientific techniques are outlined in US Publications 2015/0307629, and 2014/0288275, as well as PCT Publication WO2014/145806, as well as US Applications 62/085,027, 14/952,714, and 15/141,350, all of which are expressly incorporated by reference in their entirety and particularly for the techniques outlined therein. 5.1 EXAMPLE 1: Treatment of Solid Cancerous Tumors (Phase 1)
XmAh" 20717 Treatment Plan
[00353] This is a two-part Phase 1, multiple-dose, ascending-dose escalation study and expansion designed to define a Maximum Tolerated Dose and/or Recommended Dose (MTD/RD) and regimen, as well as preliminarily assessing potential anti-tumor activity of XmAb®20717 in subjects with selected advanced solid cancerous tumors. All eligible subjects have relapsed or refractory disease after standard therapy.
[00354] XmAb®20717 is a humanized bsAb that binds both PD1 and CTLA4. The
XmAb®20717 pharmaceutical composition is a sterile liquid supplied in single-use glass vials. Each 10 mL vial is filled with 10.5 mL of pharmaceutical composition containing 10.0 ±1.0 mg/mL of XmAb®20717, in 20 mM histidine, 250 mM sorbitol, and 0.01% (w/v) polysorbate-80 at pH 6.2. Each product vial is intended to deliver 10.0 mL of drug solution. [00355] Prior to administration, XmAb®20717 is diluted to the final required concentration in an ethylene/polypropylene copolymer infusion bag containing 0.9% Sodium Chloride Injection, USP. After dilution, the bag containing XmAb®20717 should be gently inverted 2 to 3 times to mix the solution. The bag should not be shaken.
[00356] XmAb®20717 administration should begin as soon as possible after the dosing solution is made. If there is a delay in administration, the dosing solution may be stored at 2 - 8 °C for no more than 24 hours or at room temperature for no more than 4 hours prior to infusion. The full-calculated dose is administered based on the subject’s actual baseline weight measurement in kilograms. Following the first dose, subsequent doses are modified only if the subject’s weight changes by more than 10% from the Day -1 weight, at which point it is recalculated using the current weight. In Part A of the study, subjects were enrolled into escalating dose cohorts to establish an MTD/RD(s) for a dosing regimen consisting of infusions on Days 1 and 15 of each 28-day cycle.
[00357] The decision to escalate to higher-dose cohorts proceeds according to the Dose Escalation Plan, and the final decision to escalate to a higher dose level is based on review of the aggregate safety data for all subjects through Cycle 1 Day 28. For each escalation cohort, the first subject in the cohort was dosed and observed for a minimum of 24 hours before study drug was administered to the remainder of the cohort. All subjects were assessed for the development of dose-limiting toxicity (DLT) during treatment with XmAb®20717. The assessment period is defined as: Cycle 1, Days 1 to 28. Part B of the study began once the MTD/RD(s) and dosing regimen were established. In Part B, additional subjects with advanced melanoma (excluding uveal), renal cell carcinoma (clear cell predominant type), and non-small cell lung carcinoma are enrolled into disease-specific expansion cohorts of up to 20 subjects each.
Dosing Schedule
[00358] Each subject was administered XmAb®20717 IV at a constant infusion rate over 1 hour. The initial treatment period for each subject in this study was 2 cycles. Each cycle was 28 days long and consisted of 2 doses of XmAb®20717, on Days 1 and 15. Six dose levels were planned for the dose-escalation phase of the study (Part A). The dose levels are: 0.15, 0.3, 1.0, 3.0, 6.0, and 10.0 mg/kg. A subject’s first dose was based on the Day -1 baseline weight in kilograms. Subsequent doses were modified only if the subject’s weight changed by more than 10% from the Day -1 weight, at which point the dose was recalculated using the subject’s current weight. That dose was continued for the remainder of the trial, unless there was a subsequent 10% weight change.
Table 3. Dose Level Scheme
Figure imgf000128_0001
[00359] A minimum of 3 subjects were enrolled in each dose-escalation cohort. No 2 subjects within a cohort started treatment with XmAb®20717 on the same day; the first subject was dosed and observed for a minimum of 24 hours before study drug was administered to the remainder of the cohort. All subjects were assessed for the development of dose-limiting toxi cities (DLT) during treatment with XmAb®20717. If none of the first 3 subjects experienced a DLT during the period, escalation to the next dosing level occurred. If any of the first 3 subjects in a dosing cohort experienced a DLT during the period, the cohort was expanded to a total of 6 human subjects or until a second subject in the cohort experienced a DLT. If there were no additional DLTs, escalation to the next dose level occurred. If there is 1 or more additional DLTs, the MTD has been exceeded, and the next lower dose level is expanded to 6 subjects. If no more than 1 subject experiences a DLT at the deescalated dose level, it is the MTD. Table 4. Dose Escalation Scheme
Figure imgf000129_0001
DLT= dose-limiting toxicity
[00360] Results: As of Feb 5, 2020, 34 patients were treated in cohorts 1-6 at fixed doses of 0.15 to 10 mg/kg. Patients had a median age of 57 years (range 32-81), a median time since initial diagnosis of 42 months (range 3 -313) and a median of 4 prior systemic therapies (range 0-9). 68% of patients had a TNM stage of III/ IV and 68% had been exposed to checkpoint therapy.
[00361] XmAb®20717 treatment was generally well-tolerated through the highest dose cohort tested. Overall rates of Gr3/4 immune-related AEs occurred in 8 (24%) patients including elevations of transaminases 3 (9%), rash 2 (6%), lipase and amylase 1 (3%, without clinical symptoms or radiographic evidence of pancreatitis), lipase (alone) 1 (3%), pruritus 1 (3%), hyperglycemia 1 (3%), arthritis 1 (3%) and colitis 1 (3%), all reversible.
[00362] Responses were evaluated based on RECIST 1.1 criteria and there was 1 complete response reported (melanoma, progressed on prior pembrolizumab) at 10 mg/kg (highest dose level). Dose-dependent pharmacodynamic activity consistent with dual PD1/CTLA4 blockade was noted, namely a proliferative burst of both CD8 and CD4 T cells and induction of IFN-inducible chemokines (Table 5).
Table 5. Maximum change from baseline in the first two cycles
Figure imgf000129_0002
[00363] Conclusions: XmAb®20717 was generally safe and demonstrated PD activity in heavily pretreated patients with selected advanced solid tumors.
5.2 EXAMPLE 2: Treatment of Metastatic Castration-Resistant Prostate Cancer (Phase 2)
[00364] Dual PD-l/CTLA-4 blockade has been previously shown to improve outcomes in patients with mCRPC relative to those observed for agents directed at a single checkpoint (Sharma P, et al. Cancer Cell. 2020;38:489-499). Additional strategies to optimize response to immune checkpoint inhibitor (ICI) therapy in patients with mCRPC include: 1) selection of patients with tumors with molecular characteristics that sensitize to ICIs, such as those associated with aggressive variant disease (Lee L, et al. JCO Precis Oncol. 2018: 1-8;
Aparicio AM, et al. Clin Cancer Res. 2016;22: 1520-1530), CDK12 inactivation (Antonarakis ES, et al. JCO Precis Oncol. 2020; 4:370-381; Wu YM, et al. Cell. 2018;173: 1770-1782), and microsatellite instability-high (MSI-H) or mismatch repair-deficient (MMRD) status (Abida W, et al. JAMA Oncol. 2019;5:471-478); and/or 2) altering the tumor microenvironment to promote antitumor immunity by combining ICIs with chemotherapy or targeted agents also has the potential to increase clinical benefit (Picardo SL, Hansen AR. Ann Transl Med. 2019; 7:346).
[00365] Vudalimab (XmAb®20717) is a humanized bispecific monoclonal antibody that simultaneously targets PD-1 and CTLA4, and binds preferentially to PD1/CTLA4 dualpositive cells.
[00366] Preliminary data from a Phase 1 study in heavily pretreated patients with advanced solid tumors showed that monotherapy treatment with 10 mg/kg of XmAb®20717 every two weeks (Q2W) was generally well tolerated. The most common irAEs were rash, pruritus, and increased transaminases. Treatment with XmAb®20717 was associated with complete and partial responses in tumor types typically responsive to single-agent immune checkpoint inhibitor (ICI) therapy (e.g., melanoma, RCC, and NSCLC), as well as those that are not typically responsive to single-agent checkpoint inhibition (e.g., mCRPC and ovarian cancer). Durability of responses in the mCRPC patients (PRs in 2 of 4 mCRPC patients with measurable disease) was 41.3 and 27 weeks, and both patients were without progression on bone scans, and had confirmed PSA decreases > 50% following treatment.
[00367] As shown in FIG. 3, potent antitumor immune response was observed in an mCRPC patient with partial response following treatment with XmAb®20717 10 mg/kg Q2W. Multiplex immunofluorescence staining of paired pre-treatment and posttreatment biopsies demonstrated increases in cellular immunity (CD8+ T cells), marked induction of MHC I antigen presenting machinery (B2M), and IFN pathway response (upregulation of PD-L1).
[00368] Results from the Phase 1 study, showed that XmAb®20717 (vudalimab) monotherapy was well-tolerated and associated with complete and partial responses in patients with multiple tumor types, including mCRPC.
[00369] Therefore, the Phase 2, multicenter, parallel-group, open-label study (NCT05005728) was designed to evaluate the safety and antitumor activity of vudalimab (XmAb®20717), a bispecific anti-PDl x anti-CTLA4 antibody, in combination with other anticancer agents in subgroups of mCRPC patients with and without specific tumor molecular subtypes (FIG. 4 and FIG. 5).
XmAb®20717 Treatment Plan
[00370] This is a Phase 2, multiple-dose, multiple-arm, parallel assignment study to evaluate the safety and antitumor activity of XmAb®20717 in subjects with metastatic castration-resistant prostate cancer (mCRPC) who have progressed after treatment with at least 2 prior lines of anticancer therapy. The study enrolls subjects in five cohorts (i.e., Cohorts A-E), with up to 20 subjects enrolled in Cohorts A, B, C, and E, and up to 5 subjects enrolled in Cohort D (FIG. 4). Cohorts are molecularly defined as follows based on the results of acceptable, documented prior diagnostic.
[00371] Cohort A (AVPCa): Subjects with aggressive variant (anaplastic) adenocarcinoma of the prostate (AVPCa) receive XmAb®20717 (10 mg/kg infusion every 2 weeks) plus carboplatin target area under the serum concentration-time curve of 4 (AUC 4) intravenously (IV) over 30 minutes every 3 weeks and cabazitaxel 20 mg/m2 IV (or docetaxel 60 mg/m2, if docetaxel naive) every 3 weeks.
[00372] Cohort B (homologous recombination deficiency [HRD]/cyclin-dependent kinase 12[CDK12] poly-adenosine diphosphate ribose polymerase [PARP] Progressors): Subjects who have progressed on prior PARP inhibitors with at least one of the specified homologous recombination deficiencies receive XmAb®20717 (10 mg/kg infusion every 2 weeks) plus carboplatin AUC 4 IV over 30 minutes every 3 weeks and cabazitaxel 20 mg/m2 IV (or docetaxel 60 mg/m2, if docetaxel naive) every 3 weeks.
[00373] Cohort C (HRD/CDK12 PARP Naive): Subjects with at least one of the specified molecular abnormalities and who have not yet received a PARP inhibitor receive olaparib 300 mg orally twice daily and XmAb®20717 (10 mg/kg infusion every 2 weeks). [00374] Cohort D (MSI-H or MMRD): Subjects whose tumors have been shown to be microsatellite instability-high [MSI-H] or mismatch repair deficient [MMRD] receive XmAb®20717 alone (10 mg/kg infusion every 2 weeks).
[00375] Cohort E (No Targetable Mutations): Subjects receive XmAb®20717 (10 mg/kg infusion every 2 weeks) plus carboplatin AUC 4 IV over 30 minutes every 3 weeks and cabazitaxel 20 mg/m2 IV (or docetaxel 60 mg/m2, if docetaxel naive) every 3 weeks.
[00376] Subjects with a positive molecular test for one of the following molecular abnormalities are enrolled and receive treatment in Cohort A: Positive for aberrancy in at least 2 of the following genes: Rbl, TP53, and/or PTEN.
[00377] Subjects with a positive molecular test for one of the following molecular abnormalities are enrolled and receive treatment in Cohort B or C: Positive for HRD in one or more of the following genes: BRCA1, BRCA2, ATM, PALB2, CHEK2, and/or FANCA; and/or positive for biallelic loss of CDK12.
[00378] Subjects with a targeted whole exome sequencing or next generation sequencing analysis of a metastatic lesion which is negative for Cohort A and B molecular abnormalities, as well as negative for microsatellite instability-high [MSI-H] or mismatch repair deficient [MMRD], are enrolled and receive treatment in Cohort E.
[00379] All patients receive vudalimab 10 mg/kg intravenously every 2 weeks. Cohorts A, B, and E (n = 20 each) also receive carboplatin AUC 4 + cabazitaxel 20 mg/m2 (or docetaxel 60 mg/m2, if not received prior) every 3 weeks; Cohort C (n = 20) also receive olaparib 300 mg 2x/day; and Cohort D (n = 5) receive vudalimab monotherapy. The primary objective is to evaluate the safety/tolerability of treatment based on adverse events. Secondary objectives include evaluating objective response RECIST 1.1, as modified by PCWG3), radiographic progression-free survival, and PSA response. Exploratory objectives include assessing pharmacodynamic activity in peripheral blood and tumor, and correlations of response with cohort-specific molecular tumor characteristics. Enrollment has been initiated.
[00380] Male human subjects with a positive MSI-H/MMRD status are enrolled and receive treatment as described herein: the male human subjects are administered XmAb®20717 at an intravenous dose of 10 mg/kg on Days 1 and 15 of each 28-day cycle. [00381] XmAb®20717 is a humanized bsAb that binds both CTLA4 and PD1. The
XmAb®20717 pharmaceutical composition is a sterile liquid supplied in single-use glass vials. Each 10 mL vial is filled with 10.5 mL of pharmaceutical composition containing 10.0 ±1.0 mg/mL of XmAb®20717, in 20 mM histidine, 250 mM sorbitol, and 0.01% (w/v) polysorbate-80 at pH 6.2. Each product vial is intended to deliver 10.0 mL of drug solution. [00382] Prior to administration, XmAb®20717 is diluted to the final required concentration in an ethylene/polypropylene copolymer infusion bag containing 0.9% Sodium Chloride Injection, USP. After dilution, the bag containing XmAb®20717 should be gently inverted 2 to 3 times to mix the solution. The bag should not be shaken.
[00383] XmAb®20717 administration should begin as soon as possible after the dosing solution is made. If there is a delay in administration, the dosing solution may be stored at 2 - 8 °C for no more than 24 hours or at room temperature for no more than 4 hours prior to infusion. The full-calculated dose is administered based on the subject’s actual baseline weight measurement in kilograms. Following the first dose, subsequent doses are modified only if the subject’s weight changes by more than 10% from the Day -1 weight, at which point it is recalculated using the current weight.
[00384] Subjects undergo biochemical and tumor assessments according to PCWG3 criteria described herein.
[00385] Primary Objective: Evaluate the safety and tolerability of vudalimab alone and in combination with other anticancer therapies in patients with mCRPC
[00386] Secondary Objective: Characterize PK and immunogenicity of vudalimab; and assess antitumor activity of vudalimab alone and in combination with other anticancer agents, based on biochemical response, rPFS (RECIST 1.1, as modified by PCWG3), objective response rate, and duration of response.
[00387] Exploratory Objective: Characterize pharmacodynamics, based on cell surface markers on selected immune system cells in peripheral blood; assess changes in immune cell density and intratumoral and juxta-tumoral immune and tumor cell expression of PD-L1, PD- 1, and other immune checkpoint markers; correlate clinical response with tumor and circulating tumor DNA mutation profiles, interferon transcriptional signature, and immune profiling characteristics of cells in the tumor microenvironment by transcriptomic analysis of tumor tissue; and correlate clinical responses with specific genetic defects of molecularly defined cohorts.
[00388] Recruitment
[00389] Subjects are recruited through the clinics at each participating institution. Each subject is assigned a subject screening number at the time of consent.
[00390] Screening
[00391] Subjects are consented before undergoing any screening procedures. After consent, subjects must undergo all the assessments listed for the screening period on the Schedule of Assessments (Table 6) to determine preliminary eligibility. The staff at each clinical site arranges the subject’s study visit schedule.
[00392] Determination of Eligibility
[00393] After preliminary eligibility is established, site staff submits an enrollment package to Xencor as detailed in the Subject Registration Guidelines. The Xencor Medical Monitor (or designee) reviews the enrollment documents provided and confirm the subject’s eligibility. If eligibility is confirmed, at this time, the subject is assigned a subject enrollment number and a cohort. Study treatment cannot begin until the subject’s eligibility has been confirmed and a subject number and treatment assignment have been provided to the site.
[00394] Subjects who sign a consent form but do not initiate protocol treatment for any reason (e.g., subjects who are screen failures) are replaced.
[00395] Treatment Assignment
[00396] Subject Screening Number: Subjects who consent for the study are assigned a Subject Screening Number. Subject Enrollment Number: Subjects eligible to receive study treatment are assigned a Subject Enrollment Number.
[00397] Dosing Schedule
[00398] XmAb®20717 is administered at a dose of 10 mg/kg on Days 1 and 15 of each 28- day cycle. Subjects are enrolled as follows:
[00399] Cohort A (AVPCa): Subjects with AVPCa receive XmAb®20717 (10 mg/kg infusion every 2 weeks) plus carboplatin target AUC of 4 (AUC 4) IV over 30 minutes every 3 weeks and cabazitaxel 20 mg/m2 IV (or docetaxel 60 mg/m2, if docetaxel naive) every 3 weeks.
[00400] Cohort B (HRD/CDK12 poly-adenosine diphosphate ribose polymerase [PARP] Progressors): Subjects who have progressed on prior PARP inhibitors with at least one of the specified homologous recombination deficiencies receive XmAb®20717 (10 mg/kg infusion every 2 weeks) plus carboplatin AUC 4 IV over 30 minutes every 3 weeks and cabazitaxel 20 mg/m2 IV (or docetaxel 60 mg/m2, if docetaxel naive) every 3 weeks.
[00401] Cohort C (HRD/CDK12 PARP Naive): Subjects with at least one of the specified homologous recombination deficiencies and who have not yet received a PARP inhibitor receive olaparib 300 mg orally twice daily and XmAb®20717 (10 mg/kg infusion every 2 weeks).
[00402] Cohort D (MSI-H or MMRD): Subjects whose tumors have been shown to be MSI-H or MMRD receive XmAb®20717 alone (10 mg/kg infusion every 2 weeks). [00403] Cohort E (No Targetable Mutations): Subjects receive XmAb®20717 (10 mg/kg infusion every 2 weeks) plus carboplatin AUC 4 IV over 30 minutes every 3 weeks and cabazitaxel 20 mg/m2 IV (or docetaxel 60 mg/m2, if docetaxel naive) every 3 weeks.
[00404] Subjects in Cohorts A, B, or E may receive up to 8 cycles of carboplatin. Additional cycles of carboplatin may be considered if the Investigator and Medical Monitor agree that a subject is deriving clinical benefit and does not have significant toxicity.
[00405] Subjects in Cohorts A, B, or E who have not received prior docetaxel receive docetaxel 60 mg/m2 IV every 3 weeks instead of cabazitaxel 20 mg/m2 every 3 weeks.
[00406] Discontinuation of Therapy
[00407] In the absence of treatment delays because of AEs, protocol-mandated treatment continues until a criterion, including, but not limited to, the following applies: • Withdrawal by subject: subject decides to withdraw from the study; • Holding of XmAb®20717 for > 12 weeks if due to a treatment-related AE, unless continued treatment is approved by the Medical Monitor; • Holding of XmAb®20717 for a continuous time > 4 weeks if caused for reason other than treatment-related AE; • Holding of concurrent chemotherapy for > 21 days because of persistent cytopenia; • Subject failure to follow study requirements; • Progressive disease and/or no clinical benefit as determined by the treating physician per PCWG3 guidelines (Scher, 2016); • Intercurrent illness that prevents further administration of treatment; • AE: unacceptable AE(s) that may or may not be directly related to treatment but that, in the judgment of the treating physician, makes it dangerous for the subject to be retreated; • Physician decision: general or specific changes in the subject’s condition that render the subject unacceptable for further treatment in the judgment of the Investigator; • Study termination by sponsor.
[00408] Subjects who show signs of progression may continue treatment on study past initial progression if, as determined by the Investigator, they could still clinically benefit from continued treatment, as outlined in the PCWG3 recommendations. If a subject voluntarily withdraws from the study, attempts should be made to contact the subject to determine and record the reason(s) for discontinuation. All subjects who discontinue the study secondary to an AE must be followed until resolution or stabilization of the AE.
[00409] Dose Adjustment Criteria
[00410] General Safety Considerations
[00411] The following should be taken into consideration in decisions regarding management of treatment-related AEs: • The study drug and commercial drugs administered in this study have class-specific safety profiles based on their mechanisms of action, but may also cause AEs that overlap; • As a general approach, all AEs should be managed with supportive care at the earliest signs of toxicity, including both pharmacological and nonpharmacological treatments, according to consensus management guidelines; • Study treatments may be continued in the event of Grade 1 AEs if appropriate supportive care has been initiated to ameliorate symptoms. Should this be ineffective, or if toxicities become unacceptable, dose modifications of study treatment should be considered to prevent worsening of toxicity; • Grade 2 and 3 AEs usually require dose modification, including dose reductions and/or interruptions. Dose interruptions of any study drug for AEs may occur at any time and independently at the discretion of the Investigator; • Dose modifications as specified in the United States package insert (USPI) should be followed for each commercial drug administered as part of the combination arms on this study; • If XmAb®20717 is interrupted for more than 12 weeks, treatment should be discontinued unless continuation is approved by the Medical Monitor; • Reductions in the XmAb®20717 dose require approval of the Medical Monitor.
[00412] Criteria for Adjustment or Stopping Doses:
[00413] Dose Modification and Toxicity Management for Immune-Related Adverse Events (IrAEs)
[00414] IrAEs may involve every organ or tissue (Michot, et al. Eur J Cancer.
2016; 54: 139-48). Most irAEs occur within the first 12 weeks of exposure to an immune- checkpoint inhibitor, but some of them may appear with a delayed onset. Diagnosis of irAEs should be based on exposure to XmAb®20717 and a reasonable immune-based mechanism of the observed AE. Whenever possible, histologic examination or other immune-based diagnostic evaluations should be used to support the diagnosis. Other etiologic causes, including AEs due to tumor progression, should be ruled out.
[00415] The spectrum of irAEs is wide and can be general or organ-specific. Examples of general irAEs in subjects treated with immune-checkpoint inhibitors are fatigue, fever, and chills. Organ-specific irAEs consist of pneumonitis, colitis, hepatitis, nephritis and renal dysfunction, skin adverse reactions, encephalitis, myocarditis, and endocrinopathies.
[00416] Early recognition and management of irAEs associated with immune-oncology agents may mitigate severe toxicity. Medical management of irAEs should focus on suppressing the immune response with nonsteroidal and steroidal anti-inflammatory medication. Management algorithms, which provide guidelines on holding, rechallenging, and discontinuation of treatment, have been developed by the National Comprehensive Cancer Network (NCCN) and should be followed for subjects with suspected irAEs. Reductions in the XmAb®20717 dose require approval of the Medical Monitor.
[00417] Dose Modifications for Myelosuppression
[00418] Subjects receiving chemotherapy may develop treatment-related neutropenia and thrombocytopenia, despite prophylactic growth factor support. For management of chemotherapy-related myelosuppression, refer to the USPI for each specific agent. Provided there are no other signs, symptoms, or laboratory abnormalities suggestive of immunotoxicity, dosing of XmAb®20717 can be continued, despite myelosuppression, while the chemotherapy is held and/or reduced. However, if myelosuppression (platelets < 50,000 cells/mm3, absolute neutrophil (ANC) < 1500 cells/mm3, or hemoglobin (Hgb) < 8.0 g/dL despite transfusion) persists beyond 14 days after a prior cycle of chemotherapy, XmAb®20717 can be held to enable work-up of chemotherapy -unrelated causes, including immune-related thrombocytopenia, neutropenia, and/or anemia. If chemotherapy cannot be resumed within 21 days due to persistent cytopenia, the subject should be discontinued from all study treatment.
[00419] Criteria for Study Termination
[00420] If the Investigator or the Sponsor becomes aware of conditions or events that suggest a possible hazard to subjects if the clinical study continues, the study may be terminated after appropriate consultation among the involved parties.
[00421] Conditions that prompt such a consultation and may warrant termination of the clinical study include, but are not limited to, the following: • The discovery of an unexpected or unacceptable risk to the subjects enrolled in the clinical study; • Failure to enroll subjects at the required rate; • A decision by the Sponsor to suspend or discontinue development of XmAb®20717; • Sponsor decision. The clinical study may also be terminated at the Sponsor’s discretion for these or any other reasons. Should the study be terminated, and/or a site closed for whatever reason, all documentation pertaining to the study and investigational medicinal product (IMP) must be returned to the Sponsor. Any actions required for assessing or maintaining subject safety continue as required, despite termination of the study or site.
[00422] Study Assessments
[00423] The Schedule of Assessments is shown herein.
[00424] Pretreatment Evaluations
[00425] Only those subjects who meet all inclusion and no exclusion criteria may be enrolled into this study. Prior to the initiation of any on-study testing, including screening testing, the subject must have signed the informed consent form (ICF) and received a Subject Screening Number. The pretreatment period lasts for up to 28 days and includes screening evaluations and baseline assessments (defined as the assessment immediately prior to the first dose).
[00426] Prior to administration of XmAb®20717, each subject must have completed all screening activities and received approval for enrollment and a cohort assignment from Xencor.
[00427] Screening Period (Day -28 to Day -2)
[00428] Subjects undergo a Screening Visit(s) 2 to 28 days prior to the planned first day of study treatment. Please see the footnotes in the Schedule of Assessments (Table 6) and below for acceptable time windows for specific assessments. Screening procedures and assessments are as follows: • Obtain signed informed consent, • Obtain documentation of targeted sequencing of metastatic prostate cancer to determine mutational status of MSI-H or MMRD;
• Review inclusion and exclusion criteria; • Collect tissue from formalin-fixed paraffin embedded (FFPE) archival tumor tissue (20 slides, if available, or from fresh pretreatment biopsy); • Collect a blood sample for assessment of ctDNA; • Demographics; • Medical history; • Disease-specific history, including any available genomic information on the primary or metastatic tumor and sequencing data; • Physical examination (PE); • PSA testing within 14 days of the first dose of drug; • Computed tomography (CT) or magnetic resonance imaging (MRI) within 28 days prior to the first dose of study drug for baseline tumor assessment per RECIST 1.1 described herein, as modified by PCWG3 described herein; • Bone scan, if not previously performed within 56 days of the first dose of study drug; • Eastern Cooperative Oncology Group (ECOG) performance status; • Vital signs; • Electrocardiogram (ECG), standard 12-lead; • Complete blood count (CBC) with differential;
• Coagulation panel; • Chemistry panel, including amylase and lipase; • Urinalysis; • Testosterone; • Screening test for hepatitis B surface antigen (HBsAg) and hepatitis B core antibody (HBcAb); a subject whose HBsAg is negative and HBcAb is positive may be enrolled if a hepatitis B virus [HBV]DNA test is negative and either the subject is treated with potent antiviral therapy or is retested for HBV DNA every month); • Screening tests for human immunodeficiency virus (HIV) and hepatitis C virus (i.e., HCVRNA); • Record prior and ongoing concomitant medications; • Record AEs (using the National Cancer Institute’s Common Terminology Criteria for Adverse Events [NCI-CTCAE] for grading).
[00429] Subject Enrollment
[00430] Subjects who have completed screening and baseline activities, and whose eligibility checklists have been approved by the Medical Monitor, are enrolled onto the trial. [00431] Baseline Assessments (Day-1 or Day 1 Predose)
[00432] If a procedure or assessment is performed on both Day -1 and Day 1, the one performed closest to the time of dosing is considered the baseline. Please see the footnotes in the Schedule of Assessments and below for acceptable time windows for specific assessments. Baseline procedures and assessments are as follows: • ECOG performance status; • Vital signs; • PE, including height and weight; • ECG, standard 12-lead; • CBC with differential; • Coagulation panel; • Chemistry panel, including amylase and lipase; • Thyroid function tests: thyroid-stimulating hormone (TSH), triiodothyronine (T3), free thyroxine (fT4); • Adrenocorticotropic hormone(ACTH), cortisol (8 AM); »HgBAlC; • Urinalysis; • Blood for cell surface markers by flow cytometry and similar bioanalytical methods (See Laboratory Manual for detailed instructions); • Blood for peripheral cytokine levels (See Laboratory Manual for detailed instructions); • Blood sample stored for potential RNA/transcriptomic profiling (PAXgene); • Serum sample for pembrolizumab or nivolumab levels (subjects in Cohort D who have received pembrolizumab or nivolumab within 18 weeks prior to first dose of study drug); • PSA; • Record AEs; • Record prior and ongoing concomitant medications.
[00433] Treatment Cycle Assessments
[00434] The schedule of required procedures and clinical site study visit days for each cycle is detailed in the Schedule of Assessments. The day prior to Cycle 1 Day 1 is Day-1. [00435] Clinical Assessments
[00436] Predose PEs and clinical evaluations may be performed up to 24 hours prior to a scheduled infusion of XmAb®20717, except where indicated otherwise: • Abbreviated, symptom-directed PE, including weight; • Vital signs (predose assessments must be performed immediately prior to infusion); • ECOG performance status; • Record AEs; • Record prior and ongoing concomitant medications.
[00437] Laboratory Assessments
[00438] Details for laboratory assessments are provided; details for PK, pharmacodynamics, and flow cytometry are provided in the Laboratory Manuals. Procedures during treatment cycles and for follow-up after End of Treatment (EOT) are detailed herein. Required procedures are also specified in the Schedule of Assessments.
[00439] Laboratory assessments include: • CBC; • Coagulation panel; • Chemistry panel, including amylase and lipase; • Thyroid function tests: TSH, T3, fT4; • ACTH, cortisol (8 AM); • HgB A1C; • Urinalysis; • Blood for cell surface markers by flow cytometry and similar bioanalytical methods (See Laboratory Manual for detailed instructions); • PK (See Laboratory Manual for detailed instructions); • Blood for peripheral cytokine levels (See Laboratory Manual for detailed instructions); • ADA blood samples (See Laboratory Manual for detailed instructions); • Blood sample stored for potential RNA/transcriptomic profiling (PAXgene); • ECG, standard 12-lead; Tumor assessment by CT/MRI (RECIST 1.1;
Eisenhauer et al, Eur J Cancer. 2009; 45:228-47, as modified by PCWG3 (Scher et al. J Clin Oncol. 2016; 34(12): 1402-18); • PSA measurement (except for Cohort A); • Bone scans per PCWG3 (Scher et al. J Clin Oncol. 2016; 34(12): 1402-18); • Post-treatment fresh tumor biopsies should be obtained but are optional and require specific subject consent; • Blood for assessment of ctDNA.
[00440] Pharmacokinetic/Pharmacodynamic Assessments :
[00441] Serum Sampling for Pharmacokinetic Analyses, Anti-Drug Antibodies, and Cytokines/Inflammatory Factors
[00442] The Sponsor or designee provides cryotubes, labels, and requisition forms. Serum cryotubes are labeled at the clinical site with the subject enrollment number, date, visit day and time point, and time of sampling. Samples are stored on site at -70°C until the Sponsor notifies the sites to ship the samples on dry ice to the designated lab for sample analysis. Detailed instructions for processing and shipping serum samples are provided in the Laboratory Manual. Venous blood samples for serum analyses of ADA and the cytokine panel are obtained according to the Schedule of Assessments. ADA samples may also be analyzed for soluble factors (including but not limited to sCTLA4, sPDl, and sPDLl) that may interfere with the assay. Blood samples for analyses of PK are obtained according to the Sampling for PK table.
[00443] Pharmacodynamics
[00444] Detailed instructions for processing and shipping of peripheral blood and tumor biopsy tissue for pharmacodynamic assessments are provided in the Laboratory Manual. For the sampling schedules, see the Schedule of Assessments. The Sponsor/designated vendor provides blood sampling tubes, labels, requisition forms, and shipping containers.
[00445] In peripheral venous blood, baseline and serial assessment of B-cell, natural killer cell, and T-cell numbers, as well as markers of T-cell activation, are assessed. A blood sample is collected at baseline and on treatment and stored for potential RNA/transcriptomic profiling. Archival tissue and/or pre- and post-XmAb®20717 fresh tumor biopsies, if available, are examined by immunohistochemical and fluorescent immunohistochemical assays for immune cell density, intratumoral and juxta-tum oral immune and tumor cell expression of PDL1, PD1, and other immune checkpoint markers, transcriptomic analysis of the tumor and tumor microenvironment, and next generation sequencing analysis of mutations and tumor mutational burden, for correlation with clinical responses. A blood sample is collected for ctDNA mutation profiling.
[00446] End of Treatment
[00447] Subjects have their EOT assessments at the end of their last cycle of treatment. If a subject terminates before the end of a cycle, the EOT assessments are performed on the day of study termination. Subjects with a positive ADA at study termination are followed every 28 days (± 3 days) until ADA is negative or until administration of another anticancer therapy. Follow-up cease once all scheduled samples have been collected or when the subject begins another anticancer treatment regimen. Subjects are followed for AEs for 70 days after EOT or until the first administration of another anticancer therapy, whichever comes first.
[00448] Post-Treatment Follow-up Period (14 Days, 28 Days, and 70 Days after EOT) [00449] Subjects have visits 14 days post-EOT, 28 days post-EOT, and 70 days post-EOT. Scans for subjects who discontinued treatment for reasons other than disease progression should be collected until disease progression. Once these visits and assessments have been completed, the subject is considered as having completed participation in the clinical trial. If a subject enrolls into another trial or requires a change in anticancer treatment before either of these scheduled visits, the visits may be performed earlier. If a subject is unable/unwilling to return for any scheduled visits after the end of treatment, he/she is considered as having completed study requirements at the end of treatment.
[00450] Long-Term Follow-up Period (6 and 12 Months After EOT)
[00451] Subjects are contacted by site staff by telephone, email, or mail at 6 and 12 months after their active participation in the study ends to gather information about disease progression and survival. Scans for subjects who discontinued treatment for reasons other than disease progression should be collected until disease progression. Completion of the long-term follow-up period is not required for a subject to be considered as having completed the clinical trial.
[00452] Screening Period
[00453] Subjects undergo a Screening Visit(s) 2 to 28 days prior to the planned first day of study treatment. Screening procedures and assessments are as follows: Obtain signed informed consent; Obtain documentation of targeted sequencing of metastatic prostate cancer to determine mutational status of MSI-H or MMRD; Review inclusion and exclusion criteria; Collect tissue from formalin-fixed paraffin embedded (FFPE) archival tumor tissue (20 slides, if available, or from fresh pretreatment biopsy); Collect a blood sample for assessment of ctDNA; Demographics; Medical history; Disease-specific history, including any available genomic information on the primary or metastatic tumor and sequencing data; Physical Examination (PE); PSA testing within 14 days of the first dose of drug (except subjects in Cohort A); Computed tomography (CT) or magnetic resonance imaging (MRI) within 28 days prior to the first dose of study drug for baseline tumor assessment per RECIST 1.1 (Eisenhauer et al. Eur J Cancer. 2009; 45:228-47), as modified by PCWG3 (Scher et al. J Clin Oncol. 2016; 34(12): 1402-18); Bone scan, if not previously performed within 56 days of the first dose of study drug; Eastern Cooperative Oncology Group (ECOG) performance status; Vital signs; Electrocardiogram (ECG), standard 12-lead; Complete blood count (CBC) with differential; Coagulation panel; Chemistry panel, including amylase and lipase; Urinalysis; Testosterone; Screening test for hepatitis B surface antigen(HBsAg)and hepatitis B core antibody (HBcAb); a subject whose HBsAg is negative and HBcAb is positive may be enrolled if a hepatitis B virus [HBV] DNA test is negative and either the subject is treated with potent antiviral therapy or is retested for HBV DNA every month); Screening tests for human immunodeficiency virus (HIV) and hepatitis C virus (i.e., HCV-RNA); Record prior and ongoing concomitant medications; Record Adverse Events (using the National Cancer Institute’s Common Terminology Criteria for Adverse Events [NCI-CTCAE] for grading) [00454] Subjects who have completed screening and baseline activities, and whose eligibility checklists have been approved by the Medical Monitor, is enrolled onto the trial. [00455] Please see the footnotes in the Schedule of Assessments and below for acceptable time windows for specific assessments. Baseline procedures and assessments are as follows: ECOG performance status; Vital signs; Physical Examination, including height and weight; ECG, standard 12-lead; CBC with differential; Coagulation panel; Chemistry panel, including amylase and lipase; Thyroid function tests: thyroid-stimulating hormone (TSH), triiodothyronine (T3), freethyroxine (fT4); Adrenocorticotropic hormone(ACTH), cortisol (8 AM)»HgBAlC; Urinalysis; Blood for cell surface markers by flow cytometry and similar bioanalytical methods; Blood for peripheral cytokine levels; Blood sample stored for potential RNA/transcriptomic profiling(PAXgene); PSA (except subjects in Cohort A); Record AEs; Record prior and ongoing concomitant medications.
[00456] Predose PEs and clinical evaluations may be performed up to 24 hours prior to a scheduled infusion of XmAb®20717, except where indicated otherwise: Abbreviated, symptom-directed PE, including weight; Vital signs (predose assessments should be performed immediately prior to infusion); ECOG performance status; Record AEs; Record prior and ongoing concomitant medications. [00457] Laboratory assessments include: CBC; Coagulation panel; Chemistry panel, including amylase and lipase; Thyroid function tests: TSH, T3, fT4; ACTH, cortisol (8 AM); HgB A1C; Urinalysis; Blood for cell surface markers by flow cytometry and similar bioanalytical methods; PK; Blood for peripheral cytokine levels; ADA blood samples; Blood sample stored for potential RNA/transcriptomic profiling; ECG, standard 12-lead; Tumor assessment by CT/MRI (RECIST 1.1; Eisenhauer et al, Eur J Cancer. 2009; 45:228-47, as modified by PCWG3 (Scher et al. J Clin Oncol. 2016; 34(12): 1402-18); PSA measurement (except Cohort A); Bone scans per PCWG3 (Scher et al. J Clin Oncol. 2016; 34(12): 1402- 18); Post-treatment fresh tumor biopsies should be obtained but are optional and require specific subject consent; Blood for assessment of ctDNA.
Table 6. Schedule of Assessments
Figure imgf000144_0001
Figure imgf000145_0001
Figure imgf000146_0001
ACTH = adrenocorticotropic hormone; ADA = anti-drug antibody; CBC = complete blood count; CT = computed tomography; ctDNA = circulating tumor DNA; d = day; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; EOT = end of treatment; FFPE = formalin-fixed paraffinized embedded; fT4 = free thyroxine; HBcAb = hepatitis B core antibody; HBsAg = hepatitis B surface antigen; HCV = hepatitis C virus; Hgb A1C = hemoglobin A1C; HIV = human immunodeficiency virus; HRD = homologous recombination deficiency; IV = intravenous; MMRD = mismatch repair deficient; mo = month; MRI = magnetic resonance imaging; MSI-H = microsatellite instability-high; PE = physical examination; PK = pharmacokinetic; PSA = prostatespecific antigen; RECIST = Response Evaluation Criteria in Solid Tumors; T3 = triiodothyronine; TSH = thyroid-stimulating hormone. a The Day 8 and Day 22 assessments can be performed if the subject has chemotherapy infusions on those days.
b For subjects undergoing biopsy of accessible metastatic tumor, the procedure can be performed after the subject has consented and registered to the study. Fresh prostate biopsy is acceptable if there is clear local disease and no other measurable disease site or biopsiable bone lesion. c Complete medical history and PE at screening. For all the other time points an abbreviated, symptom-directed PE is to be performed. A thorough diseasespecific history can be recorded at screening, including prior surgery, radiotherapy, and systemic therapy (including duration of treatment, reason for discontinuation, and best overall response), Gleason score at diagnosis, metastatic disease status at diagnosis, PSA levels for the prior 6 months, and any available genomic information on the primary or metastatic tumor and sequencing data. d Blood pressure and pulse rate, body temperature, respiratory rate. On days of XmAb®20717 infusions, vital signs should be taken predose and 30 minutes (± 5 minutes) after start of infusion, immediately before end of infusion, and 30 (± 5) and 60 (± 5) minutes after end of infusion. For subjects in Cohorts A, B, and E, on days where carboplatin and cabazitaxel (or docetaxel) are the only infusions, vital signs should be taken predose. On nondosing days, vital signs should be measured before blood sampling. Vital signs should be taken with subject in the same position. For subjects in Cohorts A, B, and E, on days where carboplatin and cabazitaxel (or docetaxel) are the only infusions, vital signs should be taken predose. e Baseline body weight to be collected on either Day - 1 or Day 1. f If the assessment is performed or the sample is collected within 3 days prior to dosing on Day 1, it does not need to be repeated on Day 1. g On dosing days in the first 2 cycles of therapy, ECGs should be performed prior to infusion, 2 to 4 hours after end of infusion, and if clinically indicated.
On dosing days after the first 2 cycles of therapy, ECGs should be performed prior to infusion. ECGs should be performed after the subject has been resting supine or semirecumbent for > 5 minutes. All ECGs should be taken with the subject in the same position. h May be performed up to 24 hours prior to infusion. These safety laboratories can be performed by both the central laboratory and local clinical site laboratories to allow review of the results by clinical site personnel before XmAb®20717 infusion.
‘ May be performed up to 4 weeks prior to screening. j Cortisol should be drawn as close to 8 AM as possible. k Preinfusion on day of dose.
1 A blood sample can be collected at baseline and on treatment and stored for potential RNA/transcriptomic profiling. m XmAb®20717 can be administered as a 1-hour IV infusion (± 10 minutes unless there is approval from the Medical Monitor for a different infusion rate and duration). Subjects are observed for at least 1 hour following the end of infusion. For subjects in Cohort C, olaparib are administered orally twice daily. See dosing schedules for chemotherapy for subjects in Cohorts A, B, and E. For subjects in Cohort C, olaparib are administered orally twice daily. See dosing schedules for chemotherapy for subjects in Cohorts A, B, and E. For subjects in Cohort C, olaparib are administered orally twice daily.
" [HOLD]
0 For Cycles 3 and higher, ADA sampling is performed prior to infusion on Day 15. Subjects with a positive ADA at termination can be followed every 28 days (± 3 days) until ADA reverts to baseline or until the next intervening treatment. p This sampling should be performed predose on Day 1 for those subjects in Cohort D (MSI-H/MMRD) who have received pembrolizumab or nivolumab within 18 weeks prior to the first dose of study drug. q Tumor assessment per RECIST 1.1, as modified by PCWG3. Radiographic evaluations and tumor measurements can be undertaken every 9 weeks (± 1 week) for 28 weeks, then every 12 weeks (± 1 week) for assessment of both response and disease progression. During post-treatment follow-up, scans for subjects who discontinued treatment for reasons other than disease progression can be collected until disease progression. Radiologic documentation can be provided for subjects removed from study for progressive disease. The date of radiographic evaluations can be calculated from the date of first treatment.
Images can be evaluated locally for response and progression. EOT assessment can be performed only if such an assessment has not been performed in the past 60 days.
For CT scans, MRI, and bone scans, imaging for the Cycle 2 Day 26 time point may be performed within 7 days rather than within 2 days.
Pretreatment PSA can be performed within 14 days prior to the first dose of drug. Post-treatment PSA can be performed at the end of Cycle 1 and repeated every 2 cycles (Cycle 3, Cycle 5, Cycle 7, etc.) thereafter in subjects except those in Cohort A.
Historical bone scan, if performed within 56 days of Cycle 1 Day 1, is acceptable for pretreatment.
[00458] Inclusion Criteria for Subjects of the Study include:
Able to provide written informed consent;
Adult (age > 18 years);
Sex: Male;
Histologically confirmed diagnosis of carcinoma of the prostate;
Documented progressive mCRPC based on at least one (or one or more than one) of the following criteria:
- PSA progression, defined as at least 2 rises in PSA with a minimum of a 1 week interval (1.0 ng/mL is the minimal starting value if confirmed rise is the only indication of progression)
Soft-tissue progression per RECIST 1.1
- Progression of bone disease (evaluable disease) or 2 or more new bone lesions by bone scan;
Prostate cancer must have progressed after treatment with at least 2 prior lines of anticancer therapy approved for treatment of metastatic prostate cancer; prior treatment of subjects in Cohort D (MSI-H or MMRD) should include a checkpoint inhibitor approved by FDA for that indication;
Subjects who did not have a surgical orchiectomy should be on androgen suppression treatment (e.g., luteinizing hormone-releasing hormone agonist) with castrate level of testosterone (< 50 ng/dL) and be willing to continue the treatment throughout the study;
Documentation of the following genetic features, based on prior appropriately validated metastatic tissue analysis (targeted or whole exome sequencing panel performed by Clinical Laboratory Improvement Amendments-certified laboratory):
Cohort A (AVPCa), subjects should be positive for aberrancy of at least 2 of the following: Rbl, TP53, PTEN;
Cohort B (HRD), subjects must meet one of the following criteria: • Positive for HRD in one or more of the following genes: BRCA1, BRCA2, ATM, PALB2, CHEK2, and/or FANCA; • Positive for biallelic loss of CDK12;
Cohort C (HRD) - At least one of the following criteria: • Positive for HRD in one or more of the following genes: BRCA1, BRCA2, ATM, PALB2, CHEK2, and/or FANCA; • Positive for biallelic loss of CDK12; Cohort D, subjects must have positive MSI-H/MMRD status;
Cohort E, subjects must have had a targeted whole exome sequencing or next generation sequencing analysis of a metastatic lesion that rules out eligibility for other cohorts;
- Evaluable disease according to PCWG3 (Prostate Cancer Working Group 3) criteria;
- Adequate archival metastatic tumor tissue or agree to undergo a biopsy of at least 1 metastatic site (fresh biopsy of primary prostate is only allowed if there is clear local disease and no other measurable disease site or biopsiable bone lesion);
- ECOG performance status of 0 or 1 ;
- Able and willing to complete the study according to the study schedule.
[00459] Exclusion Criteria for Subjects of the Study include:
Currently receiving anticancer therapies other than androgen deprivation therapy (ADT);
Treatment with any other anticancer therapy within 2 weeks of the start of study drug (z.e., other immunotherapy, chemotherapy, radiation therapy, etc.);
Prior treatment with any CTLA4, PD1, PDL1, or PDL2-directed immunotherapy, except subjects in Cohort D, who have had prior FDA-approved checkpoint inhibitor therapy;
Grade 4 immune-mediated AE related to prior immunotherapy (applicable to subjects eligible for Cohort D);
- Failure to recover from any toxicity related to previous anticancer treatment to < Grade 2;
- Have known active central nervous system metastases and/or carcinomatous meningitis. Subjects with previously treated brain metastases may participate provided they are radiologically stable, z.e., are without evidence of progression for at least 4 weeks by repeat imaging (note that the repeat imaging should be performed during study screening), are clinically stable, and are without requirement of steroid treatment for at least 14 days prior to first dose of study treatment;
Platelet count < 100 * 109/L;
- Hemoglobin level < 9.0 g/dL;
- Absolute neutrophil count < 1.7 x io9 for subjects who receive cabazitaxel; < 1.0 x 109/L for all others; - Aspartate aminotransferase at screening > 3 x upper limit of normal (ULN) for subjects without known liver involvement by tumor or > 5 x ULN for subjects with known liver involvement by tumor;
- Alanine aminotransferase at screening > 3 x ULN for subjects without known liver involvement by tumor or > 5 x ULN for subjects with known liver involvement by tumor;
- Bilirubin > 1.5 x ULN (unless prior diagnosis and documentation of ongoing hemolysis or Gilbert’s syndrome has been made);
- Estimated creatinine clearance < 50 mL/minute calculated by the Cockcroft Gault or Modification of Diet in Renal Disease formulas;
- Active known or suspected autoimmune disease (except vitiligo; type 1 diabetes mellitus or residual hypothyroidism due to an autoimmune condition that is treatable with hormone replacement therapy only; psoriasis, atopic dermatitis, or another autoimmune skin condition that is managed without systemic therapy; or arthritis that is managed without systemic therapy beyond oral acetaminophen and nonsteroidal anti-inflammatory drugs);
- Have any condition requiring systemic treatment with corticosteroids, prednisone equivalents, or other immunosuppressive medications within 14 days prior to first dose of study drug (except inhaled or topical corticosteroids or brief courses of corticosteroids given for prophylaxis of contrast dye allergic response). Subjects who are currently taking prednisone from a previous prostate cancer therapy are permitted to enroll in the study;
- Receipt of an organ allograft;
Known history of left ventricular ejection fraction < 40%;
- History or evidence of any other clinically unstable/uncontrolled disorder, condition, or disease other than their primary malignancy that, in the opinion of the Investigator, would pose a risk to patient safety or interfere with study evaluations, procedures, or completion;
- Evidence of any serious bacterial, viral, parasitic, or systemic fungal infections within the 30 days prior to the first dose of study drug;
- Receipt of a live-virus vaccine within 30 days prior to the first dose of study drug (seasonal flu vaccines that do not contain live virus are permitted);
- A human immunodeficiency virus (HIV) positive subject with CD4+ T-cell (CD4+) counts < 350 cells/pL, or an HIV viral load greater than 400 copies/mL, or a history of an AIDS (acquired immunodeficiency syndrome)-defming opportunistic infection within the past 12 months, or who has not been on established antiretroviral therapy (ART) for at least 4 weeks prior to initiation of study drug dosing. (Effective ART is defined as a drug, dosage, and schedule associated with reduction and control of the viral load.);
- Positive test for hepatitis C RNA (a subject who is hepatitis C virus [HCV] antibody positive but HCV RNA negative due to documented, curative prior antiviral treatment or natural resolution is eligible);
[00460] Positive test for hepatitis B surface antigen (HBsAg) or hepatitis B core antibody (HBcAb; a subject whose HBsAg is negative and HBcAb is positive may be enrolled if a hepatitis B virus [HBV] DNA test is negative and the subject is retested for HBsAg and HBV DNA every 2 months.
[00461] Results:
[00462] Preliminary data on the first 9 patients enrolled in this phase 2 study, with a focus on safety in the first 8 patients treated with vudalimab in combination with carboplatin and either cabazitaxel or docetaxel was determined. The demographics and baseline characteristics of those 9 patients (as of September 7, 2022) is summarized in Table 7. FIG.
6 shows the duration of treatment for the patients described in Table 7.
Table 7. Demographics and Baseline Characteristics (September 7, 2022 date cutoff)
Figure imgf000152_0001
AVPC = aggressive variant prostate cancer; PARPiN HRD = PARPi naive homologous recombination deficient; PARPiP HRD = PARPi progressor homologous recombination deficient; NR = not recorded in database; NTM = no targetable mutation [00463] The preliminary clinical activity of the patients described in Table 7 as of September 7, 2022, is shown in Table 8.
Table 8. Physician Assessment of Best Overall Response (September 7, 2022 date cutoff)
Figure imgf000153_0001
AVPC = aggressive variant prostate cancer; PARPiN HRD = PARPi naive homologous recombination deficient; PARPiP HRD = PARPi progressor homologous recombination deficient; NTM = no targetable mutation; Non-CR/Non-PD refers to persistence of one or more non-target lesion(s) and/or maintenance of tumor marker level above the normal limits
[00464] The change in prostate specific antigen (PSA) was determined for those 9 patients in Table 7 as compared to baseline (FIG. 7). It was observed that 3 patients had decreases in PSA from baseline > 50%: Patient 40102: 27.9 to 4.7 ng/mL at end of Cycle 1 and 9.2 ng/mL ~ 8 weeks after end of treatment; Patient 40501 : 110.8 to 23.2 ng/mL at end of Cycle 3, increasing to 83.4 ng/mL at ~23 weeks; and Patient 40502: 828.9 to 90.5 ng/mL at end of Cycle 1, and persistently low (0.97 ng/mL) through continuing treatment at ~35 weeks.
[00465] As of September 7, 2022, treatment-related serious adverse events (SAEs) occurring within the first cycle of therapy were reported for 5 of the 8 patients treated with vudalimab + chemotherapy, and included vomiting (Grade 3), maculopapular rash (Grade 2), and colitis (Grade 2) in 1 patient, and sepsis (Grade 3), Guillain-Barre syndrome (Grade 3), and nausea (Grade 3), and diarrhea (Grade 2) in 1 patient each. An additional patient had Grade 3 maculopapular rash and diarrhea, and leukocytosis (not meeting SAE criteria) within the first cycle of therapy. Other treatment-related SAEs included decreases in platelet and neutrophil counts (Grade 4) and sinusitis febrile neutropenia, and anemia (Grade 3) in 1 patient, and Grade 4 hemolytic anemia in 1 patient. All events resolved with medical management, including steroids where appropriate, and/or interruption or cessation of study therapy. Overall, 4 patients discontinued study treatment due to adverse events.
[00466] FIG. 8 shows treatment-related adverse events and immunotherapy-related adverse events. With the exception of Guillain-Barre syndrome (a rare event associated with ICI therapy), the types of irAEs observed in the patients are generally consistent with vudalimab experience at a dose of 10 mg/kg from the Phase 1 monotherapy study (n = 110) (Shum E, et al. J Immunother Cancer. 2021;9:A553). A decision to change the vudalimab and chemotherapy regimen was prompted by the frequency, severity, and incidence in these 8 patients of treatment-related serious and/or severe adverse events leading to discontinuation of treatment - not all of which are clearly irAEs. The decision was made to maintain the vudalimab dose and modify the chemotherapy regimen before proceeding with further enrollment into chemotherapy cohorts.
[00467] The dosing regimen is changed to restrict carboplatin and carbazitaxel or docetaxel in combination with vudalimab to patients with aggressive variant disease, and use single-agent carbazitaxel or docetaxel therapy in combination with vudalimab in the remaining chemotherapy cohorts (Table 9). Enrollment into chemotherapy cohorts restart following implementation of the amended protocol with the revised regimens. The vudalimab and olaparib and vudalimab monotherapy cohorts remain open for enrollment.
Table 9. Treatment by Cohort With Revised Chemotherapy Regimens
Figure imgf000154_0001
Figure imgf000155_0001
*If docetaxel naive fDose reductions of chemotherapy for adverse events per standard practice; maximum 8 cycles of carboplatin permitted.
5.3 EXAMPLE 3: Evaluation of XmAb®20717 Activity
[00468] The activity of XmAb®20717 was determined in an in vitro assay measuring IL-2 secretion from human lymphocytes stimulated with SEB, a method of assessing in vitro activity that has been used for other checkpoint inhibitors, including nivolumab. SEB- stimulated PBMC were treated with XmAb®20717 or comparators/controls for 24 hours, and lymphocyte function was determined by measuring by ELISA the amount of IL-2 in culture supernatants.
[00469] When compared to an anti-RSV isotype-control bivalent antibody (XENP 15074), XmAb®20717 promoted a 4.1 -fold increase in IL-2 secretion while XENP 16432, a benchmark anti-PDl bivalent antibody derived from the Fv of nivolumab with substitutions in the Fc domain similar to those in the XmAb®20717 Fc domain, promoted a 2.6-fold increase in IL-2 secretion versus control. When compared to PD1 blockade by a bivalent PD1 antibody, XmAb®20717 promoted a 1.5-fold increase in IL-2 secretion.
[00470] To determine if the avidity arising from XmAb®20717’s simultaneous binding to PD1 and CTLA4 contributed to IL-2 secretion, the intact bispecific antibody was compared to a mixture of its monovalent and monospecific component antibodies. Compared to a mixture of XENP20111 (a monovalent anti-PDl scFv-Fc component antibody of XmAb®20717) and XENP20059 (a monovalent anti-CTLA4 Fab-Fc component antibody of XmAb®20717), XmAb®20717 promoted a 1.6-fold increase in IL-2 secretion, suggesting that the increased avidity of XmAb®20717 for dual-positive PD1 and CTLA4-expressing T cells contributes to its observed in vitro.
[00471] Unless otherwise indicated, all numbers expressing quantities of ingredients, properties such as molecular weight, reaction conditions, and so forth used in the specification and claims are to be understood as being modified in all instances by the term “about.” Accordingly, unless indicated to the contrary, the numerical parameters set forth in the specification and attached claims are approximations that may vary depending upon the desired properties sought to be obtained by the present disclosure. At the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of the claims, each numerical parameter should at least be construed in light of the number of reported significant digits and by applying ordinary rounding techniques.
[00472] Notwithstanding that the numerical ranges and parameters setting forth the broad scope of the disclosure are approximations, the numerical values set forth in the specific examples are reported as precisely as possible. Any numerical value, however, inherently contains certain errors necessarily resulting from the standard deviation found in their respective testing measurements.
[00473] Recitation of ranges of values herein is merely intended to serve as a shorthand method of referring individually to each separate value falling within the range. Unless otherwise indicated herein, each individual value is incorporated into the specification as if it were individually recited herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., “such as”) provided herein is intended merely to better illuminate the disclosure and does not pose a limitation on the scope of the disclosure otherwise claimed. No language in the specification should be construed as indicating any non-claimed element essential to the practice of the disclosure.
[00474] Groupings of alternative elements or embodiments of the disclosure disclosed herein are not to be construed as limitations. Each group member can be referred to and claimed individually or in any combination with other members of the group or other elements found herein. It is anticipated that one or more members of a group can be included in, or deleted from, a group for reasons of convenience and/or patentability. When any such inclusion or deletion occurs, the specification is deemed to contain the group as modified thus fulfilling the written description of all Markush groups used in the appended claims.
[00475] Certain embodiments of this disclosure are described herein, including the best mode known to the inventors for carrying out the disclosure. Of course, variations on these described embodiments will become apparent to those of ordinary skill in the art upon reading the foregoing description. The inventor expects skilled artisans to employ such variations as appropriate, and the inventors intend for the disclosure to be practiced otherwise than specifically described herein. Accordingly, this disclosure includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. Moreover, any combination of the above-described elements in all possible variations thereof are encompassed by the disclosure unless otherwise indicated herein or otherwise clearly contradicted by context.
[00476] It is to be understood that the embodiments of the disclosure disclosed herein are illustrative of the principles of the present disclosure. Other modifications that can be employed are within the scope of the disclosure. Thus, by way of example, but not of limitation, alternative configurations of the present disclosure can be utilized in accordance with the teachings herein. Accordingly, the present disclosure is not limited to that precisely as shown and described.
[00477] While the present disclosure has been described and illustrated herein by references to various specific materials, procedures and examples, it is understood that the disclosure is not restricted to the particular combinations of materials and procedures selected for that purpose. Numerous variations of such details can be implied as will be appreciated by those skilled in the art. It is intended that the specification and examples be considered as exemplary only, with the true scope and spirit of the disclosure being indicated by the following claims. All references, patents, and patent applications referred to in this application are herein incorporated by reference in their entirety.
[00478] It will be appreciated by those skilled in the art that changes could be made to the embodiments described above without departing from the broad inventive concept thereof. It is understood, therefore, that this invention is not limited to the particular embodiments disclosed, but it is intended to cover modifications within the spirit and scope of the present invention as defined by the present description.
[00479] Although the invention is described in detail with reference to specific embodiments thereof, it will be understood that variations which are functionally equivalent are within the scope of this invention. Indeed, various modifications of the invention in addition to those shown and described herein will become apparent to those skilled in the art from the foregoing description and accompanying drawings. Such modifications are intended to fall within the scope of the appended claims. Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Such equivalents are intended to be encompassed by the following claims.

Claims

WHAT IS CLAIMED IS:
1. A method of treating a prostate cancer in a male subject in need thereof, the method comprising:
(a) administering a bispecific antibody to the male subject at a dose of between about 5-15 mg/kg, wherein the dose of the bispecific antibody is intravenously administered to the male subject on Day 1 of a first treatment cycle and about every two weeks (Q2W) thereafter;
(b) administering carboplatin to the male subject at a therapeutically effective dose that results in a target area under the serum concentration-time curve of 3 (AUC3) in the male subject, wherein the dose of the carboplatin is intravenously administered to the male subject twice in the first treatment cycle, wherein the twice is on Day 1 and about three weeks after Day 1 of the first treatment cycle;
(c) administering a taxane to the male subject at a dose of between about 10 mg/m2 and about 55 mg/m2, wherein the dose of the taxane is intravenously administered to the male subject twice in the first treatment cycle, wherein the twice is on Day 1 and about three weeks after day 1 of the first treatment cycle;
(d) administering carboplatin to the male subject at a therapeutically effective dose that results in a target area under the serum concentration-time curve of 4 (AUC4) in the male subject, wherein the dose of the carboplatin is intravenously administered to the male subject between Day 13 and Day 17 of a second treatment cycle and about every three weeks (Q3W) thereafter; and
(e) administering the taxane to the male subject at a dose of between about 15 mg/m2 and about 65 mg/m2, wherein the dose of the taxane is intravenously administered to the male subject between Day 13 and Day 17 of the second treatment cycle and about every three weeks (Q3W) thereafter; wherein each treatment cycle is about 28 days; wherein the prostate cancer is an aggressive variant (anaplastic) adenocarcinoma of the prostate (AVPCa); wherein the dose of the taxane in (e) is higher than the dose of the taxane in (c); and wherein the bispecific antibody comprises a first polypeptide comprising an amino acid sequence of SEQ ID NO: 1, a second polypeptide comprising an amino acid sequence of SEQ ID NO:2, and a third polypeptide comprising an amino acid sequence of SEQ ID NO:3.
2. A method of treating a prostate cancer in a male subject in need thereof, the method comprising:
(a) administering a bispecific antibody to the male subject at a dose of 10 mg/kg, wherein the dose of the bispecific antibody is intravenously administered to the male subject on day 1 of a first treatment cycle and about every two weeks (Q2W) thereafter;
(b) administering carboplatin to the male subject at a therapeutically effective dose that results in a target area under the serum concentration-time curve of 3 (AUC3) in the male subject, wherein the dose of the carboplatin is intravenously administered to the male subject twice in the first treatment cycle, wherein the twice is on day 1 and about three weeks after day 1 of the first treatment cycle;
(c) administering carbazitaxel to the male subject at a dose of 15 mg/m2, wherein the dose of the carbazitaxel is intravenously administered to the male subject twice in the first treatment cycle, wherein the twice is on day 1 and about three weeks after day 1 of the first treatment cycle;
(d) administering carboplatin to the male subject at a therapeutically effective dose that results in a target area under the serum concentration-time curve of 4 (AUC4) in the male subject, wherein the dose of the carboplatin is intravenously administered to the male subject between day 13 and day 17 of a second treatment cycle and about every three weeks (Q3W) thereafter; and
(e) administering the carbazitaxel to the male subject at a dose of 20 mg/m2, wherein the dose of the carbazitaxel is intravenously administered to the male subject on day 15 of the second treatment cycle and about every three weeks (Q3W) thereafter; wherein each treatment cycle is 28 days; wherein the prostate cancer is an aggressive variant (anaplastic) adenocarcinoma of the prostate (AVPCa); and wherein the bispecific antibody comprises a first polypeptide comprising an amino acid sequence of SEQ ID NO: 1, a second polypeptide comprising an amino acid sequence of SEQ ID NO:2, and a third polypeptide comprising an amino acid sequence of SEQ ID NO:3.
3. A method of treating a prostate cancer in a male subject in need thereof, the method comprising:
(a) administering a bispecific antibody to the male subject at a dose of 10 mg/kg, wherein the dose of the bispecific antibody is intravenously administered to the male subject on day 1 of a first treatment cycle and about every two weeks (Q2W) thereafter;
(b) administering carboplatin to the male subject at a therapeutically effective dose that results in a target area under the serum concentration-time curve of 3 (AUC3) in the male subject, wherein the dose of the carboplatin is intravenously administered to the male subject twice in the first treatment cycle, wherein the twice is on day 1 and about three weeks after day 1 of the first treatment cycle;
(c) administering docetaxel to the male subject at a dose of 50 mg/m2, wherein the dose of the docetaxel is intravenously administered to the male subject twice in the first treatment cycle, wherein the twice is on day 1 and about three weeks after day 1 of the first treatment cycle;
(d) administering carboplatin to the male subject at a therapeutically effective dose that results in a target area under the serum concentration-time curve of 4 (AUC4) in the male subject, wherein the dose of the carboplatin is intravenously administered to the male subject between day 13 and day 17 of a second treatment cycle and about every three weeks (Q3W) thereafter; and
(e) administering the docetaxel to the male subject at a dose of 60 mg/m2, wherein the dose of the docetaxel is intravenously administered to the male subject on day 15 of the second treatment cycle and about every three weeks (Q3W) thereafter; wherein each treatment cycle is 28 days; wherein the prostate cancer is an aggressive variant (anaplastic) adenocarcinoma of the prostate (AVPCa); and wherein the bispecific antibody comprises a first polypeptide comprising an amino acid sequence of SEQ ID NO: 1, a second polypeptide comprising an amino acid sequence of SEQ ID NO:2, and a third polypeptide comprising an amino acid sequence of SEQ ID NO:3.
4. A method of treating a prostate cancer in a male subject in need thereof, the method comprising:
(a) administering a bispecific antibody to the male subject at a dose of between about 5-15 mg/kg, wherein the dose of the bispecific antibody is intravenously administered to the male subject on Day 1 of a first treatment cycle and about every two weeks (Q2W) thereafter; and
(b) administering a taxane to the male subject at a dose of between about 10 mg/m2 and about 80 mg/m2, wherein the dose of the taxane is intravenously administered to the male subject on Day 1 of the first treatment cycle and about every three weeks (Q3W) thereafter; wherein each treatment cycle is about 28 days; wherein the prostate cancer progressed after the male subject received a polyadenosine diphosphate ribose polymerase (PARP) inhibitor prior to the administering of (a) and/or wherein the prostate cancer does not have a targetable mutation; and wherein the bispecific antibody comprises a first polypeptide comprising an amino acid sequence of SEQ ID NO: 1, a second polypeptide comprising an amino acid sequence of SEQ ID NO:2, and a third polypeptide comprising an amino acid sequence of SEQ ID NO:3.
5. A method of treating a prostate cancer in a male subject in need thereof, the method comprising: (a) administering a bispecific antibody to the male subject at a dose of 10 mg/kg, wherein the dose of the bispecific antibody is intravenously administered to the male subject on day 1 of a first treatment cycle and about every two weeks (Q2W) thereafter; and
(b) administering carbazitaxel to the male subject at a dose of 20 mg/m2, wherein the dose of the carbazitaxel is intravenously administered to the male subject on day 1 of the first treatment cycle and about every three weeks (Q3W) thereafter; wherein each treatment cycle is 28 days; wherein the prostate cancer progressed after the male subject received a polyadenosine diphosphate ribose polymerase (PARP) inhibitor prior to the administering of (a) and/or wherein the prostate cancer does not have a targetable mutation; and wherein the bispecific antibody comprises a first polypeptide comprising an amino acid sequence of SEQ ID NO: 1, a second polypeptide comprising an amino acid sequence of SEQ ID NO:2, and a third polypeptide comprising an amino acid sequence of SEQ ID NO:3.
6. A method of treating a prostate cancer in a male subject in need thereof, the method comprising:
(a) administering a bispecific antibody to the male subject at a dose of 10 mg/kg, wherein the dose of the bispecific antibody is intravenously administered to the male subject on day 1 of a first treatment cycle and about every two weeks (Q2W) thereafter; and
(b) administering docetaxel to the male subject at a dose of 75 mg/m2, wherein the dose of the docetaxel is intravenously administered to the male subject on day 1 of the first treatment cycle and about every three weeks (Q3W) thereafter; wherein each treatment cycle is 28 days; wherein the prostate cancer progressed after the male subject received a polyadenosine diphosphate ribose polymerase (PARP) inhibitor prior to the administering of (a) and/or wherein the prostate cancer does not have a targetable mutation; and wherein the bispecific antibody comprises a first polypeptide comprising an amino acid sequence of SEQ ID NO: 1, a second polypeptide comprising an amino acid sequence of SEQ ID NO:2, and a third polypeptide comprising an amino acid sequence of SEQ ID NO:3.
7. A method of treating prostate cancer in a male subject in need thereof, the method comprising:
(a) administering a bispecific antibody to the male subject at a dose of between about 5-15 mg/kg, wherein the dose of the bispecific antibody is intravenously administered to the male subject on day 1 of a first treatment cycle and about every two weeks (Q2W) thereafter; and
(b) administering olaparib to the male subject at a dose of between about 500 to about 700 mg per day on day 1 of a first treatment cycle and every day thereafter; wherein each treatment cycle is about 28 days; wherein the male subject has not been previously treated with a polyadenosine diphosphate ribose polymerase (PARP) inhibitor; and wherein the bispecific antibody comprises a first polypeptide comprising an amino acid sequence of SEQ ID NO: 1, a second polypeptide comprising an amino acid sequence of SEQ ID NO:2, and a third polypeptide comprising an amino acid sequence of SEQ ID NO:3.
8. The method of any one of claims 1 to 3, wherein the AVPCa has a mutation or other aberrancy in at least two genes independently selected from the group consisting of Rbl, TP53 and PTEN.
9. The method of any one of claims 4 to 7, wherein the prostate cancer is not an aggressive variant (anaplastic) adenocarcinoma of the prostate (AVPCa).
10. The method of any one of claims 4 to 6 and 9, wherein the prostate cancer has a homologous recombination deficiency (HRD).
11. The method of any one of claims 4 to 6, 9, and 10, wherein the prostate cancer has a biallelic loss of cyclin-dependent kinase 12 (CDK12).
12. The method of any one of claims 4 to 6, and 9 to 11, wherein the male subject has been previously treated with a polyadenosine diphosphate ribose polymerase (PARP) inhibitor.
13. The method of any one of claims 4 to 6, and 9 to 12, wherein the prostate cancer does not have a targetable mutation.
14. The method of any one of claims 7 and 9, wherein the dose of the olaparib is 600 mg per day.
15. The method of claim 14, wherein the 600 mg per day is administered twice per day in an amount of 300 mg each.
16. The method of any one of claims 1, 4, 7, 8, 14, and 15, wherein the dose of the bispecific antibody is 10 mg/kg.
17. The method of any one of claims 1, 4, 8-13, and 16, wherein the taxane is carbazitaxel.
18. The method of any one of claims 1, 8, and 16, wherein the taxane is carbazitaxel and the dose is 15 mg/m2 for (c) and 20 mg/m2 for (e).
19. The method of any one of claims 4, 9-13, and 16, wherein the taxane is carbazitaxel and the dose is 20 mg/m2.
20. The method of any one of claims 1, 4, 8-13, and 16, wherein the taxane is docetaxel if the male subject has not been treated with docetaxel prior to the first treatment cycle.
21. The method of any one of claims 1, 8, and 16, wherein the taxane is docetaxel if the male subject has not been treated with docetaxel prior to the first treatment cycle, and the dose is 50 mg/m2 for (c) and 60 mg/m2 for (e).
22. The method of any one of claims 4, 9-13, and 16, wherein the taxane is docetaxel if the male subject has not been treated with docetaxel prior to the first treatment cycle, and the dose is 75 mg/m2.
23. The method of any one of claims 3, 6, 8, and 9 to 13, wherein the male subject has not been treated with docetaxel prior to the first treatment cycle.
24. The method of any one of claims 1, 8, 16 to 18, 20, and 21, wherein the carboplatin is intravenously administered on day 15 of the second treatment cycle.
25. The method of any one of claims 1, 8, 16 to 18, 20, and 21, wherein the taxane is intravenously administered on day 15 of the second treatment cycle.
26. The method of any one of claims 1-25, wherein the male subject has received at least two systemic therapies prior to the first treatment cycle.
27. The method of any one of claims 1-25, wherein the male subject has received at least three systemic therapies prior to the first treatment cycle.
28. The method of any one of claims 1-27, wherein the male subject has been treated with chemotherapy prior to the first treatment cycle.
29. The method of any one of claims 1-28, wherein the male subject has been treated with radiation therapy prior to the first treatment cycle.
30. The method of any one of claims 1-29, wherein the male subject is an adult male subject.
31. The method of claim 30, wherein the adult male subject is 50 years of age or older.
32. The method of any one of claims 1-31, wherein the method results in a decrease in prostate specific antigen (PSA) in a biological sample obtained from the male subject compared to a reference.
33. The method of claim 32, wherein the decrease in PSA is a decrease of about or at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or more than 95% as compared to the reference.
34. The method of claim 33, wherein the decrease is about or at least about 50% as compared to the reference.
35. The method of any one of claims 32-34, wherein the reference is the level of PSA in a biological sample obtained from the male subject prior to the first treatment cycle.
36. The method of any one of claims 32-34, wherein the reference is the level of PSA at baseline.
37. The method of any one of claims 32-34, wherein the reference is the level of PSA in a biological sample obtained from the male subject in a previous time point.
38. The method of any one of claims 32-37, wherein the biological sample is blood, plasma, and/or serum.
39. The method of any one of claims 1-38, further comprising orally administering a steroid to the male subject.
40. The method of any one of claims 1 to 3, 8, 16 to 18, 20, 21, and 23-29, wherein the carboplatin is administered for about 8 treatment cycles.
41. The method of any one of claims 1-40, wherein the male subject has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
42. The method of any one of claims 1-41, wherein the method results in stable disease classification of the prostate cancer as determined by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.
43. The method of any one of claims 1-42, wherein the method results in partial response classification of the prostate cancer as determined by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.
44. The method of any one of claims 1-43, wherein the method is for about or at least about 3 treatment cycles.
45. The method of any one of claims 1-44, wherein the method is for about or at least about 6 treatment cycles.
46. The method of any one of claims 1-45, wherein the method is for about or at least about 8 treatment cycles.
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